David I. Dolling

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Summary Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir–emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64–96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3–11·3). 13 men (90% CI 9–23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study.

Objective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom. Design Multicentre observational study. Setting All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care. Participants 14 584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009. Main outcome measure Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization. Results 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively). Conclusions The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.

Phylogenetic analyses reveal HIV-1 infections between men misclassified as heterosexual transmissions.

Objective:HIV-1 subtype B infections are associated with MSM in the UK. Yet, around 13% of subtype B infections are found in those reporting heterosexual contact as transmission route. Using phylogenetics, we explored possible misclassification of sexual exposure among men diagnosed with HIV in the UK. Design:Viral gene sequences linked to patient-derived information were used to identify phylogenetic transmission chains. Methods:A total of 22 481 HIV-1 subtype B pol gene sequences sampled between 1996 and 2008 were analysed. Dated phylogenies were reconstructed and transmission clusters identified as clades of at least two sequences with a maximum genetic distance of 4.5%, a branch support of at least 95% and spanning 5 years. The characteristics of clusters containing at least one heterosexually acquired infection were analysed. Results:Twenty-nine percent of the linked heterosexuals clustered exclusively with MSM. These were more likely to be men than women. Estimated misclassification of homosexually acquired infections ranged between 1 and 11% of the reported male heterosexuals diagnosed with HIV. Black African heterosexual men were more often phylogenetically linked to MSM than other ethnic group, with an estimated misclassification range between 1 and 21%. Conclusion:Overall, a small proportion of self-reported heterosexual men diagnosed with HIV could have been infected homosexually. However, up to one in five black African heterosexual men chose not to disclose sex with men at HIV diagnosis and preferred to be identified as heterosexual. Phylogenetic analyses can enhance surveillance-based risk information and inform national programmes for monitoring and preventing HIV infections.

The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults

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.

Evaluating the extent of potential resistance to pre-exposure prophylaxis within the UK HIV-1-infectious population of men who have sex with men

Recent studies have shown that pre‐exposure prophylaxis (PrEP) can substantially reduce the chance of acquiring HIV infection. However, PrEP efficacy has been found to be compromised in macaque studies if the challenge virus is antiretroviral therapy (ART)‐resistant. Our objective was to evaluate the likelihood that a UK man who has sex with men (MSM) would be exposed to PrEP‐resistant HIV in a homosexual encounter with an HIV‐infectious partner.

Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study

Objectives To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir. Methods Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list. Results Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience. Conclusions Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.

HIV-1 Subtype and Virological Response to Antiretroviral Therapy: A Confirmatory Analysis

TO THE EDITOR—In an analysis of data from the Swiss HIV Cohort Study, Scherrer et al intriguingly reported significantly better virological outcomes in white patients infected with human immunodeficiency virus type 1 (HIV-1) non-B subtypes compared with subtype B [1]. However, the authors pointed out the need for confirmatory analyses in other cohort studies. We previously published a similar analysis using merged data from the UK HIV Drug Resistance Database and UK Collaborative HIV Cohort studies but including all patients regardless of ethnicity [2]. We have modified and updated this analysis using the same methods employed in the Swiss study (analysis A) with 2 modifications: patients who received mono/ dual nucleoside reverse transcriptase inhibitors (NRTIs) before initiation of combination antiretroviral therapy (≥3 drugs from ≥2 classes) were excluded, as were patients with intermediate/highlevel resistance to any drug in the initial regimen [3]. Overall, 3471 patients were included in the analysis, of whom 3213 were infected with subtype B virus and 258 with a non-B subtype. Of the non-B subtypes, 110 (43%) were subtype C, 45 (17%) subtype CRF_AE, 39 (15%) subtype A, 22 (9%) subtype CRF_AG, and 42 (16%) other non-B subtypes. The subtype B group was comprised mainly of homosexual men (93%), whereas exposure group in the non-B subtype group was more diverse (44% homosexual men, 27% heterosexual men, 22% heterosexual women). Mean CD4 count (236 cells/mm) and viral load (4.88 log10 copies/mL) at baseline were similar in the 2 groups, as was the class of nonNRTI drug in the initial regimen (67% nonnucleoside reverse transcriptase inhibitor, 25% boosted protease inhibitor [PI], 4% unboosted PI). Figure 1 shows the cumulative proportionof patientswho experienced virological failure over a total 11 117 person-years of follow-up. The 2 curves appear to separate after approximately 1 year, with a lower rate of failure observed in the nonB subtype group. Note that the definition of virological failure encompasses both failure to achieve initial suppression and viral rebound following suppression; Figure 1 suggests that the subtype difference is related to the latter rather than the former. The unadjusted and adjusted (for age, sex, exposure group, baseline viral load, baseline CD4 count, non-NRTI drug class) hazard ratios (HRs) were 0.72 (95% confidence interval [CI], .49–1.06) and 0.78 (95% CI, .51–1.20; P = .26), respectively. Given the infrequent use of regimens that included an unboosted PI, it is most relevant to compare our results with the Swiss analysis that excluded this drug class. The adjusted HR was 0.78 (95% CI, .43–1.40), identical to that found in our analysis though also not reaching statistical significance. It is noted that the distribution of non-B subtypes were very different in the 2 studies, the most common in the Swiss study being CRF_AG. The Figure 1. Kaplan-Meier analysis of time to virological failure. Abbreviation: HAART, highly active antiretroviral therapy.

The Context of Sexual Risk Behaviour Among Men Who Have Sex with Men Seeking PrEP, and the Impact of PrEP on Sexual Behaviour

There are still important gaps in our understanding of how people will incorporate PrEP into their existing HIV prevention strategies. In this paper, we explore how PrEP use impacted existing sexual risk behaviours and risk reduction strategies using qualitative data from the PROUD study. From February 2014 to January 2016, we conducted 41 in-depth interviews with gay, bisexual and other men who have sex with men (GBMSM) enrolled in the PROUD PrEP study at sexual health clinics in England. The interviews were conducted in English and were audio-recorded. The recordings were transcribed, coded and analysed using framework analysis. In the interviews, we explored participants’ sexual behaviour before joining the study and among those using or who had used PrEP, changes to sexual behaviour after starting PrEP. Participants described the risk behaviour and management strategies before using PrEP, which included irregular condom use, sero-sorting, and strategic positioning. Participants described their sexual risk taking before initiating PrEP in the context of the sexualised use of drugs, geographical spaces linked with higher risk sexual norms, and digitised sexual networking, as well as problematic psychological factors that exacerbated risk taking. The findings highlight that in the main, individuals who were already having frequent condomless sex, added PrEP to the existing range of risk management strategies, influencing the boundaries of the ‘rules’ for some but not all. While approximately half the participants reduced other risk reduction strategies after starting PrEP, the other half did not alter their behaviours. PrEP provided an additional HIV prevention option to a cohort of GBMSM at high risk of HIV due to inconsistent use of other prevention options. In summary, PrEP provides a critical and necessary additional HIV prevention option that individuals can add to existing strategies in order to enhance protection, at least from HIV. As a daily pill, PrEP offers protection in the context of the sex cultures associated with sexualised drug use, digitised sexual applications and shifting social norms around sexual fulfilment and risk taking. PrEP can offer short or longer-term options for individuals as their sexual desires change over their life course offering protection from HIV during periods of heightened risk. PrEP should not be perceived or positioned in opposition to the existing HIV prevention toolkit, but rather as additive and as a tool that can and is having a substantial impact on HIV.