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Objective: To quantify mitochondrial function in skeletal muscle of people treated with contemporary antiretroviral therapy., Design: Cross-sectional observational study., Methods: Quantitative multiplex immunofluorescence was performed to determine mitochondrial mass and respiratory chain complex abundance in individual myofibres from tibialis anterior biopsies. Individual myofibres were captured by laser microdissection and mitochondrial DNA (mtDNA) content and large-scale deletions were measured by real-time PCR., Results: Forty-five antiretroviral therapy (ART)-treated people with HIV (PWH, mean age 58 years, mean duration of ART 125 months) were compared with 15 HIV negative age-matched controls. Mitochondrial complex I (CI) deficiency was observed at higher proportional levels in PWH than negative controls ( P = 0.008). Myofibre mitochondrial mass did not differ by HIV status. No ART class was significantly associated with mitochondrial deficiency, including prior exposure to historical NRTIs (nucleoside analogue reverse transcriptase inhibitors) associated with systemic mitochondrial toxicity. To exclude an effect of untreated HIV, we also studied skeletal muscle from 13 ART-naive PWH (mean age 37). These showed negligible CI defects, as well as comparable myofibre mitochondrial mass to ART-treated PWH. Most CI-deficient myofibres contained mtDNA deletions. No mtDNA depletion was detected., Conclusion: Here, we show that PWH treated with contemporary ART have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this was not mediated by prior exposure to mitochondrially toxic NRTIs, suggesting novel mechanisms of mitochondrial dysfunction in contemporary ART-treated PWH. These findings are relevant for better understanding successful ageing in PWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The increasing availability of antiretroviral therapy (ART) worldwide is yet to result in decreasing HIV-related mortality among adolescents (10-19 years old) living with HIV (ALHIV) in part because of poor adherence. the poor adherence might itself be due to high level of depression. We assess the prevalence of depressive symptomatology and it's associated with adherence among ALHIV receiving ART care in Brazzaville and Pointe Noire, Republic of Congo (RoC).Adolescents aged 10 to 19 years, on antiretroviral therapy (ART), followed in the two Ambulatory Treatment Centers (ATC) in Brazzaville and Pointe Noire, RoC were included in this cross-sectional study. From April 19 to July 9, 2018, participants were administered face to face interviews using a standardized questionnaire that included the nine-item Patient Health Questionnaire (PHQ-9). Participants who reported failing to take their ART more than twice in the 7 days preceding the interview were classified as non-adherent. Bivariate and multivariable log-binomial models were used to estimate the prevalence ratio (PR) and 95% confidence interval (95%CI) assessing the strength of association between predictors and presence of depressive symptoms (PHQ-9 score ≥9).Overall, 135 adolescents represented 50% of ALHIV in active care at the 2 clinics were interviewed. Of those, 67 (50%) were male, 81 (60%) were 15 to 19 years old, 124 (95%) had been perinatally infected, and 71 (53%) knew their HIV status. Depressive symptoms were present in 52 (39%) participants and 78 (58%) were adherent. In univariate analyses, the prevalence of depressive symptoms was relative higher among participants who were not adherent compared to those who were (73% vs 33%; PR: 2.20 [95%CI: 1.42-3.41]). In multivariate analysis, after adjustment for report of been sexually active, alcohol drinking, age category (10-14 and 15-19), not in school, loss of both parents, the association between depression and adherence was strengthened (PR: 2.06 [95%CI: 1.23-3.45]).The prevalence of depressive symptoms in adolescents living with HIV is high and was strongly associated with poor adherence even after adjustment of potential confounders. Efforts to scale-up access to screening and management of depression among ALHIV in sub-Saharan is needed for them to realize the full of ART.

: Associations between markers of liver and renal dysfunction and nucleotide reverse transcriptase inhibitor plasma exposure are ill-defined. As part of a large cohort study (Pharmacokinetic and Clinical Observations in People over Fifty), we analysed associations between alanine aminotransferase and estimated glomerular filtration rate results in people living with HIV on tenofovir disoproxil fumarate, emtricitabine, abacavir and lamivudine. While we found no associations between nucleotide reverse transcriptase inhibitor concentrations and alanine aminotransferase, lower estimated glomerular filtration rate values were associated with greater tenofovir, emtricitabine and lamivudine exposure, whereas abacavir showed no associations.

Objectives: Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited., Design: Prospective cohort study., Methods: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 ml/min per 1.73 m or 25% eGFR decrease when eGFR ≤ 60 ml/min per 1.73 m) were followed to incident serious clinical events (SCE); end stage renal and liver disease (ESRL and ESLD), cardiovascular disease (CVD), AIDS-defining and non-AIDS-defining malignancies (NADM), other AIDS or death, 6 months after last visit or 1 February 2016. Poisson regression models considered associations between SCE and modifiable risk factors., Results: During 2.7 (IQR 1.1-5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE [incidence rate 68.9/1000 PYFU (95% confidence interval 63.4-74.4)] with 8.3% (6.9-9.0) estimated to experience any SCE at 1 year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD [65.9 (43.8-100.9)] and death [4.8 (4.3-5.3)]. Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, whereas dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR less than 30 ml/min per 1.73 m predicted CVD and death and low BMI predicted other AIDS and death., Conclusion: In an era where many HIV-positive persons require less monitoring because of efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

Objective: HIV cohorts are an important source of clinical data for informing public health policies and programmes. However, the generalizability of cohort findings to the wider population of people diagnosed with HIV in each country remains unclear. In this work, we assessed the representativeness of six large national HIV cohorts within Europe., Design and Methods: Individual-level cohort data were provided from national cohorts in France, Germany, Greece, Italy, Spain and the United Kingdom. Analysis focused on new HIV diagnoses reported to The European Surveillance System (TESSy) during three time periods (2000-2004, 2005-2009 and 2010-2013), to allow for temporal changes. Cohort and TESSy records were matched and compared by age, sex, transmission mode, region of origin and CD4+ cell count at diagnosis. The probability of being included in each cohort given demographic characteristics was estimated and used to generate weights inversely proportional to the probability of being included., Results: Participating cohorts were generally representative of the national HIV-diagnosed population submitted to TESSy. However, people who inject drugs, those born in a country other than that reporting the data, those with low CD4 cell counts at diagnosis, and those more than 55 years were generally underrepresented in the cohorts examined., Conclusion: These European cohorts capture a representative sample of the HIV-diagnosed populations in each country; however some groups may be underrepresented.

Objective: We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/μl and initiation with CD4 cell count less than 350 cells/μl., Design: Cohort study based on routinely collected data from the HIV-CAUSAL collaboration., Methods: For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics., Results: In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/μl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/μl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/μl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2)., Conclusion: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Objectives: To compare rates of all-cause, liver-related, and AIDS-related mortality among individuals who are HIV-monoinfected with those coinfected with HIV and hepatitis B (HBV) and/or hepatitis C (HCV) viruses., Design: An ongoing observational cohort study collating routinely collected clinical data on HIV-positive individuals attending for care at HIV treatment centres throughout the United Kingdom., Methods: Individuals were included if they had been seen for care from 2004 onwards and had tested for HBV and HCV. Crude mortality rates (all cause, liver related, and AIDS related) were calculated among HIV-monoinfected individuals and those coinfected with HIV, HBV, and/or HCV. Poisson regression was used to adjust for confounding factors, identify independent predictors of mortality, and estimate the impact of hepatitis coinfection on mortality in this cohort., Results: Among 25 486 HIV-positive individuals, with a median follow-up 4.5 years, HBV coinfection was significantly associated with increased all-cause and liver-related mortality in multivariable analyses: adjusted rate ratios (ARR) [95% confidence intervals (95% CI)] were 1.60 (1.28-2.00) and 10.42 (5.78-18.80), respectively. HCV coinfection was significantly associated with increased all-cause (ARR 1.43, 95% CI 1.15-1.76) and liver-related mortality (ARR 6.20, 95% CI 3.31-11.60). Neither HBV nor HCV coinfection were associated with increased AIDS-related mortality: ARRs (95% CI) 1.07 (0.63-1.83) and 0.40 (0.20-0.81), respectively., Conclusion: The increased rate of all-cause and liver-related mortality among hepatitis-coinfected individuals in this HIV-positive cohort highlights the need for primary prevention and access to effective hepatitis treatment for HIV-positive individuals.

Objectives: The objectives of this analysis were to investigate predictors of progression, stabilization or improvement in estimated glomerular filtration rate (eGFR) after development of chronic renal impairment (CRI) in HIV-positive individuals., Design: Prospective observational study., Methods: The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study participants progressing to CRI defined as confirmed, at least 3 months apart, and eGFR 70 ml/min per 1.73 m or less were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared with the median eGFR defining CRI, and changes were grouped into improvement (>+10 ml/min per 1.73 m), stabilization (-10 to +10 ml/min per 1.73 m) and progression (<-10 ml/min per 1.73 m). Adjusted polynomial regression models assessed odds of better eGFR outcomes after CRI, assuming that eGFR improvement is better than stabilization which in turn is better than progression., Results: Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilized and 12% progressed. Individuals remaining on tenofovir (TDF) or atazanavir boosted with ritonavir (ATV/r) 24 months post-CRI had worse eGFR outcomes compared with those unexposed [TDF: 0.47 (0.35-0.63) and ATV/r: 0.63 (0.48-0.82)]. Individuals off TDF for 12-24 months [0.75 (0.50-1.13)] or off ATV/r for more than 12 months [1.17 (0.87-1.57)] had similar eGFR outcomes as those unexposed to these antiretrovirals. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes., Conclusion: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer term eGFR outcomes as in those unexposed, suggesting that these drug-associated eGFR declines may be halted or reversed after their cessation.

Objective: To compare regimens consisting of either ritonavir-boosted atazanavir or efavirenz and a nucleoside reverse transcriptase inhibitor (NRTI) backbone with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States included in the HIV-CAUSAL Collaboration., Methods: HIV-positive, antiretroviral therapy-naive, and acquired immune deficiency syndrome (AIDS)-free individuals were followed from the time they started an atazanavir or efavirenz regimen. We estimated an analog of the "intention-to-treat" effect for efavirenz versus atazanavir regimens on clinical, immunologic, and virologic outcomes with adjustment via inverse probability weighting for time-varying covariates., Results: A total of 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths) and 18,786 individuals started an efavirenz regimen (389 deaths, 825 AIDS-defining illnesses or deaths). During a median follow-up of 31 months, the hazard ratios (95% confidence intervals) were 0.98 (0.77, 1.24) for death and 1.09 (0.91, 1.30) for AIDS-defining illness or death comparing efavirenz with atazanavir regimens. The 5-year survival difference was 0.1% (95% confidence interval: -0.7%, 0.8%) and the AIDS-free survival difference was -0.3% (-1.2%, 0.6%). After 12 months, the mean change in CD4 cell count was 20.8 (95% confidence interval: 13.9, 27.8) cells/mm lower and the risk of virologic failure was 20% (14%, 26%) lower in the efavirenz regimens., Conclusion: Our estimates are consistent with a smaller 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with atazanavir regimens. No overall differences could be detected with respect to 5-year survival or AIDS-free survival.

Objectives: Although several antiretroviral drugs, including the d-drugs stavudine (d4T) and didanosine (ddI), may cause biomarker-defined hepatotoxicity, their association with clinically defined end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) remains unknown., Design: Prospective cohort study., Methods: Data collection on adverse events of anti-HIV drugs study (D:A:D) participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or α-fetoprotein along with imaging), death, 6 months after last visit or 1 February 2014. Associations between ESLD/HCC and cumulative use of individual antiretrovirals were investigated using Poisson regression adjusting for potential confounders., Results: During a median follow-up of 8.4 years, 319 ESLD/HCC cases occurred [incidence 1.01/1000 person-years (95% confidence interval 0.90-1.12)] with a 1-year mortality rate of 62.6%. After adjustment, cumulative (per 5 years) exposure to d4T [relative rate 1.46 (95% confidence interval 1.20-1.77)], ddI [1.32 (1.07-1.63)], tenofovir [TDF, 1.46 (1.11-1.93)] and (fos)amprenavir [APV; 1.47 (1.01-2.15)] was associated with increased ESLD/HCC rates. Longer exposure to emtricitabine [0.51 (0.32-0.83)] and nevirapine [0.76 (0.58-0.98)] were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation., Conclusion: Cumulative use of d4T, ddI, TDF and APV were independently associated with increased ESLD/HCC rates, and intensified monitoring of liver function should hence be considered among all individuals exposed for longer time periods. The use of d-drugs should furthermore be avoided, where there are alternatives available, and focus should be put on those with longer-term d-drugs exposure who remain at increased ESLD/HCC risk. The unexpected, and viral hepatitis-independent, TDF association calls for further investigations.

Objective: Few studies have described mortality and clinical outcomes after myocardial infarction (MI) in the HIV-positive population. This study evaluated changes in short-term mortality after MI in HIV-positive individuals in the D:A:D Study, and investigated possible reasons for any changes seen., Design: Prospective cohort study., Methods: Demographic, cardiovascular disease (CVD)/HIV-related characteristics and CVD-related interventions (invasive cardiovascular procedures and drug interventions) were summarized at the time of and following an MI. Associations between calendar year and mortality in the first month after MI were identified using logistic regression with adjustment for confounders, including interventions received in the first month after MI., Results: One thousand and eight HIV-positive individuals experiencing an MI over the period 1999-2014 were included. The absolute number of MIs decreased from 214 (1999-2002) to 154 (2011-2014). Whilst the CVD risk profile remained high over time, the HIV status improved. The use of CVD-related interventions after MI appeared to increase over time. The proportion of individuals who died in the first month after MI dropped from 26.6% in 1999-2002 to 8.4% in 2011-2014. Later calendar year was associated with decreased short-term mortality; this effect was attenuated after adjusting for CVD-related interventions received in the first month after MI [odds ratio changed from 0.88 (95% confidence interval 0.83, 0.93) to 0.97 (0.91, 1.02)]., Conclusion: Improvements in short-term survival after MI appear to be largely driven by improved medical management of CVD risk in HIV-positive individuals after MI. Efforts are still needed to treat CVD risk factors and increase access to CVD-related interventions.

Objective: The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART)., Methods: Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50 copies/ml or less at delivery in 2006-2011, who started life-long cART during pregnancy (n = 321) or conceived on cART (n = 618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200 copies/ml) was assessed by Kaplan-Meier analysis; adjusted hazard ratios (aHRs) for the 0-3 and 3-12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models., Results: In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0-7.7] experienced viral rebound by 3 months, and 2.2% (1.4-3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58-4.39)] but not during the 3-12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22-32%) experienced viral rebound by 3 months, and 3.0% (1.6-4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [<3 months: aHR 6.63 (3.58-12.29); 3-12 months: aHR 4.05 (2.03-8.09)]., Conclusion: In women on suppressive cART, the risk of viral rebound is increased following delivery, especially in the first 3 months, which may be related to reduced adherence, indicating the need for additional adherence support for postpartum women.

Objectives: To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART)., Design: Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012., Methods: We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall-Wallis, analysis of variance and Fisher's exact tests were used to evaluate between-group differences., Results: Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42-55%; P = 0.006), more likely to be on ART (100 vs. 55-68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54-58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA., Conclusion: RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.

Objectives: To evaluate the prevalence, impact, and risk factors for pain among a cohort of human immunodeficiency virus (HIV)-infected adults treated with combination antiretroviral therapy if indicated according to current guidelines., Methods: This was a cross-sectional epidemiological observational study. All patients attending 1 HIV-outpatient center in the United Kingdom 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% among whom 63% reported current pain. The prevalence of pain at most anatomic 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 to 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 health care utilization.

Objective: 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)., Design: 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)., Methods: 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., Results: 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: adjusted hazard ratio (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., Conclusion: 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.

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.

Objective: 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., (© 2014 American Academy of Neurology.)

Objective: Few data describe antiretroviral treatment (ART)-related adverse events when treatment is initiated at CD4(+) cell counts more than 350 cells/μl. We compared rates of laboratory-defined adverse events (LDAEs) according to CD4(+) cell count at ART initiation., Design: Analysis of on-going cohort study., Methods: ART-naive persons initiating ART from 2000 to 2010 were included. Chi-square, analysis of variance (ANOVA) and Kruskal-Wallis tests compared characteristics among those starting ART with a CD4(+) cell count of 350 or less, 351-499 and at least 500 cells/μl. Time-updated Poisson regression compared rates of LDAE in the three CD4(+) cell strata. Cox proportional hazard models compared risk of ART discontinuation., Results: Nine thousand, four hundred and six individuals were included: median age 37 years, 61% white, 80% men, median viral load 4.8 log copies/ml. Four hundred and forty-seven (4.9%) and 1099 (11.7%) started ART with a CD4(+) cell count at least 500 and 351-499 cells/μl, respectively. One thousand, two hundred and eighty-three (13.6%) patients experienced at least one LDAE. The rate of LDAE did not differ between those starting ART with a CD4(+) cell count 351-499 and less than 350 cells/μl [relative rate 0.90, 95% confidence interval (CI) 0.74-1.09)], but an increased risk of ART discontinuation was observed (hazard ratio 1.58, 95% CI 1.10-2.27). Those starting ART at CD4(+) cell count at least 500 cells/μl had an increased rate of LDAE (relative rate 1.44, 95% CI 1.13-1.82) but were not more likely to discontinue ART (hazard ratio 1.15, 95% CI 0.64-2.09)., Conclusion: This study demonstrates the need to consider ART-related toxicities when initiating therapy at CD4(+) cell counts at least 500 cells/μl. Whilst evidence from randomized controlled trials is awaited, the timing of ART initiation in terms of benefits and risks of ART remains an important question.

Objective: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART)., Methods: Patients aged more than 20 years who started ART during 2000-2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4 cell count and viral load before ART and in each of years 1-5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4 cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20-85 years., Results: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years. At start of ART, expected age at death [95% confidence interval (CI)] of 35-year-old men with CD4 cell count less than 200, 200-349, at least 350 cells/μl was 71 (68-73), 78 (74-82) and 77 (72-81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4 cell count in the first year of ART from less than 200 to 200-349 or at least 350 cells/μl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48-61) (CD4 cell count <200 cells/μl and no viral suppression) to 80 (76-83) years (CD4 cell count ≥350 cells/μl and viral suppression)., Conclusion: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4 cell count significantly improve their life expectancy if they have a good CD4 cell count response and undetectable viral load.

Objectives: HIV-controllers spontaneously maintain HIV viremia at an undetectable level. We aimed to describe the delay to control from seroconversion, the duration of control, and risk factors for losing control., Methods: HIV-controllers were identified from a pooled dataset of 24 seroconverter cohorts from Europe, Australia, and Canada (CASCADE). HIV-controllers had at least five consecutive viral loads less than 400/500 copies/ml, while antiretroviral therapy naive, for at least 5 years after seroconversion. End of control was defined as two consecutive viral loads above 2000 copies/ml. Duration of control was described using Kaplan-Meier estimates; factors associated with duration of control were identified using a Cox model. CD4⁺ cell count evolution during control was described using a mixed model., Results: Of 9896 eligible seroconverters, we identified 140 (1.4%) HIV-controllers, the largest database of HIV-controllers followed from seroconversion. For 64 with viral load measured within 24 months from seroconversion, median delay to control was 16.7 (interquartile range: 7.8-37.9) months. Probability of maintaining control 20 years after seroconversion was 0.74 [95% confidence interval (CI): 0.64-0.85]. Occurrence of blips followed by return to undetectability did not increase the risk of loss of control [hazard ratio: 0.81 (95% CI: 0.10-6.70)]. However, CD4⁺ cell loss during control was significantly accelerated in individuals with blips., Conclusion: In most individuals, control occurred rapidly after seroconversion; however, more than 3 years were required to achieve control in 25% of HIV-controllers. Control may be sustained even when CD4⁺ cell levels are below 500 cells/μl, opening important new perspectives to understand the physiopathology underlying control., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Objective: HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART., Methods: Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks., Results: Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure., Conclusion: The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.

Objective: To evaluate the change in categories of risk of death by adding D-dimer to conventional mortality risk factors., Design: Cohort study., Methods: Data on HIV-infected participants receiving standard combination antiretroviral therapy in two clinical trials (Evaluation of Subcutaneous Proleukin in a Randomized International Trial and Strategic Management of antiretroviral therapy), who had baseline D-dimer measured, were randomly split into two equal training and a validation datasets. A multivariable survival model was built using the training dataset and included only conventional mortality risk factors measured at baseline. D-dimer was added to create the comparison model. The level of reclassification of mortality risk, for those with at least 5-years of follow-up, was then assessed by tabulating mortality risk defined as low (≤2% predicted rate), moderate (2-5%) or high (>5%). Reclassification analyses were then repeated on the validation dataset., Results: The analysis population at baseline had a mean age of 43 years, median CD4(+) cell count of 535 cells/μl (IQR: 420-712), and 83% had HIV RNA of at least 500 copies/ml. In the training dataset (n=1946, 8939 person-years), there were 83 deaths at a rate of 0.93 per 100 person-years. Addition of D-dimer to the reference model resulted in 6% or fewer (P>0.05) being correctly reassigned, either up or down, to a new risk category, in both, training and validation datasets. The integrated discrimination improvement in training and validation datasets was 0.60% (P=0.084) and 0.45% (P=0.168), respectively., Conclusion: In this relatively well population, at the given risk cutoffs, D-dimer appeared to only modestly improve the discernment of risk. Risk reclassification provides a method for assessing the clinical utility of biomarkers in HIV cohort studies., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Objective: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration., Methods: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting., Results: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens., Conclusions: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Objectives: To explore the relationship between elevated triglyceride levels and the risk of myocardial infarction (MI) in HIV-positive persons after adjustment for total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and nonlipid risk factors., Background: Although elevated triglyceride levels are commonly noted in HIV-positive individuals, it is unclear whether they represent an independent risk factor for MI., Methods: The incidence of MI during follow-up was stratified according to the latest triglyceride level. Multivariable Poisson regression models were used to describe the independent association between the latest triglyceride level and MI risk after adjusting for TC and HDL-C, nonlipids cardiovascular disease (CVD) risk factors, HIV and treatment-related factors., Results: The 33,308 persons included in the study from 1999 to 2008 experienced 580 MIs over 178,835 person-years. Unadjusted, the risk of MI increased by 67% [relative risk (RR) 1.67, 95% confidence interval 1.54-1.80] per doubling in triglyceride level. After adjustment for the latest TC and HDL-C level, the RR dropped to 1.33 (95% confidence interval 1.21-1.45); this effect was further attenuated by other CVD risk factors and the RR was reduced to 1.17 (95% confidence interval 1.06-1.29). In models that additionally adjusted for HIV and treatment factors, the risk was further diminished, although remained significant (RR 1.11, 95% confidence interval 1.01-1.23)., Conclusion: Higher triglyceride levels were marginally independently associated with an increased risk of MI in HIV-positive persons, although the extent of reduction in RR after taking account of latest TC, latest HDL-C and other confounders suggests that any independent effect is small.

Background: The Coding Causes of Death in HIV (CoDe) Project aims to deliver a standardized method for coding the underlying cause of death in HIV-positive persons, suitable for clinical trials and epidemiologic studies., Methods: The project incorporates detailed data collection, a classification system, and a centralized adjudication process performed by 2 independent reviewers. The methodology was tested in the Data Collection on Adverse events of Anti-HIV Drugs Study , and independent reviews of causes of death were compared. Logistic regression models identified factors associated with initial agreement by reviewers on underlying cause of death., Results: A total of 491 reported fatal cases were adjudicated; in only 5% of cases the cause of death remained undetermined after adjudication. Reviewers initially agreed on the underlying cause for 339 (69%) deaths. As compared with deaths due to AIDS-related causes, the odds of agreement were more than 80% lower when deaths were ultimately deemed to be due to non-AIDS-related causes (odds ratio = 0.17 [95% confidence interval = 0.08-0.37]) or undetermined causes (0.11 [0.04-0.36]). The odds of initial agreement were also lower for deaths occurring in subjects with hypertension (0.43 [0.22-0.85]) and depression (0.43 [0.23-0.80])., Conclusions: The extent and format of data collected in the CoDe Project appear to be sufficient for an informed review, and the proposed coding scheme is adequate for obtaining an underlying cause of death.

Objective: Treatment guidelines recommend initiation of therapy for individuals experiencing rapid CD4 cell decline. It is not known, however, whether the rate of CD4 cell decline before combination antiretroviral therapy (cART) is related to immunological response following cART., Methods: We estimated precART and postcART CD4 cell slopes by mixed models and categorized patients into two groups according to whether estimated precART slopes were above or below the 75th percentile. We compared immunological responses of the two groups through both mixed models and survival techniques. Models were stratified by CD4 cell at baseline, adjusted for HIV RNA, age, sex, HIV transmission group, year of seroconversion, initiation during primary infection, hepatitis C virus and hepatitis B virus serostatus, and cART class., Results: Of 2038 eligible patients, 1531 and 507 experienced median (interquartile range) precART CD4 cell slope of −105 (−471 to −61) and −42 (−62 to −80) cells/μl, respectively, over 2 years. After adjusting for potential confounders, individuals with shallower decline experienced a slower rate of CD4 cell recovery following cART initiation of +9.5 [95% confidence interval (CI) +6.6 to +12.2] compared to +13.9 (+13.0 to +14.8) cells/μl per month among those with steeper precART decline (P < 0.001). After stratifying by the baseline CD4 cell count, the adjusted relative hazard of an increase from baseline of more than 50 cells/μl was 0.70 (95% CI 0.62−0.79) for those with a shallower vs. steeper precART decline., Conclusion: Findings highlight the existence of a subgroup of individuals with shallower precART CD4 cell decline who experience poorer CD4 cell increases after cART; new studies in this group may provide information to optimize responses to therapy.

Background: We investigate changes made to therapy after a resistance test result and identify factors associated with switching regimen., Methods: Patients receiving antiretroviral therapy (ART) who had a resistance test performed during 1998-2007 were included in the analysis. A switch was defined as starting at least two drugs/starting a drug from a class not previously experienced within 4 months of the resistance test result. Logistic regression was used to identify factors independently associated with switching regimen., Results: Of the 5123 test results included in the analyses, 1874 (36.6%) were followed by a switch within 4 months of the test result. Independent factors associated with switching included genotypic sensitivity score (GSS) of the current regimen [odds ratio (OR) 4.86, 95% confidence interval (CI) 3.95, 5.97 for GSS less than 1 compared to GSS of at least 3] and a higher number of previous failures [1.12 (1.06, 1.18) per additional failed regimen]. Patients with fewer drug options were less likely to switch [0.36 (0.27, 0.48) comparing 0-3 drug options with ≥10 drug options]., Conclusions: Only 37% of patients switched regimen within 4 months of the resistance test result. Whilst toxicity concerns of available drugs may somewhat explain this finding, it is also likely that there is a lack of treatment options available for patients who did not switch.

Purpose of Review: We discuss two data analysis issues for studies that use binary clinical outcomes (whether or not an event occurred): the choice of an appropriate scale and transformation when biomarkers are evaluated as explanatory factors in logistic regression and assessing the ability of biomarkers to improve prediction accuracy for event risk., Recent Findings: Biomarkers with skewed distributions should be transformed before they are included as continuous covariates in logistic regression models. The utility of new biomarkers may be assessed by measuring the improvement in predicting event risk after adding the biomarkers to an existing model. The area under the receiver operating characteristic (ROC) curve (C-statistic) is often cited; it was developed for a different purpose, however, and may not address the clinically relevant questions. Measures of risk reclassification and risk prediction accuracy may be more appropriate., Summary: The appropriate analysis of biomarkers depends on the research question. Odds ratios obtained from logistic regression describe associations of biomarkers with clinical events; failure to accurately transform the markers, however, may result in misleading estimates. Although the C-statistic is often used to assess the ability of new biomarkers to improve the prediction of event risk, other measures may be more suitable.

Objective: To identify risk factors for acute renal failure (ARF) in HIV-infected patients., Design: Observational cohort study of HIV-infected patients attending a South London HIV centre between January 1999 and December 2008., Methods: ARF was defined as a transient, more than 40% reduction in renal function as assessed by estimated glomerular filtration rate. Multivariate Poisson regression analysis was used to identify baseline and time-updated factors associated with ARF., Results: The incidence of ARF was 2.8 (95% confidence interval 2.41-3.24) episodes per 100 person-years. We observed a stepwise increase in ARF incidence with time accrued at lower CD4 cell count and at lower estimated glomerular filtration rate, with adjusted incidence rate ratios of 1 (reference), 1.56 (0.97-2.48), 2.08 (1.11-3.91), 6.38 (3.18-12.78) and 10.29 (5.11-20.98) for CD4 cell counts of more than 350, 201-350, 101-200, 51-100 and of 50/microl or less, and 1 (reference), 1.46 (0.86-2.51), 4.19 (2.37-7.42) and 27.00 (16.13-44.95) for estimated glomerular filtration rate more than 90, 75-89, 60-74 and less than 60 ml/min, respectively. Ethnicity, hepatitis B or C coinfection, exposure to combination antiretroviral therapy with or without indinavir, tenofovir or atazanavir and HIV viraemia were not associated with ARF., Conclusion: Current levels of immunodeficiency and renal function were independent predictors of HIV-associated ARF.

Objectives: To identify biological factors associated with HIV transmission in men who have sex with men (MSM)., Design: A longitudinal phylogenetic analysis of HIV-1 from an MSM cohort, incorporating clinical and epidemiological data., Methods: Potential individuals were HIV-infected MSM attending a sexual health clinic between 2000 and 2006. Individuals were classified such that they could move from recent to chronic infection categories. HIV-1pol gene sequences were obtained from plasma virus or proviral DNA and clusters estimated by maximum likelihood and conservative genetic distance differences. The single most likely transmitter generating each recent infection was ascertained and risk factors around time of likely transmission explored using Poisson regression modelling., Results: Out of 1144 HIV-infected MSM, pol sequence data were obtained for 859 (75%); 159 out of 859 (19%) were recently HIV infected at diagnosis. A single most likely transmitter was identified for 41 out of 159 (26%), of which 11 were recently infected (27%) and 30 chronically infected. Factors associated with transmission in multivariable analysis were: younger age {rate ratio per 5 years older 0.68 [95% confidence interval (CI) 0.54-0.86], P=0.0009}, higher viral load [rate ratio per log higher 1.61 (95% CI 1.15-2.25), P=0.005], recent infection [rate ratio 3.88 (95% CI 1.76-8.55), P=0.0008] and recent sexually transmitted disease [rate ratio 5.32 (95% CI 2.51-11.29), P=0.0001]. HAART was highly protective in a univariable model, RR 0.14 (95% CI 0.07-0.27, P=0.0001)., Conclusion: Onward transmission of HIV among MSM is significantly associated with recent infection, sexually transmitted diseases and higher viral load, and reduced by effective HAART. The majority of new infections appear to occur from individuals whose infection was undiagnosed at the time of transmission.

Introduction: This study describes the characteristics of the metabolic syndrome in HIV-positive patients in the Data Collection on Adverse Events of Anti-HIV Drugs study and discusses the impact of different methodological approaches on estimates of the prevalence of metabolic syndrome over time., Methods: We described the prevalence of the metabolic syndrome in patients under follow-up at the end of six calendar periods from 2000 to 2007. The definition that was used for the metabolic syndrome was modified to take account of the use of lipid-lowering and antihypertensive medication, measurement variability and missing values, and assessed the impact of these modifications on the estimated prevalence., Results: For all definitions considered, there was an increasing prevalence of the metabolic syndrome over time, although the prevalence estimates themselves varied widely. Using our primary definition, we found an increase in prevalence from 19.4% in 2000/2001 to 41.6% in 2006/2007. Modification of the definition to incorporate antihypertensive and lipid-lowering medication had relatively little impact on the prevalence estimates, as did modification to allow for missing data. In contrast, modification to allow the metabolic syndrome to be reversible and to allow for measurement variability lowered prevalence estimates substantially., Discussion: The prevalence of the metabolic syndrome in cohort studies is largely based on the use of nonstandardized measurements as they are captured in daily clinical care. As a result, bias is easily introduced, particularly when measurements are both highly variable and may be missing. We suggest that the prevalence of the metabolic syndrome in cohort studies should be based on two consecutive measurements of the laboratory components in the syndrome definition.

Objective: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication., Design: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication., Results: Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41-0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22-0.37) for less than 100 cells/microl, 0.33 (0.25-0.44) for 100 to less than 200 cells/microl, 0.38 (0.28-0.52) for 200 to less than 350 cells/microl, 0.55 (0.41-0.74) for 350 to less than 500 cells/microl, and 0.77 (0.58-1.01) for 500 cells/microl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49-0.67) for less than 1 year since initiation to 0.21 (0.14-0.31) for 5 years or more (P value for trend <0.001)., Conclusion: We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Objective: To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom., Design: Observational cohort study., Setting: Seven leading HIV centres and affiliated renal clinics in the United Kingdom., Participants: A total of 21 951 patients in whom renal function was measured., Main Outcome Measure: Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT)., Results: Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998-1999 to 0.92% in 2006-2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year., Conclusion: The prevalence of HIV/ESRF increased during the HAART era to reach nearly 1% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stem the rising trend of HIV/ESRF.

Objective: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART)., Design: Observational multicentre cohorts., Methods: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification., Results: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA., Conclusion: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients.

Objective: Many patients infected with HIV still present with an AIDS diagnosis. The aim of this study was to evaluate the virological, immunological and clinical outcomes of HAART in these patients., Design: The present study was a multi-cohort study. All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004 from eight hospital cohorts, were evaluated., Results: A total of 760 patients were included [268 (35.3%) had pneumocystis and 168 (22.1%) tuberculosis]. Six hundred and twenty-four patients (82.1%) started HAART a median of 31 days after HIV diagnosis. One hundred and fifty-three patients started a nonnucleoside transcriptase inhibitor-based regimen (20.1%), 409 a protease inhibitor-based regimen (53.8%) and 62 other regimens (8.2%). In adjusted analyses, HAART was started sooner in more recent years, in patients with lower CD4 cell count and in those with Kaposi's sarcoma, whereas it was started later in those with tuberculosis. Five hundred and five patients (89%) attained a viral load of less than 500 copies/ml. The factors associated with a better virological response were later calendar year, lower initial viral load and cytomegalovirus disease. Virological rebound was more common in those receiving nucleoside reverse transcriptase inhibitor-based regimens, in those with tuberculosis and in earlier calendar years. One hundred and twenty-five (16%) patients died; 61 had received HAART (48.6%). Mortality was more likely in those who were older, those with a higher viral load at diagnosis, those with nonsexual HIV risks and those with lower CD4 cell count and haemoglobin levels over follow-up., Conclusion: Virological suppression was achieved in most AIDS patients, though mortality remains high in these individuals.

Objective: To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART., Design: Analysis of data from an ongoing HIV cohort study., Methods: The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts > or = 350 cells/microl among patients in the UK CHIC Study., Results: In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350-499, 500-649 and > 650 cells/microl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500-649 cells/microl compared with those with CD4 cell count > or = 650 cells/microl was 1.55 [95% confidence interval (CI), 1.11-2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count > or = 350 cells/microl , there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76-0.93; P = 0.001), independent of viral load and age., Conclusions: The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count > or = 350 cells/microl range in ART-naive people.

Objective: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy., Design: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003., Methods: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions., Results: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone., Conclusion: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.

Introduction: Although HAART has led to a reduction in overall mortality among HIV-infected individuals, its impact on death from specific causes is unknown., Methods: Twenty-two cohorts of HIV-infected individuals with known dates of seroconversion are pooled in the CASCADE collaboration. Causes of death (COD) were categorized into three AIDS-related and seven non-AIDS-related causes. The unknown causes were assigned a separate category. The cumulative incidence for each COD was calculated in the presence of the other competing COD, for the pre-HAART and HAART eras. A multivariate regression analyses for the cumulative rate of progression to the different COD was performed., Results: A total of 1938 of 7680 HIV-seroconverters died. Pre-HAART, AIDS opportunistic infections (OI) was the most common COD, followed by unknown and HIV/AIDS-unspecified. In the HAART era, the cumulative incidence for all AIDS-related COD decreased, OI remaining the most important. Large reductions in death due to other infections and organ failure were seen. Cumulative death risk decreased in the HAART era for most causes. The effect of HAART was not the same for all risk groups. The cumulative risk of death from AIDS-related malignancies, OI and non-AIDS-related malignancies decreased significantly among homosexual men (MSM), whereas the risk of dying from (un)-intentional death increased significantly among injecting drug users (IDU). A non-significant increase in hepatitis/liver-related death was seen in MSM, IDU and haemophiliacs., Conclusion: Overall and cause specific mortality decreased following the introduction of HAART. OI remain the most common COD in the HAART era, suggesting that AIDS-related events will continue to be important in the future. Future trends in COD should be monitored using standardized guidelines.

Background: HIV infection per se and HAART can alter mitochondrial functionality, leading to a decrease in mitochondrial DNA content., Objective: To evaluate whether treatment interruption monitored by CD4 cell count can restore mitochondrial DNA content in peripheral blood lymphocytes., Methods: Mitochondrial DNA content was measured in platelet-free CD4 and CD8 T cells by real-time polymerase chain reaction; flow cytometry was used to identify and quantify activated CD4 and CD8 T lymphocytes., Results: The 30 patients had been treated for a mean of 107 months (range, 27-197). Median CD4 cell count at discontinuation was 702 cells/microl (range, 547-798). Median observational time from HAART discontinuation was 11.3 months (range, 4-26). Discontinuation of treatment provoked significant increases in mitochondrial DNA in CD8 T cells, which started only 6 months after therapy discontinuation [5.12 copies/cell per month from 0 to 6 months (P = 0.37) and 26.96 copies/cell per month from 6 to 12 months (P < 0.0001)]., Conclusions: This study is the first showing that mitochondrial DNA content can increase in peripheral blood lymphocytes during treatment interruption, but only after at least 6 months of interruption. Consequently, interruptions of shorter periods, whether by clinician or patient decision, are unlikely to allow restoration of mitochondrial DNA and so decrease HAART-related toxicity.

Background: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice., Methods: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI)., Results: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008)., Conclusion: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.

Our findings show a high rate of loss to follow-up in HIV-positive teenagers compared with adults. Of concern is the fact that this group also have high rates of sexually transmitted infections, unprotected sex and pregnancy. There is an urgent need to examine the reasons for this and adopt strategies to minimize risk-taking behaviour and to improve access to appropriate healthcare.

Background: Relatively little is known about the long-term durability of viral suppression in individuals initially achieving a viral load of less than 50 copies/ml within 24 weeks of starting antiretroviral therapy, nor the extent to which therapy interruption accounts for the loss of suppression., Methods: We intensely followed all 336 antiretroviral-naive patients attending the Goethe Universitat Clinic who began multi-drug combination regimens and in whom a viral load of less than 50 copies/ml was achieved within 24 weeks, in order to assess the risk of viral load rebound. Inspection of case notes allowed the distinction of viral rebound according to whether there was an associated complete interruption of therapy., Results: A total of 61 patients experienced viral rebound during 543.1 person-years of follow-up, giving a 25.3% risk of rebound by 3.3 years from first achieving viral suppression. However, for 47 of the patients with viral rebound there was an associated documented complete interruption of antiretroviral therapy, mostly as a result of co-morbidities, leaving 14 who appear to represent a failure of the virological efficacy of therapy (viral breakthrough; 5.2% risk by 3.3 years). The risk of viral breakthrough declined with the increased duration of suppression (P = 0.01)., Conclusion: The intrinsic virological effectiveness of multi-drug antiretroviral therapy in previously drug-naive individuals appears to be such that viral suppression, once achieved, can be maintained for several years in patients not interrupting therapy. The major challenge is to develop regimens that can be taken consistently and safely for such long periods of time.

Objective: To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus., Methods: Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (> or = 2 months)., Results: Treatment interruption resulted in viral load increases (mean 0.7 log 10 copies/ ml; P = 0.0001) and CD4 cell count decreases (mean 89 x 10(6) cells/l; P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 x 10(6) cells/l; P= 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation; P= 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P= 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P = 0.0003); it improved with the number of new drugs received (RH 2.12; P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006)., Conclusions: Changes in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered.

Objective: HIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues., Methods: We studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens., Results: Mean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors., Conclusion: These results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.

Objective: New antiretroviral strategies aim to reduce plasma HIV RNA (viral load) to below the limits of detectability of assays with the objective of reducing viral replication in order to stop or reverse the pathogenic process and prevent development of drug resistance. First use of a protease inhibitor might offer the most realistic chance of achieving this aim. Our objective was to study the virological response to protease inhibitors in patients taking them for the first time., Methods: A total of 901 patients from a large outpatient clinic were followed a mean of 15 months from the time of starting a protease inhibitor until 1 May 1998. Viral load and CD4 cell count measurements were made on average every 34 days., Results: Overall there was a 79% [95% confidence interval (CI), 76-82] probability of the patients achieving a viral load < 500 copies/ml by 24 weeks after starting the protease inhibitor. In a multiple Cox regression model, those with lower initial viral load [relative hazard (RH), 0.72; P < 0.0001], higher CD4 cell count (RH, 1.07; P = 0.002), those starting other new drugs at same time as the protease inhibitor (RH, 1.46 for two versus none; P = 0.003), those who were antiretroviral-naive, and those using indinavir or nelfinavir were more likely to achieve such levels. In those 651 patients achieving viral load < 500 copies/ml within 24 weeks, there was an estimated 53% (95% CI, 51-55) probability of rebound of viral load to > 500 copies/ml by 52 weeks from the first undetectable value. Again, those who had started other new drugs at the same time as the protease inhibitor (RH, 0.57; P = 0.003 for starting two versus none) tended to experience a lower probability of viral load rebound, as did those with higher initial CD4 cell count (RH, 0.87 per 100 x 10(6)/l higher; P = 0.0007). Those who took saquinavir achieved less durable virological responses than those who took other protease inhibitors., Conclusions: Starting protease inhibitor therapy with two other new antiretroviral drugs simultaneously with protease inhibitor therapy offers a better best chance of achieving sustained viral load < 500 copies/ml than starting fewer new drugs.