Caroline A Sabin

UK Department of Health, Londinium, England, United Kingdom

Are you Caroline A Sabin?

Claim your profile

Publications (507)3831.61 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: With the aging of the population living with HIV, the absolute risk of cardiovascular disease (CVD) is increasing. There is a need to further facilitate the identification of persons at elevated risk in routine practice. Prospective information was collected on 32,663 HIV-positive persons from 20 countries in Europe and Australia, who were free of CVD at entry into the Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Cox regression models (full and reduced) were developed that predict the risk of a global CVD endpoint. The predictive performance of the D:A:D models were compared with a recent CVD prediction model from the Framingham study, which was assessed recalibrated to the D:A:D dataset. A total of 1010 CVD events occurred during 186,364.5 person-years. The full D:A:D CVD prediction model included age, gender, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, high-density lipoprotein, CD4 lymphocyte count, cumulative exposure to protease- and nucleoside reverse transcriptase-inhibitors, and current use of abacavir. A reduced model omitted antiretroviral therapies. The D:A:D models statistically significantly predicted risk more accurately than the recalibrated Framingham model (Harrell's c-statistic of 0.791, 0.783 and 0.766 for the D:A:D full, D:A:D reduced, and Framingham models respectively; p < 0.001). The D:A:D models also more accurately predicted five-year CVD-risk for key prognostic subgroups. An updated, easily recalibrated, global CVD-risk equation tailored to HIV-positive persons was developed using routinely collected CVD risk parameters and incorporating markers on immune function (CD4 lymphocyte count), and exposure to antiretroviral therapies. The estimated CVD risk can be used to quantify risk and to guide preventive care. © The European Society of Cardiology 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    04/2015; DOI:10.1177/2047487315579291
  • [Show abstract] [Hide abstract]
    ABSTRACT: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2015; 68(5):568-577. DOI:10.1097/QAI.0000000000000523 · 4.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is important to have methods available to estimate the number of people who have undiagnosed HIV and are in need of antiretroviral therapy (ART). The method uses the concept that a predictable level of occurrence of AIDS or other HIV-related clinical symptoms which lead to presentation for care, and hence diagnosis of HIV, arises in undiagnosed people with a given CD4 count. The method requires surveillance data on numbers of new HIV diagnoses with HIV-related symptoms, and the CD4 count at diagnosis. The CD4 count-specific rate at which HIV-related symptoms develop are estimated from cohort data. 95% confidence intervals can be constructed using a simple simulation method. For example, if there were 13 HIV diagnoses with HIV-related symptoms made in one year with CD4 count at diagnosis between 150-199 cells/mm3, then since the CD4 count-specific rate of HIV-related symptoms is estimated as 0.216 per person-year, the estimated number of person years lived in people with undiagnosed HIV with CD4 count 150-199 cells/mm3 is 13/0.216 = 60 (95% confidence interval: 29-100), which is considered an estimate of the number of people living with undiagnosed HIV in this CD4 count stratum. The method is straightforward to implement within a short period once a surveillance system of all new HIV diagnoses, collecting data on HIV-related symptoms at diagnosis, is in place and is most suitable for estimating the number of undiagnosed people with CD4 count <200 cells/mm3 due to the low rate of developing HIV-related symptoms at higher CD4 counts. A potential source of bias is under-diagnosis and under-reporting of diagnoses with HIV-related symptoms. Although this method has limitations as with all approaches, it is important for prompting increased efforts to identify undiagnosed people, particularly those with low CD4 count, and for informing levels of unmet need for ART.
    PLoS ONE 03/2015; 10(3):e0121992. DOI:10.1371/journal.pone.0121992 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Syphilis recognition in HIV-positive patients has important implications. Initial data from this study, established in June 2012 to better understand the natural history of syphilis and treatment response, examine the characteristics of patients including sexual behaviour, rates of concurrent sexually transmitted infections (STI) and type of treatment given. Patients were recruited from Ireland, Poland and Germany. Data gathered included demographics, method of syphilis acquisition, stage of syphilis infection, HIV status, nadir and current CD4 counts and HIV viral suppression rates. Data were then subanalysed into HIV-positive and HIV-negative groups. Of 175 patients recruited, 68% were HIV-positive and 86.3% were men who have sex with men. Most HIV-positive patients presented with secondary syphilis (55.7% vs 13.2%) (p=0.0001) while the majority of HIV-negative patients had primary syphilis noted at the time of recruitment (47.2% vs18.9%, p=0.0002). Approximately half of all patients had a HIV RNA viral load <40 copies/mL (55%). Previous syphilis infection occurred more frequently in HIV-positive than HIV-negative patients (p=0.0001). Concurrent STIs at the time of syphilis diagnosis were found in 26.8%, of whom 31 (25.4%) were HIV-positive (p=0.64). HIV-positive patients received doxycycline more frequently than their HIV-negative counterparts (33.6% vs 1.9%, p=0.0001) while HIV-negative patients were treated with long-acting penicillin in 88.7% of cases vs 58% of HIV-positive patients (p=0.0002). A 40% rate of unsuppressed viraemia, high levels of STIs and varying treatment regimens represent a public health risk for Europe, suggesting the model of sexual healthcare delivery in HIV-positive patients requires further evaluation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Sexually Transmitted Infections 03/2015; DOI:10.1136/sextrans-2014-051844 · 3.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.
    PLoS Medicine 03/2015; 12(3):e1001809. DOI:10.1371/journal.pmed.1001809 · 14.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study is to assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART). Two observational studies: the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC). Combined data from UK CHIC and NSHPC were used to identify factors associated with LEE (grade 1-4) and severe LEE (grade 3-4). Women starting ART in 2000-2012 were included irrespective of pregnancy status. Cox proportional hazards were used to assess fixed and time-dependent covariates including pregnancy status, CD4 cell count, drug regimen and hepatitis B virus/hepatitis C virus (HBV/HCV) coinfection. One-quarter (25.7%, 982/3815) of women were pregnant during follow-up, 14.2% (n = 541) when starting ART. The rate of LEE was 14.5/100 person-years in and 6.0/100 person-years outside of pregnancy. The rate of severe LEE was 3.9/100 person-years in and 0.6/100 person-years outside of pregnancy. The risk of LEE and severe LEE was increased during pregnancy [LEE: aHR 1.66 (1.31-2.09); severe LEE: aHR 3.57 (2.30-5.54)], including in secondary analyses excluding 541 women pregnant when starting ART. Other factors associated with LEE and severe LEE included lower CD4 cell count (<250 cells/μl), HBV/HCV coinfection and calendar year. Although few women developed severe LEE, this study provides further evidence that pregnancy is associated with an increased risk of LEE and severe LEE, reinforcing the need for regular monitoring of liver biomarkers during pregnancy.This is an open access article distributed under the Creative Commons Attribution-Non Commercial License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. http://creativecommons.org/licenses/by-nc/4.0.
    AIDS (London, England) 02/2015; 29(7). DOI:10.1097/QAD.0000000000000620 · 6.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: The prevalence of overweight and obesity is increasing among HIV-infected patients. Whether standard antiretroviral drug dosage is adequate in heavy individuals remains unresolved. We assessed the virological and immunological responses to initial efavirenz (EFV)-containing regimens in heavy compared to normal-weight HIV-infected patients. DESIGN: Observational European cohort collaboration study. METHODS: Eligible patients were antiretroviral-naïve with documented weight prior to EFV start and follow-up viral loads after treatment initiation. Cox regression analyses evaluated the association between weight and time to first undetectable viral load (<50 copies/ml) after treatment initiation, and time to viral load rebound (two consecutive viral load >50 copies/ml) after initial suppression over 5 years of follow-up. Recovery of CD4 cell count was evaluated 6 and 12 months after EFV initiation. Analyses were stratified by weight (kg) group (I - <55; II - >55, <80 (reference); III - >80, <85; IV - >85, <90; V - >90, <95; VI - >95). RESULTS: The study included 19 968 patients, of whom 9.1, 68.3, 9.1, 5.8, 3.5, and 4.3% were in weight groups I-VI, respectively. Overall, 81.1% patients attained virological suppression, of whom 34.1% subsequently experienced viral load rebound. After multiple adjustments, no statistical difference was observed in time to undetectable viral load and virological rebound for heavier individuals compared to their normal-weight counterparts. Although heaviest individuals had significantly higher CD4 cell count at baseline, CD4 cell recovery at 6 and 12 months after EFV initiation was comparable to normal-weight individuals. CONCLUSION: Virological and immunological responses to initial EFV-containing regimens were not impaired in heavy individuals, suggesting that the standard 600 mg EFV dosage is appropriate across a wide weight range.
    AIDS 11/2014; 29(2). DOI:10.1097/QAD.0000000000000530 · 6.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Combination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D-deficient patients. Materials and Methods In a single-centre longitudinal study investigating BMD in HIV-positive men, serum 25(OH)D, calcium, phosphate, PTH and alkaline phosphatase (ALP) were measured. Lumbar spine, non-dominant total hip and non-dominant femoral neck BMD (g/cm2) were measured using dual-energy X-ray absorptiometry. BT was assessed by serum type 1 procollagen (P1NP) and carboxy-terminal collagen cross-links (CTX). Mann–Whitney U tests compared serum markers and BT, and t-tests compared BMD according to TDF in all and 25(OH)D-deficient patients. Results A total of 422 men were recruited: mean age 47 (SD 9.8) years, 94% white ethnicity, 93% MSM, diagnosed HIV positive for median 9.6 (IQR 5.0,15.5) years, median CD4 547 (IQR 411,696) cells/µL, HIV RNA <40 copies/mL in 87% (96% of those on cART). 25(OH)D (nmol/L) was normal (>75), insufficient (50–75), deficient (25–50) and severely deficient (<25) in 14%, 29%, 50% and 7%, respectively. Of 381 men on cART, 77% were currently on TDF. TDF was not associated with median calcium (p=0.69) or phosphate (p=0.52), but patients had higher (but normal) median ALP [81 (IQR 69,103) vs. 73 (IQR 60,89) IU/L, p=0.005) compared to non-TDF cART. There was no difference in the association between vitamin D and PTH according to whether someone currently was (r=0.11, p=0.06, Figure 1) or was not using TDF (r=0.12, p=0.29, Figure 1). TDF was also not associated with PTH, BMD or BT in either all patients on cART (Table 1a) or in patients with 25(OH)D deficiency (Table 1b). Conclusions In this largely TDF-experienced cohort of HIV-positive men, there was no association between TDF and 25(OH)D deficiency, hyperparathyroidism, reduced BMD or increased BT, although patients on TDF had higher but normal ALP. We found no evidence to support additional monitoring of bone markers in patients on TDF regardless of 25(OH)D status.
    Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19568. DOI:10.7448/IAS.17.4.19568 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results. Material and Methods Combined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1–4). Women starting ART in 2000–11 aged 16–49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE. Results Of the 3426 women included, one-quarter (25.0%, n=857) were pregnant during follow-up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person-years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26–2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm3 vs. 251–350 cells/mm3 aHR 1.25 [1.02–1.54], p=0.03), HBV/HCV co-infection (aHR 1.94 [1.58–2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15–2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02–1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06–1.50], p-value 0.008; maraviroc 4.19 [1.34–13.1], p=0.01; and nevirapine 1.59 [1.30–1.95], p-value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63–0.87], p<0.001) as was increasing time on an NNRTI-based regimen (aHR 0.91 [0.86–0.96], p<0.001 per additional year). Conclusions Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.
    Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19486. DOI:10.7448/IAS.17.4.19486 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV-positive individuals. We investigated whether such differences exist in the D:A:D study. Materials and Methods Follow-up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10-year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors. Results At enrolment, women (n=13,039; median (interquartile range) 34 (29–40) years) were younger than men (n=36,664, 39 (33–46) years, p=0.001), and were less likely to be current smokers (29% vs. 39%, p=0.0001), to have diabetes (2% vs. 3%, p=0.0001) or to have hypertension (7% vs. 11%, p=0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person-years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti-hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high-risk group, initiation rates of most interventions (with the exception of anti-hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1). Conclusion Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions.
    Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19516. DOI:10.7448/IAS.17.4.19516 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Most people achieve and maintain viral load (VL) suppression on first-line antiretroviral therapy (ART) but for a minority this does not happen. It is unclear whether those who have maintained VL suppression for several years will be able to continue to do so, or if rates of VL failure – due to poor adherence, ART interruption and/or resistance – remain at appreciable levels. Methods Eligible participants were ART-naïve and started treatment after 1st January 2000, with ≥3 antiretrovirals and ≥9 months follow-up. VL failure was defined as failure to achieve VL suppression (≤50 copies/mL) by 9 months on ART or a single VL >200 copies/mL after 9 months after start of ART. Kaplan-Meier estimates were used to examine the cumulative probability of experiencing a VL >200 copies/mL over time, irrespective of treatment interruption (Figure 1). Follow-up was censored at last VL assessment but not at treatment interruption. In a sensitivity analysis, VL failure was instead defined as two consecutive VL >1000 copies/mL. Results A total of 13,556 participants were included. Median (IQR) age at start of ART was 37 (32–43), median follow-up 4.1 (2.3–6.7) years, pre-ART VL 71,400 (17,400–221,900) copies/mL and pre-ART CD4 count 204 (110–290) cells/mm3. Fifty-one percent were white, 71% male and 50% MSM. Of which, 5,351 (39%) participants experienced a VL >200 copies/mL. In sub-groups of participants the proportion experiencing a VL >200 copies/mL by one year after start of ART were: <50 years 22%, ≥50 years 17%, men 20%, women 26%, MSM 19%, black heterosexuals 23%, white heterosexuals 26% and other 23%. The median time to VL >200 copies/ml was 8 years. In sensitivity analyses based on 12,811 participants, 4274 (33%) experienced two consecutive VL >1000 copies/mL. Table 1 presents the rate of experiencing a VL >200 copies/mL (two consecutive VL >1000 copies/mL) by time since start of ART. The rate of VL >200 copies/mL declines over time, from 30 per 100 person-years after up to two years after ART, to two per 100 person-years after up to 11.5 years after ART. A sum of 2,047 (15%) participants stopped ART at some point (10, 14 and 17% had stopped ART by 1, 3, and 5 years, respectively). Conclusions Although resistance will often not be present and, even if present, several drug options will likely remain, first occurrence of VL > 200 copies/mL after having attained viral suppression continues to occur after 10 years on ART.
    Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19527. DOI:10.7448/IAS.17.4.19527 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Several resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance mutations on CD4 slopes in patients undergoing episodes of viral failure. Materials and Methods Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test during the episode were included. Mutations were identified using the IAS-US (2013) list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log-scale), risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope. Results A total of 2731 patients experiencing a median of 1 (range 1–4) episodes were included in this analysis. The prevalence of any resistance per episode was 88.4%; NNRTI resistance was most common (78.5%). Overall, CD4 counts declined by 17.1 (−19.7; −14.5) cells per year; this decline was less marked with partial viral suppression (current HIV RNA more than 1.5 log below the setpoint; p=0.01). In multivariable models adjusting for viral load, CD4 decline was slower during episodes with detected resistance compared to episodes without detected resistance (21.0 cells/year less, 95% CI 11.75–30.31, p<0.001). Among those with more than one resistance mutation, there was only weak evidence that class-specific mutations had any effect on the CD4 slope (Table 1). The effects of individual mutations (incl. M184V) were explored, but none were significantly associated with the CD4 slope; for these comparisons, a Bonferroni-corrected p-value level was 0.003. Conclusions In our study population, detected resistance was associated with slightly less steep CD4 declines. This may be due to a biological effect of resistance on CD4 slopes, or other unmeasured factors such as poor adherence among individuals without resistance. Among individuals with detected drug resistance, we found no evidence suggesting that the presence of individual mutations was associated with beneficial CD4 slope changes.
    Journal of the International AIDS Society 11/2014; 17(4(Suppl 3)):19737. DOI:10.7448/IAS.17.4.19737 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction A recent meta-analysis of 4 RCTs showed an increased rate of suicidality events (suicidal ideation or attempted/completed suicide) associated with efavirenz (EFV) compared to other regimens, but only a trend towards a higher rate of completed/attempted suicides, as only 17 events occurred. We investigated the association between EFV use and completed suicide. Materials and Methods All D:A:D participants were followed from study entry to the first of death, last study visit or 1 February 2013. Deaths are centrally validated using cause of death methodology, which assigns underlying, immediate and up to four contributing causes of death. Two endpoints were considered: 1) suicide or psychiatric disease as the underlying cause, and 2) suicide or psychiatric disease mentioned as an underlying, immediate or contributing cause of death (anywhere). Adjusted rate ratios were calculated using Poisson regression. Results A total of 4420 deaths occurred in 49,717 people over 371,333 person-years (PY) (rate 11.9 per 1000 PY; 95% CI 11.6–12.3). A total of 193 deaths (rate 0.52; 0.45–0.59) had an underlying cause of suicide or psychiatric disease, and 482 deaths (1.30; 1.18–1.41) had suicide or psychiatric disease mentioned anywhere. A strong association with current CD4 count was seen: for suicide or psychiatric disease mentioned anywhere, rates were: 3.18 (2.55–3.80) for <200 cells/uL, 1.60 (1.29–1.90) for 201–350 cells/uL, 1.07 (0.86–1.29) for 351–500 cells/uL, 0.95 (0.80–1.09) for >500 cells/uL and 1.30 (1.18–1.41) for unknown. Highest rate of suicide or psychiatric deaths were seen in ART-experienced people currently off ART, but no differences were seen according to current ART regimen, which remained after adjustment (Table 1). Consistent results were obtained when considering additional endpoints of suicide alone as the underlying cause and death from suicide or any possibly related cause (psychiatric disease, drug overdose, alcohol related, accidental or violent), as well as considering recent EFV use in the previous 3 and 6 months. Conclusions The finding of no higher death rates from suicide amongst those receiving EFV is reassuring. However, there is likely confounding by indication in our observational study. In light of conflicting results from RCTs, this potentially could suggest that in clinical practice EFV may be less frequently prescribed in those with underlying psychiatric conditions.
    Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19512. DOI:10.7448/IAS.17.4.19512 · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: To evaluate the prevalence, impact and risk factors for pain among a cohort of HIV-infected adults treated with combination anti-retroviral therapy (cART) if indicated according to current guidelines. Methods: This was a cross-sectional epidemiological observational study. All patients attending one HIV-outpatient centre in the UK in a 10-month period were eligible. Patients completed a validated questionnaire enquiring about demographics, HIV factors and symptoms of pain. Results: Of 1050 eligible participants, 859 (82%) completed a questionnaire. The 1-month period prevalence of pain lasting >1 day was 62.8% amongst whom 63% reported current pain. The prevalence of pain at most anatomical sites was broadly similar to that observed in population studies using the same questionnaires except that we found considerably higher rates of foot/ankle pain. The median duration of pain was 3 years (range 0-51 y) and the median pain score was 5.0 on an 11-point visual analogue score. Over 40% of people in pain had consulted their primary care physician and >20% were taking analgesics daily. Independent risk factors for current pain were older age (P=0.001), time since diagnosis of HIV infection (P=0.001) and receipt of a protease inhibitor-based regimen (P=0.04). Discussion: Pain, and notably foot/ankle pain, is common among adults living with prevalent HIV and is associated with substantial morbidity and healthcare utilisation. Copyright
    Clinical Journal of Pain 10/2014; DOI:10.1097/AJP.0000000000000162 · 2.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Some individuals remain AIDS-free with a high and stable CD4 cell count without antiretroviral therapy (ART) for many years. We estimated long-term progression-free survival after HIV seroconversion and aimed to identify factors associated with loss of long-term non-progression (LTNP) status. Methods For this cohort study, we used data for individuals with well-estimated dates of HIV-1 seroconversion from the CASCADE Collaboration a network of 28 HIV seroconverter cohort studies in Europe, Australia, Canada, and sub-Saharan Africa. The fi rst cohort began enrolling patients in 1979, and for this analysis we used data pooled in May 1, 2011. We defi ned non-progression as being HIV-positive without AIDS, ART-naive, and with CD4 counts of 500 cells per μL or higher. We defi ned LTNP as non-progression during the fi rst 10 years after seroconversion. We used longitudinal methods to characterise LTNP. Findings Of the 4979 HIV seroconverters in our dataset, 3708 (75%) were men. Median time to progression was 2·07 years (95% CI 1·96–2·17), giving estimated progression-free survivals of 18·4% (17·2–19·6) 5 years, 4·0% (3·6–4·5) 10 years, and 1·4% (0·9–1·5) 15 years after seroconversion. The rate of progression did not change beyond 10 years after seroconversion (0·28 [95%CI 0·26–0·31] per person-year at 10 years after seroconversion, 0·24 [0·19–0·29] per person-year at 15 years, and 0·18 [0·10–0·33] per person-year at 20 years). At 10 years since HIV seroconversion, 283 individuals had LTNP, of whom 202 subsequently lost this status (median time to loss of status 2·49 years [2·05–2·92]). In univariable analyses, loss of LTNP status was associated with CD4 cell count at 10 years after seroconversion (p<0·0001) and HIV RNA load at 10 years after seroconversion (p=0·005), but not age (p=0·544), mode of infection (p=0·621), sex (p=0·676), or calendar year of seroconversion (p=0·397). In the multivariable analyses, loss of LTNP status was associated with lower CD4 counts at 10 years after seroconversion (p<0·0001). After exclusion of CD4 cell counts from the model, higher HIV RNA load at 10 years after seroconversion was independently associated with loss of LTNP status (p=0·009). Interpretation Progression-free survival is rare. Most individuals with LTNP eventually lose immunological and clinical control of HIV infection eventually. Funding European Union Seventh Framework Programme.
    The Lancet HIV 10/2014; 1(1):e41-e48.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ethnic differences have the potential to confound associations between HIV-1 subtype and immunologic progression. We compared declines in CD4 cell counts during untreated infection for the most prevalent HIV-1 subtypes, focusing on distinguishing between the effects of viral subtype and ethnicity. We combined data from 4 European and 6 Canadian cohorts, selecting adults in the stable chronic phase of untreated HIV infection. We estimated the change in square root CD4 cell count over time for subtypes and ethnicities using mixed models, adjusting for covariates selected for their potential effect on initial CD4 cell count or its decline. Data from 9772 patients were analyzed, contributing 79 175 measurements of CD4 cell count and 24 157 person-years of follow-up. Overall, there were no appreciable differences in CD4 cell count decline for viral subtypes A, CRF01_AE, CRF02_AG, C and G compared with viral subtype B; whereas the decline in CD4 cell count in patients of African ancestry was considerably slower than in patients of other ethnicity. When ethnic groups were studied separately, there was evidence for slower declines in CD4 cell count in viral subtypes C, and possibly A and G, compared with viral subtype B in patients of African ancestry but not among patients of other ethnicities, suggesting an interaction between subtype and ethnicity. Ethnicity is a major determinant of CD4 cell count decline; viral subtype differences may have existed but were small compared with the effect of ethnicity and were most apparent in patients of African ancestry. In developing countries, slower CD4 cell count declines among individuals of African descent may translate to a longer asymptomatic phase and increase the opportunity for HIV transmission.
    10/2014; 2(4):E318-E329. DOI:10.9778/cmajo.20140017
  • [Show abstract] [Hide abstract]
    ABSTRACT: Low bone mineral density (BMD) is common in HIV-positive patients, although the role played by HIV infection versus sociodemographic and metabolic factors remains unclear.
    AIDS (London, England) 09/2014; 28(14):2051-60. DOI:10.1097/QAD.0000000000000353 · 6.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: End-stage kidney disease (ESKD) is a major complication of HIV infection. We observed a 3.8 fold increase in ESKD prevalence among black patients in the UK CHIC cohort during the 12 year study period. As of 2005, 107 patients had an ESKD diagnosis, 69 (64%) of whom were considered suitable for kidney transplantation (KT) and 34 (32%) had received a KT. Survival was similar for KT recipients and those awaiting KT (85% and 89% at five years respectively, p=0.53). Our results endorse the use of KT to manage ESKD in HIV positive patients.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Methods Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. Findings 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Interpretation Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Funding Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.
    The Lancet 07/2014; 384(9939):241–248. DOI:10.1016/S0140-6736(14)60604-8 · 39.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown.METHODS: HIV-infected, antiretroviral therapy-naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8-9), or high (>9) CPE score. We estimated "intention-to-treat" hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up.RESULTS: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58).CONCLUSIONS: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.
    Neurology 06/2014; 83(2). DOI:10.1212/WNL.0000000000000564 · 8.30 Impact Factor

Publication Stats

18k Citations
3,831.61 Total Impact Points

Institutions

  • 2014–2015
    • UK Department of Health
      Londinium, England, United Kingdom
  • 1998–2015
    • University College London
      • • Department of Infection and Population Health
      • • Department of Primary Care and Population Health (PCPH)
      Londinium, England, United Kingdom
    • Royal Free Academy of PMC
      Londinium, England, United Kingdom
  • 2003–2013
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2012
    • King's College London
      Londinium, England, United Kingdom
  • 2010–2012
    • British HIV Association
      Londinium, England, United Kingdom
  • 1994–2012
    • Royal Free London NHS Foundation Trust
      • Department of Haematology
      Londinium, England, United Kingdom
    • University of London
      Londinium, England, United Kingdom
  • 1998–2011
    • University of Bristol
      • School of Social and Community Medicine
      Bristol, ENG, United Kingdom
  • 2005–2009
    • Université Victor Segalen Bordeaux 2
      Burdeos, Aquitaine, France
    • Federal University of Minas Gerais
      Cidade de Minas, Minas Gerais, Brazil
    • University of Milan
      Milano, Lombardy, Italy
    • International Society for Disease Surveillance
      Brighton, England, United Kingdom
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2008
    • Medical Research Council (UK)
      • MRC Clinical Trials Unit
      Londinium, England, United Kingdom
    • Azienda Ospedaliera San Paolo - Polo Universitario
      Milano, Lombardy, Italy
  • 2007
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • Brighton and Sussex University Hospitals NHS Trust
      Brighton, England, United Kingdom
  • 1993–2007
    • The Haemophilia Society
      Londinium, England, United Kingdom
  • 2006
    • ICL
      Londinium, England, United Kingdom
    • The University of Calgary
      • Department of Microbiology, Immunology and Infectious Diseases
      Calgary, Alberta, Canada
    • Public Health England
      Londinium, England, United Kingdom
  • 2004–2006
    • Mrc Harwell
      Oxford, England, United Kingdom
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2001–2005
    • Chelsea and Westminster Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
    • Brunel University
      • Health Economics Research Group
      London, ENG, United Kingdom
  • 2003–2004
    • Copenhagen University Hospital Hvidovre
      Hvidovre, Capital Region, Denmark
  • 1999–2003
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • Hospital Frankfurt Hoechst
      Frankfurt, Hesse, Germany
  • 2002
    • University of Reading
      Reading, England, United Kingdom
  • 2000
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 1997
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 1995
    • University of Nottingham
      Nottigham, England, United Kingdom
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom