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Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies
Abstract
Background:
The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies.
Methods:
We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL.
Findings:
Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL).
Interpretation:
Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.
... Antiretroviral therapy (ART) has increased the life expectancy of people living with HIV (PLWH), allowing them to live longer with this chronic medical condition [1,2]. In line with the World Health Organization (WHO), China renewed its national ART guidelines in 2016 [3], and ART coverage increased from 67% in 2015 to 80% in 2017 [4]. ...
... On the one hand, ART brings signi cant clinical bene ts for PLWH, such as improving physical health status, facilitating immune system recovery (e.g., higher CD4 cell counts), and slowing disease progression [28,29]. There is also evidence that viral suppression by ART greatly reduces the risk of transmitting HIV to sexual partners [1,2], potentially improving relationships between PLWH and their sexual partners. On the other hand, although advances in ART have largely reduced its side effects, recent studies have shown that about 25.0-53.3% of PLWH still experience severe side effects in their rst year after ART initiation [30,31]. ...
... Relatively few participants reported an improvement in their sex-partner relationship, but for those who did, it was protective against depressive and anxiety symptoms. Health communication messages should therefore be disseminated to PLWH and their sexual partners emphasizing that viral suppression by ART greatly reduces the risk of transmitting HIV through sex [1,2]. This may remove concerns about resuming sexual behaviour and improve intimacy between sexual partners. ...
Background: Mental health problems (e.g., depression and anxiety) are among the most commonly reported comorbidities of HIV. Antiretroviral therapy (ART) coverage has increased sharply. The purposes of this prospective cohort study were to investigate the ART-related experiences and whether they were associated with mental health problems among a sample of people living with HIV undergoing ART in China.
Methods: The participants were 400 people living with HIV who had started ART for the first time in Guangzhou city. They were followed-up one-year after ART initiation. Probable depression and moderate/severe anxiety were measured at baseline and Month 12, while experiences related to ART (e.g., side effects and regained self-confidence) were measured at Month 6. Univariate and multivariate logistic regressions were used to explore the associations between baseline characteristics, ART-related experiences and mental health status.
Results: Among the 300 participants (75.0%) who completed all three surveys, a significant decline in prevalence of probable depression (23.0% at baseline vs. 14.0% at Month 12, P = 0.002) and moderate/severe anxiety (14.7% at baseline vs. 8.7% at Month 12, P = 0.023) was observed during the follow-up period. After adjustment for mental health status and potential confounders at baseline, a number of ART-related experiences at Month 6 were associated with probable depression and/or moderate/severe anxiety measured at Month 12. Improved physical health, relationships with sexual partners, and self-confidence were associated with decreased mental health issues, while the side effects of ART, AIDS-related symptoms, and inconvenience in daily life due to ART use were associated with increased mental health issues.
Conclusions: ART-related experiences were associated with mental health problems, tailored mental health promotion interventions targeting these experiences are needed.
... In the early phase of the ART programme in India, when ART was initiated at CD4 ≤200/mm 3 , higher mortality was noted in cases with advanced immunosuppression which highlighted the need for timely diagnosis and ART initiation. 5,6 In the subsequent years, the programme adopted changes in the CD4 guidelines for ART initiation, based on the global evidence supporting reduction in morbidity and mortality with early ART initiation. The CD4 cutoffs for ART initiation were raised to 250 cells/mm 3 or less during 2009-2012 and 350 cells/mm 3 or less during 2012-2016. ...
... The CD4 cutoffs for ART initiation were raised to 250 cells/mm 3 or less during 2009-2012 and 350 cells/mm 3 or less during 2012-2016. 6,7 After the release of results from landmark multi-centric international clinical trials, the ART initiation guidelines further raised the CD4 cutoffs to 500 cells/mm 3 or less during July 2016-June 2017. 8 The crucial role of ART in prevention of transmission was established through clinical trials and two different cohort studies. ...
Background
India's free antiretroviral therapy (ART) programme was initiated in 2004. People living with HIV who were registered with ART centres (ARTC) were initiated on ART based on the CD4 count cutoffs as per prevailing guidelines. The others with higher counts remained on six-monthly follow up. We estimated retention rates among people living with HIV receiving ART in the programme and their determinants during 2012–2017.
Methods
In this retrospective cohort study, the records of people living with HIV aged ≥15 years, registered between April 2012 and March 2017 (reference period) in 81 of 396 ARTC across 33 Indian states were reviewed. ‘People living with HIV not on ART’ were defined as all those who were registered but not eligible for ART initiation or not started ART through the reference period. ‘People living with HIV on ART’ were those who were already on ART or initiated on ART as per prevailing guidelines. Relevant data from the clinic records were extracted and analysed for ‘Not on ART’ and ‘On ART’ groups separately using life-table method, Cox proportional hazards model to estimate retention probability and potential determinants.
Findings
Of 154,154 registered people living with HIV, 82.3% received ART (‘on ART’) during 2012–2017. Proportion retained was lower among ‘not on ART’ vs ‘on ART’ people living with HIV and was statistically significant (71.1% vs 88.9%, p < 0.001). Five-year retention probability was 57% for ‘not on ART’ and 81% for ‘on-ART’ people living with HIV (p < 0.001). The incidence of cases who were lost to follow up was 12.9 and 4.3/100 person-years among ‘not on ART’ & ‘on ART’ people living with HIV, respectively. Determinants of becoming lost to follow up (Adjusted HR, 95% CI) included ‘being in not on ART’ (Adjusted HR: 2.95, 95% CI: 2.85–3.05) ‘being male’ (1.08, 1.05–1.11); ‘having CD4 count 351–500 cells/mm³’ at registration (1.21, 1.16–1.26); and ‘having tuberculosis’ (1.15, 1.10–1.19).
Interpretation
New programmatic strategies for improving retention of people living with HIV in care may benefit by focussing on males, younger ages (15–29 years), CD4 counts during registration, history of or new TB diagnoses and early intervention within the first year.
Funding
This study was supported with NOA# SAMS/NACP/IE-ART/NARI/2017/09 dated March 27, 2017, awarded by Strategic Alliance Management Services Pvt. Ltd. (SAMS) with funding support from the Global Fund.
... A collaborative analysis of 18 HIV cohort studies was done in relation to "when to start consortium." [3] The major concern shown during the analysis was the lack of long-term trials and the lack of data from RCTs. Major limitations of analysis were non-AIDS defining events, severe and non-severe AIDS events, and drug-related toxic events not included. ...
... It was observed that CD4 counts <250 cells/mm 3 , tripled the rate of AIDS or mortality, and increased the rate of serious adverse events. [3] HIV outpatients' study also emphasized survival benefits in patients who started ART with CD4 counts of 350-500 cells/mm 3 compared to deferred treatment when CD4 count was below 350 cells/mm 3 . [4] Therefore, the cut-off for CD4 counts chosen for our study was 350 cells/mm 3 . ...
Background:
Antiretroviral therapy (ART) is the cornerstone for the treatment of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). Our study aimed to compare the impact of early versus delayed access to ART over clinical and immunological outcomes in HIV-positive adults.
Methods:
The prospective, randomized, open-label study was conducted for nine months, and comprised HIV-positive adults who presented to the ART center. Patients who presented early in their course of disease with baseline cluster of differentiation (CD) 4 count ≥350/mm3 were recruited in the early arm and in the late arm, if <350/mm3. The primary objectives were to evaluate disease progression in terms of the Centers for Disease Control and Prevention (CDC) stages, functional status, and opportunistic infections. Statistical analysis was done by applying an unpaired t-test, analysis of variance (ANOVA), Chi-square test, and Kaplan-Meier analysis with a P value <0.05 as significant at a 95% confidence interval.
Results:
A total of 134 HIV-positive patients meeting eligibility criteria were randomized. All patients including 60 in the early and 74 in the late arm received tenofovir + lamivudine + efavirenz (TLE). There was a significant difference in CDC stages and immunological status at baseline and post ART initiation (p-value < 0.001). TB-HIV co-infections were significantly (p-value = 0.006) more in late arm.
Conclusion:
The study suggests CD4 counts at ART initiation, as the most important factor in predicting post-treatment recovery in terms of clinical and immunological outcomes.
... In response to The Joint United Nations Programme on HIV/AIDS (UNAIDS) new targets for human immunodeficiency virus (HIV) treatment beyond 2015, experts lunched new approach across the world to reach the goal of 90-90-90 by 2020; this means that by 2020, 90% of all people living with HIV (PLHIV) would be expected to know their HIV status, 90% of all people diagnosed with HIV infection would receive sustained antiretroviral treatment (ART), and 90% of all people receiving ART would have viral suppression [1]. HIV test-treat-retain cascade analysis is a model to identify gaps at any stage of service delivery, and formulate potential solutions to enhance the coverage of these services [2]. ...
... initiated testing and counseling.2 Lost to follow-up ...
Introduction: Human immunodeficiency virus (HIV) test-treat-retain cascade analysis, is a model to
identify gaps at every stage of service delivery, and formulate potential solutions to enhance coverage
of these services, as we aimed to carry out in the present study.
Material and methods: In order to detect problems, develop solutions, and further prioritize them at differ-
ent stages of HIV cascade, Fishbone analysis model (WHO 2018) was used. At first, an Excel file including
15 sheets was constructed, each sheet for a significant demographic data of sub-group covering all key
populations. Within each sheet, cascade diagram for diagnostic services, connection to services, treatment,
and suppression of viral load was demonstrated. Excel file was sent to 28 key persons. Participants were
instructed to identify problems in each stage and list all probable reasons for every specific problem. These
reasons were classified into six groups based on Fishbone model, including: 1) policies/guidelines; 2) ser-
vice/program management; 3) human resources; 4) supplies; 5) services delivery methods; and 6) patient/
client-related factors. Subsequently, participants were instructed to propose their potential solutions to ad-
dress these obstacles. Finally, four key informants prioritized the problems and suggested solutions.
Results: Analysis of the most important solutions (with 10-12 scores) proposed by key persons of the five
groups, including the increase of society awareness, addressing the stigma of HIV disease in mass media,
collaboration between politics and health parties to enhance society knowledge, expanding the treatment
and counseling centers and facilities across the country, healthcare workers training to provide valid and
reliable guidance and information to people who live with HIV, and refer them to designated centers for
care, counseling, and treatment as well as appropriate patient detection, mapping procedure, and gather-
ing precise statistics, and finally, employment of professional caregivers in counseling and testing centers.
Conclusions: Based on the identified gaps, innovative strategies to improve HIV testing and early case
detection, particularly for key populations, are critical to reach the 90-90-90 target of the UNIAID.
... On the one hand, ART brings significant clinical benefits for PLWH, such as improving physical health status, facilitating immune system recovery (e.g., higher CD4 cell counts), and slowing disease progression [28,29]. There is also evidence that viral suppression by ART greatly reduces the risk of transmitting HIV to sexual partners [1,2], potentially improving relationships between PLWH and their sexual partners. On the other hand, although advances in ART have largely reduced its side effects, recent studies have shown that about 25.0-53.3% of PLWH still experience severe side effects in their first year after ART initiation [30,31]. ...
... Relatively few participants reported an improvement in their sex-partner relationship, but for those who did, it was protective against depressive and anxiety symptoms. Health communication messages should therefore be disseminated to PLWH and their sexual partners emphasizing that viral suppression by ART greatly reduces the risk of transmitting HIV through sex [1,2]. This may remove concerns about resuming sexual behaviour and improve intimacy between sexual partners. ...
Background
Mental health problems (e.g., depression and anxiety) are among the most commonly reported comorbidities of HIV. Antiretroviral therapy (ART) coverage has increased sharply. The purposes of this prospective cohort study were to investigate the ART-related experiences and whether they were associated with mental health problems among a sample of people living with HIV undergoing ART in China.
Methods
The participants were 400 people living with HIV who had started ART for the first time in Guangzhou city. They were followed-up 1-year after ART initiation. Probable depression and moderate/severe anxiety were measured at baseline and Month 12, while experiences related to ART (e.g., side effects and regained self-confidence) were measured at Month 6. Univariate and multivariate logistic regressions were used to explore the associations between baseline characteristics, ART-related experiences and mental health status.
Results
Among the 300 participants (75.0%) who completed all three surveys, a significant decline in prevalence of probable depression (23.0% at baseline vs. 14.0% at Month 12, P = 0.002) and moderate/severe anxiety (14.7% at baseline vs. 8.7% at Month 12, P = 0.023) was observed during the follow-up period. After adjustment for mental health status and potential confounders at baseline, a number of ART-related experiences at Month 6 were associated with probable depression and/or moderate/severe anxiety measured at Month 12. Improved physical health, relationships with sexual partners, and self-confidence were associated with decreased mental health issues, while the side effects of ART, AIDS-related symptoms, and inconvenience in daily life due to ART use were associated with increased mental health issues.
Conclusions
ART-related experiences were associated with mental health problems, tailored mental health promotion interventions targeting these experiences are needed.
... To what extent delaying initiation of HAART may compromise its effectiveness remains unclear. There appears to be a consensus that HAART therapy should be initiated based primarily on a CD4 + count between 200 and 350 cells/mm 3 rather than viral load [4,5]. Results from a recently published multi-cohort study (ART Cohort study) which analyzed patients from Europe and North America have shown a clear benefit of initiation of HAART based on the CD4 + cell counts. ...
... Very similar observations have been made in recent reports from Botswana [9,12,13]. These observations are interesting and very revealing against the background of widely held consensus that therapy should be initiated at CD4 + counts between 200 and 350 cells/µL [4][5][6][7][8]. It has significant implications for resource limited settings where delay in initiating therapy is very common. ...
... On the one hand, ART brings signi cant clinical bene ts for PLWH, such as improving physical health status, facilitating immune system recovery (e.g., higher CD4 cell counts), and slowing disease progression [31,32]. There is also evidence that viral suppression by ART greatly reduces the risk of transmitting HIV to sexual partners [1,2], potentially improving relationships between PLWH and their sexual partners. On the other hand, although advances in ART have largely reduced its side effects, recent studies have shown that about 25.0-53.3% of PLWH still experience severe side effects in their rst year after ART initiation [33,34]. ...
... Relatively few participants reported an improvement in their sex-partner relationship, but for those who did, it was protective against depressive and anxiety symptoms. Health communication messages should therefore be disseminated to PLWH and their sexual partners emphasizing that viral suppression by ART greatly reduces the risk of transmitting HIV through sex [1,2]. This may remove concerns about resuming sexual behaviour and improve intimacy between sexual partners. ...
Background: Antiretroviral therapy (ART) coverage has increased sharply. This prospective observational cohort study investigated the association between experiences related to ART and mental health problems among a sample of people living with HIV in China.
Methods: The participants were 400 people living with HIV who had started ART for the first time in Guangzhou city. They were followed-up one-year after ART initiation. Probable depression and moderate/severe anxiety were measured at baseline and Month 12, while experiences related to ART were measured at Month 6. Univariate and multivariate logistic regressions were used to explore the predictors of mental health status.
Results: Among the 300 participants (75.0%) who completed all three surveys, a significant decline in prevalence of probable depression (23.0% at baseline vs. 14.0% at Month 12, P = 0.002) and moderate/severe anxiety (14.7% at baseline vs. 8.7% at Month 12, P = 0.023) was observed during the follow-up period. After adjustment for mental health status and potential confounders at baseline, a number of ART-related experiences at Month 6 were associated with probable depression and/or moderate/severe anxiety measured at Month 12. Improved physical health, relationships with sexual partners, and self-confidence were associated with decreased mental health issues, while the side effects of ART, AIDS-related symptoms, and inconvenience in daily life due to ART use were associated with increased mental health issues.
Conclusions: ART-related experiences were predictors of mental health problems, tailored mental health promotion interventions targeting these experiences are needed.
... While immediate (early) ART-start following confirmed HIV diagnosis is now universal gold standard HIV management in the present universal test-and-treat (UTT) strategy [22,25], previous management guidelines were to the contrary. Hitherto, potential PLHIV typically, were entered into care and observed moving down the HIV cascade of care continuuma linear and unidirectional continuum of care [26][27][28] comprising of HIV testing, retention in pre-ART care, ART-initiation, and sustained suppression on ARTuntil they meet ART eligibility criteria by manifesting specific clinical features of advanced HIV disease (AHD) [29][30][31][32][33][34]. This strategy potentially promoted lost-to-follow-up and late ART-initiation. ...
Background
Despite globally adapted universal test-and-treat (UTT) strategy of HIV management, survival time-to-antiretroviral-therapy initiation (TTAT) remains heterogenous and affected by diverse factors which remain unexplained in Malawi. This study explored correlates to TTAT-initiation in Malawi among adults living with HIV.
Methods
A multicentre retrospective cohort study was undertaken from eight centres. Medical records of ( n =9,953) adult patients aged 15+ years old, were reviewed. A life table, the Kaplan-Meier log-rank, and Cox Proportion Hazard regression were used to calculate survival TTAT-initiation and its correlates, respectively. Adjusted Hazard ratio less than 1 (aHR <1) signified factors negatively associated, while aHR >1 meant factors positively associated with TTAT-initiation. Hazard ratio with 95% Confidence interval (95%CI) and p <0.05 were used to declare statistical significance.
Results
Data from (n=9,953) adult HIV patients were abstracted from hospital medical records. Patients median age was 40 (IQR: 33-48 years). 60.8% were females, 45.2% were younger adults of 20-39 years, and 78.8% were either married or cohabiting. 48.1% had advanced HIV disease; WHO clinical stage III, 24.5% had WHO stage IV, whereas 27.5% were asymptomatic; thus; 24.9% initiated ART due to low CD4+ count and 2.6% under PMTCT’s Option-B+. Findings from TTAT-initiation survival function analysis show that each patient had a single entry into the study and provided a total of 5,414 event-time-intervals, giving a 100% total event-failure without censored observations. Mean and median survival times were 527.2 days and 6 (IQR 0-5,414) days, respectively. Treatment-initiation (time at risk) was observed at the rate of 0.002 per 5,247,268 person-years. From multivariable Cox PH regression analysis, independent factors identified to be negatively associated with early (timely) antiretroviral treatment-initiation included; older age of 55+ years by 16% [aHR 0.84, 95%CI: (0.71–0.97)], male gender by 4% [aHR=0.96, 95%CI: (0.92–0.98)], bacterial causes by 5% [aHR=0.95, 95%CI: (0.89–0.99)], mycobacterial causes by 14% [aHR=0.86, 95%CI: (0.81–0.92)], high viraemia VL>1,000 copies/mL by 17% [aHR=0.83, 95%CI: (0.81–0.95)], registered in secondary tier and tertiary tier health facilities by 21% [aHR 0.79, 95%CI: (0.73-0.86) and 14% [aHR 0.86, 95%CI: (0.79-0.93) respectively, longer HIV survivorship (duration) by 58% to 85%, and having respiratory symptoms like coughing or breathlessness by 7% [0.93 95%CI: (0.88–0.97)]. These factors acted as barriers to early time-to-ART-initiation. In contrast younger adults of 20-39 years; [aHR=1.04, 95%CI: (1.02–1.19)], early mid-aged patients of 40-54 years; [aHR=1.03, 95%CI: (1.01– 1.21)], incomplete basic education level; [aHR 1.09, 95%CI: (1.02-1.20)], secondary education level; [aHR=1.06, 95%CI: (1.01-1.12)], Northern and Southern regions ethnicity; [aHR=1.07, 95%CI: (1.02–1.16)] and [aHR=1.06, 95%CI: (1.01–1.12) respectively, manifesting chronic headache or fevers; [aHR=1.12, 95%CI: (1.04–1.21)], being asymptomatic; [aHR=1.02, 95%CI: (1.02–1.13), ( p< 0.041)], being immunosuppressed with WHO clinical stage III; [aHR=1.86, 95%CI: (1.21-3.45)], WHO clinical stage IV; [aHR=2.80, 95%CI: (1.20-3.22)], protozoal pathological infection; [aHR=1.06, 95%CI: (1.02-1.15)], low CD4+ cell count <250 cells/µL; [aHR=1.05, 95%CI: (1.01–1.09), self-employment [aHR=1.04, 95%CI: (1.00–1.09)], and year of HIV diagnosis variable, were all positively associated with treatment-initiation and acted as precursors to early (timely) ART-initiation.
Conclusion
The study demonstrates that apart from meeting clinical eligible, different clinical and nonclinical factors contributed to time-to-treatment initiation among adults living with HIV. These factors; which are still prevalent in Malawi, have contributed to the spiralling and high mortality and morbidity from HIV/AIDS in Malawi and– hence, a knowledge of their existence, coupled with efforts to counteract and halt their occurrences, and strategies to strengthen and sustain the gained milestones in all tiers of health facility establishments across Malawi cannot be overemphasised.
... Being retained in care and achieving HIV viral suppression carries significant benefits both for the individual patient and for broader public health goals. Not only does HIV viral suppression provide numerous individual health benefits [14][15][16][17], including achieving a life-expectancy near that of people without HIV [18], it also lowers the risk of viral transmission through sex among heterosexual couples as well as MSM [19][20][21]. Additionally, previous work has seen that PLWH in the general population may often fall in and out of care, putting them at risk for poorer HIV care outcomes [22,23]. ...
Background
The use of telemedicine has grown significantly since the COVID-19 pandemic and has the potential to improve access to specialized care for otherwise underserved populations. Incarcerated people living with HIV (PLWH) could potentially benefit from expanded access to HIV care through telemedicine.
Methods
All PLWH who were incarcerated within the Tennessee Department of Corrections and received care through the HIV telemedicine clinic at Regional One Hospital between 5/1/2019 through 2/28/2022 were identified from the electronic health records (EHR). Demographics, laboratory data, vaccine history, and treatment outcomes were abstracted from the EHR. Retention in care and viral suppression were defined using Centers for Disease Control and Prevention definitions.
Results
Of the 283 incarcerated PLWH receiving care from this telemedicine clinic, 78% remained retained in care and 94% achieved or maintaining viral suppression at 12 months. Many preventative care measures remained unperformed or undocumented, including vaccinations and testing for concurrent sexually transmitted infections. There were 56 patients (20%) found to have chronic hepatitis C in this population, with 71% either cured or still on treatment in this study period.
Conclusions
Retention in care and viral suppression rates were excellent among incarcerated PLWH receiving telemedicine care for their HIV. HIV related primary health care screenings and vaccinations, however, were less consistently documented and represent areas for improvement.
... TFA consists of the availability of ART to all PLHIV, regardless of their CD4+ T cell counts [5]. Evidence shows that immediate ART initiation improves morbidity and mortality among PLHIV while simultaneously allowing more PLHIV to become "undetectable", and thus "untransmittable" [6][7][8][9][10][11]. Of note, Brazil was the first developing country to implement the TFA policy, 2 years earlier than it was officially recommended by the World Health Organization [12][13][14]. ...
Introduction
The impact of specific policies on HIV care has been scarcely investigated. In this study we aimed to analyze the impact of the Treatment For All policy (TFA‐2013) and the adoption of integrase strand transfer inhibitors (INSTIs‐2017) as first‐line therapy on clinical indicators of people living with HIV (PLHIV) in Brazil.
Methods
We assessed the public database of Brazil's Ministry of Health and extracted data from 2009 to 2019. We investigated the impact of TFA and INSTIs with a time‐series analysis of four health indicators in PLHIV: antiretroviral treatment (ART) initiation with a CD4+ count >500/mm³; ART initiation <1 month after the first CD4+ measurement; viral load suppression (VLS); and treatment adherence. We explored trends over time by gender, age, macroregion of residency and municipal‐level social vulnerability index.
Results
We included 753 316 PLHIV in 2019. Most were males (64.81%) in the 30–49 years age category (50.86%). We observed an overall improvement in all HIV clinical indicators, with notable impact of TFA on timely ART initiation and VLS, and mild impact of INSTIs on treatment adherence. Such improvements were heterogeneous, with remarkable gaps in gender, age and socioeconomic groups that have persisted over time. Indicators point to inferior outcomes among children, older adults, women and people living in socially vulnerable locations.
Conclusions
Recent Brazilian public policies have had positive impacts on key HIV clinical indicators. However, our results highlight the need for specific policies to improve HIV care for children, older adults, women and socially vulnerable groups.
... 7 Also, our analyses showed that PLWH with immune suppression (CD4 <200 cells/lL), detectable HIV viraemia and chronic comorbidities, and some subpopulations (migrants, people aged 75 years) could be at increased risk of severe COVID-19. 8,26 Since its beginning, PISCIS has contributed data to multiple international HIV cohort consortia collaborating in or leading innovative research in HIV treatment initiation timing, 27,28 combined ART response and effectiveness, 29-31 patient prognosis and mortality, 29,32 AIDS-defining and non-AIDSdefining illnesses, 33,34 immunological response and virological response significance 35 and HIV drug resistance and virological failure. 36 All publications can be found at [https://piscisco hort.org/articles/]. ...
Why was the cohort set up?
The PISCIS Cohort was initiated in 1998 with the aims of enhancing formal HIV surveillance and facilitating clinical-epidemiological applied research by means of standardizing programmatic data collection and management from HIV units in participating hospitals in Catalonia and Balearic Islands, Spain. In Catalonia, the cohort is formally recognized as part of the longitudinal public health surveillance (under the Decree 203/2015 of 15 September 15, 2015¹) and is part of the Catalan AIDS/HIV/sexually transmitted infections (STI) Integrated Surveillance System (SIVES).²
The PISCIS cohort is coordinated and managed by the Centre for Epidemiological Studies of Sexually Transmitted Infections and HIV/AIDS in Catalonia (CEEISCAT) as the responsible unit of HIV/STI surveillance and monitoring and evaluation of these infections for the Catalan Health Department. Moreover, the PISCIS cohort has received support through specific research project grants from different agencies, including the Foundation for Innovation and Prospective Health in Spain (FIPSE), Health Research Fund (FIS), Fundació La Marató de TV3, Obra Social La Caixa and funds received from international collaborations such as RESPOND, HIV-CAUSAL, ART-CC and COHERE. Finally, it depends on the voluntary dedication of clinicians and research coordinators in the participating hospitals who support the sending and maintenance of data.
... In addition to preventing vertical transmission, ART reduces maternal morbidity and mortality, and improves birth outcomes [4,5]. These benefits are more evident when pregnant and breastfeeding women living with HIV are initiated on a potent, safe, and well-tolerated ART regimens early in pregnancy or as soon as they are diagnosed while pregnant or breastfeeding [6][7][8]. ...
Introduction
Antiretroviral therapy (ART) is very effective in preventing vertical transmission of HIV but some women on ART experience different virologic, immunologic, and safety profiles. While most pregnant women are closely monitored for short-term effects of ART during pregnancy, few women receive similar attention beyond pregnancy. We aimed to assess retention in care and clinical and laboratory-confirmed outcomes over 3 years after starting ART under Malawi’s Option B + program.
Methods
We conducted a prospective cohort study of pregnant women newly diagnosed with HIV who started tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/3TC/EFV) for the first time at Bwaila Hospital in Lilongwe, Malawi between May 2015 and June 2016. Participants were followed for 3 years. We summarized demographic characteristics, pregnancy outcomes, and clinical and laboratory adverse events findings using proportions. Log-binomial regression models were used to estimate the overall risk ratios (RR) and the corresponding 95% confidence interval (CI) for the association between index pregnancy (i.e. index pregnancy vs. subsequent pregnancy) and preterm birth, and index pregnancy and low birthweight.
Results
Of the 299 pregnant women who were enrolled in the study, 255 (85.3%) were retained in care. There were 340 total pregnancies with known outcomes during the 36-month study period, 280 index pregnancies, and 60 subsequent pregnancies. The risks of delivering preterm (9.5% for index pregnancy and13.5% for subsequent pregnancy: RR = 0.70; 95% CI: 0.32–1.54), or low birth weight infant (9.8% for index pregnancy and 4.2% for subsequent pregnancy: RR = 2.36; 95% CI: 0.58–9.66) were similar between index and subsequent pregnancies. Perinatally acquired HIV was diagnosed in 6 (2.3%) infants from index pregnancies and none from subsequent pregnancies. A total of 50 (16.7%) women had at least one new clinical adverse event and 109 (36.5%) women had at least one incident abnormal laboratory finding. Twenty-two (7.3%) women switched to second line ART: of these 64.7% (8/17) had suppressed viral load and 54.9% (6/17) had undetectable viral load at 36 months.
Conclusion
Most of the women who started TDF/3TC/EFV were retained in care and few infants were diagnosed with perinatally acquired HIV. Despite switching, women who switched to second line therapy continued to have higher viral loads suggesting that additional factors beyond TDF/3TC/EFV failure may have contributed to the switch. Ongoing support during the postpartum period is necessary to ensure retention in care and prevention of vertical transmission.
... It is important to determine the optimal timing for treatment to achieve the best outcome over the long and short terms. However, in previous studies, the correlation between these factors (covariates) was not sufficiently considered, and the results were presented in the form of simply correcting the factors in a regression equation 5,6 . Therefore, it is essential to consider a strong correlation between variables to prevent the over-or under-estimation of the estimated value of outcome variables. ...
The beginning of human immunodeficiency virus (HIV) infection treatment depends on various factors, which are significantly correlated with the initial CD4 cell number. However, a covariate correlation between these factors may not reflect the correct outcome variable. Thus, we evaluated the effects of a combination of fixed factors (reduced dimensions), which determine when to start treatment for the first time, on short-term outcome, long-term outcome, and survival, considering correlations between factors. Multiple correspondence analysis was performed on variables obtained from 925 patients who participated in a Korean HIV/acquired immunodeficiency syndrome cohort study (2006–2017). Five reduced dimension groups were derived according to clinical data, viral load, CD4 cell count at diagnosis, initial antiretroviral therapy, and others. The dimension group with high initial viral loads (55,000 copies/mL) and low CD4 cell counts (< 200 cells/mm³) should start treatment promptly after diagnosis. Groups with high initial CD4 cell counts (> 350 cells/mm³) that did not require immediate treatment according to previous guidelines had a higher failure rate for long-term relative CD4 recovery. Our results highlight the importance of early diagnosis and treatment to positively influence long-term disease outcomes, even if the initial immune status is poor, given the patient’s combination of early diagnostic symptoms.
... Late presentation, or accessing care with a CD4 cell-count <350 cells/μL or with an AIDSdefining illness, has several consequences on an individual clinical, public health, and health systems level [1]. On the individual clinical level, those presenting late in HIV-care often experience higher morbidity and mortality [2,3]. In addition, a lower CD4-cell count results in a higher risk for opportunistic infections and AIDS-defining malignancies, including Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancers [4]. ...
Introduction
In Europe, half of people living with HIV (PLWH) present late to care, with associated higher morbidity and mortality. This study aims to assess short- and long-term costs of HIV-care based on time of presentation and identify other factors contributing to higher costs in the first and fifth year after antiretroviral therapy (ART) initiation.
Material and methods
We included ATHENA cohort data which prospectively includes 98% of PLWH in the Netherlands. PLWH who initiated ART in 2013 were included and followed over five years. PLWH were divided in three categories based on CD4 cell-count at time of ART initiation: timely presentation (CD4>350cells/μL), late presentation (CD4 200-350cells/μL or >350cells/μL with AIDS-defining illness) and very late presentation (CD4<200cells/μL). The total HIV-care cost was calculated distinguishing ART medication and non-ART medication costs (hospitalization, outpatient clinic visits, co-medications, and HIV-laboratory tests).
Results
From 1,296 PLWH, 273 (21%) presented late and 179 (14%) very late. Nearly half of those who entered HIV-care in a very late stage were of non-Dutch origin, with 21% originating from sub-Saharan Africa. The mean cost per patient in the first year was €12,902 (SD€11,098), of which about two-thirds due to ART (€8,250 (SD€3,142)). ART costs in the first and fifth year were comparable regardless of time of presentation. During the first year on treatment, non-ART medication costs were substantially higher among those with late presentation (€4,749 (SD€8,009)) and very late presentation (€15,886 (SD€ 21,834)), compared with timely presentation (€2,407(SD€4,511)). Higher non-ART costs were attributable to hospitalization and co-medication. The total non-ART costs incurred across five years on treatment were 56% and 246% higher for late and very late presentation respectively as compared to timely presentation.
Conclusion
Very late presentation is associated with substantial costs, with non-ART costs nearly seven times higher than for those presenting timely. Hospitalization and co-medication costs are likely to continue to drive higher costs for individuals with late presentation into the future. Programs that identify individuals earlier will therefore likely provide significant short- and long-term health cost savings.
... One of the main objectives of the HIV Causal collaboration is to implement this type of analysis. 45 Within ART-CC 46 and HIV Causal, 47 we took time-dependent confounding variables into account, using two different approaches, in order to determine when best to start cART. We concluded that treatment deferral until the CD4 cell count was below 350/mm 3 was associated with an increased risk of AIDS and death. ...
The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid-and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120 000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of
... Our study implicated that XRCC4 rs1056503 was associated with HIV-1 infection, which was consistent with the above reports. Rs1056503 is located in the 5′ regulatory region of XRCC4 gene, which may cause changes in mRNA expression level and XRCC4 The AIDS patients with CD4+ T cell count less than 350 cells/μl should be given antiretroviral therapy or other treatments according to the World Health Organization (WHO) [31][32][33]. In the present study, we found a significant difference in frequencies of XRCC5 rs16855458 genotypes between the two subgroups of cases, where genotypes AA and AC were associated with lower numbers of CD4+ T cells. ...
Background and aims:
Men who have sex with men (MSM) are at high risk of HIV infection. The nonhomologous end joining (NHEJ) pathway is the main way of double-stranded DNA break (DSB) repair in the higher eukaryotes and can repair the DSB timely at any time in cell cycle. It is also indicated that the NHEJ pathway is associated with HIV-1 infection since the DSB in host genome DNA occurs in the process of HIV-1 integration. The aim of the present investigation was to evaluate associations of single-nucleotide polymorphisms (SNPs) in NHEJ pathway genes with susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China.
Methods:
A total of 481 HIV-1 seropositive men and 493 HIV-1 seronegative men were included in this case-control study. Genotyping of 22 SNPs in NHEJ pathway genes was performed using the SNPscan™ Kit.
Results:
Positive associations were observed between XRCC6 rs132770 and XRCC4 rs1056503 genotypes and the susceptibility to HIV-1 infection. In gene-gene interaction analysis, significant SNP-SNP interactions of XRCC6 and XRCC4 genetic variations were found to play a potential role in the risk of HIV-1 infection. In stratified analysis, XRCC5 rs16855458 was significantly associated with CD4+ T cell counts in AIDS patients, whereas LIG4 rs1805388 was linked to the clinical phases of AIDS patients.
Conclusions:
NHEJ gene polymorphisms can be considered to be risk factors of HIV-1 infection and AIDS progression in the northern Chinese MSM population.
... In this study, M184I/V was the most common DRAM detected in patients with LLV, with a prevalence of 28.6%. It is worth noting that M184I/V is mainly selected by FTC or 3TC, which is one of the important backbones in the ART regimens of NFATP [48][49][50][51]. K103N was the second most common DRAM (19.2%) detected in this study and usually selected by EFV or NVP, which are the most widely used NNRTI in NFATP [11,35,39]. ...
Background
Maintaining plasma HIV RNA suppression below the limit of quantification is the goal of antiretroviral therapy (ART). When viral loads (VL) remain in low-level viremia (LLV), or between 201 and 999 copies/mL, the clinical consequences are still not clear. We investigated the occurrence of LLV with drug resistance and its effect on CD4 cell counts in a large Chinese cohort.
Methods
We analysed data of 6,530 ART-experienced patients (42.1 ± 10.9 years; 37.3% female) from the China’s national HIV drug resistance (HIVDR) surveillance database. Participants were followed up for 32.9 (IQR 16.7–50.5) months. LLV was defined as the occurrence of at least one viral load (VL) measurement of 50–200 copies/mL during ART. Outcomes were drug resistance associated mutations (DRAM) and CD4 cell counts levels.
Results
Among 6530 patients, 58.0% patients achieved VL less than 50 copies/mL, 27.8% with VL between 50 and 999 copies/mL (8.6% experienced LLV), and 14.2% had a VL ≥ 1000 copies/mL. Of 1818 patients with VL 50–999 copies/mL, 182 (10.0%) experienced HIVDR, the most common DRAM were M184I/V 28.6%, K103N 19.2%, and V181C/I/V 10.4% (multidrug resistance: 27.5%), and patients with HIVDR had a higher risk of CD4 cell counts < 200 cells/ μL (AOR 3.8, 95% CI 2.6–5.5, p < 0.01) comparing with those without HIVDR. Of 925 patients with VL ≥ 1000 copies/mL, 495 (53.5%) acquired HIVDR, the most common DRAM were K103N 43.8%, M184I/V 43.2%, M41L 19.0%, D67N/G 16.4%, V181C/I/V 14.5%, G190A/S 13.9% and K101E 13.7% (multidrug resistance: 75.8%), and patients with HIVDR had a higher risk of CD4 cell counts < 200 cells/ μL (AOR 5.8, 95% CI 4.6–7.4, p < 0.01) comparing with those without HIVDR.
Conclusion
Persistent with VL 50–999 copies/mL on ART is associated with emerging DRAM for all drug classes, and patients in this setting were at increased risk of CD4 cell counts < 200 cells/ μL , which suggest resistance monitoring and ART optimization be earlier considered.
... 21 However, MSM who are living with HIV often reported lower ART coverage rates compared to national coverage rates. 22,23 Limited literature suggests that the ART coverage rates range from 26.1% in 2011 24 to 60.3% in 2016 among MSM in China. 16 ...
Background
Men who have sex with men (MSM) are disproportionately affected by HIV globally and in China. Early antiretroviral therapy (ART) can reduce HIV-related illness, improve quality of life, and decrease HIV incidence rates. Given the high vulnerability of and limited research on ART coverage in China, we describe the ART initiation rate and correlates of ART initiation using Anderson’s health service utilization model.
Methods
We conducted a cross-sectional survey and collected blood samples for HIV and HCV testing and CD4 count among MSM recruited in Chengdu and Shanghai, China (N= 1,633). Using stepwise logistic regression, we explored factors associated with ART initiation postulated by Anderson’s health service utilization model.
Results
More than half of the participants had not started ART (53.5%). Older age and Han ethnicity were associated with a higher probability of ART initiation. Being married, higher monthly income (> US$464.35), retirement, depression, and condomless anal sex predicted a lower probability of ART initiation.
Conclusions
The ART initiation rate among MSM in this study is lower than the national level of ART coverage among all people living with HIV (PLWH) in China. ART initiation is best predicted by demographic characteristics such as age and ethnicity. Participants who are retired, married, reported depressive symptoms, and sexual risk behavior are less likely to have initiated ART. Future studies could examine whether integrating mental health and sexual health services into the current HIV care continuum is beneficial to ART initiation among MSM. Strategies should be developed to promote ART initiation among certain populations such as young MSM and ethnic minorities in China.
... However, under these better situations, the biggest clinical question at that time was when to start cART because, as described, long term treatment caused severe side effects and complications, problems of adherence, and drug resistance. A couple of observational studies reported outcome comparisons between the early or deferred cART in asymptomatic HIV infected-patients and demonstrated that an initiation threshold of CD4 counts was around 200/mm 3 to 350/mm 3 (48)(49)(50)(51). A large international randomized study, the Strategies for Management of Anti-Retroviral Therapy study (SMART study), was conducted to explore whether cART could be interrupted when CD4 counts elevated over 350/ mm 3 . ...
Forty years have passed since the first five AIDS cases in Los Angeles were reported in 1981. Looking back at the history, these 40 years could be divided into 3 phases. During the first 15 years, when there was little efficacious therapy against HIV, clinical research was directed to develop diagnosis and treatment for opportunistic infections, mainly Pneumocystis jirovecii pneumonia. When combination antiretroviral therapy (cART) became available in 1996, taking cART had been troublesome to most patients following 10 years because some of them had severe side effects, diet restrictions, high pill burdens, drug interactions, etc. It was not easy for patients to keep high adherence and, therefore, the virus easily obtained drug resistance. Although the prognosis has been dramatically improved, patients had been still living with hard times during the second phase. Along with advancement of anti-retroviral drugs that have allowed simple treatment possible, their life expectancy has further improved and is reaching almost nearly the general population in the following 15 years. However, some patients have recently faced an additional load to treat life-related comorbidities and non-AIDS defining malignancies. The problem is that these diseases start to occur in the 40s- or 50s-year-old generations and that means HIV-infected persons are suffering from pre-mature aging. AIDS no longer signifies death. However, we still have a lot to improve for their quality of life.
... www.nature.com/scientificreports/ suppresses peripheral viremia below the limit of detection on standard clinical assays is typically linked to CD4 reconstitution 3 that leads to improved health outcomes 4,5 . Nevertheless, a sizeable proportion of PLWH who achieve viral suppression (VS) do not experience CD4 reconstitution after starting treatment, with findings ranging from approximately 20% in high income settings such as the Danish HIV Cohort Study 6 to over 50% in lower income settings such as northwestern Tanzania 7 . ...
A significant minority of people living with HIV (PLWH) achieve viral suppression (VS) on antiretroviral therapy (ART) but do not regain healthy CD4 counts. Clinical factors affecting this immune non-response (INR) and its effect on incident serious non-AIDS events (SNAEs) have been challenging to understand due to confounders that are difficult to control in many study settings. The U.S. Military HIV Natural History Study (NHS) and African Cohort Study (AFRICOS). PLWH with sustained VS (< 400 copies/ml for at least two years) were evaluated for INR (CD4 < 350 cells/µl at the time of sustained VS). Logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for factors associated with INR. Cox proportional hazards regression produced adjusted hazard ratios (aHRs) for factors associated with incident SNAE after sustained VS. INR prevalence was 10.8% and 25.8% in NHS and AFRICOS, respectively. Higher CD4 nadir was associated with decreased odds of INR (aOR = 0.34 [95% CI 0.29, 0.40] and aOR = 0.48 [95% CI 0.40, 0.57] per 100 cells/µl in NHS and AFRICOS, respectively). After adjustment, INR was associated with a 61% increase in relative risk of SNAE [95% CI 1.12, 2.33]. Probability of "SNAE-free" survival at 15 years since sustained VS was approximately 20% lower comparing those with and without INR; nearly equal to the differences observed by 15-year age groups. CD4 monitoring before and after VS is achieved can help identify PLWH at risk for INR. INR may be a useful clinical indicator of future risk for SNAEs.
... 5 There are several important implications of delayed recognition of HIV. [6][7][8][9][10] First, the longer patients have untreated disease the more opportunities there are for transmission. 11,12 Second, healthcare costs correlate inversely with CD4 + cell counts 13,14 ; the annual cost for a patient with a CD4 count of <200 cells/mm 3 is approximately double that of a patient with a count that is >500 cells/mm 3 . ...
Background
Understanding care patterns of persons living with HIV prior to diagnosis can inform prevention opportunities, earlier diagnosis, and engagement strategies. We examined healthcare utilization among HIV-positive individuals and compared them to HIV-negative controls.
Methods
Data were from a retrospective cohort from Manitoba, Canada. Participants included individuals living with HIV presenting to care between 2007 and 2011, and HIV-negative controls, matched (1:5) by age, sex, and region. Data from population-based administrative databases included physician visits, hospitalizations, drug dispensation, and chlamydia and gonorrhea testing. Diagnoses associated with physician visits were classified according to International Classification of Diseases chapters. Conditional logistic regression models were used to compare cases/controls, with adjusted odds ratios (AORs) and their 95% confidence intervals (95% CI) reported.
Results
A total of 193 cases and 965 controls were included. Physician visits and hospitalizations were higher for cases, compared to controls. In the 2 years prior to case date, cases were more likely to be diagnosed with “blood disorders” (AOR: 4.2, 95% CI: 2.0–9.0), be treated for mood disorders (AOR: 2.4, 95% CI: 1.6–3.4), and to have 1+ visits to a hospital (AOR: 2.2, 95% CI: 1.4–3.6).
Conclusion
Opportunities exist for prevention, screening, and earlier diagnosis. There is a need for better integration of healthcare services with public health.
... Patients with high baseline CD4 + cell counts who initiated ART after one year had 9% higher risk of AIDS-related death than those with lower baseline CD4 + cell counts who initiated ART after 90 days but within one year of diagnosis. Patients with higher CD4 + levels at baseline who missed treatment opportunities had a worse prognosis than those with lower CD4 + levels at baseline [16,17]. Arguments for delaying ART initiation based on the use of a CD4 + cell count threshold include concerns about drug resistance, side effects, and resource allocation [18][19][20][21][22][23]. ...
Background
The conventional survival analysis model on HIV/AIDS prognosis is the Cox proportional hazard model, which deals with only one event type, death, regardless of the cause. Few studies have used a competing risk model to evaluate the predictors of AIDS-related mortality.
Objective
To estimate the influence of antiretroviral therapy (ART) initiation time and baseline CD4⁺ cell counts on acquired immunodeficiency syndrome (AIDS)-related death among former plasma donors.
Methods
A retrospective cohort study was conducted involving 11,905 human immunodeficiency virus (HIV) or AIDS patients in a high-risk area of Henan province in China between 1995 and 2016. Demographic and clinical data were collected. Sub-distribution hazard ratios (sHRs) for AIDS-related mortality with baseline CD4⁺ cell counts and ART initiation time were determined using a competing risk model.
Results
Patients who initiated ART within 90 days of HIV/AIDS diagnosis (sHR: 0.24, 95% CI: 0.22–0.27) or had baseline CD4⁺ counts of >500 cells/μL (sHR: 0.23, 95% CI: 0.19–0.28) were associated with lower AIDS-related mortality risk. Patients with ART initiation time >1 year but CD4⁺ counts >350 cells/μL (sHR: 4.42, 95% CI: 3.30–5.91) had a higher AIDS-related mortality risk than those with ART initiation time >90 days but CD4⁺ counts ≤350 cells/μL (sHR: 4.33, 95% CI: 3.58–5.23).
Conclusions
Our results demonstrate that patients with high CD4⁺ cell counts and late ART had a 9% higher risk of AIDS-related death than those with low CD4⁺ cell counts and early ART. This study confirms the great significance of immediate ART initiation among former plasma donor HIV patients in China.
... Antiretroviral therapy (ART) during pregnancy nearly eliminates the risk of mother-to-child transmission of HIV and improves health and survival for women with HIV [1,2]. Despite over two decades of clinical experience of ART use in pregnancy, the debate about whether ART increases the risk of adverse perinatal outcomes continues due to conflicting data [3,4]. ...
Objective
To evaluate the associations of HIV infection with preterm birth (PTB), and of HIV antiretroviral therapy (ART) with PTB.
Methods
We analysed singleton live‐born pregnancies among women from 1995 to 2019 in the Women's Interagency HIV Study, a prospective cohort of US women with, or at risk for, HIV. The primary exposures were HIV status and ART use before delivery [none, monotherapy or dual therapy, or highly active antiretroviral therapy (HAART)]. The primary outcome was PTB < 34 weeks, and, secondarily, < 28 and < 37 weeks. We analysed self‐reported birth data, and separately modelled the associations between HIV and PTB, and between ART and PTB, among women with HIV. We used modified Poisson regression, and adjusted for age, race, parity, tobacco use and delivery year, and, when modelling the impact of ART, duration from HIV diagnosis to delivery, nadir CD4 count, and pre‐pregnancy viral load and CD4 count.
Results
We analysed 488 singleton deliveries (56% exposed to HIV) to 383 women. The risk of PTB < 34 weeks was similar among women with and without HIV, but the risk of PTB < 37 weeks was higher [32% vs. 23%; adjusted risk ratio (aRR) = 1.43; 95% confidence interval (CI): 1.07–1.91] among women with HIV. The risk of PTB < 34 weeks was lower among women with HIV receiving HAART than among those receiving no ART (7% vs. 26%; aRR:0.19; 95% CI: 0.08–0.44). The associations between HAART and PTB < 28 and < 37 weeks were similar.
Conclusions
Antiretroviral therapy exposure was associated with a decreased risk of PTB among a US cohort of women with HIV. Given the growing concerns about ART and adverse pregnancy outcomes, this finding that ART may be protective for PTB is reassuring.
... ART may also results in above mentioned cytopenias [2]. When compared to HIV/AIDS patient not on ART, patients in whom ART was started earlier showed better survival rates observed in patients on ART against the HIV virus [3][4][5]. Use of highly active antiretroviral therapy (HAART) in western developed countries significantly decreases AIDS-related deaths. This decrease in deaths and mortality changed the earlier picture of HIV infection from one of rapidly fatal disease to a chronic still manageable infection [6]. ...
Background: Hematological abnormalities are most common complications found in human immunodeficiency virus (HIV) infection and these complications increase with the advanced stage of diseases. Hematological disorders which are generally observed in HIV infection are different cytopenias like anemia, leukopenia and thrombocytopenia. Various type of cytopenias in HIV has been associated with different factors like sex, age, race or ethnicity, geographical location and CD4 count. So present study was planned with the aim to study the prevalence of cytopeniaviz anemia, thrombocytopenia and leucopenia in Indian population. Material and Methods: This cross-sectional study was conducted at a Dr. Shankarrao Chavan Goernment Medical College Nanded in Maharashtra, India. The present study was approved by the local ethical committee of the institute. Total two hundred subjects were selected for study. To avoid the bias due to preexisting illness or previous treatment affecting hematological profile, proportions were compared using chi-square test of significance. Student t test was done as indicator of statistical significance. Data was analysed by using Statistical Package for Social Science (SPSS) software version 16.0. P value < 0.05 considered as significant and p value > 0.05 non-significant. Results: In present study the prevalence of different types of cytopenia in decreasing order was anemia (75.5%) thrombocytopenia (8.5%) and leucopenia (2%). Discussion: The result observed in the present study were similar to other studies done in India and abroad. There were also few studies with the higher or lower prevalence of these cytopenias than the present study. These differences in observations might be due to the factors like age, sex, ART status and the population from different geographical locations. The present study provide some baseline data from Indian population and can be useful for future studies in people living with HIV/AIDS.
... Acquired immune deficiency syndrome (AIDS) is a chronic, potentially life-threatening, immunocompromised status caused by human immunodeficiency virus (HIV) [1]. In addition to morbidity and mortality [2][3][4][5][6][7], AIDS events are associated with negative outcomes, such as relatively high rates of HIV transmission to sexual partners [8,9], relatively high rates of treatment failure after combination antiretroviral therapy (cART) [10], a poor immunological response to cART [11], and possible neurological sequelae [12]. Therefore, surveying the trends of AIDS incidence in persons with HIV (PWH) and characterizing the determinants of AIDS events are essential to HIV care. ...
IntroductionAcquired immune deficiency syndrome (AIDS) events at distinct time points after human immunodeficiency virus (HIV) diagnosis require various AIDS prevention strategies. However, no nationwide epidemiological surveillance studies have been conducted to explore the trends of distinct AIDS event time points in various at-risk populations. The aim of this study was to explore the issues and characterize the determinants of AIDS status after HIV diagnosis.Methods
This nationwide cohort study enrolled HIV-positive Taiwanese during 1984–2016. AIDS events were classified into three time points (≤ 3, 4–12, > 12 months) by their occurrence time after HIV diagnosis. The periods of HIV/AIDS diagnosis were divided into six categories according to the calendar year of HIV/AIDS diagnosis: 1984–1991, 1992–1996, 1997–2001, 2002–2006, 2007–2011, and 2012–2016. HIV-positive Taiwanese during 1984–2011 were then selected to determine the factors associated with four AIDS statuses within 5 years after HIV diagnosis (no AIDS, AIDS ≤ 3 months, within 4–12 months, > 12 months) using multinomial logistic regression.ResultsOf 33,142 cases, we identified 15,254 (46%) AIDS events. The overall AIDS incidence (events/100 person-years) peaked during 1992–1996 (20.61), then declined, and finally stabilized from 2002 (8.96–9.82). The evolution of the proportion of distinct time points of AIDS events following HIV diagnosis changed significantly in heterosexuals and intravenous drug users (IDUs) during 1984–2016 (decline at ≤ 3 months in IDUs, decline at 4–12 months in IDUs, and increase at > 12 months in heterosexuals and IDUs) but not among men who have sex with men (MSM). Time points at ≤ 3 months remained at > 50% among MSM and at > 55% among heterosexuals. In multinomial logistic regression, IDUs (vs. men who have sex with men; MSM) had a lower risk of all AIDS statuses; heterosexuals (vs. MSM) had a higher risk of AIDS events ≤ 3 months after HIV diagnosis.Conclusion
The magnitude of AIDS in Taiwan has been stable since 2002. Enhancing early diagnosis among people with sexual contact and optimizing the HIV care continuum among heterosexuals and IDUs should be priorities for further AIDS prevention strategies.
... The As an indicator of AIDS clinical characteristics, CD4 + T cell count re ects the count of the patient's body immune cells. The AIDS patients with CD4 + T cell count less than 350 cells/µl should be given antiretroviral therapy or other treatments according to the World Health Organization (WHO) [28][29][30]. In our study, we found that there was a signi cant difference of rs16855458 genotype frequency in XRCC5 gene between two case subgroups, and genotypes of AA and AC were associated with a small number of CD4 + T cells. ...
Background: Men who have sex with men (MSM) are at high risk of HIV infection. Non-homologous end joining (NHEJ) pathway is the main way of double-stranded DNA break (DSB) repair in the higher eukaryotes, and can repair the DSB timely at any time in cell cycle. The objective of this study was to investigate the association of SNPs of the NHEJ pathway genes with susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China.
Results: In the present study, a total of 481 HIV-1 seropositive men and 493 HIV-1 seronegative men were included. And genotyping of 22 SNPs in NHEJ pathway genes was performed using the SNPscanTM Kit. Our results disclosed significant associations of XRCC6 rs132770 and XRCC4 rs1056503 genotypes with susceptibility to HIV-1 infection. The generalized multifactor dimensionality reduction (GMDR) analysis found a significant SNP-SNP interaction between the XRCC6 and XRCC4 variants in the risk of HIV-1 infection. In stratified analysis, the positive effects of XRCC5 rs16855458 and LIG4 rs1805388 on the CD4+ T cell count and clinical phase of disease were validated.
Conclusions: Our results confirmed that the NHEJ gene polymorphisms played an important role in HIV-1 infection and AIDS progression in the northern Chinese MSM population.
... Therapiebeginns bei CD4 + -Zellzahlen zwischen 500/µl und 200/µl (Sterne et al., 2009, Palella et al., 2003, Phillips et al., 2007, Deutsche AIDS-Gesellschaft e.V. ...
Die HIV-Infektion wird von einer Hyperimmunaktivierung begleitet, die vermutlich eine treibende Kraft in der Pathogenese der Entwicklung von AIDS darstellt. Die Rolle der B-Zellen im Rahmen dieser Veränderungen und dem Einfluss einer Prednisolontherapie wird durch die ProCort-Studie genauer beschrieben. Diese stellt eine zweijährige, Placebo-kontrollierte, randomisierte Doppelblindstudie dar, bei der die Patienten 5mg Prednisolon täglich einnahmen. Mittels durchflusszytometrischen Messungen wurden bestimmte B-Zellpopulationen differenziert und quantifiziert. Die resultierenden Ergebnisse wurden weiterhin mit bekannten Immunaktivierungsmarkern korreliert. In der Arbeit konnte gezeigt werden, dass Studienteilnehmerinnen durch eine Prednisolontherapie signifikant mehr Memory-B-Zellen bzw. resting Memory-B-Zellen im Vergleich zur Placebogruppe aufweisen. Ferner konnte die Bedeutung der B-Zellen als prognostischer Marker der HIV-Infektion dadurch unterstützt werden, dass die genannten B-Zellreihen signifikant negative Korrelationen zu anderen, bereits etablierten Progressionsmarkern (CD4/CD8-Ratio, CD8/CD38/HLADR-Aktivierung, suPAR, sCD14) vorlagen. Zusammenfassend zeigt die Arbeit, dass die Veränderungen im B-Zellkompartment Teil des Immunaktiverungsprozesses im Rahmen der HIV- Infektion sind und Prednisolon modulierende Einflüsse darauf hat.
... Examples of impactful findings include research utilizing biospecimens to evaluate prognostic markers for HIV and AIDS and to understand the HIV reservoir (37)(38)(39)(40), studies on the associations of HIV infection and HIV therapies with comorbidity (18,(41)(42)(43), and studies comparing PLWH and HIV-seronegative persons in the cohorts to understand the associations of HIV infection with comorbidity and mortality (28,44). In addition, the MACS and WIHS have contributed to many impactful multicohort analyses, such as the examples in references 45-48, each of which has been cited over 950 times (45)(46)(47)(48). ...
In 2019, NIH combined the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study into the MACS/WIHS Combined Cohort Study (MWCCS). Participants completing a visit October 2018-September 2019 (targeted for MWCCS enrollment) are described by HIV serostatus and compared to people living with HIV (PLWH) in the U.S. Participants include 2115 women, 1901 men, median age 56 years (IQR 48-63), 62% PLWH. Study sites encompass the South (18%), Mid-Atlantic/Northeast (45%), West Coast (22%), and Midwest (15%). Participant race/ethnicity approximates that of U.S. PLWH. Longitudinal data and specimens collected for 35 years (men) and 25 years (women) were combined. Differences in data collection and coding were reviewed and key risk factor and comorbidity data harmonized. For example, recent use of alcohol (62%) and tobacco (28%) are common, as are dyslipidemia (64%), hypertension (56%), obesity (42%), impaired daily activities (31%), depressive symptoms (28%), and diabetes (22%). The repository includes serum, plasma, cells, cell pellets, urine, cervical vaginal lavage, oral, B-cell lines, stool, and semen specimens. Demographic differences between the MACS and WIHS can confound analyses by sex. The merged MWCCS is both an ongoing observational cohort and a valuable resource of harmonized longitudinal data and specimens for HIV-related research.
... Despite the decline in rate of LHD, almost 30% (N ¼ 1,255) of HIV-diagnosed individuals were diagnosed late in 2013. From a clinical perspective, late presentation with HIV leads to poor prognosis for the infected individuals in terms of rapid progression to AIDS [36][37][38][39] and lower survival probability 37-42 which could result in higher direct medical costs and productivity loss for the health system and society, respectively. [43][44][45] From a public health perspective, LHD results in missed opportunities to prevent HIV transmission. ...
We aimed to identify subgroups within age, racial/ethnic, and transmission categories that drive increased risk for late HIV diagnosis (LHD).
A 1996–2013 retrospective study of HIV-diagnosed individuals (N = 77,844) was conducted. The proportion of individuals with LHD (AIDS diagnosis within 365 days of HIV diagnosis) was determined, stratified by age, race/ethnicity, and transmission category. Logistic regression with interaction terms was used to identify groups/subgroups at risk for LHD during 1996–2001, 2002–2007, and 2008–2013.
Respectively, 78%, 27%, 38%, and 31% were male, White, Black, and Hispanic. Overall, 39% had LHD with a 6.7% reduction for each year increase (OR = 0.93, 95% CI = 0.93–0.94, p < 0.01). Older age was significantly associated with increased odds of LHD (OR range = 1.90–4.55). Compared to their White counterparts, all Hispanic transmission categories (OR range = 1.31–2.58) and only Black female heterosexuals and men who have sex with men (MSM) (OR range = 1.14–1.33) had significantly higher odds of LHD during 1996–2001 and/or 2002–2007. Significance was limited to Hispanic MSM (all age categories), MSM/IDUs (30–59 years), and heterosexuals (18–29 years) and Black MSM (30–39 years) during 2008–2013.
Older individuals and Hispanics (driven by MSM) are at increased risk for LHD. HIV testing interventions directed at seniors and Hispanic MSM can further reduce rates of LHD.
... The mainstay of HIV treatment is antiretroviral therapy (ART). Historically, ART was initiated in patients with a CD4 count of below 350 or those diagnosed with an AIDS-defining illness [15][16][17]. In 2015 however, the START and TEMPRANO trials were published, leading to a change in practice where all HIV positive patients were commenced on ART from the time of diagnosis [18,19]. ...
Background
To investigate a possible association between glaucoma and the use of anti-retroviral therapy (ART) for HIV in the Australian population.
Methods
A retrospective review of Australian Pharmaceutical Benefits Scheme data was undertaken from July 2012 to December 2016, inclusive. Three patient groups were compared: those on both topical intraocular pressure (IOP) -lowering medication and ART, those on ART only, and those on IOP-lowering medication only, using the 2016 Australian resident population to estimate prevalence. Odds ratios (95% confidence intervals, [CI]) with Fishers exact test for p values were calculated stratified by age and gender.
Results
The number of prescriptions for topical glaucoma medications in the general Australian population increased progressively by age with a peak prevalence in those aged 80 years and above. Prevalence of ART was highest in males aged 40–49 and 50–59 years (0.41% [CI 0.40, 0.42] and 0.44% [CI 0.43, 0.45], respectively). Our analysis identified an increase in the prescription of IOP-lowering medication in males on ART aged 30–39 (OR 2.23 [CI 1.32, 3.75], p = 0.007) and 40–49 (OR 1.86 [CI 1.42, 2.43], p < 0.001), compared to those not on ART. There were no statistically significant increased odds for females or males aged 50 years or more.
Conclusion
Compared with the known increase in glaucoma prevalence with age in the general Australian population, a statistically significant increased prevalence in use of IOP-lowering medications was found in males on ART aged 30–49 years. The mechanism for this is yet to be determined, but possible causes include sequelae of HIV infection, a drug-induced side effect, or increased medical surveillance.
... 24 Early initiation of ART in the course of disease is associated with better survival. 25,26 and better long-term immune reconstitution. 27,28 Introduction of highly active antiretroviral therapy (HAART) in developed countries in the late 90s has resulted in a remarkable decrease in AIDS-related mortality. ...
... In the present study ( The optimum patients initiating HAART with CD4 counts was found to be 350-500 cells/mm3 that had a 94% increased risk of death by (Kitahata et al., 2009) in a large cohort study, about those with baseline CD4 counts above 500 cells/mm3. Another study documented an increased risk of death when HAART was deferred until the CD4 count fell below 350 cells/mm3 ( (Kitahata et al., 2009); (Sterne, May, Costagliola, & al, 2009) this was the same initiation HAART responses to antiretroviral therapy in our study to be followed as previously mentioned. ...
Human Immunodeficiency Virus HIV (HIV) pathogenesis is extraordinarily complex and involves both immunodeficiencies that lead to opportunistic infections and acquired immunodeficiency syndrome (AIDS) as well as excessive inflammation and systemic immune activation. HIV infection identified by a progressive loss of CD4+ T cells and massive dysregulation of the immune system, which ultimately leads to AIDS. HIV/AIDS remains a significant public health problem in KSA. The number of reported HIV infections has increased from 20% in early 2001 to 40% in 2009. The number of HIV infections that was estimated is almost one and one-half times reported. It means that problem of underreporting of HIV/AIDS cases still exists. The study design consisted of sixty-six HIV-1/AIDS Saud's patients under highly active antiretroviral therapy (HAART1 and HAART2) and other twenty healthy individuals as a control. The total of absolute counts of mature human lymphocyte subsets was estimated in whole blood by flow cytometer while the concentration of 12 cytokines was measured and associated with viral load in plasma using Luminex multi-analyte profiling. The present study case of Saud's cohort indicated significant gender disparity between the two groups with a male preponderance in the treatment group (P=0.003). Human leukocyte antigen (HLA) genotype associated with the immune response. it was recognized in our study a meaningful data in Class II antibodies under the differences of gender at a level value( 0.008 ). It was found 113 females representing a percentage of 74.3 % have not any Class II antibodies. The results indicated considerable differences between control and HAART 2 with the element (CD3 +8) as T-suppressor lymphocyte for the HAART2 with a mean (1109.62), against (779.82) for the control group. There are also considerable differences between control and HAART2with element (CD3+4,CD3+4+8,CD4/CD8) , in favor of control group with mean (960.41 ) against ( 511.17 ) with element ( CD3+4 ) with mean ( 23.75 ) against ( 16.64 ) with element ( CD3+4+8 ) , with mean ( 1.29 ) against ( 0.53 ) with element ( CD4/CD8 ). Concerning cytokines, the results showed no considerable differences between control and HAART1group in IL 17F, IL-17A, IL-33, and IL-6, since the indication level of mean values of these variables successively attained ( 0.145, 0.077, 0.352, 0.167 ), and all of them were greater than ( P≥0.05 ).On the other hand, all cytokines in HAART2 were vastly different than control, especially IL-17 groups.
The results showed enormous differences between control and HAART2 groups with elements (IL-17F, INF-γ, IL-10, IL-17A, IL-22, IL 33, IL-2, IL-21, IL-4, IL-6, IL-27, TNF-α). All of them had strong values at the level of 0.01 while, IL-33 and IL-27 were significant at the level of 0.05. The ROC analysis for IL-17A showed the cutoff value (12.230 pg/ml) with the level of sensitivity (93%) and specificity (79%) to be used as a marker during treatment with HAART2 to follow the patients during the disease prognosis (HIV/AIDS). The present study reflected the correlation of IL 17 level with other cytokines and the immunophenotype characteristic of CD4+ as a T-Helper cell. It is an important site especially for AIDS Saudi patients under medication to be followed up by physicians to decrease the HIV/AIDS morbidity and mortality in KSA.
Uncontrolled HIV infection eventually leads to acquired immunodeficiency syndrome (AIDS), a state of severe immunosuppression which allows for other opportunistic infections or malignancies to be acquired. There is a high morbidity and mortality associated with sustained, elevated HIV viral loads; however, access to and treatment with antiretroviral therapy (ART) reduce the morbidity substantially. Combination antiretroviral therapy has been shown to improve immune function, reduce HIV reservoirs, and reduce transmission of HIV infection to others. While a cure for HIV remains elusive, novel medication classes and new medications, including long-acting injectables, have greatly simplified treatment, improving the quality of life of those affected and dramatically decreasing transmission rates. Antiretroviral medications have become more commonly used for pre-exposure prophylaxis among individuals at high risk as one of the key components of reducing transmission.
Psychiatric factors play a significant role in the ongoing human immunodeficiency virus (HIV) pandemic. In less than four decades, advances in HIV medical care and research have transformed acquired immune deficiency syndrome (AIDS) from a rapidly fatal illness of unknown cause into a chronic, manageable illness. Vast strides have been made in clinical care and pathogenesis research in the fields of HIV prevention and psychiatric care, including pre- (PreP) and and post-exposure (PEP) prophylaxis. Although AIDS is an entirely preventable infectious illness, HIV transmission continues throughout the world. Transmission of HIV continues to be fueled by many factors, including stigma of HIV and mental illness as well as discrimination, criminalization, and risky behaviors. A comprehensive biopsychosocial approach to sexual health and mental health and diminution of stigma are key to both HIV prevention and HIV care. Integration of psychiatric care into HIV prevention and treatment entails use of a biopsychosocial approach that maintains a view of each individual with HIV as a member of a family, community, and society who deserves to be treated with dignity and compassion. This textbook provides an update on HIV medicine and psychiatry; introduces the concept of HIV/AIDS as “the great magnifier of maladies”; explores the paradoxes and disparities of HIV care; explains how HIV psychiatry is a paradigm for the psychiatric care of the medically ill (psychosomatic medicine); and sets the stage for an understanding of how integrated care can prevent transmission of HIV and reduce morbidity and mortality in persons with HIV.
The role of competing risks in the analysis of time-to-event data is increasingly acknowledged. Software is readily available. However, confusion remains regarding the proper analysis: When and how do I need to take the presence of competing risks into account? Which quantities are relevant for my research question? How can they be estimated and what assumptions do I need to make? The main quantities in a competing risks analysis are the cause-specific cumulative incidence, the cause-specific hazard, and the subdistribution hazard. We describe their nonparametric estimation, give an overview of regression models for each of these quantities, and explain their difference in interpretation. We discuss the proper analysis in relation to the type of study question, and we suggest software in R and Stata. Our focus is on competing risks analysis in medical research, but methods can equally be applied in other fields like social science, engineering, and economics.
Expected final online publication date for the Annual Review of Statistics and Its Application, Volume 11 is March 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Introduction
In utero exposure to HIV and/or triple antiretroviral therapy (ART) have been shown to be associated with preterm births and low birth weight (LBW), but data from low-resources settings with high burden of HIV remain limited. This study utilized retrospective data to describe pregnancy outcomes among Rwandan women living with HIV (WLHIV) and HIV-negative women and to assess the association of HIV and ART with LBW.
Methods
This study used data from a large cohort of WLHIV and HIV-negative women in Rwanda for a cross-sectional analysis. Retrospective data were collected from antenatal care (ANC), delivery, and Prevention of Mother to Child Transmission (PMTCT) registries within the Central Africa International Epidemiology Databases to Evaluate AIDS (CA-IeDEA) in Rwanda. Data from women with documented HIV test results and known pregnancy outcomes were included in the analysis. Analyses for predictors of LBW (< 2,500 g) were restricted to singleton live births. Logistic models were used to identify independent predictors and estimate the odd ratios (OR) and 95% confidence intervals (CI) measuring the strength of their association with LBW.
Results and discussion
Out of 10,608 women with known HIV status and with documented pregnancy outcomes, 9.7% (n = 1,024) were WLHIV. We restricted the sample to 10,483 women who had singleton live births for the analysis of the primary outcome, LBW. Compared with HIV-negative women, WLHIV had higher rates of stillbirth, preterm births, and LBW babies. Multivariable model showed that WLHIV and primigravidae had higher odds of LBW. Lower maternal weight and primigravidae status were associated with greater odds of LBW. Among WLHIV, the use of ART was associated with significantly lower odds of LBW in a bivariate analysis. Even in a sample of relatively healthier uncomplicated pregnancies and women who delivered in low-risk settings, WLHIV still had higher rates of poor pregnancy outcomes and to have LBW infants compared to women without HIV. Lower maternal weight and primigravidae status were independently associated with LBW. Given that supplementary nutrition to malnourished pregnant women is known to decrease the incidence of LBW, providing such supplements to lower-weight WLHIV, especially primigravidae women, might help reduce LBW.
Female Genital Mutilation (FGM) is a procedure of historical,
cultural and religious derivation that continues its practice
worldwide, involving partial or total removal of the external female
genitalia. The stand of many international bodies, including the
United Nations, is that it epitomises a violation of the human rights
of girls and women. Australian state and territorial law prohibits
and categorises FGM as a criminal offence, as do RANZCOG
guidelines for medical practitioners. Reducing the practice of
FGM worldwide encompasses involvement in awareness and
education programs at an individual and societal level, beginning
with local communities, elders/leaders, young men and women,
and traditional health practitioners. Approaching the request for
FGM or reinfibulation in an Australian healthcare setting requires
an understanding of the socio-cultural influences surrounding the
practice and empathy towards the needs of the patient and their
cultural identity. It also requires a comprehensive understanding of
the myriad physical and psychological health risks posed by FGM
The history of human immunodeficiency virus (HIV) is important to the immunologist as the immune deficiency was recognized long before the virus responsible for acquired immunodeficiency syndrome (AIDS) was identified as a retrovirus and named the HIV. The HIV virus, if uncontrolled, causes the AIDS by depletion of CD4+ T cells, and our understanding of the normal ranges for CD4+ T cells in infants, children, and adults stems from our investigations of HIV. The depletion of the CD4+ T cells causes a slow deterioration of immunity and immune regulation leading to a cascade of immune deficits and opportunistic infections. Early in infection CD8+ T cells may help control infection, but if untreated the infection eventually leads to dysregulation of CD8+ T cells and eventually dysregulation of B cells. An inability to make antibody is a late manifestation of AIDS. The HIV infection presents and progresses differently in infants and children than it does in adults and the infection in infants progresses more rapidly and leads to faster immunological and neurological deterioration if untreated. In the era of potent and reliable antiretroviral therapy it is reasonable to predict that AIDS will become less and less common as HIV testing is offered routinely, and nearly all cases of HIV are detected very early before damage to the immune system has occurs. Treatment as prevention and postexposure prophylaxis are discussed in this chapter. Hypersensitivity reactions that have historically been more common in HIV are also discussed, as they are particularly important to the immunologist.
L’épidémie du VIH dans les pays d’Afrique de l’Ouest est mixte ou concentrée parmi les populations clés dont les hommes ayant des relations sexuelles avec d’autres hommes (HSH). Depuis 2010, l’organisation Mondiale de la Santé (OMS) recommande aux décideurs en santé de ces pays de cibler les HSH. Elle recommande une offre globale de prévention du VIH incluant la stratégie « Dépister et Traiter ». Le dépistage du VIH est une étape clé dans la lutte contre le VIH. Elle permet de classer la personne qui le réalise négative ou positive et de proposer ensuite l’action la mieux adaptée. Lorsqu’il est administré régulièrement, il permet la détection précoce des personnes infectées par le VIH. Depuis 2015, l’OMS recommande l’initiation du traitement antirétroviral (ARV) chez toute personne infectée par le VIH indépendamment de son état clinique et/ou biologique. La stratégie « Dépister et Traiter » consiste à coupler ces deux composantes de la lutte contre le VIH. Cependant, des données de cette stratégie chez les HSH sont manquantes. Notre travail de recherche, réalisé à partir du projet CohMSM ANRS 12324-Expertise France a pour objectif d’évaluer la stratégie « Dépister et Traiter » dans l’infection par le VIH chez des HSH en Afrique de l’Ouest.Nos résultats montrent que l’observance au suivi préventif trimestriel incluant le dépistage du VIH chez les HSH séronégatifs est bonne. Cependant, l’incidence du VIH est élevée aussi bien globalement que spécifiquement par site. En plus, l’observance au suivi préventif trimestriel n’a pas d’impact sur la réduction des nouvelles infections par le VIH. Chez les HSH séropositifs qui découvrent leur statut VIH, la grande majorité (95%) accepte d’initier le traitement ARV lorsque celui-ci leur est proposé immédiatement. Parmi eux, 1/4 l’initie le même jour, et 2/3 rapidement (entre 0-7 jours après la découverte du diagnostic positif au VIH). Cependant, leur rétention dans les soins reste sous optimale. L’initiation rapide du traitement ARV favorise la suppression de la charge virale du VIH. Cependant, elle n’a d’impact ni sur la rétention dans les soins des participants sous traitement, ni sur leur réponse immunologique.Notre travail souligne l’urgence de renforcer l’offre de prévention des HSH séronégatifs par l’ajout de la prophylaxie pré-exposition du VIH par voie orale (PrEP). Chez les HSH séropositifs, il supporte les recommandations de l’OMS pour l’initiation rapide du traitement ARV. Nos résultats sont en faveur de la stratégie « Dépister et Traiter » dans l’infection par le VIH chez des HSH en Afrique de l’Ouest.Mots clés: VIH; dépistage; traitement antirétroviral; HSH; Afrique.
Heterosexuals living with HIV report feeling additional HIV stigma compared to homosexual men, which may affect clinical outcomes. Yet, beyond routinely collected surveillance data, little is known about the characteristics of individuals who acquire HIV heterosexually and clinical outcomes by mode of sexual acquisition have not been directly compared. Using data from the Australian HIV Observational Database, we compared clinical characteristics of those with heterosexually-acquired (Het-HIV) to homosexually-acquired HIV (Hom-HIV) to investigate any differences and their implications for clinical management. 513 Het-HIV and 1467 Hom-HIV patients were included and contributed 3,127 and 9,457 person-years of follow-up, respectively. Compared with Hom-HIV, Het-HIV were more often born outside Australia (62.5% vs 39.9%, p<0.001), less likely to have Hepatitis C (4.8% vs 7.8%, p=0.029) and had lower median CD4 counts at diagnosis (292 vs 450 cells/µL, p<0.001) and cART initiation (270 vs 340 cells/µL, p<0.001). Despite these lower CD4 counts, there were no significant differences between groups for time to the major clinical endpoints of cART initiation, viral suppression, virological failure or all-cause mortality. Het-HIV had a lower risk of loss-to-follow-up than Hom-HIV (aHR 0.78; 95% CI 0.64-0.95). Further studies examining factors associated with, and interventions to inform retention in care are required.
Background
Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice.
Methods
Using the PubMed database, a scoping review of studies in which DTRs were optimised using observational data was performed in October 2020. Data extracted from eligible articles included target medical condition, source and type of data, statistical methods, and translational relevance of the included studies.
Results
From 209 PubMed abstracts, 37 full-text articles were identified, and a further 26 were screened from the reference lists, totalling 63 articles for inclusion in a narrative data synthesis. Observational DTR models are a recent development and their application has been concentrated in a few medical areas, primarily HIV/AIDS (27, 43%), followed by cancer (8, 13%), and diabetes (6, 10%). There was substantial variation in the scope, intent, complexity, and quality between the included studies. Statistical methods that were used included inverse-probability weighting (26, 41%), the parametric G-formula (16, 25%), Q-learning (10, 16%), G-estimation (4, 6%), targeted maximum likelihood/minimum loss-based estimation (4, 6%), regret regression (3, 5%), and other less common approaches (10, 16%). Notably, studies that were primarily intended to address real-world clinical questions (18, 29%) tended to use inverse-probability weighting and the parametric G-formula, relatively well-established methods, along with a large amount of data. Studies focused on methodological developments (45, 71%) tended to be more complicated and included a demonstrative real-world application only.
Conclusions
As chronic and progressive conditions become more common, the need will grow for personalised treatments and methods to estimate the effects of DTRs. Observational DTR studies will be necessary, but so far their use to inform clinical practice has been limited. Focusing on simple DTRs, collecting large and rich clinical datasets, and fostering tight partnerships between content experts and data analysts may result in more clinically relevant observational DTR studies.
HIV-infected individuals on combined antiretroviral therapy (ART) with virologic suppression exhibit sustained immune dysfunction. Our recent work has highlighted that monocytic myeloid derived suppressor cells (M-MDSC) are elevated in these individuals and suppress immune responses. Factors responsible for M-MDSC expansion in vivo are unknown. Here we compared circulating frequency of M-MDSC in HIV-infected persons from the US and India where HIV subtype-B or –C predominate, respectively. We further investigated soluble mediators of residual immune activation in two cohorts and determined their correlation with M-MDSC expansion. Our findings show that M-MDSC are elevated and correlate with plasma levels of IL-6 in both cohorts. Chemokines CXCL10, CCL4 and CXCL8 were also elevated in HIV-infected individuals, but were not correlated with M-MDSC. These findings support that IL-6 is important in M-MDSC expansion which is independent of HIV subtype.
As of the end of 2015, there were an estimated 37 million people living with HIV worldwide, with the majority residing in sub-Saharan Africa. International efforts have expanded access to lifesaving antiretroviral therapy to approximately 19.5 million people living with HIV in low- and middle-income countries. This global access has led to substantial reduction in HIV-related morbidity and mortality and contributed to a decline in new HIV infections; success has been particularly evident in the prevention of mother-to-child transmission. However, certain populations remain disproportionately affected worldwide, including adolescent girls and young women, commercial sex workers, men who have sex with men, and people who inject drugs. In this chapter, we summarize global HIV epidemiology, review the most relevant clinical syndromes, and discuss the pertinent programmatic approaches to epidemic control and prevention.
Many applied decision-making problems have a dynamic component: The policymaker needs not only to choose whom to treat, but also when to start which treatment. For example, a medical doctor may choose between postponing treatment (watchful waiting) and prescribing one of several available treatments during the many visits from a patient. We develop an “advantage doubly robust” estimator for learning such dynamic treatment rules using observational data under the assumption of sequential ignorability. We prove welfare regret bounds that generalize results for doubly robust learning in the single-step setting, and show promising empirical performance in several different contexts. Our approach is practical for policy optimization, and does not need any structural (e.g., Markovian) assumptions.
This chapter provides an introduction into the diverse field of data mining, as viewed from the perspective of a clinical statistician. We start with a discussion of data mining and its relationship with machine learning and classical statistics. To facilitate the presentation of material, we map some common problems occurring in analysis of clinical data onto general machine learning tasks, such as supervised, unsupervised, and semi-supervised learning. We then review key concepts of data mining and machine learning with emphasis on methods that are most relevant for analyses of clinical data. We also present our view of the key elements of a statistical analysis plan that ensure principled data mining of randomized clinical trials. This topic is rarely addressed, yet of interest for many clinical statisticians who are routinely using data mining to gain insights and knowledge from the available data beyond the “pre-specified analyses.”
Context Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society–USA panel has updated its recommendations as warranted by new developments in the field.Objective To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described.Data Sources and Study Selection A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel.Data Extraction and Synthesis Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel.Conclusions Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/μL and before it declines to 200/μL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.
It is unclear whether delay in initiation of antiretroviral therapy (ART) may lead to a poorer viral load response for patients with human immunodeficiency virus (HIV).
To characterize the relationship of viral load response to ART with baseline CD4 cell count and baseline viral load.
Inception cohort of 3430 therapy-naive patients with HIV, of whom 3226 patients had at least 1 viral load count after the start of ART.
Three cohort studies of patients cared for in HIV clinics in Europe between 1996 and 2000.
All patients initiating ART consisting of at least 3 drugs initiated in or after 1996 and for whom CD4 cell count and viral load were available in the prior 6 months (at most).
Viral load decrease to below 500 copies/mL; viral load rebound to above 500 copies/mL (2 consecutive values).
Of 3226 patients during the median follow-up of 119 weeks, 2741 (85%) experienced viral suppression to less than 500 copies/mL by 32 weeks. Relative hazards (RHs) of achieving this were 1.08 (95% confidence interval [CI], 0.98-1.21) and 0.94 (95% CI, 0.84-1.04) for baseline CD4 cell counts between 200 and 349 x 10(6)/L and baseline CD4 cell counts lower than 200 x 10(6)/L, respectively, compared with baseline CD4 cell counts of 350 x 10(6)/L or higher, after adjustment for several factors including baseline viral load. For baseline viral load, the RHs were 0.95 (95% CI, 0.84-1.07) and 0.65 (95% CI, 0.58-0.74), for 10 000 to 99 999 and 100 000 copies/mL or greater, respectively, compared with less than 10 000 copies/mL, but the probability of viral load lower than 500 copies/mL at week 32 was similar in all 3 groups. Subsequent rebound above 500 copies/mL was no more likely with a lower baseline CD4 cell count or higher viral load.
In this study, lower CD4 cell counts and higher viral loads at baseline were not associated with poorer virological outcome of ART. Those with baseline viral loads of greater than 100 000 copies/mL had a slower rate of achieving viral suppression.
The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection.
To summarize new data in the field and to provide current recommendations for the antiretroviral management and laboratory monitoring of HIV infection. This report provides guidelines in key areas of antiretroviral management: when to initiate therapy, choice of initial regimens, patient monitoring, when to change therapy, and how best to approach treatment options, including optimal use of recently approved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced patients.
A 14-member panel with expertise in HIV research and clinical care was appointed. Data published or presented at selected scientific conferences since the last panel report (August 2006) through June 2008 were identified.
Data that changed the previous guidelines were reviewed by the panel (according to section). Guidelines were drafted by section writing committees and were then reviewed and edited by the entire panel. Recommendations were made by panel consensus.
New data and considerations support initiating therapy before CD4 cell count declines to less than 350/microL. In patients with 350 CD4 cells/microL or more, the decision to begin therapy should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readiness for treatment. In addition to the prior recommendation that a high plasma viral load (eg, >100,000 copies/mL) and rapidly declining CD4 cell count (>100/microL per year) should prompt treatment initiation, active hepatitis B or C virus coinfection, cardiovascular disease risk, and HIV-associated nephropathy increasingly prompt earlier therapy. The initial regimen must be individualized, particularly in the presence of comorbid conditions, but usually will include efavirenz or a ritonavir-boosted protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine). Treatment failure should be identified and managed promptly, with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNA level below assay detection limits.
The Multicenter AIDS Cohort Study was designed to 1) elucidate the natural history of the infection causing acquired immunodeficiency
syndrome (AIDS), 2) identify risk factors for occurrence and clinical expression of the infection, and 3) establish a repository
of biologic specimens for future study. A variety of recruitment techniques, including special assurance of confidentiality,
were used to enroll participants. Nearly 5,000 homosexual men volunteered for semiannual interview, physical examination,
and laboratory testing in four metropolitan areas. A significant majority of these men in each center (69–83%) reported having
50 or more lifetime sexual partners, and over 80% had engaged in receptive anal intercourse with at least some of their partners
in the previous two years. By the time of the participants' initial evaluation (April 1984-April 1985), infection with the
human immunodeficiency virus (HIV) had occurred in higher proportions of men in Los Angeles (51%) and Chicago (43%) than in
Baltimore/Washington, DC (31%) and Pittsburgh (21%), presumably as a result of the higher number of partners and proportion
with whom these men had engaged in high-risk practices (e.g., receptive anal intercourse). Follow-up evaluations are underway
in this comprehensive longitudinal investigation of HIV infection.
To study differences in pre-AIDS mortality between European cohorts of injecting drug users (IDU) and to evaluate whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count.
The study population consisted of 664 IDU with documented intervals of HIV seroconversion from eight cohort studies. Differences in pre-AIDS mortality were studied between European sites; an evaluation of whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count was carried out using Poisson regression.
One hundred and seven IDU died, of whom 57 did not have AIDS. Pre-AIDS causes of death were overdose/suicide (49%), natural causes such as bacterial infections/cirrhosis (40%), and unintentional injuries/unknown (11%). Considering pre-AIDS death and AIDS as competing risks, 14.7% were expected to have died without AIDS and 17.3% to have developed AIDS at 7 years from seroconversion. No statistically significant differences in pre-AIDS mortality were found between European regions, men and women, age categories and calendar time periods. Overall pre-AIDS mortality did not increase with time since seroconversion, but did increase with decreasing CD4 count. Evaluating cause-specific mortality, only pre-AIDS mortality from natural causes appeared to be associated with time since seroconversion as well as immunosuppression. For natural causes, the death rate per 100 person-years was 0.13 the first 2 years after seroconversion, 0.73 in years 2-4 [risk relative (RR) to years 0-2, 5.6], 1.83 in years 4-6 (RR, 14.0) and 1.54 for > or = 6 years (RR, 11.7). This rate was 0 for a CD4 cell count > or = 500 x 10(6)/l, 1.06 for 200-500 x 10(6)/l and 4.06 for < 200 x 10(6)/l (RR versus > or = 200 x 10(6)/l, 7.0). In multivariate analysis, both CD4 count and time since seroconversion appeared to be independently associated with death from natural causes; CD4 count appeared to be the strongest predictor (adjusted RR, 5.9).
A high pre-AIDS mortality rate was observed among IDU. No significant differences were observed across European sites. Pre-AIDS mortality from natural causes but not from overdose and suicide was associated with HIV disease progression.
To examine trends in disease progression and survival among patients enrolled in the Swiss HIV cohort study during 1988-96 and to assess the influence of new antiretroviral combination therapies.
Prospective multicentre study, with follow up visits planned at six monthly intervals.
Seven HIV units at university centres and cantonal hospitals in Switzerland.
3785 men (mean age 35.0 years) and 1391 women (30.3 years) infected with HIV. 2023 participants had a history of intravenous drug misuse; 1764 were men who had sex with men; 1261 were infected heterosexually; and 164 had other or unknown modes of transmission. 601 participants had had an AIDS defining illness.
During more than 15,000 years of follow up, there were 1456 first AIDS defining diagnoses and 1903 deaths. Compared with those enrolled during 1988-90, the risk of progression to a first AIDS diagnosis was reduced by 18% (relative risk 0.82 (95% confidence interval 0.73 to 0.93)) among participants enrolled in 1991-2, by 23% (0.77 (0.65 to 0.91)) among those enrolled in 1993-4, and by 73% (0.27 (0.18 to 0.39)) among those enrolled in 1995-6. Mortality was reduced by 19% (0.81 (0.73 to 0.90)), 26% (0.74 (0.63 to 0.87)), and 62% (0.38 (0.25 to 0.97)) respectively. Compared with no antiretroviral treatment, the risk of an initial AIDS diagnosis after CD4 lymphocyte counts fell to < 200 cells x 10(6)/1 was reduced by 16% (0.84 (0.73 to 0.97)) with monotherapy, 24% (0.76 (0.63 to 0.91)) with dual therapy, and 42% (0.58 (0.37 to 0.92)) with triple therapy. Mortality was reduced by 23% (0.77 (0.68 to 0.88)), 31% (0.69 (0.60 to 0.80)), and 65% (0.35 (0.20 to 0.60)) respectively.
The introduction of antiretroviral combination therapies outside the selected patient groups included in clinical trials has led to comparable reductions in disease progression and mortality.
Plasma viral load from 71 HIV-1-infected neonates was measured by using Amp-RT, an ultrasensitive quantitative reverse transcriptase (RT) assay and by nucleic acid sequence-based amplification (NASBA), an RNA-based quantitative assay. Results were then compared with those obtained from detection of proviral DNA in peripheral blood mononuclear cells (PBMCs) by polymerase chain reaction (PCR) using Turnbull analysis. At 5 days of life, 50% of neonates were positive by Amp-RT, 30% were NASBA positive, and 20% were DNA-PCR positive. Through the first 12 days of life, Amp-RT was more sensitive than either NASBA or DNA-PCR in detecting HIV-1 infection. Amp-RT values correlated well with NASBA RNA values, with an overall Pearson's r = 0.63 (95% confidence interval [CI], 0.40-0.78). In proportional hazards analysis of infants aged 14 to 61 days (N = 31), a one-log increase in RNA-based viral load was associated with a > fivefold risk of disease progression when using the U.S. Centers for Disease Control and Prevention (CDC) clinical Category C (CDC-C) or death as an endpoint (p = .014). Kaplan-Meier analysis of these data found that RNA viral loads were able to predict disease progression using CDC-C/death as an endpoint (p = .013). Early quantitative viral load measurements may assist clinicians in diagnosing HIV-1 infection, stratifying risk of disease progression, and implementing a treatment plan using highly active antiretroviral therapy for infants within the first few weeks of life.
(C) 2001 Lippincott Williams & Wilkins, Inc.
BACKGROUND:We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association of cumulative exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors with the risk of myocardial infarction.METHODS:We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus. The incidence rates of myocardial infarction during the follow-up period were calculated, and the associations between myocardial infarction and exposure to protease inhibitors or nonnucleoside reverse-transcriptase inhibitors were determined.RESULTS:Three hundred forty-five patients had a myocardial infarction during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively.CONCLUSIONS:Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.
Background
Because the benefits of zidovudine (AZT) in HIV-infected individuals are small and do not last long the Delta trial was designed to test whether combinations of zidovudine with didanosine (ddl) or zalcitabine (ddC) were more effective than AZT alone in extending survival and delaying disease progression.
Methods
The trial was randomised, double blind, and international. 3207 participants were allocated to either AZT (600 mg per day) alone (1055), AZT plus ddI (400 mg per day) (1080), or AZT plus ddC (2·25 mg per day) (1072). Participants either had symptoms of HIV disease (if AIDS, with a CD4cell count of >50×106/L) or a CD4 count of less than 350×106/L; 2124 had not had zidovudine before (Delta 1) and 1083 had for at least 3 months (Delta 2).
Findings
Over a median follow-up of 30 months, 699 participants died, and 936 of the 2765 without AIDS at entry developed AIDS or died. In participants who had not had AZT before, both combination regimens had substantial benefits in terms of survival (regardless of disease stage at entry); a relative reduction in mortality of 42%, compared to AZT alone (95% CI 25% to 55%), for AZT plus ddl and of 32% (95% CI 22% to 47%) for AZT plus ddC. In participants who had had AZT before, the addition of ddI improved survival (p=0·05; relative reduction 23% [95% CI 0% to 41%]) but there was no direct evidence of benefit from the addition of ddC (p=0·47; relative reduction 9% [95% CI—17% to 29%]). The overall difference in survival between the treatment groups was significant (p<0·0001; a relative reduction in mortality, compared to AZT alone, of 33% (95% CI 20% to 44%) for AZT plus ddI and 21% (95% CI 6% to 34%) for AZT plus ddC). Benefit in terms of disease progression was seen mainly in participants not previously treated with AZT and overall. There was no unexpected toxicity from the combination treatments.
Interpretation
Initiation of treatment with combinations of AZT plus ddI or ddC prolongs life and delays disease progression compared with AZT alone. The addition of ddI to participants already treated with AZT also improves survival, although the benefit appears less.
Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31, 1992 (total 5419 person-years; median 3.3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% CI 90-94%) in Imm and 94% (92-95%) in Def (log-rank p = 0.13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p = 0.18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups. Median changes from baseline at 3 months were +20 cells/mu L (Imm) and -9 cells/mu L (Def), a difference of 29 cells/mu L (95% CI 16-42; p < 0.0001) which persisted for up to 3 years. Thus such persistent differences in CD4 cell count do not necessarily imply long-term differences in clinical outcome. 6 participants had life-threatening adverse events that were judged to be possibly drug related: 4 occurred on trial capsules before unblinding (3 on zidovudine, 1 on placebo) and 2 occurred on open zidovudine. Despite a daily dose of 1 g of zidovudine, the frequency of severe haematological and other adverse events on trial therapy was low but significantly higher in the Imm group: 16 Imm and 2 Def participants stopped trial drug for haematological events and the estimated proportions with haemoglobin dropping below 10 g/dL were 5% and 1%, respectively, at 1 year and 8% and 2%, respectively, at 3 years. Another 83 (9%) Imm and 36 (4%) Def participants stopped for other adverse events, predominantly gastrointestinal or neurological symptoms (headaches) or malaise.
Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice.
We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008).
In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.
Background: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice. Methods: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Results: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of ≥1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard, 0.31; 95% CI, 0.15-0.61; p = 0.0008). Conclusion: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.
BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy.
After initiation of a treatment for human immunodeficiency virus type 1 infection containing a protease inhibitor, immune restoration associated with increases in CD4-positive (CD4+) T lymphocyte count may be delayed. In a sample of patients who had been prescribed protease inhibitors for the first time, the authors tested to see whether there was a minimal duration of CD4+ cell count increase before the increase had an impact on the occurrence of opportunistic infections. The evolution (difference between time t and baseline) of CD4+ cell count was modeled using a mixed effects linear model. Changes in CD4+ count estimated by this model were then included as time-dependent covariates in a proportional hazards model. Finally, the authors tested for the existence of a CD4+ change x time interaction. The authors used a sample of 553 French patients first prescribed protease inhibitors in 1996 and followed for a median of 16 months. During the first 120 days, there was no association between CD4+ change and the rate of opportunistic infections. After 120 days, each 50-cell/mm 3 increase in CD4+ count was associated with a 60% (95% confidence interval: 45, 72) reduction in the incidence of opportunistic infections. These results, based on modeling of CD4+ cell response, at least indirectly reinforce the concept of a delayed but possible immune recovery with the use of protease inhibitors. The findings support the potential for interruption of certain types of prophylaxis against opportunistic infections under reasonable conditions of duration of antiretroviral therapy and sustained CD4+ cell response.
To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.
THE LAST 3 years have been a remarkable time to be involved in the care
of patients with human immunodeficiency virus (HIV) infection. Improvements
in antiretroviral therapy have decreased the rates of death and opportunistic
infections by about 70% in our clinic (W.J.B., R.R.R., and D.L.C., unpublished
data, 1998) and brought an atmosphere of hope to patients and clinicians.
However, we read with concern the 1997 recommendations from the International
AIDS Society–USA Panel regarding the use of therapy for all patients
with an HIV RNA level greater than 5000 to 10000 copies/mL, regardless of
CD4 cell count.1 Aggressive treatment of early
HIV infection was also recommended by a panel convened by the Department of
Health and Human Services.2 The Department
of Health and Human Services panel was more conservative and presented the
potential advantages and disadvantages of aggressive, early therapy, but eventually
recommended treatment of any patient with a CD4 cell count less than 0.50×109/L (<500/µL) or a viral load greater than 10000 to 20000 copies/mL.
Context Current recommendations for initiation of antiretroviral therapy in
patients infected with human immunodeficiency virus type 1 (HIV) are based
on CD4 T-lymphocyte cell counts and plasma HIV RNA levels. The relative prognostic
value of each marker following initiation of therapy has not been fully characterized.Objective To describe rates of disease progression to death and AIDS or death
among patients starting triple-drug antiretroviral therapy, stratified by
baseline CD4 cell count and HIV RNA levels.Design, Setting, and Participants Population-based analysis of 1219 antiretroviral therapy–naive
HIV-positive men and women aged 18 years or older in British Columbia who
initiated triple-drug therapy between August 1, 1996, and September 30, 1999.Main Outcome Measure Cumulative mortality rates from the initiation of triple-drug antiretroviral
therapy to September 30, 2000, determined using various CD4 cell and plasma
HIV RNA thresholds.Results As of September 30, 2000, 82 patients had died of AIDS-related causes,
for a crude AIDS-related mortality rate of 6.7%. The product limit estimate
(SE) of the cumulative mortality rate at 12 months was 2.9% (0.5%). In univariate
analyses, a prior diagnosis of acquired immunodeficiency syndrome (AIDS),
CD4 cell count, use of protease inhibitors, and HIV RNA level were associated
with mortality. There was no difference in mortality by age or sex. Only CD4
cell count remained statistically significant in the multivariate analysis.
After controlling for AIDS, protease inhibitor use, and plasma HIV RNA level
at baseline, patients with CD4 cell counts of less than 50/µL were 6.67
(95% confidence interval [CI], 3.61-12.34) times and those with counts of
50/µL to 199/µL were 3.41 (95% CI, 1.93-6.03) times more likely
to die than those with counts of at least 200/µL.Conclusion Our data demonstrate uniformly low rates of disease progression to death
and AIDS or death among patients starting antiretroviral therapy with CD4
cell counts of at least 200/µL. In our study, disease progression to
death and AIDS or death was clustered among patients starting therapy with
CD4 cell counts less than 200/µL.
Objectives: To study differences in pre-AIDS mortality between European cohorts of injecting drug users (IDU) and to evaluate whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count. Methods: The study population consisted of 664 IDU with documented intervals of HIV seroconversion from eight cohort studies. Differences in pre-AIDS mortality were studied between European sites; an evaluation of whether pre-AIDS mortality increased with time since HIV seroconversion and decreasing CD4 count was carried out using Poisson regression. Results: One hundred and seven IDU died, of whom 57 did not have AIDS. Pre-AIDS causes of death were overdose/suicide (49%), natural causes such as bacterial infections/cirrhosis (40%), and unintentional injuries/unknown (11%). Considering pre-AIDS death and AIDS as competing risks, 14.7% were expected to have died without AIDS and 17.3% to have developed AIDS at 7 years from seroconversion. No statistically significant differences in pre-AIDS mortality were found between European regions, men and women, age categories and calendar time periods. Overall pre-AIDS mortality did not increase with time since seroconversion, but did increase with decreasing CD4 count. Evaluating cause-specific mortality, only pre-AIDS mortality from natural causes appeared to be associated with time since seroconversion as well as immunosuppression. For natural causes, the death rate per 100 person-years was 0.13 the first 2 years after seroconversion, 0.73 in years 2–4 [risk relative (RR) to years 0–2, 5.6], 1.83 in years 4–6 (RR, 14.0) and 1.54 for ≥ 6 years (RR, 11.7). This rate was 0 for a CD4 cell count ≥ 500 × 106/l, 1.06 for 200–500 × 106/l and 4.06 for < 200 × 106/l (RR versus ≥ 200 × 106/l, 7.0). In multivariate analysis, both CD4 count and time since seroconversion appeared to be independently associated with death from natural causes; CD4 count appeared to be the strongest predictor (adjusted RR, 5.9). Conclusions: A high pre-AIDS mortality rate was observed among IDU. No significant differences were observed across European sites. Pre-AIDS mortality from natural causes but not from overdose and suicide was associated with HIV disease progression.
Background and objective
The aims of this study were to describe the process of implementation of the PISCIS cohort, and to describe the clinical and epidemiological characteristics and trends of antiretroviral treatment (ART) among patients enrolled from 1998 through 2003.
Patients and method
Prospective cohort study of HIV-infected patients aged ≥ 16 years newly attended in 10 Catalonian hospitals and one Balearic Islands hospital. Analysis were done using the Mantel's χ2 test for trend.
Results
A total of 5,968 patients (mean age 39 yrs; 75% men) were recruited with a mean follow-up of 26.4 months (13,130 person-years). A total of 2,763 patients were newly diagnosed and among these, the most frequent transmission route was the heterosexual one (43%), followed by homosexual (31%). We observed an increasing trend in the proportion of persons < 35 years and immigrants. Among newly diagnosed, 43% had < 200 CD4 T cells/μl in the nearest determination from HIV diagnosis. In the year 2003, 83% of patients were on ART. A decrease of the protease inhibitor-based regimen (from 85% in 1998 to 25% in 2003; p < 0.001) and an increase of nucleoside and non-nucleoside analogue reverse transcriptase inhibitors-containing regimens were observed over time among naïve patients who started ART with three or more drugs.
Conclusions
HIV infected patients’ cohorts are feasible in our setting and are an important tool in clinical and public health. The heterosexual route of transmission was the most frequent among newly diagnosed patients. The diagnosis delay is high and, on the other hand, ARV regimens have been changing according to the recommended guidelines.
Objective: To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy.
Methods: From the French Hospital Database on HIV, 1402 protease inhibitor-naïve patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes.
Results: During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naïve patients.
Conclusion: In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.
Little is known about how widely HIV-related drugs are used outside controlled clinical trials. We therefore assessed factors associated with use of antiretroviral(ARV) therapy and primary prophylactic regimens to prevent HIV-associated opportunistic infections. Baseline data from a prospective study from May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count <500 cells/µl, followed in 37 centers from 16 European countries, were analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV drug at the time of the study. ARV therapy was more frequently used among patients from southern and central Europe as compared with patients from northern Europe, especially among patients with CD4 counts >200 cells/µl (73%, 57%, and 42%, respectively, p< 0.0001). Ofpatients on ARV therapy, 34% received open-label combination therapy. This proportion was higher in central Europe compared with other regions (27%, 50%, and 31% for southern, central, and northern Europe, respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/µl, without marked regional differences. In patients without esophageal candidiasis or other invasive fungal infections, antifungal drugs were far less frequently used in patients from southern and central Europe compared with patients from northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of patients with a CD4 count <100 cells/µl received rifabutine as primary prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies are used differently in different parts of Europe, whereas primary PCP prophylaxis is uniformly administered to most at-risk patients. U.S. recommendations on the use of antimycobacterial prophylaxis have not been implemented in Europe.
Objective: To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment.
Methods: The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged ≥14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described.
Results: A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P=0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P<0.0001; test for trend). There was a statistically significant decline in the proportion of follow-up time spent as an in-patient among patients with CD4 T-cell counts of £50¥106/l from >30% before 1990 to <5% during 1997 (P=0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission.
Conclusions: Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.
Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear.
Methods: We analyzed data on 20,379 treatment-naive HIV-1-infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths).
Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count <25 cells/μL had persistently higher progression rates than individuals with a baseline CD4 count >350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART).
Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART.
Objective: To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment.
Methods: The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points.
Results: Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-10.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04-1.26 versus hard-gell saquinavir).
Conclusions: If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.
A working group of the European AIDS Clinical Society (EACS) have developed these guidelines for European clinicians to help them in the treatment of adults with HIV infection. This third version of the guidelines includes, as new topics, the assessment of patients at initial and subsequent clinic visits as well as post-exposure prophylaxis. A revision of the 2005 guidelines based on current data includes changes in the sections on primary HIV infection, when to initiate therapy, which drug combinations are preferred as initial combination regimens for antiretroviral-naïve patients, how to manage virological failure and the treatment of HIV during pregnancy.
In Europe, there is a wide range of clinical practices in antiretroviral therapy depending on various factors such as drug registration, national policies, local availability, reimbursement and access to treatment. These can vary greatly from one country to another, especially in Central and Eastern parts of Europe.
These guidelines are intended to help clinicians achieve the best care for their patients. In some countries, particularly where the quality of and access to care are not optimal, these guidelines should help AIDS societies and physicians or patient group organizations to negotiate with their national health authorities with a view to implementing what should be the standard of care for HIV-infected patients all over Europe.
This paper describes the rationale and design features of the Swiss HIV Cohort Study (SHCS) and the baseline characteristics of participants enrolled up to March 31st 1993. The objectives include epidemiological, clinical and laboratory research.
The SHCS is a prospective cohort study of HIV infected adolescents and adults seen at the outpatient clinics of the Swiss University Hospitals in Basle, Berne, Geneva, Lausanne and Zurich and the Cantonal Hospital St. Gall. The multicentre collaboration was initiated in September 1988 by the Swiss Federal Office of Public Health. Data collected prior to this date by several participating centers using a similar protocol were included, the earliest records dating back to 1982. Follow-up visits are scheduled every 6 months. ENROLLMENT: As of March 31st 1993, 6253 participants (M: 4580, F: 1675) were included with a total of 16015 person-years of follow-up (mean 2.6 years). HIV transmission categories were 46% intravenous drug users (IDU), 32% men who had sex with men (MSM), 18% heterosexual contacts (HET) and 4% other. The proportion of MSM among male participants decreased from 62% in 1985 to 40% in 1987, to remain stable thereafter. The proportion of IDU among males was around 40% throughout, whereas in females, there was a pronounced decline from 90% IDU in 1985 to 50% in 1992. Conversely, there was a striking increase in registrations of women presumably infected by HET, from 8% in 1985 to 50% in 1992. Among men, the proportion classified as HET increased from 2% to 15%. It is estimated, that a large proportion of all Swiss AIDS patients (70%) and HIV infected individuals (32%-47%) are enrolled in the Swiss HIV Cohort Study. Losses to follow-up, however, are common.
The SHCS serves multiple purposes as a research project, as infrastructure for multidisciplinary research and as a tool to improve patient care. Several international and national trials, post-marketing surveillances and expanded access protocols were or still are based upon its infrastructure. The large number of female participants and of participants AIDS-free at entry, make the database especially valuable.
BACKGROUND:: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. METHODS:: We analyzed data on 20,379 treatment-naive HIV-1-infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). RESULTS:: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count <25 cells/muL had persistently higher progression rates than individuals with a baseline CD4 count >350 cells/muL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). CONCLUSIONS:: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART.
National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997.
Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid.
The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
Introduction General Conditions for the Randomization-Validity of Infinite-m Repeated-Imputation Inferences Examples of Proper and Improper Imputation Methods in a Simple Case with Ignorable Nonresponse Further Discussion of Proper Imputation Methods The Asymptotic Distribution of (Q̄m, Ūm, Bm) for Proper Imputation Methods Evaluations of Finite-m Inferences with Scalar Estimands Evaluation of Significance Levels from the Moment-Based Statistics Dm and Δm with Multicomponent Estimands Evaluation of Significance Levels Based on Repeated Significance Levels
The chair of Social and Preventive Medicine at the University of Zurich has been created in the year 1962. A description of the teaching activities is given. As regards research the main directions are: epidemiology and prevention of cardiovascular diseases, hygiene of sports, drug abuse, nutrition and health education. The services offered by the Institute include councelling in health matters and vaccinations for travellers.
The relation between serological and immunologic profiles and the risk of developing AIDS was assessed in 306 initially asymptomatic,
human imunodeficiency virus-infected homosexual men studied for 30 mo. Twenty-nine men developed AIDS (attack rate, 16.8%).
The attack rate in core antibody-negative men was 35.7%; this rate was 43.9% in antigen-positive men, 51.9% in men with low
(< 0.5 × 109/L) CD4+ cell counts, 6.8% in core antibody-positive men, 6.9% in antigen-negative men, and 6.1% in men with normal CD4+ cell
counts. The disappearance of core antibody, the expression of antigen, and the occurrence of low CD4+ cell counts preceded
AIDS by a median of624, 544, and466 d, respectively. Seronegativity for core antibody preceded AIDS in 21 of 26 patients,
20 of whom were also antigen positive. Four more cases of AIDS developed among the antigen-negative, core antibody-positive
men with low CD4+ cell counts. Only one patient with AIDS escaped detection by using these three markers.
Early treatment of asymptomatic human immunodeficiency virus type 1 (HIV-1) infection remains controversial. In the AIDS Clinical Trials Group 019 study, zidovudine was shown in 1990 to slow the clinical progression to AIDS in infected but asymptomatic subjects.1 However, a follow-up of those subjects found no evidence of longer survival with the use of zidovudine.2 Furthermore, the Concorde study found that there was not only no survival benefit from early treatment with zidovudine, but also no effect on the overall progression of disease.3 Now, in this issue of the Journal, Volberding et al. report the further results of the AIDS . . .
Mycobacterium avium complex causes disseminated disease in as many as 15 to 40 percent of patients with human immunodeficiency virus (HIV) infection in the United States, causing fever, night sweats, weight loss, and anemia1–7. Disseminated M. avium complex disease characteristically occurs in patients with very advanced HIV disease and peripheral-blood CD4 T-lymphocyte counts below 100 cells per cubic millimeter. Effective prevention and therapy of M. avium complex infection would probably improve the quality and duration of survival for HIV-infected persons. During the first decade of the HIV pandemic in the United States, health care providers recognized that M. . . .
The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine.
A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death.
The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results.
Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.
To determine the incidence of AIDS-defining opportunistic infections and malignancies over a 5-year period from 1992 to 1996.
Subcohort of 1003 homosexual men with HIV infection and CD4 count less than 200 x 10(6) cells/l from the Frankfurt AIDS Cohort Study.
Data including the earliest date that a CD4 T-lymphocyte count < 200 x 10(6)/l was reached and the dates of AIDS-defining events were compiled from medical records. Incidence analyses for AIDS-defining events and death during the subsequent 5 years (1992-1996) were performed using rates per 100 person-years of exposure.
During the observation period, the number of patients per year with CD4 T-lymphocyte counts < 200 x 10(6)/l varied between 402 and 511. In 1992, 56.7% of patients experienced at least one AIDS-defining illness, and 20.7% in 1996. The annual number of AIDS-defining events per 100 patient-years of observation declined from 143.5 in 1992 to 38.3 in 1996, and the number of AIDS-related deaths fell from 25.7 to 12.9. Analysis of the number of events confirmed this trend for malignancies and single opportunistic infections, with the exception of mycobacterial diseases.
The incidence of AIDS-defining events in patients with advanced HIV infection at Frankfurt University Hospital has declined by more than 70% from 1992 to 1996.
To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors.
Retrospective study in two German tertiary care treatment centres.
A total of 198 HIV-infected patients treated with protease inhibitors in 1996.
Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures.
A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001).
An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.
Little is known about how widely HIV-related drugs are used outside controlled clinical trials. We therefore assessed factors associated with use of antiretroviral (ARV) therapy and primary prophylactic regimens to prevent HIV-associated opportunistic infections. Baseline data from a prospective study from May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count <500 cells/microl, followed in 37 centers from 16 European countries, were analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV drug at the time of the study. ARV therapy was more frequently used among patients from southern and central Europe as compared with patients from northern Europe, especially among patients with CD4 counts >200 cells/microl (73%, 57%, and 42%, respectively, p < 0.0001). Of patients on ARV therapy, 34% received open-label combination therapy. This proportion was higher in central Europe compared with other regions (27%, 50%, and 31% for southern, central, and northern Europe, respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/microl, without marked regional differences. In patients without esophageal candidiasis or other invasive fungal infections, antifungal drugs were far less frequently used in patients from southern and central Europe compared with patients from northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of patients with a CD4 count <100 cells/microl received rifabutine as primary prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies are used differently in different parts of Europe, whereas primary PCP prophylaxis is uniformly administered to most at-risk patients. U.S. recommendations on the use of antimycobacterial prophylaxis have not been implemented in Europe.
To investigate the factors related to viral load becoming undetectable among patients from Southern Alberta who started a protease inhibitor for the first time, and to determine the factors related to subsequent re-emergence of detectable viral load amongst those patients whose viral load initially became undetectable.
A total of 243 patients from the Southern Alberta Clinic had started a protease inhibitor for the first time and had been followed up for a median time of 32 weeks. Standard survival techniques including Kaplan-Meier techniques and Cox proportional hazards models were used to determine which factors were related to viral load becoming undetectable.
At 24 weeks after first exposure to a protease inhibitor, 52.8% of the patients [95% confidence interval (Cl), 45.2-56.6] had achieved an undetectable viral load. In a multivariate analysis, those with a higher initial viral load were less likely to become undetectable [relative hazard (RH), 0.50; 95% Cl, 0.35-0.70; P < 0.0001], whereas those starting more new drugs (RH per new drug, 1.54; 95% Cl, 1.01-2.11; P = 0.048) were significantly more likely to achieve an undetectable viral load. Amongst 111 patients whose viral load became undetectable, Kaplan-Meier analysis indicated that 15.5% of patients experienced re-emergence of detectable viral load at 24 weeks after the first undetectable viral load. A higher CD4 cell count was associated with a lower risk of viral load becoming detectable (RH, 0.73; 95% Cl, 0.53-1.00; P = 0.049), as was treatment with indinavir (versus any other protease inhibitor RH, 0.17; 95% Cl, 0.03-0.86; P = 0.033).
A significant proportion of patients in a routine clinic setting achieved an undetectable viral load measurement after first starting a protease inhibitor; viral load in patients with a higher CD4 cell count was more likely to become and stay undetectable. There was no evidence that patients who were drug-naive experienced significantly worse virological effects than drug-experienced patients, as long as the same number of new drugs was started at the date of first exposure to a protease inhibitor. Further follow-up of these patients is warranted to study the longer term effects of treatment with protease inhibitors.
The efficacy of triple-drug antiretroviral regimens in the treatment of patients infected with HIV has been established in several randomized clinical trials. However, the effectiveness of these new regimens in patient populations outside clinical trials remain unproven. This study compared mortality and AIDS-free survival among HIV-infected patients in British Columbia who were treated with double- and triple-drug regimens.
The authors used a prospective, population-based cohort design to study a population of HIV-positive men and women 18 years or older for whom antiretroviral therapy was first prescribed between Oct. 1, 1994, and Dec. 31, 1996; all patients were from British Columbia. Rates of progression from the initiation of antiretroviral therapy to death or to diagnosis of primary AIDS were determined for patients who initially received an ERA-II regimen (2 nucleoside analogue reverse transcriptase inhibitors [NRTIs] including lamivudine or stavudine, or both) and for those who initially received an ERA-III regimen (triple-drug regimen consisting of 2 NRTIs and a protease inhibitor [indinavir, ritonavir or saquinavir] or a non-NRTI [nevirapine]).
A total of 500 men and women (312 receiving an ERA-III regimen and 188 an ERA-III regimen) were eligible. Patients in the ERA-III group survived significantly longer than those in the ERA-II group. As of Dec. 31, 1997, 40 patients had died (35 in the ERA-II group and 5 in the ERA-III group), for a crude mortality rate of 8.0%. The cumulative mortality rates at 12 months were 7.4% (95% confidence interval [CI] 5.9% to 8.9%) for patients in the ERA-II group and 1.6% (95% CI 0.7% to 2.5%) for those in the ERA-III group (log rank p = 0.003). The likelihood of death was more than 3 times higher among patients in the ERA-II group (mortality risk ratio 3.82 [95% CI 1.48% to 9.84], p = 0.006). After adjustment for prophylaxis for Pneumocystis carinii pneumonia or Mycobacterium avium infection, AIDS diagnosis, CD4+ cell count, sex and age at initiation of therapy, the likelihood of death among patients in the ERA-II group was 3.21 times higher (95% CI 1.24 to 8.30, p = 0.016) than in the ERA-III group. Cumulative rates of progression to AIDS or death at 12 months were 9.6% (95% CI 7.7% to 11.5%) in the ERA-II group and 3.3% (95% CI 1.8% to 4.8%) in the ERA-III group (log rank p = 0.006). After adjustment for prognostic variables (prophylaxis for P. carinii pneumonia or M. avium infection, CD4+ cell count, sex and age at initiation of treatment), the likelihood of progression to AIDS or death at 12 months among patients in the ERA-II group was 2.37 times higher (95% CI 1.04 to 5.38, p = 0.040) than in the ERA-III group.
This population-based cohort study confirms that patients initially treated with a triple-drug antiretroviral regimen comprising 2 NRTIs plus protease inhibitor or a non-NRTI have a lower risk of morbidity and death than patients treated exclusively with 2 NRTIs.
The prevalence and severity of lipodystrophy syndrome with long-term therapy for HIV-1 infection that includes a protease inhibitor is unknown. We studied the natural course of the syndrome to develop diagnostic criteria and identifying markers that predict its severity.
We assessed 113 patients who were receiving HIV-1 protease inhibitors (mean 21 months) and 45 HIV-1-infected patients (28 with follow-up) never treated with a protease inhibitor. Lipodystrophy was assessed by questionnaire (including patients' rating of severity), physical examination, and dual-energy x-ray absorptiometry. Body composition and fasting lipid and glycaemic variables were compared with data obtained 8 months previously. Oral glucose tolerance was investigated.
There was 98% concordance between patients' reports of the presence or absence of lipodystrophy (reported by 83% of protease-inhibitor recipients and 4% of treatment-naïve patients; p=0.0001) and physical examination. Patients' ratings of lipodystrophy were significantly associated with declining total body fat (p=0.02). Lower body fat was independently associated with longer duration of protease-inhibitor therapy and lower bodyweight before therapy, and more severe lipodystrophy was associated with higher previous (p < 0.03) and current (p < or = 0.01) triglyceride and C-peptide concentrations, and less peripheral and greater central fat (p=0.005 and 0.09, respectively). Body fat declined a mean 1.2 kg over 8 months in protease-inhibitor recipients (p=0.05). The prevalence of hyperlipidaemia remained stable over time (74% of treated patients vs 28% of naïve patients; p=0.0001). Impaired glucose tolerance occurred in 16% of protease-inhibitor recipients and diabetes mellitus in 7%; in all but three patients these abnormalities were detected on 2 h post-glucose load values.
Diagnosis and rating severity of lipodystrophy is aided by the combination of physical examination, patient's rating, and measurement of body fat, fasting triglycerides, and C-peptide. Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity. Lipodystrophy was common and progressive after almost 2 years of protease inhibitor therapy, but was not usually severe. Hyperlipidaemia and impaired glucose tolerance were also common.
To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment.
The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged > or = 14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described.
A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P < 0.0001; test for trend). There was a statistically significant decline in the proportion of follow-up time spent as an in-patient among patients with CD4 T-cell counts of < 50 x 10(6)/l from > 30% before 1990 to < 5% during 1997 (P = 0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission.
Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.
The use of highly active antiretroviral therapy (HAART) in the treatment of HIV-1-infected individuals has provided a considerable amount of information regarding the dynamics of viral replication and has resulted in enormous advances in HIV therapeutics. The profound suppression of plasma viremia in HIV-infected individuals receiving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS. Nonetheless, the persistance of reservoirs of HIV, including latently infected, resting CD4+ T cells that can give rise to infectious HIV upon stimulation in vitro, has posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART. Although a recent study has demonstrated th at the size of the pool of latently infected, resting CD4+ T cells can be markedly diminished with intermittent interleukin (IL-2) and continuous HAART, complete eradication of HiV in infected individuals remains extremely problematic. Here we discuss recent developments in studies of the latent reservoir of HIV in patients receiving HAART and implications for the long-term treatment of infected individuals and eradication of the infection.
To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment.
The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points.
Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-1 0.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04-1.26 versus hard-gell saquinavir).
If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.
Optimal sequencing of zidovudine and stavudine in antiretroviral therapy has not been elucidated.
To examine the impact of the sequence of therapeutic regimens containing zidovudine and stavudine on HIV-1 RNA and CD4 lymphocyte counts over 12 months.
Observational, multicenter, longitudinal cohort study.
Four large outpatient, HIV practices participating in the community-based Collaborations in HIV Outcomes Research-U.S. (CHORUS) cohort study.
940 HIV-infected patients.
Comparison of HIV-1 RNA and CD4 lymphocyte responses in patients sequenced from zidovudine to stavudine or from stavudine to zidovudine using repeated measures regression models fit to outcomes by application of generalized estimating equation (GEE) methodology.
Patients treated with zidovudine prior to stavudine (n = 834) achieved a greater mean drop from baseline HIV-1 RNA (p = .01) and higher proportion of undetectable HIV-1 RNA results (p = .05) over 12 months than those sequenced from stavudine to zidovudine (n = 106). CD4+ lymphocyte increases did not differ between the groups (p = .6).
Prior zidovudine therapy was not associated with long-term attenuation of HIV-1 RNA or CD4 response to subsequent stavudine-containing regimens. Zidovudine before stavudine may have benefit in a strategic long-term therapeutic plan.