Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity.
Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat.
Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved.
IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.
This study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once-daily combination.
Nine antiretroviral-naïve HIV-infected adults who received FTC [200 mg once a day (q.d.)], ddI (400 mg q.d. if > or =60 kg; 250 mg q.d. if <60 kg) and EFV (600 mg q.d.) were studied. The following pharmacokinetic (PK) parameters were determined over 24 h at steady-state after 4 weeks of treatment: area under the plasma concentration vs. time curve (AUC(0-24 h)), maximum (Cmax) and minimum (Cmin) plasma concentrations, time to reach Cmax (Tmax), and the elimination half-life (t(1/2)). EFV plasma concentrations were also measured during follow-up.
Median PK parameters for FTC, ddI and EFV, respectively, were as follows. AUC(0-24 h): 7.2, 7.0 and 36.4 h x mg/L; Cmax: 1.8, 2.6 and 2.5 mg/L; Cmin: 0.04, <0.01 and 1.0 mg/L; Tmax: 1.8, 1.1 and 2.5 h; t(1/2): 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10-13 h postdosing were higher during follow-up than during the PK study (2.57 vs. 1.19 mg/L, P<0.01).
The simultaneous administration of FTC, ddI and EFV did not affect the PK parameters of FTC when compared to historical controls. EFV Cmax and Cmin were lower than expected, but the data may have been slightly underestimated in this study. High ddI AUC and Cmax were measured in these patients, and further studies are warranted to confirm this finding.
To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors.
Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz.
Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks.
Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings.
Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women.
HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis.
Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature.
Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.
Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long-term viro-immunological follow-up of HIV-infected patients harbouring virus with protease insertions.
Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected.
Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI-naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI-naïve patients were infected with an HIV-1 non-B subtype. Follow-up of these PI-naïve patients showed that the insert-containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI-experienced patients, 63% were infected with HIV-1 subtype B; one had been antiretroviral-free for 5 years and seven were heavily PI-experienced (median duration of follow-up 24 months; range 10-62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI-resistance mutations, and following long-term exposure to PIs. The insert-containing virus persisted for a median of 32 months (range 12-62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity.
Our data, obtained during long-term follow-up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI-based regimens, although further work is required to confirm it.
Optimal diagnosis and timely treatment of atypical mycobacteriosis, and especially Mycobacterium kansasii disease, remain a serious challenge for clinicians engaged in the management of the immunocompromised host.
From more than 2700 hospitalizations (over 1800 patients) attributable to HIV-associated disorders over an 11-year period, 12 patients were found to have a confirmed M. kansasii infection. This reflects the recent reduction in the frequency of this HIV-related complication, which virtually disappeared after the introduction of potent antiretroviral combinations in 1996. In the early 1990s, the lack of effective antiretroviral regimens made frequent the association with AIDS, a mean CD4 lymphocyte count of nearly 20 cells/microL, and an extremely variable chest X-ray features. The recent detection of a further case was attributable to late recognition of very advanced HIV disease, complicated by multiple opportunistic disorders.
Mycobacterium kansasii respiratory or disseminated infection continues to occur, and poses diagnostic problems in terms of late or missed identification as a result of slow culture and frequently concurrent opportunistic disease. Serious therapeutic difficulties also arise from the unpredictable in vitro antimicrobial susceptibility profile of these organisms, and from the need to start an effective combination therapy that does not interfere with other medications as soon as possible.
Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein-Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma.
A total of 130 ART-naïve patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL).
Four lymphomas occurred, a median of 61 weeks [range 40-94 weeks] after randomization at a median CD4 cell count of 396 cells/μL (IQR 234-536 cells/μL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8).
IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.
Individual randomized trials of first-line antiretroviral treatment do not consistently show an association between higher baseline HIV-1 RNA and lower efficacy.
A MEDLINE search identified 21 HIV clinical trials with published analyses of antiretroviral efficacy by baseline HIV-1 RNA, using a standardized efficacy endpoint of HIV-1 RNA suppression <50 copies/mL at week 48.
Among 21 clinical trials identified, eight evaluated only nonnucleoside reverse transcriptase inhibitor (NNRTI)-based combinations, eight evaluated only protease inhibitor-based regimens and five compared different treatment classes. Ten of the trials included tenofovir (TDF)/emtricitabine (FTC) as only nucleoside reverse transcriptase inhibitor (NRTI) backbone, in addition but not restricted to abacavir (ABC)/lamivudine (3TC) (n = 7), zidovudine (ZDV)/3TC (n = 4) and stavudine (d4T)/3TC (n = 1). Across trials, the mean percentage of patients achieving HIV-1 RNA < 50 copies/mL at week 48 was 81.5% (5322 of 6814) for patients with baseline HIV-1 RNA < 100 000, vs. 72.6% (3949 of 5556) for patients with HIV-1 RNA > 100 000 copies/mL. In the meta-analysis, the absolute difference in efficacy between low and high HIV-1 RNA subgroups was 7.4% [95% confidence interval (CI) 5.9-8.9%; P < 0.001]. This difference was consistent in trials of NNRTI-based treatments (difference = 6.9%; 95% CI 4.3-9.6%), protease inhibitor-based treatments (difference = 8.4%; 95% CI 6.0-10.8%) and integrase or chemokine (C-C motif) receptor 5 (CCR5)-based treatments (difference = 6.0%; 95% CI 2.1-9.9%) and for trials using TDF/FTC (difference = 8.4%; 95% CI 6.0-10.8%); there was no evidence for heterogeneity of this difference between trials (Cochran's Q test; not significant).
In this meta-analysis of 21 first-line clinical trials, rates of HIV-1 RNA suppression at week 48 were significantly lower for patients w ith baseline HIV-1 RNA > 100 000 copies/mL (P < 0.001). This difference in efficacy was consistent across trials of different treatment classes and NRTI backbones.
The World Health Organization (WHO) recommends task-shifting HIV care to nurses in low-resource settings with limited numbers of physicians. However, the effect of such task-shifting on the health-related quality of life (HRQL) of people living with HIV (PLHIV) has seldom been evaluated. We aimed to investigate the effect of task-shifting HIV care to nurses on HRQL outcomes in PLHIV initiating antiretroviral therapy (ART) in rural district hospitals in Cameroon.
Outcomes in PLHIV were longitudinally collected in the 2006-2010 Stratall trial. PLHIV were followed up for 24 months by nurses and/or physicians. Six HRQL dimensions were assessed during face-to-face interviews using the WHO Quality of Life (WHOQOL)-HIV BREF scale: physical health; psychological health; independence level; social relationships; environment; and spirituality/religion/personal beliefs. The degree of task-shifting was estimated using a consultant ratio (i.e. the ratio of nurse-led to physician-led visits). The effect of task-shifting and other potential correlates on HRQL dimensions was explored using a Heckman two-stage approach based on linear mixed models to adjust for the potential bias caused by missing data in the outcomes.
Of 1424 visits in 440 PLHIV (70.5% female; median age 36 years; median CD4 count 188 cells/μL at enrolment), 423 (29.7%) were task-shifted to nurses. After multiple adjustment, task-shifting was associated with higher HRQL level for four dimensions: physical health [coefficient 0.7; 95% confidence interval (CI) 0.1-1.2; P = 0.01], psychological health (coefficient 0.5; 95% CI 0.0-1.0; P = 0.05), independence level (coefficient 0.6; 95% CI 0.1-1.1; P = 0.01) and environment (coefficient 0.6; 95% CI 0.1-1.0; P = 0.02).
Task-shifting HIV care to nurses benefits the HRQL of PLHIV. Together with the previously demonstrated comparable clinical effectiveness of physician-based and nurse-based models of HIV care, our results support the WHO recommendation for task-shifting.
To evaluate the long-term pharmacokinetics and safety of adding ritonavir 100 mg twice-daily to a nelfinavir 1250 mg twice-daily regimen in HIV-infected patients.
This was a prospective, randomized, open-label, controlled 24-week study. Sixteen patients receiving a nelfinavir 1250 mg twice-daily regimen with plasma viral load <1000 HIV-1 RNA copies/mL were randomized to continue treatment or to have ritonavir 100 mg twice-daily added. Safety, including fasting lipid levels, was evaluated at weeks 4, 12 and 24. Patients who were randomized to have ritonavir added (n=9) participated in three 12-h pharmacokinetic evaluations at baseline, week 4 and week 24.
Increases in median nelfinavir steady-state plasma concentrations at 12 h (C(12)) from 512 to 773 ng/mL [median difference 450 ng/mL; 95% confidence interval (CI) 116--1510 ng/mL] and in median active nelfinavir metabolite M 8 C(12) from 107 to 603 ng/mL (median difference 545 ng/mL; 95% CI 370--891) were seen after the addition of low-dose ritonavir (baseline to week 24). There were no differences between the nelfinavir or M 8 pharmacokinetic parameters at weeks 4 and 24. No significant changes or differences in the concentration of fasting total cholesterol, low-density lipoprotein (LDL) cholesterol or total triglycerides or in the occurrence of adverse events were observed within or between the two groups.
Nelfinavir and especially M 8 concentrations are increased when low-dose ritonavir is added to a nelfinavir-containing regimen. The combination seems to be safe and the nelfinavir/ritonavir regimen could be an option in patients with low nelfinavir+M 8 concentrations.
The aim of the study was to demonstrate the noninferiority of polyacrylamide hydrogel (PH) vs. polylactic acid (PLA) for the treatment of facial lipoatrophy in HIV-infected adults.
A randomized, blinded, multicentre, noninferiority 96-week study was carried out. Patients with facial lipoatrophy were randomly assigned to receive intradermal injections with PH or PLA, and were blinded to the filler. The primary efficacy endpoint was patient satisfaction at week 48 assessed using a visual analogue scale score (VAS). Secondary efficacy end-points included cheek thickness and skin-fold, lipoatrophy grading and quality of life. Safety was assessed by the reporting of adverse events.
A total of 148 patients were included in the study; 93% were men, the median age was 47 years, the median CD4 count was 528 cells/μL, and the median duration of antiretroviral therapy was 12 years. Mean VAS increased from 2.8 at baseline to 7.1 and 7.5 in the PLA and PH arms, respectively, at week 48 (P=0.0002 for noninferiority) and was sustained at week 96 (6.7 and 7.9 in the PLA and PH arms, respectively; P=0.003 for noninferiority). Cheek thickness and skin-fold increases and lipoatrophy improvement were similar in the two arms. Quality of life remained unchanged or improved depending on the questionnaire used. In injected patients, subcutaneous nodules emerged in 28 (41%) and 26 (37%) patients in the PLA and PH arms, respectively (P=0.73). Four patients in the PH arm developed severe inflammatory nodules, a median of 17 months after the last injection.
PH and PLA have similar efficacies in the treatment of facial lipoatrophy, but PH may be associated with more delayed inflammatory nodules.
Uncontrolled viral replication and antiretroviral treatment (ART) may independently contribute to hepatic mitochondrial toxicity. The present study was designed to explore the longitudinal effects of treatment modifications on hepatic mitochondrial function by means of noninvasive (13) C-methionine breath test (MeBT) diagnostics.
A total of 113 HIV-infected patients underwent two consecutive MeBTs over an interval of 11.8±3.5 months. Forty-nine patients remained on stable ART or no therapy; 28 participants switched ART; 27 patients (re)initiated ART, and nine individuals underwent a structured treatment interruption (STI) of ART between MeBTs 1 and 2. Breath test results were expressed as cumulative percentage dose of (13) CO(2) recovered after 1.5 h test time (cPDR(1.5h) ).
Initiation of ART in treatment-naïve individuals and patients on STI was associated with a significant improvement of hepatic mitochondrial function (P<0.05). Cessation of ART or a prolonged delay in initiating therapy in treatment-naïve patients in turn led to a significant decline of (13) C-exhalation compared with baseline (P<0.05). A marked increase in (13) C-exhalation was observed in individuals who switched from stavudine or ddI to tenofovir or abacavir (+170%; P<0.001), while no differences between MeBTs 1 and 2 were found in individuals on ART who had remained on stable regimens or in those who changed a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) component.
The present data suggest that hepatic mitochondrial function in HIV disease is a dynamic process with a high regenerative capacity and highlight the pathogenic relevance of HIV replication. Our findings suggest that modern ART per se does not negatively impact hepatic mitochondrial function.
The aim of the study was to investigate changes in plasma biomarkers of cardiovascular risk and lipids in a CD4-guided antiretroviral therapy interruption study.
This was a substudy of a prospective, randomized, multicentre treatment interruption study. At months 12, 24 and 36, monocyte chemotactic protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin), and tissue plasminogen activator (t-PA) were measured using a multiplex cytometric bead-based assay. Total cholesterol (total-c), high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG) were determined using standard methods.
Fifty-four patients were included in the study [34 in the treatment continuation (TC) arm and 20 in the treatment interruption (TI) arm]. There were no differences at baseline between the groups, except in CD4 cell count, which was higher in the TI arm (P = 0.026), and MCP-1, which was higher in the TC arm (P = 0.039). MCP-1 and sVCAM-1 were increased relative to baseline at the three study time-points in the TI arm, with no changes in the TC arm. Soluble CD40L and sP-selectin were increased at month 36 in both arms, with a greater increase in the TI arm (P = 0.02). t-PA was increased in both arms at the three time-points. Total-c, HDL-c and low-density lipoprotein cholesterol (LDL-c) were decreased in the TI arm at the three time-points, with no changes in the total-c/HDL-c ratio. HIV viral load positively correlated with MCP-1 at months 12 and 24. Regression analysis showed a significant negative association of HDL-c with MCP-1 and sVCAM-1.
A significant increase in cardiovascular risk biomarkers persisting over the prolonged study period was seen in the TI arm. This factor may contribute to the increased cardiovascular risk observed in previous studies.
In the MONotherapy in Europe with Tmc114 (MONET) trial, darunavir/ritonavir (DRV/r) monotherapy showed noninferior efficacy vs. two nucleoside reverse transcriptase inhibitors (NRTIs) plus DRV/r at the primary 48-week analysis. The trial was continued to week 144 to assess the durability of the results.
A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with two NRTIs (n=129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs.
Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch=failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference= +0.5%; 95% CI -8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144.
In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.
Study 903 was a 144-week, randomized, double-blind, active-controlled study of tenofovir disoproxil fumarate (TDF) therapy in treatment-naive HIV-1-infected patients. Patients received either TDF (n = 299) or stavudine (d4T) (n = 301) with lamivudine (3TC) and efavirenz (EFV). Resistance analyses were performed at baseline and at virological failure to determine the effects of baseline resistance and the patterns of resistance at virological failure.
Plasma HIV-1 from patients at baseline and at virological failure (>400 HIV-1 RNA copies/mL at week 144 or early discontinuation) was analysed phenotypically and by population sequencing.
Sixteen per cent of patients were classified as having virological failure (47 on TDF and 49 on d4T; P = 0.91). Patients with non-B HIV-1 subtypes or baseline nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations responded similarly to the overall population. Resistance to EFV (K103N and others) or 3TC (M184V) developed most frequently (8.3% and 5.8%, respectively) and similarly in the two arms. In the d4T arm, a variety of NRTI mutations developed: K65R (n = 2), L74V (n = 2), V75M (n = 1), and T69A + Y115H (n = 1). K65R developed in eight TDF patients (2.7%); in seven of these eight patients, within 48 weeks. All eight patients began new regimens with a protease inhibitor (PI) and NRTIs, including two patients who remained on TDF; five of the eight patients achieved HIV RNA <50 copies/mL in second-line therapy with the remaining patients having no follow-up or being nonadherent.
Treatment of HIV-1 with TDF, 3TC and EFV was highly effective, with <3% of patients developing resistance to TDF over 144 weeks.
To evaluate the long-term safety and efficacy of the combination of hydroxychloroquine, hydroxyurea and didanosine.
We recruited antiretroviral-naive patients with viral loads less than 100 000 HIV-1 RNA copies/mL and CD4 counts greater than 150 cells/microL. All patients received hydroxychloroquine (200 mg), hydroxyurea (500 mg) and didanosine (125-200 mg) twice daily. Clinical and laboratory safety assessments and measurements of viral load and CD4 count were made at regular intervals, and genotypic resistance testing was performed on samples with detectable viral load at 48, 96 and 144 weeks.
Fourteen of the 17 patients who commenced therapy remained on treatment at 144 weeks. Treatment was well tolerated but caused neutropenia, usually mild and transient, in 12 patients (71%). Mean viral load was reduced by 1.6 log(10) copies/mL below baseline (P<0.001), eight patients (47%) had undetectable viral load (<400 copies/mL), and two patients (12%) had detectable viral load but no detectable resistance mutations at week 144. Four patients (24%) had detectable viral load together with major resistance mutations (three with both 74 V and 184 V, and one with both 62 V and 65R) at week 144, but still had viral load suppression below baseline. Mean CD4 count was increased by 106 cells/microL above baseline (P=0.07) at week 144.
This novel and well-tolerated combination controls viral replication during long-term follow up, with development of few resistance mutations. With careful monitoring it may be a useful strategy for delaying highly active antiretroviral therapy (HAART) and associated toxicity in selected patients with low initial viral loads.
To study the impact of effective highly active antiretroviral therapy (HAART) on the preservation of long-term CD4 memory cells induced by vaccines in HIV-1-infected patients.
Thirty HIV-1-positive patients on HAART with undetectable viral load were randomized into three groups: 10 received HIV-1 rgp160 vaccine, 10 received tetanus vaccine and 10 patients were not immunized. As controls, 10 HIV-negative volunteers were immunized with tetanus vaccine. The results were compared with an rgp160 vaccine study performed before the era of HAART on patients with comparable CD4 levels. All patients were monitored for 2 years for T-cell proliferative responses, T-cell subset levels, serum IgG and viral load.
After 1 year all patients immunized with rgp160 had strong T-cell responses to the rgp160 antigen. After 2 years this response was preserved in the HAART-treated group, but not in the rgp160 immunized non-HAART group, despite comparable CD4 levels. Recall effects of the CD4-specific responses towards other antigens were seen in the rgp160-immunized HAART group.
Immunization with rpg 160 leads to positive effects on HIV-specific T-cell proliferative responses in patients both with and without HAART. Immune responses after immunization is better preserved in HAART-treated patients who have low viral amounts than in individuals with high viral load and no HAART despite comparable CD4 levels during 2 years' follow-up. Interruption of HAART with return of a high viral load might thus have negative effects on T-cell functions in the long term, even if CD4 levels are kept at clinically acceptable levels.
The aim of the study was to evaluate the interleukin-17 (IL-17) plasma level in HIV-1-infected patients and its relation to central obesity.
Eighty-four HIV-1-infected patients [42 with visceral obesity (group A) and 42 without visceral obesity (group B)] and 46 HIV-negative subjects [23 with visceral obesity (group C) and 23 without visceral obesity (group D)] were enrolled in the study. Sonographic measurements of perirenal fat diameter/body mass index (PRFD/BMI) were used to assess visceral adipose tissue thickness.
HIV-1-infected patients had higher plasma levels of IL-17 than HIV-negative subjects [837.8 ± 260 pg/mL (mean ± standard deviation) vs. 395.3 ± 138.6 pg/mL, respectively; P < 0.001]. Furthermore, HIV-1-infected patients with a diagnosis of visceral obesity had lower levels of IL-17 than HIV-infected lean patients (756.9 ± 282.9 pg/mL vs. 918.7 ± 208.4 pg/mL, respectively; P < 0.01). IL-17 (r = -0.21; P = 0.03) and waist circumference (r = 0.48; P < 0.001) were significantly associated with visceral adipose tissue thickness. A negative correlation of IL-17 (r = -0.23; P < 0.001) with PRFD/BMI was found.
This study suggests a linear negative association between IL-17 and visceral adipose tissue thickness.
This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1-infected adults.
ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine.
Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4–18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2–4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed.
Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients.
Given the extent of data on the natural history of HIV infection and the effect of antiretroviral therapy (ART), it should be possible to develop a model that encapsulates and can simulate these processes, providing a means of exploring various clinical and epidemiological questions. We aimed to develop such a model and use it to reconstruct the HIV-infected population in the UK to 2006.
A stochastic computer simulation model was developed that incorporates much of our understanding of the underlying processes of HIV disease progression and the effect of ART.
The model generally fitted well to a range of data in treated and untreated infection. UK reconstructions suggest that, of around 68 500 people alive with HIV infection at the end of 2006, around 34,000 (49%) were on ART, with an increasing proportion of these on first-line regimens (75% in 2006). The number of patients who have failed virologically on the original three main drug classes (estimated at around 4300 in 2006) is increasing only gradually, and an increasing proportion of these patients have suppressed viral load.
The beneficial effects of ART at a population level look set to continue as the number of patients exhausting the three original drug classes remains small.
The aim of this study was to analyse the trends of mortality and causes of death among HIV-infected patients in Taiwan from 1984 to 2005.
Registered data and death certificates for HIV-infected patients from Taiwan Centers for Disease Control were reviewed. Mortality rate and causes of deaths were compared among patients whose HIV diagnosis was made in three different study periods: before the introduction of highly active antiretroviral therapy (HAART) (pre-HAART: from 1 January 1984 to 31 March 1997), in the early HAART period (from 1 April 1997 to 31 December 2001), and in the late HAART period (from 1 January 2002 to 31 December 2005). A subgroup of 1161 HIV-infected patients (11.4%) followed at a university hospital were analysed to investigate the trends of and risk factors for mortality.
For 10 162 HIV-infected patients with a mean follow-up of 1.97 years, the mortality rate of HIV-infected patients declined from 10.2 deaths per 100 person-years (PY) in the pre-HAART period to 6.5 deaths and 3.7 deaths per 100 PY in the early and late HAART periods, respectively (P<0.0001). For the 1161 patients followed at a university hospital (66.8% with CD4 count <200 cells/microL), HAART reduced mortality by 89% in multivariate analysis, and the adjusted hazard ratio for death was 0.28 (95% confidence interval 0.24, 0.33) in patients enrolled in the late HAART period compared with those in the pre-HAART period. Seventy-six per cent of the deaths in the pre-HAART period were attributable to AIDS-defining conditions, compared with 36% in the late HAART period (P<0.0001). The leading causes of non-AIDS-related deaths were sepsis (14.7%) and accidental death (8.3%), both of which increased significantly throughout the three study periods. Compared with patients acquiring HIV infection through sexual contact, injecting drug users were more likely to die from non-AIDS-related causes.
The mortality of HIV-infected patients declined significantly after the introduction of HAART in Taiwan. In the HAART era, AIDS-related deaths decreased significantly while deaths from non-AIDS-related conditions increased.
To examine changes over a 2-year period in both the mortality rate and the causes of death in a geographically defined HIV-infected population.
A database search of primary care information for the dates and causes of death for all patients documented with HIV infection and living in Southern Alberta between 1984 and 2003 was undertaken. Sociodemographic and clinical characteristics were obtained. Causes of death were then individually confirmed by reviewing the patients' hospital charts, autopsy reports, or death certificates and coded using the International Classification of Diseases, 9th Revisions. AIDS deaths were reconciled with Public Health Reports. The time span was divided into pre-highly active antiretroviral therapy (HAART) (1984-1996) and current HAART (1997-2003) periods.
Between 1984 and 2003, there were 560 deaths in the 1987 individuals living with HIV infection in Southern Alberta. Of these, 436 deaths (78%) occurred pre-HAART and 124 (22%) in the current HAART period. The crude mortality rate declined from 117 deaths per 1000 patient-years pre-HAART to 24 in the current HAART period. In the pre-HAART era, 90% of all deaths were AIDS related whereas only 67% were AIDS related in the current HAART era. The leading causes of AIDS deaths were AIDS multiple causes (31%), Mycobacterium avium complex (18%), Pneumocystis pneumonia (10%) and non-Hodgkin's lymphoma (7%). The proportion of non-AIDS related deaths increased from 7% pre-HAART to 32% in the current HAART era. Accidental deaths, including drug overdose (29%), suicide (7%) and violence (3%), hepatic disease (19%), non-AIDS related malignancies (19%), and cardiovascular disease (16%) accounted for the majority of non-AIDS related deaths. No deaths directly caused by drug toxicity were found. Overall, 21% of patients who died were antiretroviral (ARV)-naive. A total of 14% of patients dying from AIDS were ARV-naive in contrast to 35% dying from non-HIV related conditions. Of all those dying from AIDS, 23% died<3 months after their initial diagnosis, reflecting late presentation. In the current HAART era, 87% of patients who died from AIDS were extensively treated, reflecting HAART treatment failures due mostly to multiclass drug resistance (42%), inexorable disease progression despite ARV (32%), lack of ability or interest to be maintained on a lifelong HAART programme (21%) and, rarely, drug intolerance (<1%).
Deaths from AIDS-related causes have decreased significantly, but deaths from non-AIDS related conditions have increased, both as an absolute number of deaths and as a proportion of all deaths in HIV-infected patients. The increasing age of the HIV population, and the increased mean CD4 count, increased proportion of intravenous drug users, increased hepatitis B virus and hepatitis C virus coinfection rate, and increased history of smoking seen in our population also influenced the mortality rate and causes of death. These factors must also be considered in projecting future trends in mortality of an HIV-infected population.
To investigate the major primary and contributory causes of death among HIV patients in Singapore.
A retrospective observational cohort study of all adult patients seen at the national referral centre for HIV in Singapore between 1985 and 2001.
Data were extracted from the patients' records by 10 trained health care workers. AIDS-defining conditions were established using predefined criteria. For each case, a single principal cause of death and up to three contributory causes were identified.
A total of 1504 patients aged 17 years or over were seen before the end of 2001, of whom 504 have died. The most frequent principal causes of death were Mycobacterium avium (17.5%), Mycobacterium tuberculosis (9.7%), pneumonia (cause unknown) (6.5%) and Cryptococcus neoformans (6.7%). Three hundred and eighteen patients (63.1%) died from an AIDS-defining condition.
The causes of death were similar to those found in Western cohorts, except that disseminated M. avium was a more frequent cause of death.
To determine the incidence rate and risk factors for loss to follow-up (LFU) in HIV-infected individuals.
We estimated the incidence rate of LFU in 1756 HIV-infected patients enrolled in the Tourcoing Clinical Cohort from January 1985 to January 1998. We then investigated potential LFU risk factors at inclusion through a case-control study. Cases were 209 patients who had attended neither our clinic nor another HIV clinic for at least 1 year. Controls were 209 patients randomly selected from the group of HIV-infected patients followed up regularly.
The incidence of LFU was estimated at 4.3 per 100 person-years [95% confidence interval (CI) 3.7-4.9]. Independent risk factors for LFU were (i) year of enrolment before 1993 [odds ratio (OR) 6.7; 95% CI 2.7-16.5 versus after 1997]; (ii) year of enrolment between 1993 and 1997 (OR 5.1; 95% CI 2.0-13.0 versus after 1997); (iii) age<30 years (OR 1.8; 95% CI 1.0-3.5 versus >40 years); (iv) injecting drug use (OR 5.3; 95% CI 2.7-10.5 versus men who have sex with men); (v) homelessness and/or illegal immigrant status (OR 2.2; 95% CI 1.0-4.9); and (vi) lack of a primary care provider (OR 6.0; 95% CI 2.4-15.1). A history of an AIDS-defining illness (OR 0.3; 95% CI 0.2-0.6) and a history of psychiatric disease (OR 0.4; 95% CI 0.3-0.8) were both associated with a decreased risk of LFU.
This study assessed the sociodemographic, clinical and behavioural characteristics associated with LFU in HIV-infected patients. The findings of this study may allow clinicians to identify patients at risk of LFU, so that appropriate interventions may be initiated.
A diagnosis of AIDS shortly after the detection of HIV antibodies suggests a long-lasting course of the disease without care. The factors associated with a short delay between the initial HIV-1-positive test and the first AIDS-defining event were identified in 1901 patients from 1985 to 2001 in Lyon University hospitals. A total of 576 individuals (30.3%) had an interval of </=3 months between the detection of HIV infection and AIDS. The factors independently associated with a delay of </=3 months were: age from 30 to 44 years [odds ratio (OR) 2.5; 95% confidence interval (CI) 1.9-3.2]; age from 45 to 59 years (OR 5.6; 95% CI 3.9-7.8); age >/=60 years (OR 4.5; 95% CI 2.5-8.1), compared to those<30 years old; heterosexuality (OR 2.4; 95% CI 1.6-3.4); injection drug use (OR 2.1; 95% CI 1.5-2.7); and other exposures (OR 2.4; 95% CI 1.6-3.4), compared to homosexual exposure; two opportunistic infections at AIDS (OR 1.8; 95% CI 1.4-2.4) compared to one; and Pneumocystis carinii pneumonia as initial AIDS event (OR 2.6; 95% CI 1.8-3.7), compared to Kaposi's sarcoma. These results provide opportunities to refocus local public health interventions to reduce delayed access to care.
To identify predictive factors for moderate/severe liver fibrosis and to analyse fibrosis progression in paired liver biopsies from HIV-positive patients with chronic hepatitis C virus (HCV) infection.
HIV/HCV coinfected patients followed at the 2nd Department of Infectious Diseases of L. Sacco Hospital in Milan, Italy, with at least one liver biopsy specimen were retrospectively evaluated.
A total of 110 patients were enrolled in the study. In a univariate analysis, predictive factors of Ishak-Knodell stage > or =3 were a history of alcohol abuse [odds ratio (OR) 3.6, P=0.004], alanine aminotransferase level >100 IU/L at biopsy (OR 2.4, P=0.05), necro-inflammatory grade > or =9 (OR 37.14, P<0.0001) and CD4 count <350 cells/microL at nadir (OR 5.3, P=0.05). In a multivariate analysis, age >35 years (OR 3.19, P=0.04) and alcohol abuse (OR 4.36, P=0.002) remained independently associated with Ishak-Knodell stage. Paired liver biopsies were available in 36 patients; 18 showed an increase of at least one stage in the subsequent liver biopsy. Either in a univariate or in a multivariate analysis, a decrease of CD4 cell count of more than 10% between two biopsies (OR 6.85, P=0.002) was significantly associated with liver fibrosis progression.
Our findings highlight the relevance of encouraging a withdrawal of alcohol consumption in people with chronic HCV infection and of carrying out close follow-up of patients, especially if they are more than 35 years old. It is therefore mandatory to evaluate HIV/HCV coinfected patients for anti-HCV treatment and to increase CD4 cell count through antiretroviral therapy in order to reduce the risk of fibrosis progression and to slow the evolution of liver disease.
To study determinants of late HIV diagnosis in a low-HIV-prevalence (<0.1%) country where HIV spread among men who have sex with men (MSM) and heterosexuals in the 1980s, and among injecting drug users (IDUs) in the late 1990s.
Newly diagnosed HIV cases referred to the Helsinki University Central Hospital between 1985 and 2005 were reviewed to identify determinants of late HIV diagnosis, defined as diagnosis when the first CD4 count was <200 cells/microL, or when AIDS occurred within 3 months of HIV diagnosis. Determinants of late diagnosis were analysed using multivariate logistic regression.
Among 934 HIV cases, 211 (23%) were diagnosed late. In the first 4-year interval of each sub-epidemic (1985-1989 for MSM and heterosexuals, 1998-2001 for IDUs), rates of late HIV diagnosis were 13%, 18% and 6%, respectively, but increased thereafter to 29%, 27% and 37%. Late diagnosis was associated with non-Finnish ethnicity, older age, male gender, lack of earlier HIV testing, diagnosis at health care settings and later stage of the sub-epidemic.
The lower rate of late diagnosis in the first 4-year interval of each HIV sub-epidemic suggests that the early stages of the HIV epidemic in Finland were detected early. This factor may have contributed to the low prevalence of HIV infection in Finland. The stage and age of the epidemic should be taken into account when interpreting the data on late HIV diagnosis, especially in cross-country comparisons.
To define the characteristics of 1899 patients diagnosed with AIDS at Lyon University Hospitals (LUH) across four time periods corresponding to different antiretroviral eras, and to analyse the evolution of specific AIDS-defining illnesses (ADIs) with time.
All AIDS patients at LUH between 1 January 1985 and 31 December 2000 were included in the study. The data were compared using the chi(2) test and one-way analysis of variance.
The absolute number of new AIDS cases increased by 30.3% between 1985 and 1995 but decreased by 26.5% between 1996 and 2000. The proportion of women with AIDS increased significantly (P<0.001) and mean age at diagnosis also increased significantly over time (P<0.001). The proportion of infection through heterosexual contact increased dramatically, while that through homo/bisexual intercourse or injection drug use (IDU) decreased significantly (P<0.001). The absolute number of ADIs declined with the introduction of highly active antiretroviral therapies (HAART) (P<10(-6)). Pneumocystis carinii pneumonia remained the leading ADI in 1996-2000 (23.3%). A significant increase in the proportion of non-Hodgkin's lymphoma (NHL) was observed over time (P<10(-5)) but the number of new NHL cases decreased during HIV infection after 1996.
The decline in the incidence of AIDS with the advent of HAART was confirmed in our hospital cohort. The gradual increase in the proportion of NHL among ADIs underscores the long latency period between infection with HIV and the achievement of an effect of HAART on HIV-associated lymphomagenesis.
The aim of the study was to compare the HIV/AIDS burdens in Jewish and Arab Israeli males, as HIV/AIDS affects different population groups disproportionally.
The National HIV/AIDS Registry (NHAR) was used as the source of HIV/AIDS infection records, while the Israeli Central Bureau of Statistics was used to determine group-specific disease rates.
Between 1986 and 2010, 3499 HIV/AIDS-infected male Israelis were reported to the NHAR: 3369 (96.3%) Jews and 130 (3.7%) Arabs, with an average annual incidence of 5.5 and 0.8 per 100 000 of the population, respectively (P = 0.05). Of the Jews, 1018 (29.9%) were born in Ethiopia, while 2389 were Jews who were not Ethiopian-born (JNE). Most of the Arabs (n = 99; 74.8%) were Muslims, followed by Christians (21; 16.2%) and Druze (13; 10%). AIDS rather than HIV infection at the time of reporting was diagnosed in 568 (23.8%) of the JNE and 31 (23.8%) of the Arabs (p = 1). The most affected age group was those aged 25-34 years among the JNE and those aged 20-24 years among the Arabs, and the respective cumulative death rates were 24.9% (n = 594) and 32.5% (n = 40) (P = 0.1). The point prevalences in 2010 were 58.4 and 11.4 per 100 000 for JNE and Arabs, and in adults aged 15-59 years they were 71.5 and 26.3 per 100 000, respectively. In Muslims, Christians and Druze, the point prevalences were 4.2, 11.2 and 7.1 per 100 000, and in adults aged 15-59 years they were 22.6, 42.9 and 29.4, respectively. The most common risk group among JNE was men who have sex with men (MSM; n = 1223; 51.2%), followed by injecting drug users (n = 661; 27.7%), while among Arabs it was MSM (n = 63; 48.1%), followed by heterosexuals (n = 36; 27.3%).
The HIV/AIDS burden in Israeli Arab males was significantly lower than that in Jews, and in both populations the most common risk group was MSM, with the proportion of MSM increasing with time.
Following the publication of results of large-scale clinical trials, antiretroviral treatment for HIV has changed dramatically. The aim of this study was to describe changes in antiretroviral treatment and the way treatments were combined among 1806 patients with HIV seen at a single centre at the Royal Free Hospital, London, UK.
Each calendar year was divided into quarters, and the number of patients receiving treatment and participating in clinical trials was determined.
The proportion of patients on no therapy decreased from over 90% at the beginning of 1988 to under 15% at the end of 1997. Monotherapy was the only form of treatment available before 1992 but its use dropped to 2% by the end of 1997. The standard of care at the end of 1997 was triple combination therapy, used in over 40% of patients. There were dramatic changes in the use of individual agents; use of zidovudine decreased from 50% during 1989 to 25% during 1997, while use of lamivudine and stavudine saw an exponential rise in 1997. The protease inhibitors were used in equal proportions in this clinic population; the use of dual protease therapy began in 1997 and was rising rapidly by the end of the year.
There have been major changes in the use of antiretroviral therapy at this centre, particularly during 1996 and 1997. The long-term cost implications and side-effects of intensive treatment regimens remain to be addressed.
Reductions in HIV/AIDS mortality associated with highly active antiretroviral therapy (HAART) have mainly been reported from Western countries. We studied the impact on survival of patients with advanced HIV disease after the introduction of HAART in Hong Kong.
The mortality pattern in a government clinic cohort of 511 adult HIV-1-infected patients with AIDS or CD4 count <200 cells/microL from 1993 to 2002 was examined. The number of deaths, the crude mortality rate (CMR) and the death rate per 1000 person-months were recorded.
Despite an increase in the patient population, 36 deaths occurred in the HAART era (1997-2002) as compared with 56 deaths in the pre-HAART era (1993-1996). The overall annual CMR fell significantly from a high, fluctuating level of 10.8-30.4 per 100 mid-year patient population pre-HAART to a low, steady level of 0.8-6.9 per 100 mid-year population in the HAART era (P=0.004, 1996 vs 1998; P<0.001, 1996 vs 2000; P<0.001, 1996 versus 2002). A fall in CMR was observed in all demographic subpopulations, categorized by sex, ethnicity, HIV exposure risk and age (P ranged from 0.012 to<0.001). Longitudinal tracking until mid-2003 revealed a death rate of 9.2 events/1000 person-months (52 deaths with 5661.5 person-months follow up) among patients first diagnosed as having advanced disease during 1993-1996, and a lower death rate of 2.4 events/1000 person-months (25 deaths with 10551.8 person-months follow up) in patients first diagnosed as having advanced disease during 1997-2001 (rate ratio 3.9; 95% confidence interval 2.4-6.2).
There was dramatic temporal decline in mortality in patients with advanced HIV disease in all demographic subpopulations with the advent of HAART. Notwithstanding confounding variables, one reason for the universal decline may be that there was no major disparity in access to HIV care across community groups.
The aim of this study was to describe trends in the management of pregnancies in HIV-infected women and their outcomes over a 14-year period in Denmark on a national basis.
The study was a retrospective cohort study of all HIV-infected women in Denmark giving birth to one or more children between 1 June 1994 and 30 June 2008.
We identified 210 HIV-infected women with 255 pregnancies, ranging from 7 per year in 1995 to 39 per year in 2006. Thirty per cent of the women were Caucasian and 51% were Black African. Knowledge of HIV status before pregnancy increased from 8% (four of 49) in 1994-1999 to 80% (164 of 206) in 2000-2008. Only 29% (53 of 183) of the women chose to consult an infectious disease specialist when planning pregnancy, while 14% (27 of 199) received assistance with fertility. The proportion of women on antiretroviral therapy (ART) increased from 76% (37 of 49) in 1994-1999 to 98% (201 of 206) in 2000-2008. Vaginal deliveries ranged from 0 in 2003 to 35% of pregnancies in 2007. Mother-to-child transmission (MTCT) of HIV decreased from 10.4% in 1994-1999 to 0.5% in 2000-2008. All women giving birth to an HIV-positive child were diagnosed with HIV during or after delivery and did not receive prophylactic ART.
The annual number of HIV pregnancies increased fivefold during this 14-year period and substantial changes in pregnancy management were seen. No woman treated according to the national guidelines, i.e. ART before week 22, intravenous zidovudine (ZDV) during labour, neonatal ZDV for 4 to 6 weeks and no breastfeeding, transmitted HIV to her child.
To document the demographic changes in new HIV diagnoses at the Royal Free Hospital, London, UK, between 1994 and 2000.
Retrospective case note review.
Data were extracted from the Royal Free HIV database identifying new diagnoses for 1994, 1997 and 2000. All case notes were reviewed and patients were included if they had their first positive HIV test at the Royal Free Hospital, or if they first tested positive elsewhere and attended the Royal Free HIV unit for their initial HIV care. Data extracted included sex, ethnicity, age, risk factor(s) for HIV, reason for test, clinical stage of disease, CD4 count and HIV RNA viral load at diagnosis.
One hundred and forty-four patients were identified for 1994, 136 for 1997 and 110 for 2000. Over this time period the proportion of white patients dropped from 72% (n = 104) to 48% (n = 53), P = 0.0001, whilst the proportion of black Africans rose from 24% (n = 34) to 45% (n = 49), P = 0.0004. The median CD4 count at diagnosis of the white cohort was 475 cells/microL in 1994 and 286/microL in 2000, P = 0.005, whilst in the black African patients it was 240/microL and 230/microL for the same years.
There has been a reduction in new HIV diagnoses among the white population and a rise in the black Africans at this centre between 1994 and 2000. The clinical and immunological parameters of HIV disease have worsened over this time period for the white group, but have remained stable in the black Africans.
More than 10 years after the introduction of combination antiretroviral therapy (cART), we examined the trend in the proportion of deaths caused by end-stage liver disease (ESLD) in HIV-infected adults in France between 1995 and 2005.
In 2005, 34 departments prospectively recorded all deaths in HIV-infected patients who were followed in those departments (around 24 000).
were compared with those of four previous cross-sectional surveys conducted since 1995 using the same methodology. Results Among 287 reported deaths in 2005, 100 (35%) were related to AIDS, and 48 (17%) to ESLD. Three out of four patients who died from ESLD-related causes had chronic hepatitis C. Excessive alcohol consumption was reported in approximately half of the patients (48%). At death, 62% of patients had undetectable HIV viral load and the median CD4 count was 237 cells/microL. From 1995 to 2005, the proportion of deaths caused by ESLD increased from 2 to 17% (P<0.001). The proportion of deaths caused by hepatocellular carcinoma increased from 5% in 1995 to 25% in 2005 (P=0.0337).
Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients. ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients.
To determine the frequency of and reasons for hospitalization of adult HIV-infected patients compared with the general population.
Length of stay, primary/secondary diagnoses and discharge status were reviewed for all HIV-infected patients admitted to Calgary-area hospitals between 1995 and 2003. Admissions were classified as HIV- or non-HIV-related using International Classification of Diseases, 9th and 10th revisions (ICD-9/10) codes and confirmed by chart review. Summary comparative data on admissions for the general population were obtained from the regional administrative database.
HIV-infected adults were hospitalized more than twice as frequently, experienced longer stays (median length 5 vs 3 days, respectively) and had higher in-hospital mortality rates (9.1 vs 1.3 per 100 admissions, respectively) than the general population (P < 0.01). Hospitalizations of HIV-infected patients declined by 58% from 1995 to 2003. Patients newly diagnosed with HIV infection accounted for 15% of all HIV-related hospitalizations. HIV-related admissions for known HIV-infected patients decreased from 12 per 100 patient-years-followed in 1995 to 3 per 100 patient-years-followed in 2003. Low CD4 counts, AIDS, and no current use of highly active antiretroviral therapy (HAART) were strongly correlated with hospitalizations (P < 0.01). Non-HIV-related hospitalizations for HIV-infected patients increased by 42% and were associated with comorbidities (e.g. substance use and psychological disorders).
Despite the reduction in HIV-related hospitalizations following the introduction of HAART, all-cause hospitalization rates have increased and have started to erode this benefit.
Incidence rates (IRs) of Staphylococcus aureus bacteraemia (SAB) are known to be higher in HIV-infected individuals than in the general population, but have not been assessed in the era of highly active antiretroviral therapy.
From 1 January 1995 to 31 December 2007, all Danish HIV-infected individuals (n=4871) and population controls (n=92 116) matched on age and sex were enrolled in a cohort and all cases of SAB were registered. IRs and risk factors were estimated using time-updated Poisson regression analysis.
We identified 329 cases of SAB in 284 individuals, of whom 132 individuals were infected with HIV and 152 were not [crude IR ratio (IRR) 24.2; 95% confidence interval (CI) 19.5-30.0, for HIV-infected vs. non-HIV-infected individuals]. Over time, IR declined for HIV-infected individuals (IRR 0.40). Injecting drug users (IDUs) had the highest incidence and the smallest decline in IR, while men who have sex with men (MSM) had the largest decline over time. Among HIV-infected individuals, a latest CD4 count <100 cells/μL was the strongest independent predictor of SAB (IRR 10.2). Additionally, HIV transmission group was associated with risk of SAB. MSM were more likely to have hospital-acquired SAB, a low CD4 cell count and AIDS at the time of HIV acquisition compared with IDUs.
We found that the incidence of SAB among HIV-infected individuals declined during the study period, but remained higher than that among HIV-uninfected individuals. There was an unevenly distributed burden of SAB among HIV transmission groups (IDU>MSM). Low CD4 cell count and IDU were strong predictors of SAB among HIV-infected individuals.
Recent studies have reported faster progression of HIV infection than anticipated based on results from earlier studies. The aim of the present study was to examine if the virulence of HIV-1 infection changed in the period 1995-2010 among chronically HIV-infected individuals in Denmark.
We included all patients registered in the Danish HIV Cohort Study, who were diagnosed in 1995-2009, had a CD4 count > 100 cells/μL at diagnosis and had at least two CD4 measurements prior to initiation of antiretroviral therapy (ART). Changes in viral set point and rate of CD4 cell decline from enrolment until the initiation of ART by calendar year of HIV diagnosis were analysed. Time to first CD4 count < 350 cells/μL was compared among patients diagnosed in 1995-2000, 2001-2005 and 2006-2010.
We followed 1469 HIV-infected patients for a total of 5783 person-years. The median viral set point was 4.27 log10 HIV-1 RNA copies/mL [interquartile range (IQR) 3.58-4.73 log10 copies/mL]. The median CD4 cell decline per year was 57 cells/μL (IQR 10-139 cells/μL). In analyses adjusted for age, gender, origin, route of transmission and CD4 count at diagnosis, there were no associations between year of diagnosis and viral set point or CD4 cell decline. Time to first CD4 count < 350 cells/μL did not change in the study period [incidence rate ratio (IRR) 0.90 (95% confidence interval (CI) 0.76-1.06) for 2001-2005 and 1.09 (95% CI 0.79-1.34) for 2006-2010 compared with 1995-2000].
We found no evidence of changing trends in viral set point, CD4 cell decline or time to CD4 count < 350 cells/μL during the period 1995-2010 in a cohort of chronically HIV-infected individuals.
To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan-European, observational cohort study.
Generalized estimating equations were used to determine changes over time in the proportion of patients admitted and the median duration of admission. Logistic regression was used to determine factors related to admission in March 1995, March 1998 and March 2001.
The proportion of patients admitted during March declined from 7.4% in 1995 to 2.6% in 2003. After adjustment, the estimated reduction in the proportion of patients admitted was 5.5% per year [95% confidence interval (CI) 2.5-8.5%; P=0.0004], a 26% reduction. The median duration of hospital admission declined by 58% from 12 days in 1995 [interquartile range (IQR) 5-19 days] to 5 days in 2003 (IQR 3-12 days), a significant decline of 0.7 days per year after adjustment (95% CI 0.5-0.9 days; P=0.031). Patients with a lower CD4 lymphocyte count, and with an AIDS diagnosis made within the 3 months prior to March, all had increased odds of admission during March 1995, 1998 or 2001. In March 2001, patients whose treatment regimen was changed as a consequence of toxicities had increased odds of admission [odds ratio (OR) 2.34; 95% CI 1.26-4.37; P=0.0074]. In addition, patients who were hepatitis C virus-positive during March 2001 (OR 1.66; 95% CI 1.02-2.68; P=0.041) had increased odds of admission.
There has been a considerable decline in both the proportion of patients admitted to hospital and the median duration of the stay. Patients with hepatitis C had increased odds of admission, but there was little evidence of an increase in admissions among patients taking highly active antiretroviral therapy (HAART) associated with serious adverse events, although longer follow up is required.
To perform a retrospective analysis of all HIV-1 non-B variants circulating in Spain from 1995 to 2003 and extend their virological characterization.
Samples from a total of 396 HIV-infected subjects with epidemiological suspicion of being infected with non-B clades were analysed during the study period. Subtyping was carried out on the protease (PR), reverse transcriptase (RT) and envelope (env) genes.
PR sequences belonging to non-B subtypes were recognized in 43.2% of cases (23 A, 13C, 6D, 3F, 118 G, 3H, 4 J and 1 U). Subtype G and AG recombinants were the most frequent variants (69%), and were found most often in subjects from West and Central Africa. Up to 70% of pol (PR, RT) sequences belonging to subtype G harboured env sequences belonging to clade A (55%), B (13.8%) or K (3.4%). Nearly half were mosaic GA viruses, and a few were CRF 14 BG viruses. Up to 14 new recombinant viruses, which could not be assigned to previously described circulating recombinant forms (CRFs), were found.
There is great diversity in the HIV-1 variants and recombinant viruses circulating in Spain. Non-B sequences may be underestimated if only the env region is examined in phylogenetic analyses. Drug resistance testing provides the advantage of pol subtyping, and its additional use for this purpose should be encouraged.
To estimate the incidence of serum hypertriglyceridaemia > 6 mm/L (HTG) and identify associated factors in the era of highly active antiretroviral therapy (HAART).
A prospective cohort, multirisk, both genders, of HIV-infected patients was treated with several patterns of antiretrovirals. Cox's model was used to estimate the effect of explanatory variables documented at the first normal triglyceride measurement (< 2 mm/L) on the subsequent occurrence of HTG.
Among 925 patients (27% treated with a protease inhibitor (PI) containing regimen and 48% treated with other HAART combinations) followed 25 months in median with a median triglyceridaemia of 1.1 mm/L at baseline, 70 experienced an HTG, 4.2 cases per 100 person years[95% confidence interval (CI)=2,2,3,3-5]. Univariate analysis retained the following as risk factors of HTG: male gender, homosexual transmission group, greater age, higher body weight, AIDS stage, > or = 2 antiretrovirals including PI, higher triglyceride level and lower CD4+ cell count at baseline. In multivariate analysis, the risk of HTG remained associated with being male homosexual [hazard ratio (HR) = 1.68, P = 0.04], at the AIDS stage (HR = 1.84, P = 0.03), with increased triglyceride level (HR = 2.82 for 1 mm/L higher at baseline, P < 10-3), impaired CD4+ cell count (HR = 1.2 for 100 cells/microL lower, P = 0.02) and increased body weight (HR = 1.3 for 10 kg higher, P = 0.02).
Baseline triglyceride level and being overweight are risk factors of HTG, together with advanced HIV disease, but the contribution of HAART is not demonstrated.
Risk factors for death in an HIV-infected cohort in French Guiana were studied in 1374 patients between 1996 and 2005. Of these patients, 48.5% were male and 76% were immigrants. Covariates were measured at the time of consultation. There were 223 deaths. Addictions [adjusted hazard ratio (HR)=13; 95% confidence interval (CI) 5.5-30.6; P<0.001], age>60 years (HR=1.5; 95% CI 0.9-2.5; P=0.13), male gender (HR=1.5; 95% CI 1.03-2.5; P=0.03) and CD4 count<50 cells/microL (HR=9.1; 95% CI 5.1-16.3; P<0.001) were independently associated with death. These results suggest that strategies promoting early diagnosis and better follow-up of addicted patients would have a significant impact on mortality.
To determine the factors associated with clinical progression (AIDS events and death) in antiretroviral-naive patients who have begun highly active antiretroviral therapy (HAART).
HIV-infected patients naive to antiretroviral therapy were included in a prospective hospital-based cohort who began HAART between June 1996 and December 2001. Progression was explained by baseline characteristics using Cox proportional hazards models.
Overall, data for 709 patients were analysed. In multivariate analysis, factors associated with an increased risk of progression were CD4 count < 50 cells/microL [hazard ratio (HR) = 13.0 (95% confidence interval 3.8-44.3)] and between 50 and 199 cells/microL [HR = 5.1 (1.6-16.3)], when compared with patients with CD4 count>350 cells/microL; AIDS events before HAART prescription [HR = 2.1 (1.2-3.7)]; CD8 count < 400 cells/microL [HR = 1.8 (1.1-3.0)]; and older age (HR = 1.2 by 10 years (1.0-1.5)]. In a second model including CD4 percentage, factors associated with progression were CD4 < 10% [HR = 6.3 (2.2-17.9)] and 10%<CD4 < 15% [HR = 4.2 (1.4-12.5)], when compared with patients with CD4 > 20%; CD8 count; AIDS events before HAART prescription; and older age. In a third model including the CD4:CD8 ratio, factors associated with progression were CD4:CD8 < 15% [HR = 8.2 (2.3-28.8)] and 15% < CD4:CD8 < 30% [HR = 4.6 (1.3-16.0)], when compared with patients with CD4:CD8 > 45%; AIDS events before HAART prescription; and older age. The Akaike information criteria for model analysis were 803, 805 and 815, respectively.
Consideration of CD4 level in terms of CD4:CD8 ratio or CD4 percentage can be a good alternative to absolute CD4 count. Other prognostic factors such as older age, CD8 count < 400 cells/microL and AIDS events also have to be considered in the decision to initiate HAART.
We examined whether the timing of initiation of antiretroviral therapy (ART) in routine clinical practice reflected treatment guidelines, which have evolved towards recommending starting therapy at lower CD4 cell counts.
We analysed longitudinal data on 10,820 patients enrolled in the UK Collaborative HIV Cohort (UK CHIC) Study, which includes seven large clinical centres in south-east England. CD4 cell and viral load measurements performed in the period between 1 January 1997 and 31 December 2003 were classified according to whether ART was subsequently initiated or deferred, to estimate the probability of ART initiation by CD4 count and viral load over time. The effect of nonclinical factors (age, sex, ethnicity, and exposure category) was analysed by logistic regression. Kaplan-Meier analysis was used to estimate the proportion of patients who had initiated ART by a particular CD4 count among 'early' presenters (initial CD4 cell count >500 cells/microL).
There was a tendency to initiate ART at lower CD4 cell counts over time in the years 1997-2000, especially in the range 200-500 cells/microL, with little change thereafter. An estimated 34% of HIV-infected individuals having presented early initiated ART at a CD4 count <200 cells/microL. We also found an independent influence of viral load, which was particularly pronounced for CD4 <350 cells/microL. Use of injection drugs was the only nonclinical factor associated with initiation of ART at lower CD4 cell counts.
The initiation of ART in the clinics included in this analysis reflected evolving treatment guidelines. However, an unexpectedly high proportion of patients started ART at lower CD4 counts than recommended, which is only partly explained by late presentation.
To report on the cost of medical care for HIV-infected patients stratified by CD4 cell count for a regional population over a 9-year period, and to examine the effect of reporting costs of HIV care only or only in antiretroviral therapy (ART)-experienced patients.
Retrospective costing analysis on all HIV-infected patients within the Southern Alberta Cohort from April 1997 to April 2006. Costs for all drugs (ART/non-ART), in-patient (HIV/non-HIV) and out-patient care were obtained from primary sources. Costs were aggregated by patient's CD4 cell count and ART exposure and presented as mean cost per patient per month (PPPM) in 2006 Canadian dollars.
The number of patients and annual costs increased by 74% and 69%, respectively. Overall mean PPPM costs increased slightly from $1082 in 1997/1998 to $1159 in 2005/2006. PPPM costs for patients with CD4 counts < or =75 cells/microL increased from $1595 to $2687 while costs for CD4 counts >500, 201-500 and 76-200 cells/microL remained relatively stable at $979, $1057 and $1294, respectively. In-patient hospitalization costs account for most of the cost increases. Reporting costs using only ART-experienced patients would overestimate total costs by 2-9%. Costs for only HIV care were 10-24% lower than total care costs.
Care costs have remained relatively stable for most HIV patients except those with CD4 counts < or =75 cells/microL. Expensive new antiretroviral drugs have had, at present, a minimal cost impact. Enhanced testing to achieve earlier diagnosis and initiation of highly active antiretroviral therapy could potentially reduce costs of late presentation and in-patient care.
Since the inception of highly active antiretroviral therapy (HAART), mortality among HIV-infected patients has decreased, but this has been accompanied by the appearance of several complications.
To estimate the incidence of symptomatic bone disorders in HIV-infected patients of the Aquitaine cohort (from south-west France) for the period 1999-2002, and to describe cases.
We retrospectively studied the records of 2700 patients of the Aquitaine cohort, which was derived from a hospital-based surveillance system of HIV infection in France. All cases of symptomatic bone disorders diagnosed from 1 January 1999 to 30 June 2002 were reviewed.
Fourteen cases of bone disorders were diagnosed, eight cases of aseptic osteonecrosis and six cases of severe osteoporosis, representing incidences of 0.3/1000 patient-years [95% confidence interval (CI): 0.14-0.62] and 0.22/1000 patient-years (95% CI: 0.09-0.52), respectively. All patients with aseptic osteonecrosis were male, while all but one with osteoporosis were female. The ages of patients ranged from 36 to 54 years for osteonecrosis and from 39 to 50 for severe osteoporosis. At the time of clinical diagnosis, all patients were treated with nucleoside reverse transcriptase inhibitors (duration of treatment ranging from 19 to 123 months for osteonecrosis and from 46 to 132 months for severe osteoporosis). Ten patients were treated with nonnucleoside reverse transcriptase inhibitors [duration of treatment ranging from 6 to 31 months for osteonecrosis (n=6) and from 4 to 29 months for severe osteoporosis (n=4)]. Thirteen patients were treated with protease inhibitors [duration of treatment ranging from 12 to 62 months for osteonecrosis (n=8) and from 3 to 44 months for severe osteoporosis (n=5)]. All osteonecrosis and five osteoporosis patients had at least one known risk factor or comorbidity associated with the bone disorder occurrence.
In our study, the aetiology of clinical bone disorders seemed to be multifactorial, as almost all the patients had at least one possible risk factor in addition to HAART exposure.
To describe the effect and tolerance of lipid-lowering drugs (LLD; fibrates and statins) in patients treated with highly active antiretroviral therapy (HAART).
A prospective study was performed in a large cohort of HAART-treated HIV-infected patients using guidelines for case management of dyslipidaemia. Inclusion criteria were: age over 18 years; HIV infection treated with HAART including at least one protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI); total cholesterol (TC)>5.5 mmol/L and/or triglycerides (TG)>2.2 mmol/L; and initiation of fibrates or statins. Viral load, CD4 cell count, plasma lipid levels and liver enzymes were measured at baseline (M0) and 3(M3) and 12(M12) months thereafter. Muscular enzymes were not assessed.
Fibrates were prescribed to 179 patients and statins to 66 patients. There was a significant mean decrease of TG in the fibrates group between M0 and M3 [-2.29 mmol/L; 95% confidence interval (CI)=-3.53, -1.05; P<10(-4)] and between M0 and M12 (-2.25 mmol/L; 95% CI:-4.23, -0.29; P<10(-4)); a significant decrease of TC was also noticed between M0 and M3 (-0.55 mmol/L; 95% CI:-0.95, -0.15; P=0.008) but not at M12 (-0.33 mmol/L; 95% CI:-0.94, 0.26; P=0.27). In the statins group, TC significantly decreased between M0 and M3 (-0.78 mmol/L; 95% CI:-1.3, -0.27; P=0.004) and between M0 and M12 (-0.70 mmol/L; 95% CI:-1.31, -0.09; P=0.03). There was no significant difference between the decreases of TG or TC observed in patients treated with PI or NNRTI. There were no significant modifications of viral load, CD4 cell count or liver enzymes during the 12 months of followup.
In this HAART-treated cohort, fibrates and statins were safe and associated with a favourable but moderate effect on lipid plasma levels.
The aim of the study was to investigate the incidence of AIDS-defining cancers (ADCs) and virus-related and non-virus-related non-AIDS-defining cancers (NADCs) in HIV-infected patients compared with the general population, and to assess the risk factors associated with these malignancies.
We performed a retrospective cohort study for the period from 1999 to 2009 of HIV-infected patients residing in the Local Health Authority of Brescia (northern Italy). Observed cancers in patients with HIV infection were compared with expected cancers in the population living in the same area using standardized incidence ratios (SIRs). Risk factors were assessed using Poisson regression analysis.
A total of 5090 HIV-infected patients were included in the study, with 32 390 person-years of follow-up. We recorded 416 tumours in 390 HIV-infected patients. Two hundred of these (48.1%) were ADCs, 138 (33.2%) were non-virus-related NADCs and 78 (18.7%) were virus-related NADCs. An increased risk (SIR = 4.2) of cancers overall was found in HIV-infected patients. A large excess of ADCs (SIR = 31.0) and virus-related NADCs (SIR = 12.3) was observed in HIV-infected patients, while the excess risk for non-virus-related NADCs was small (SIR = 1.6). The highest SIRs were observed for Kaposi sarcoma among ADCs and for Hodgkin lymphoma among virus-related NADCs. Conversely, among non-virus-related NADCs, SIRs for a broad range of malignancies were close to unity. In multivariate analysis, increasing age and CD4 cell count < 50 cells/μL were the only factors independently associated with all cancers.
Among HIV-infected people there was an excess of ADCs and also of NADCs, particularly those related to viral infections. Ageing and severe immunodeficiency were the strongest predictors.
To ascertain current practices in the diagnosis and management of HIV and pregnancy in the North Thames Region.
Postal survey using a self-completed questionnaire sent to the head of all of the Region's 34 units involved in the care of HIV. The survey asked questions on current policy around HIV and pregnancy in the HIV units and associated antenatal clinics and was linked to a case-note survey of pregnant, HIV-positive women in the last 2 years.
Over 50% of the responding antenatal units recommended the HIV test by March 1999. Most HIV units were offering a range of antiretroviral regimens in pregnancy, although a minority (33%) did not offer triple therapy. Elective Caesarean section was the recommended mode of delivery for most women (90%) irrespective of drug therapy or viral load. Most infants were being tested for HIV infection by a combination of PCR, viral culture and antibody testing to 18 months of age. All the infants (19) followed to 6 months of age in the case-note survey were PCR negative. Reporting rates to the National Survey of HIV in Pregnancy were high (87%) but poor for the Drug Exposure Register (33%).
Management of HIV and pregnancy in the North Thames units showed a large amount of consistency with regard to testing policies and management. However, there were a few units that did not offer therapy appropriate for advanced disease despite the recommendations of national bodies and a few units still did not recommend HIV testing to all women.