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Supplemental Digital Content is available in the text, Background: Increased rates of testing, with early antiretroviral therapy (ART) initiation, represent a key potential HIV-prevention approach. Currently, in MSM in the United Kingdom, it is estimated that 36% are diagnosed by 1 year from infection, and the ART initiation threshold is at CD4+ cell count 350/μl. We investigated what would be required to reduce HIV incidence in MSM to below 1 per 1000 person-years (i.e.

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 (

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 apply a new method to ascertain likely place of HIV infection among persons born abroad and diagnosed with HIV in the United Kingdom (UK). DESIGN: Analyses of heterosexual adults born abroad, diagnosed with HIV in the UK between 2004 and 2010, and reported to the national HIV diagnoses database. METHODS: Year of infection was ascertained by applying an estimated rate of CD4 cell count decline between an individual's CD4 cell count at diagnosis and estimates of CD4-cell count at infection. A person was classified as having probably acquired HIV while living in the UK if estimated year of infection was later than reported year of arrival in the UK. RESULTS: Of 10 612 heterosexual adults born abroad included in the analyses, 85% (9065) were of black-African ethnicity. We estimate that 33% (26-39%) of persons acquired HIV while living in the UK. This percentage increased from 24% (16-39%) in 2004 to 46% (31-50%) in 2010 (P < 0.01). The estimate of 33% is three times higher than national estimates of HIV acquired in the UK based on clinic reports (11%) (P

Background and objectives: Effective antiretroviral therapy (ART) has contributed greatly toward survival for people with HIV, yet many remain undiagnosed until very late. Our aims were to estimate the life expectancy of an HIV-infected MSM living in a developed country with extensive access to ART and healthcare, and to assess the effect of late diagnosis on life expectancy. Methods: A stochastic computer simulation model of HIV infection and the effect of ART was used to estimate life expectancy and determine the distribution of potential lifetime outcomes of an MSM, aged 30 years, who becomes HIV positive in 2010. The effect of altering the diagnosis rate was investigated. Results: Assuming a high rate of HIV diagnosis (median CD4 cell count at diagnosis, 432 cells/ml), projected median age at death (life expectancy) was 75.0 years. This implies 7.0 years of life were lost on average due to HIV. Cumulative risks of death by 5 and 10 years after infection were 2.3 and 5.2%, respectively. The 95% uncertainty bound for life expectancy was (68.0,77.3) years. When a low diagnosis rate was assumed (diagnosis only when symptomatic, median CD4 cell count 140 cells/ml), life expectancy was 71.5 years, implying an average 10.5 years of life lost due to HIV. Conclusion: If low rates of virologic failure observed in treated patients continue, predicted life expectancy is relatively high in people with HIV who can access a wide range of antiretrovirals. The greatest risk of excess mortality is due to delays in HIV diagnosis. 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2012, 26:335–343

The WHO guidelines recommend antiretroviral therapy (ART) begins when CD4 cell counts reach less than 500 cells to reduce HIV transmission. In the UK, 96 000 people were living with HIV (PLWHIV) in 2011, ART coverage was 84% among the diagnosed population and 42% of PLWHIV had detectable viraemia. Using published methods, we estimate starting ART at below 500 CD4 cells could have reduced the proportion of PLWHIV with detectable viraemia from 42% to 38%, whereas halving the undiagnosed population could have led to a decrease to 28%. In the UK, it is unlikely early treatment will reduce HIV transmission unless the undiagnosed population is substantially reduced.

OBJECTIVES To describe the frequency and risk factors of non-B HIV-1 subtypes in men who have sex with men (MSM) in the UK. DESIGN Observational study. METHODS MSM diagnosed with HIV-1 infection from 1980-2007, with HIV genotype held in the UK HIV Drug Resistance Database were identified. Protease and reverse transcriptase sequences were collected and viral clade determined using the REGA algorithm. Associations between demographic variables and subtype were analysed using logistic regression. RESULTS The prevalence of non-B HIV-1 infection amongst MSM in the UK was 5.4% (437/8058). In the UK this increased with year of diagnosis from pre1996 to 2002, and has subsequently remained relatively stable at around 7-9% after 2002, with a recent increase in 2007 to 13%. Multivariate analysis showed that acquisition of non-B HIV-1 infection was independently associated with later year of HIV diagnosis (P < 0.001), black ethnicity (P < 0.001) and non-European country of birth (P = 0.01). Age was also associated with subtype with individuals aged 25-39 years being less likely to have non-B virus than those aged less than 25 years (P = 0.01). Restricting the analysis to white men born in the UK, the association between subtype and year of diagnosis remained statistically significant (P < 0.001), as did the association with age (P < 0.001). DISCUSSION The number of MSM in the UK infected with non-B clade HIV-1 is increasing, suggesting that the sociodemographic boundaries between HIV-1 viral subtypes globally are diminishing. Should viral subtypes be relevant to clinical disease progression or vaccine design, the changing pattern of distribution will need to be taken into account.

OBJECTIVE: To investigate the incidence of, and risk factors for, tuberculosis among HIV clinic attendees in the United Kingdom. DESIGN AND METHODS: Observational cohort study of 27 868 individuals in the United Kingdom Collaborative HIV Cohort collaboration, 1996-2005. RESULTS: Among individuals not taking combination antiretroviral therapy (cART), tuberculosis incidence was considerably higher among individuals of black African vs. white or other ethnicities {incidence rates 9.9 [95% confidence intervals (CIs) 7.2, 12.6], 2.5 [95% CI 1.8, 3.0] and 4.4 [95% CI 2.7, 6.0] episodes per 1000 person-years, respectively}. Tuberculosis incidence decreased with time after starting cART; among black Africans, incidence was consistently higher and remained substantial (5.3 per 1000 person-years) at 24 months and longer after starting cART. The strongest independent risk factors for tuberculosis after cART start were most recent CD4 cell count: adjusted rate ratios (aRR) 10.65 (95% CI 6.11, 18.57), 3.40 (95% CI 2.05, 5.65), 1.77 (95% CI 1.06, 2.96) and 1.84 (95% CI 1.09, 3.12) for individuals with CD4 cell counts less than 50, 50-199, 200-349 and 350-499 cells/microl, respectively, compared with at least 500 cells/microl; and black African vs. white ethnicity [aRR 2.93 (95% CI 1.89, 4.54)]. HIV risk group, shorter time on cART, later calendar period and unsuppressed viral load were also independently associated with incident tuberculosis. CONCLUSIONS: Tuberculosis incidence among people attending UK HIV clinics is substantial, particularly among those with non-white ethnicity and low CD4 cell counts, even after starting cART. Earlier HIV diagnosis is needed in order to implement interventions to prevent tuberculosis; tuberculosis preventive therapy should be considered in addition to cART.

OBJECTIVES: To compare immunological, virological and clinical outcomes in persons initiating combination antiretroviral therapy (cART of different durations within 6 months of seroconversion (early treated) with those who deferred therapy (deferred group). DESIGN: CD4 cell and HIV-RNA measurements for 'early treated' individuals following treatment cessation were compared with the corresponding ART-free period for the 'deferred' group using piecewise linear mixed models. Individuals identified during primary HIV infection were included if they seroconverted from 1st January 1996 and were at least 15 years of age at seroconversion. Those with at least 2 CD4 less than 350 cells/microl or AIDS within the first 6 months following seroconversion were excluded. RESULTS: Of 348 'early treated' patients, 147 stopped cART following treatment for at least 6 (n = 38), more than 6-12 (n = 40) or more than 12 months (n = 69). CD4 cell loss was steeper for the first 6 months following cART cessation, but subsequent loss rate was similar to the 'deferred' group (n = 675, P = 0.26). Although those treated for more than 12 months appeared to maintain higher CD4 cell counts following cART cessation, those treated for 12 months or less had CD4 cell counts 6 months after cessation comparable to those in the 'deferred' group. There was no difference in HIV-RNA set points between the 'early' and 'deferred' groups (P = 0.57). AIDS rates were similar but death rates, mainly due to non-AIDS causes, were higher in the 'deferred' group (P = 0.05). CONCLUSION: Transient cART, initiated within 6 months of seroconversion, seems to have no effect on viral load set point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months. Its long-term effects remain inconclusive and need further investigation

OBJECTIVE To describe the time from first viral rebound on highly active antiretroviral therapy to first treatment change, identify factors associated with more rapid switching, and investigate whether treatment changes are in line with treatment guidelines. DESIGN AND SETTING A multicentre cohort study. METHODS We described the time to first treatment switch among individuals experiencing confirmed virological rebound after initiating highly active antiretroviral therapy; factors associated with more rapid switching were identified using proportional hazards regression and predictors of a switch in line with guidelines were identified using logistic regression. RESULTS Thirty-four percent of the 694 patients experiencing virological rebound remained on a failing regimen for more than 6 months. Factors associated with more rapid switching were lower CD4 cell count (hazard ratio, 0.84 /100 cells/mul higher, P < 0.001), higher viral load (1.29 /log10 copies/ml higher, P < 0.001), older age (1.06 /5 years older, P = 0.07), and changing/adding drugs to the regimen prior to rebound (1.16, P = 0.16). Two hundred and eighteen of the 394 treatment changes (55%) were in line with guidelines; those receiving nonnucleoside reverse transcriptase inhibitor-containing regimens were more likely to make changes in line with guidelines (adjusted odds ratio, 2.80, P < 0.001), whereas those who had previously added drugs to their regimen were less likely to make changes in line with guidelines (0.15, P = 0.001). CONCLUSION A substantial minority of patients remain on a failing highly active antiretroviral therapy regimen for periods of 6 months or longer without adding new drugs. Changes made are often not in line with treatment guidelines, raising concerns about the development of resistance and long-term clinical outcomes in these individuals.

We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure.All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) ofor = 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VLor = 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression.Of 12 648 patients on HAART 10 237 (80.9%) achieved a VLor = 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound 'event', with 2460 events in total [rebound rate, 9.3 (range, 8.9-9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5-9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6-37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for4 years were similar to those in patients who had at no time experienced treatment failure.After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure.