UK Collaborative HIV Cohort Study Research Articles

Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies

The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.

Life expectancy of people with HIV on long-term antiretroviral therapy in Europe and North America: a cohort study

BackgroundThe life expectancy of people with HIV starting combination antiretroviral therapy (ART) has increased substantially over the past 25 years. However, individuals treated before 1996 or with less effective and more toxic regimens than those currently available might have a worse prognosis. We estimated life expectancy from 2015 onwards, comparing people with HIV who started ART in different time periods since 1996. MethodsData were derived from 20 European and North American cohorts (Antiretroviral Therapy Cohort Collaboration and UK Collaborative HIV Cohort Study), for people with HIV who started potent ART after 1996 and were still on ART in 2015, or who started ART after 2015 and survived for at least 1 year. Follow-up started on or after Jan 1, 2015. Associations between mortality and demographic characteristics and biomarkers (CD4 and CD8 count in cells per μL and HIV-1 RNA viral load) at follow-up start were estimated using multivariable Poisson models. Estimated mortality rates in 5-year age bands were entered into life tables that contain follow-up information to estimate expected remaining life expectancy, stratified by sex and variables associated with mortality, and standardised to the proportion of people with HIV in each stratum. Life expectancy was compared with the French general population, as more data were available for France than for other countries included in the analyses. FindingsOf the 206 891 people with HIV eligible for inclusion from the cohort data, 5780 died during 619 356 person-years of follow-up after 2015. For women, the standardised remaining years of life expectancy at age 40 years for individuals starting ART between 1996 and 2014 was 36·0 years (95% CI 35·4–36·6), whereas it was 39·4 years (39·0–39·8) for individuals starting after 2015 (general population comparator 46·0 years). Corresponding figures for men were 34·7 years (34·1–35·3) and 37·2 years (36·6–38·8), respectively (general population comparator 40·3 years). For women starting ART between 1996 and 2014, with a CD4 count of 0–49 cells per μL at the commencement of follow-up, remaining life expectancy at age 40 years was 19·4 years (95% CI 18·2–20·6), rising to 40·4 years (40·0–40·8) for people with a CD4 count of 500 cells per μL or greater at commencement of follow-up. Corresponding figures for women starting ART after 2015 were 24·9 years (23·9–25·9) and 42·6 years (422–43·0), respectively. For men starting ART between 1996 and 2014 with a CD4 count of 0–49 cells per μL at commencement of follow-up, remaining life expectancy at age 40 years was 18·2 years (17·0–19·4), rising to 38·2 years (37·6–38·8) for men with a CD4 count of 500 cells per μL or more at commencement of follow-up. Corresponding remaining life expectancy for men starting ART after 2015 was 23·7 years (22·7–24·7) and 39·5 years (38·9–40·1), respectively. InterpretationFor people with HIV on long-term ART with high CD4 cell counts, life expectancies are estimated to be close to those of the general population, regardless of when they started ART. However, for people with HIV with low CD4 cell counts, estimates of remaining life expectancy are up to 30 years lower than in the general population, indicating the importance of early diagnosis and sustained treatment. FundingUS National Institute on Alcohol Abuse and Alcoholism, UK Medical Research Council.

Association of pregnancy with engagement in HIV care among women with HIV in the UK: a cohort study.

Women with HIV face challenges in engaging in HIV care post partum. We aimed to examine changes in engagement in HIV care through clinic attendance before, during, and after pregnancy, compared with matched women with HIV who had never had a recorded pregnancy. In this cohort study, we describe changes in engagement in HIV care before, during, and after pregnancy among women with HIV from the UK Collaborative HIV Cohort (CHIC) study from 25 HIV clinics in the UK with a livebirth reported to the National Surveillance of HIV in Pregnancy and Childhood between Jan 1, 2000, and Dec 31, 2017. To investigate whether changes were specific to HIV, we compared these changes to those over equivalent periods among non-pregnant women with HIV in the UK CHIC study matched for ethnicity, year of conception, age, CD4 cell count, viral suppression, and antiretroviral therapy use. Analyses were via logistic regression using generalised estimated equations with an interaction between case-control status (pregnant women vs non-pregnant women) and pregnancy or pseudo pregnancy (for non-pregnant women) stage. 1116 matched pairs of pregnant and non-pregnant women were included (median age 34 years [IQR 30-38], 80·1% Black African, 12·5% white). 69 330 person-months of follow-up were recorded, 25 412 in the before stage, 18 897 during, and 25 021 after pregnancy or pseudo pregnancy stages. Among pregnant women, the proportion of time engaged in care increased during pregnancy (8477 [90·5%] of 9371 person-months) and after pregnancy (10 501 [84·6%] of 12 407), compared with before pregnancy (9979 [78·5%] of 12 707). Among non-pregnant women in the control group, engagement in HIV care remained stable across the three equivalent stages (9688 [76·3%] of 12 705 person-months before pseudo pregnancy; 7463 [78·3%] of 9526 during pseudo pregnancy; and 9892 [78·4%] of 12 614 after pseudo pregnancy). The association of engagement in HIV care with pregnancy or pseudo pregnancy stage differed significantly by case-control status (pinteraction<0·0001); the odds of engagement in HIV care were higher during pregnancy (odds ratio [OR] 3·32, 95% CI 2·68-4·12) and after pregnancy (OR 1·49, 1·24-1·79) only among pregnant women, and not among non-pregnant women, when compared with the before pseudo pregnancy stage. Women with HIV and a pregnancy resulting in a livebirth were more likely to engage in HIV care post partum when compared with before pregnancy. A detailed understanding of the reason for this finding could support interventions to maximise engagement in HIV care for all women with HIV. Medical Research Council and National Institute for Health Research.

Differences in HIV clinical outcomes amongst heterosexuals in the United Kingdom by ethnicity.

We investigated differences in clinical outcomes in heterosexual participants, by ethnicity in the UK Collaborative HIV Cohort Study from 2000 to 2017. Cohort analysis. Logistic/proportional hazard regression assessed ethnic group differences in CD4+ cell count at presentation, engagement-in-care, combination antiretroviral therapy (cART) initiation, viral suppression and rebound. Of 12 302 participants [median age: 37 (interquartile range: 31-44) years, 52.5% women, total follow-up: 85 846 person-years], 64.4% were black African, 19.1% white, 6.3% black Caribbean, 3.6% black other, 3.3% South Asian/other Asian and 3.4% other/mixed. CD4+ cell count at presentation amongst participants from non-white groups were lower than the white group. Participants were engaged-in-care for 79.6% of follow-up time; however, black and other/mixed groups were less likely to be engaged-in-care than the white group (adjusted odds ratios vs. white: black African: 0.70 (95% confidence interval (CI) 0.63-0.79], black Caribbean: 0.74 (0.63-0.88), other/mixed: 0.78 (0.62-0.98), black other: 0.81 (0.64-1.02)). Of 8867 who started cART, 79.1% achieved viral suppression, with no differences by ethnicity in cART initiation or viral suppression. Viral rebound (22.2%) was more common in the black other [1.95 (1.37-2.77)], black African [1.85 (1.52-2.24)], black Caribbean [1.73 (1.28-2.33)], South Asian/other Asian [1.35 (0.90-2.03)] and other/mixed [1.09 (0.69-1.71)] groups than in white participants. Heterosexual people from black, Asian and minority ethnic (BAME) groups presented with lower CD4+ cell counts, spent less time engaged-in-care and were more likely to experience viral rebound than white people. Work to understand and address these differences is needed.

CD4+:CD8+ T Cell Ratio Normalization and the Development of AIDS Events in People with HIV Starting Antiretroviral Therapy.

We identify factors associated with the normalization of the CD4+:CD8+ T cell ratio among UK Collaborative HIV Cohort study participants, and describe the association of the CD4+ and CD8+ T cell counts and the CD4+:CD8+ T cell ratio, with the risk of new AIDS events among individuals who achieve a suppressed viral load. Participants initiating combination antiretroviral therapy (cART) after 2006 with a CD4+:CD8+ T cell ratio <1, and viral suppression within 6 months were included. Cox proportional hazard models were used to examine associations with ratio normalization (ratio ≥1). Poisson regression models were used to investigate factors associated with the development of AIDS after viral load suppression. A total of 13,178 participants [median age: 37 (interquartile range: 31–44)] were followed for 75,336 person-years. Of the 4,042 (32.9%) who experienced ratio normalization, individuals with a high CD4+ T cell count [>500 vs. ≤200 cells/mm3, adjusted hazard ratio (95% confidence interval): 7.93 (6.97–9.01)], low CD8+ T cell count [>1,150 vs. ≤500 cells/mm3: 0.18 (0.16–0.21)], and low CD4+:CD8+ T cell ratio [>0.8 vs. <0.2: 12.36 (10.41–14.68)] at cART initiation were more likely to experience ratio normalization. Four hundred and nineteen people developed a new AIDS event. Most recent CD4+ T cell count [>500 vs. ≤200 cells/mm3: adjusted rate ratio 0.24 (0.16–0.34)] and CD4+:CD8+ T cell ratio [>0.8 vs. <0.2: 0.33 (0.21–0.52)] were independently associated with a new AIDS event. One third of study participants experienced ratio normalization after starting cART. CD4+ T cell count and CD4+:CD8+ T cell ratio are both individually associated with ratio normalization and the development of new AIDS events after cART.

Non-disclosed men who have sex with men in UK HIV transmission networks: phylogenetic analysis of surveillance data

Patients who do not disclose their sexuality, including men who do not disclose same-sex behaviour, are difficult to characterise through traditional epidemiological approaches such as interviews. Using a recently developed method to detect large networks of viral sequences from time-resolved trees, we localised non-disclosed men who have sex with men (MSM) in UK transmission networks, gaining crucial insight into the behaviour of this group. For this phylogenetic analysis, we obtained HIV pol sequences from the UK HIV Drug Resistance Database (UKRDB), a central repository for resistance tests done as part of routine clinical care throughout the UK. Sequence data are linked to demographic and clinical data held by the UK Collaborative HIV Cohort study and the national HIV/AIDS reporting system database. Initially, we reconstructed maximum likelihood phylogenies from these sequences, then sequences were selected for time-resolved analysis in BEAST if they were clustered with at least one other sequence at a genetic distance of 4·5% or less with support of at least 90%. We used time-resolved phylogenies to create networks by linking together nodes if sequences shared a common ancestor within the previous 5 years. We identified potential non-disclosed MSM (pnMSM), defined as self-reported heterosexual men who clustered only with men. We measured the network position of pnMSM, including betweenness (a measure of connectedness and importance) and assortativity (the propensity for nodes sharing attributes to link). 14 405 individuals were in the network, including 8452 MSM, 1743 heterosexual women and 1341 heterosexual men. 249 pnMSM were identified (18·6% of all clustered heterosexual men) in the network. pnMSM were more likely to be black African (p<0·0001), less likely to be infected with subtype B (p=0·006), and were slightly older (p=0·002) than the MSM they clustered with. Mean betweenness centrality was lower for pnMSM than for MSM (1·31, 95% CI 0·48-2·15 in pnMSM vs 2·24, 0·98-3·51 in MSM; p=0·002), indicating that pnMSM were in peripheral positions in MSM clusters. Assortativity by risk group was higher than expected (0·037 vs -0·037, p=0·01) signifying that pnMSM were linked to each other. We found that self-reported heterosexual men were more likely to link MSM and heterosexual women than heterosexual women were to link MSM and heterosexual men (Fisher's exact test p=0·0004; OR 2·24) but the number of such transmission chains was small (only 54 in total vs 32 in women). pnMSM are a subgroup distinct from both MSM and from heterosexual men. They are more likely to choose sexual partners who are also pnMSM and might exhibit lower-risk sexual behaviour than MSM (eg, choosing low-risk partners or consistently using condoms). Heterosexual men are the group most likely to be diagnosed with late-stage disease (ie, low CD4 counts) and non-disclosed MSM might put female partners at higher risk than heterosexual men because non-disclosed MSM have male partners. Hence, pnMSM require specific consideration to ensure they are included in public health interventions. National Institutes of Health.

Risk factors and outcomes for the Q151M and T69 insertion HIV-1 resistance mutations in historic UK data

BackgroundThe prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations.MethodsWe considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997–2014. Where available, treatment history and patient outcomes were obtained through linkage to the UK Collaborative HIV Cohort study. A matched case–control approach was used to assess risk factors associated with the appearance of each of the mutations in ART-experienced patients, and survival analysis was used to investigate factors associated with viral suppression. A further analysis using matched controls was performed to investigate the impact of each mutation on survival.ResultsA total of 180 patients with Q151M mutation and 85 with T69i mutation were identified, almost entirely from before 2006. Occurrence of both the Q151M and T69i mutations was strongly associated with cumulative period of virological failure while on ART, and for Q151M there was a particular positive association with use of stavudine and negative association with use of boosted-protease inhibitors. Subsequent viral suppression was negatively associated with viral load at sequencing for both mutations, and for Q151M we found a negative association with didanosine use but a positive association with boosted-protease inhibitor use. The results obtained in these analyses were also consistent with potentially large associations with other drugs. Analyses were inconclusive regarding associations between the mutations and mortality, but mortality was high for patients with low CD4 at detection.ConclusionsThe Q151M and T69i resistance mutations are now very rare in the UK. Our results suggest that good outcomes are possible for people with these mutations. However, in this historic sample, viral load and CD4 at detection were important factors in determining prognosis.

HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK.

BackgroundDarunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings.ObjectivesWe examined darunavir DRMs emerging in clinical practice in the UK.Patients and methodsBaseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls.ResultsOf 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group.ConclusionsOur findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility.

Predicting virological decay in patients starting combination antiretroviral therapy.

Objective:Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (≤200 copies/ml) within 6-months of starting cART.Design:Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study).Methods:Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance.Results:Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log10 viral load trajectories declined rapidly during the first 2 weeks post-cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one.Conclusions:Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART.

Failure to achieve a CD4+ cell count response on combination antiretroviral therapy despite consistent viral load suppression

To assess CD4 cell count recovery in people severely immunosuppressed at start of antiretroviral therapy (ART) who achieve and maintain viral load suppression. Eligible participants from the UK Collaborative HIV Cohort Study started ART with at least three drugs after 1 January 2000. Participants were required to have pre-ART CD4 cell count below 100 cells/μl, at least 2 years of follow-up on ART, have achieved viral load suppression (≤ 50 copies/ml) by 9 months after starting ART and to have maintained this throughout follow-up. Participants were further required to be regularly engaged with care. We calculated the proportion of people who failed to achieve a CD4 cell count of more than 100, 150, 200, 350 and 500 cells/μl by the time of the last follow-up, or 5 years from start of ART, whichever occurred first (censoring date). Of the 400 participants [median (interquartile range) pre-ART CD4 cell count of 38 (14-65) cells/μl], 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4 cell count of more than 100, 150, 200, 350 and 500 cells/μl, by the censoring date, respectively. Kaplan-Meier estimates of the proportion of people reaching each CD4 cell count threshold after 1 year on ART were 88, 70, 50, 14 and 3%, respectively, and after 3 years on ART, 98, 95, 90, 59 and 25%, respectively. Median (interquartile range) follow-up on ART was 3.9 (2.7-4.8) years. Given a person with pre-ART CD4 cell count below 100 cells/μl survives and maintains consistent viral load suppression on ART, there is over a 90% chance of reaching a CD4 cell count above 200 cells/μl by 3 years.

The increasing genetic diversity of HIV-1 in the UK, 2002–2010

Objective:HIV-1 is typically categorized by genetically distinct viral subtypes. Viral subtypes are usually compartmentalized by ethnicity and transmission group and, thus, convey important epidemiological information, as well as possibly influencing the rate of disease progression. We aim to describe the prevalence and time trends of subtypes observed among key populations living with HIV-1 in the UK.Design:Analyses of reverse transcriptase and protease sequences generated from HIV-1-positive antiretroviral-naive patients as part of routine resistance testing between 2002 and 2010 in all public health and NHS laboratories in the UK.Methods:Subtype was assigned centrally using the SCUEAL algorithm. Subtyping results were combined with data from the UK Collaborative HIV Cohort Study and the UK HIV and AIDS Reporting System. Analyses adjusted for the number of national HIV-1 diagnoses made each year within demographic subgroups. Viral subtypes were described overall, over time and by demographic subgroup.Results:Subtype B diagnoses (39.9%) have remained stable since 2005, whereas subtype C diagnoses (34.3%) were found to decline in prevalence from 2004. Across most demographic subgroups, the prevalence of non-B non-C subtypes has increased over time, in particular novel recombinant forms (9.9%), subtype G (2.7%), and CRF01 AE (2.0%).Conclusion:HIV-1 subtypes are increasingly represented across all demographic subgroups and this could be evidence of sexual mixing. Between 2002 and 2010, the prevalence of novel recombinant forms has increased in all demographic subgroups. This increasing genetic diversity and the effect of subtype on disease progression may impact future HIV-1 treatment and prevention.

Predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care.

To describe predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care. Data were obtained through the linkage of two separate studies: the UK Collaborative HIV Cohort study (UK CHIC), a cohort of adults attending 13 large HIV clinics; and the National Study of HIV in Pregnancy and Childhood (NSHPC), a national surveillance study of HIV-positive pregnant women. Pregnancy incidence was measured using the proportion of women in UK CHIC with a pregnancy reported to NSHPC. Generalized estimating equations were used to identify predictors of pregnancy and assess changes in pregnancy incidence in 2000-2009. The number of women accessing care at UK CHIC sites increased as did the number of pregnancies. Older women were less likely to have a pregnancy [adjusted relative rate (aRR) 0.44 per 10 year increment in age, [95% confidence interval (CI) (0.41-0.46)], P < 0.001] as were women with CD4 cell count less than 200 cells/μl compared with CD4 cell count 200-350 cells/μl [aRR 0.65 (0.55-0.77), P < 0.001] and women of white ethnicity compared with women of black African ethnicity [aRR 0.67 (0.57-0.80), P < 0.001]. The likelihood that women had a pregnancy increased over the study period [aRR 1.05 (1.03-1.07), P < 0.001). The rate of change did not significantly differ according to age group, antiretroviral therapy use, CD4 group or ethnicity. The pregnancy rate among women accessing HIV clinical care increased in 2000-2009. HIV-positive women with, or planning, a pregnancy require a high level of care and this is likely to continue and increase as more women of older age have pregnancies.

Patterns of retention in clinical care among HIV‐positive men in the UK CHIC Study

We examined disparities in engagement and retention‐in‐care among men in the UK Collaborative HIV Cohort (CHIC) Study according to ethnic group and mode of HIV infection. All male subjects in UK CHIC from 1996–2011 were included. We considered factors associated with both initial engagement (follow‐up&gt;1 day) and consistent retention in care (no interval between consecutive CD4/viral load (VL) measures&gt;6 months). Logistic regression was used to identify associations with ethnic group and mode of HIV infection after adjusting for covariates at study entry (age, year, use of antiretrovirals (ART), AIDS). Analyses of retention also adjusted for VL/CD4 at entry and clinic. The 33210 men had a median (interquartile range) age of 36 (30,42) years at study entry, ethnic group was white (21851, 65.8%), black African (4374, 13.2%), black other (1539, 4.6%), Asian (967, 2.9%), other (2337, 7.0%) and unknown (2142, 6.5%). Mode of infection was sex between men (MSM) (22260, 67.0%), heterosexual sex (HET) (6286, 18.9%), other (1556, 4.7%) and unknown (3108, 9.4%). 32045 (96.5%) men were initially engaged in care, with no major differences by ethnic group after adjustment. Compared to MSM, initial engagement was less likely in those with heterosexual (adjusted odds ratio 0.77 [95% confidence interval 0.63–0.95]) or other (0.43 [0.33–0.56]) modes of infection. Other factors associated with initial engagement were older age, receipt of ART and having AIDS at entry; those entering UK CHIC in 2008–2011 were less likely to engage due to the shorter follow‐up time. Of the men initially engaged in care, 12644 (44.0%) were consistently retained with no interval between consecutive CD4/VL&gt;6 months. Consistent retention was more likely in MSM than in those with other modes of infection (HET: 0.76 [0.68–0.84]; other 0.54 [0.46–0.62]). Ethnic group again did not impact greatly on subsequent retention. Other independent predictors of retention were older age, receipt of ART and AIDS at entry. Those entering UK CHIC in later years were more likely to exhibit consistent retention as were those with higher VL and lower CD4 at entry. Our study demonstrates high rates of initial engagement in care. Those infected with HIV through heterosexual sex and younger men are less likely to engage in care and, once engaged, are less likely to attend consistently. The reasons behind these differences need to be explored further to ensure equitable health care delivery.

Life expectancy of HIV‐1‐positive individuals approaches normal conditional on response to antiretroviral therapy: UK Collaborative HIV Cohort Study

Life expectancies (LEs) of patients in UK Collaborative HIV Cohort (UK CHIC) stratified by CD4 count at start of antiretroviral therapy (ART) have been estimated [1] but not gains in years of life in response to ART. We estimated LE associated with attained CD4 count and viral suppression at different durations of ART. Patients in UK CHIC aged > 20 years who started ART in 2000 to 2008 (excluding person who injects drugs) were followed to end of 2010. All-cause mortality was ascertained from clinic notes and by linkage to national records. We used the nearest CD4 count before ART and the last in each of years 1 to 5 of ART and determined whether patients were virally suppressed (HIV-1 RNA < 400 copies/mL) in the past year for those remaining under follow-up. Poisson models were used to estimate mortality rates by sex, age, latest CD4 count (<200, 200 to 349,≥350) and viral suppression for each duration of ART. Abridged life tables were constructed from age-specific mortality rates to estimate LE for ages 20 to 85 years. Results are presented as the average number of years that will be lived after exact age 35 years. A total of 17,021 patients started ART from 2000 to 2008 of whom 708 (4.2%) died; 3956 (23%) were lost to study follow-up. There was no difference in mortality between those with attained CD4 350 to 499 and ≥ 500. On starting ART, male LE at exact age 35 was 36, 44 and 42 (female LE 38, 46 and 44) years for attained CD4 < 200, 200 to 349,≥350, respectively; after 5 years on ART, it was 22, 42 and 46 (female LE 27, 46 and 51) years, respectively. Only 17% of patients had CD4 ≥ 350 at ART start, compared with 78% of patients on ART for > 5 years. The difference in LE between suppressed versus unsuppressed patients was around 11 years. The figure shows that both CD4 count and viral suppression contribute to changes in LE. Male patients that increased their CD4 in the 1st year of ART from < 200 to 200–349 or ≥ 350 gained 6 and 11 years of LE to 42 and 48 years, respectively, with similar rises for women. Overall, LE was 4 years greater for those on ART for > 5 years compared with those starting ART. Individuals that attain viral suppression and a CD4 count > 350 within 1 year of ART start have a normal LE with 35-year olds estimated to live to over 80 years on average. LE in patients with CD4 count < 200 beyond 5 years on ART drops by 15 years. Estimated LE may be biased by under-ascertainment of deaths, missing CD4 measurements and extrapolation beyond available data.

Uptake and Outcome of Combination Antiretroviral Therapy in Men Who Have Sex with Men According to Ethnic Group

We investigated differences in retention in HIV care and uptake of combination antiretroviral therapy (cART) and treatment outcomes between different ethnic men who have sex with men (MSM) groups.MSM subjects with known ethnicity and ≥1 day follow-up from 1996 to 2009 in the UK Collaborative HIV Cohort Study were included. Black and minority ethnic (BME) men were categorized as: black; Indian/Pakistani/Bangladeshi; other Asian/Oriental; and other/mixed. Logistic regression was used to identify factors associated with treatment initiation within the 6 months after each CD4 count. HIV viral load, CD4 counts, discontinuation/switch of a drug in the initial cART regimen, and development of a new AIDS event/death at 6 and 12 months were also analyzed.Of 16,406 MSM, 1818 (11.0%) were BME; 892 (49.1%) black, 139 (7.6%) Indian/Pakistani/Bangladeshi, 254 (13.9%) other Asian/Oriental, 532 (29.2%) other/mixed. The proportion of MSM with no follow-up after HIV diagnosis was higher among BME than white MSM (3.4% vs. 2.2%, P = 0.002). Permanent loss to follow-up was highest in the other/mixed and lowest in Indian/Pakistani/Bangladeshi groups (P = 0.02). Six thousand three hundred thirty-eight MSM initiated first cART from January 1, 2000, to January 1, 2009. In multivariable analyses, BME MSM were 18% less likely to initiate cART than white MSM with similar CD4 counts [adjusted odds ratio 0.82 (95% confidence interval: 0.74 to 0.91), P = 0.0001]. However, once on cART, there were no differences in virological, immunological, and clinical outcomes.This study demonstrates that despite BME MSM being a "minority within a minority" for those HIV infected, there are few ethnic disparities in access to and treatment outcomes in our setting.

Late diagnosis in the HAART era: proposed common definitions and associations with mortality

To identify a definition of presentation after clinical or immunological disease progression that will reliably identify an individual at high risk of mortality over the first 3 months after HIV diagnosis and that can be adopted as a basis for comparing over time and regions. An observational cohort study. Individuals seen for the first time at a UK Collaborative HIV Cohort study clinic from 1996 to 2006 were identified. Two immunological (CD4 cell count < 200 cells/microl and CD4 cell count <50 cells/microl) and two clinical (AIDS and severe/moderate AIDS) criteria for presentation with advanced HIV disease were compared, as well as combinations of them. The predictive ability of each diagnosis for identifying individuals who died in the first 3 months after HIV diagnosis was assessed. Fifteen thousand seven hundred and seventy-four patients were included, of whom 1495 (9.5%), 4231 (26.8%), 1523 (9.7%) and 379 (2.4%) had a CD4 cell count below 50 cells/microl, CD4 cell count below 200 cells/microl, AIDS or severe/moderate AIDS at diagnosis; CD4 cell counts were unavailable for 2264 (14.4%) patients. Two hundred and six (1.3%) patients died within the first 3 months. Sensitivities of the individual criteria ranged from 18.0% (severe/moderate AIDS) to 50.5% (CD4 cell count < 200 cells/microl) with specificities ranging from 73.5% (CD4 < 200 cells/microl) to 97.8% (severe/moderate AIDS). Combinations of clinical and immunological criteria increased the sensitivity but decreased the specificity. We propose that presentation with 'advanced HIV disease' is presentation with a CD4 cell count below 200 cells/microl or AIDS, whereas 'late' presentation is defined as presentation when the CD4 cell count is below that when treatment should be initiated (currently CD4 cell count < 350 cells/microl or AIDS).

Discordant responses on starting highly active antiretroviral therapy: suboptimal CD4 increases despite early viral suppression in the UK Collaborative HIV Cohort (UK CHIC) Study

Patients starting highly active antiretroviral therapy (HAART) may have a suboptimal CD4 increase despite rapid virological suppression. The frequency and the significance for patient care of this discordant response are uncertain. This study was designed to determine the incidence of a discordant response at two time-points, soon after 6 months and at 12 months, and to determine the relationship with clinical outcomes. Data obtained in the UK Collaborative HIV Cohort Study were analysed. A total of 2584 treatment-naïve patients starting HAART with HIV viral load (VL) > 1000 HIV-1 RNA copies/mL at baseline and < 50 copies/mL within 6 months were included in the analysis. Patients were classified at either 6-10 (midpoint 8) months or 10-14 (midpoint 12) months as having a discordant (CD4 count increase < 100 cells/microL from baseline) or concordant response (CD4 count increase >or= 100 cells/microL). Discordant responses occurred in 32.1% of patients at 8 months and in 24.2% at 12 months; 35% of those discordant at 8 months were concordant at 12 months. A discordant response was associated with older age, lower baseline VL, and (at 12 months) higher baseline CD4 cell count. In a multivariate analysis it was associated with an increased risk of death, more strongly at 12 months [incidence rate ratio (IRR) 3.35, 95% confidence interval (CI) 1.73-6.47, P < 0.001] than at 8 months (IRR 2.08, 95% CI 1.19-3.64, P = 0.010), but not with new AIDS events. Discordant responders have a worse outcome, but assessment at 12 months may be preferred, given the number of 'slow' responders. Management strategies to improve outcomes for discordant responders need to be investigated.

Population Trends in the Prevalence and Patterns of Protease Resistance Related to Exposure to Unboosted and Boosted Protease Inhibitors

In recent years, several new drugs from the protease inhibitor (PI) class designed to treat HIV infection have become available and the use of ritonavir-boosting has increased in popularity. These changes might be expected to affect the prevalence and patterns of protease resistance in the population of patients who experience treatment failure. The UK HIV Drug Resistance Database aims to capture the results of all genotypic resistance tests conducted nationally. Tests on antiretroviral therapy-experienced patients were identified through linkage with the UK Collaborative HIV Cohort Study, from which detailed clinical information on these patients, including a full antiretroviral therapy history, was obtained. Analyses were on the basis of 8,553 genotypic resistance tests carried out between 1998 and 2005, during which time the overall prevalence of protease resistance halved from 35% to 16%. Substantial declines were observed regardless of whether the patient had been exposed to unboosted PIs and/or boosted PIs. The frequency of protease resistance among patients who had received boosted PIs fell sharply until 2002 with a weaker trend thereafter, falling to 12% in 2005. Individual mutations L33F, M461/L, V82A/F/T/S/L and 184V became relatively more frequent over the period of study. The decline in protease resistance was partly due to increasing use of ritonavir-boosting. Nonetheless, the prevalence of resistance was higher than suggested by clinical trials, indicating that prolonged exposure to a boosted PI could ultimately select for major protease mutations.

The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study.

This paper describes the development of the UK Collaborative HIV Cohort (CHIC) Study. The aim of the study is to collate routinely collected data on HIV-infected individuals attending one of seven clinical centres in the UK since 1 January 1996, with the objectives of describing changes over time in the frequency of AIDS-defining illnesses, describing the uptake of and response to highly active antiretroviral therapy (HAART), and identifying factors associated with virological and immunological responses to HAART. By December 2002, demographic, clinical and laboratory data had been collected on HIV-positive patients seen at six of the seven HIV centres. Missing and inconsistent data had been investigated and the datasets audited. Records identified as relating to the same patient had been merged, and cross-checks made with UK death registers to improve the accuracy of death reporting. The cohort currently contains information on 13,833 individuals. Eighty-two per cent of the cohort are male, and the median age was 34 years at first follow-up. The main risk factors for HIV infection have been determined as sex between men (63%) and sex between men and women (24%). Twenty-five per cent of the cohort are known to have developed AIDS, and 8% have died. The UK CHIC Study provides important information on the status of individuals infected with HIV in the UK, and provides a means to study the response to HAART and to monitor changes in the clinical event and death rates that have occurred since the introduction of HAART in the UK.