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Purpose of Review: Genotypic resistance testing has become part of routine clinical management of HIV-infected patients. Focussing on observational studies, this review looks at recent advances in this area., Recent Findings: Translation of the nucleotide sequence generated by the resistance test into clinically useful information remains a major challenge. A recent key development is the availability of therapy optimization tools to predict regimens that are most likely to achieve virological suppression. Standard genotypic resistance testing only examines protease and part of reverse transcriptase; as drugs are licensed to further targets, it has become necessary to expand the repertoire for testing. Traditionally, genotypic testing has not been attempted at viral loads less than 1000 copies/ml, but recent studies indicate that major mutations are often detected at much lower levels. Similarly, various methods have been developed for the detection of minority variants including allele-specific PCR, single-genome sequencing, and ultra-deep sequencing., Summary: The technology and interpretation of genotypic resistance tests is in a phase of rapid development. It remains uncertain which of these developments will become part of routine clinical practice.

Background: The use of different lists of resistance mutations has resulted in estimates of transmitted HIV drug resistance (THDR) that are often not comparable., Methods: We estimated the rate of THDR based on the 3 definitions: > or =1 major mutation(s) listed on the International AIDS Society (IAS)-USA drug resistance mutation (DRM) 2006 list; > or =1 surveillance drug resistance mutation(s) (SDRM) on the published list by Shafer et al; and low-level/intermediate/high-level resistance to > or =1 drug(s) according to the Stanford HIVdb interpretation algorithm. Analyses were based on genotypic resistance tests conducted during 1997-2005 on antiretroviral therapy-naive patients and reported to the UK HIV Drug Resistance Database. The effect on THDR rates of revisions to the IAS-DRM list was also examined., Results: Overall, 10.0%, 9.2%, and 10.4% of the 8272 samples available for analysis were classified as having THDR by the IAS-DRM, SDRM, and Stanford definitions, respectively; however, there was discordance for 244 (3%) samples. Changes in the version of the IAS-DRM list over time resulted in 4%-7% differences in the estimated rate of THDR, which increased from 4%-5% during 1997-2000 to 5%-7% during 2001-2005., Conclusions: The choice of genotypic definition had a minor influence on the estimated rate of THDR. The SDRM list is recommended for epidemiological estimates of THDR as it has been designed with such studies in mind.

The design and analysis of active-control trials to evaluate experimental HIV pre-exposure prophylaxis (PrEP) agents pose serious statistical challenges. We recently proposed a new outcome measure, the averted infections ratio (AIR) - the proportion of infections that would be averted by using the experimental agent rather than the control agent (compared to no intervention). The main aim of the current paper is to examine the mathematical connection between AIR and the HIV incidence rate ratio, the standard outcome measure. We also consider the sample size implications of the choice of primary outcome measure and explore the connection between effectiveness and efficacy under a simplified model of adherence.

ObjectivesTo determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.MethodsResistance 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.ResultsFour 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.ConclusionsViral 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.

Introduction: Randomized trials of new agents for HIV pre‐exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well‐characterized adherence‐efficacy relationship for F/TDF to back‐calculate the (non‐PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV). Methods: The DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non‐inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV‐DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV. Results: There were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person‐years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV‐negative controls, 5% of the person‐time years had low, 9% had medium and 86% had high TFV‐DP levels. A non‐informative prior distribution for counterfactual bHIV, combined with the prior for TFV‐DP level‐efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV. Conclusions: Based on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non‐PrEP control group in randomized, active‐controlled PrEP trials that include a F/TDF‐comparator group. [ABSTRACT FROM AUTHOR]

Background: HIV treatment guidelines have traditionally recommended that all HIV-positive individuals are tested for evidence of drug resistance prior to starting ART. Testing for resistance to reverse transcriptase inhibitors and PIs is well established in routine care. However, testing for integrase strand transfer inhibitor (InSTI) resistance is less consistent.Objectives: To inform treatment guidelines by determining the prevalence of InSTI resistance in a national cohort of recently infected individuals.Patients and Methods: Recent (within 4 months) HIV-1 infections were identified using a Recent Infection Testing Algorithm of new HIV-1 diagnoses in the UK. Resistance-associated mutations (RAMs) in integrase, protease and reverse transcriptase were detected by ultradeep sequencing, which allows for the sensitive estimation of the frequency of each resistant variant in a sample.Results: The analysis included 655 randomly selected individuals (median age = 33 years, 95% male, 83% MSM, 78% white) sampled in the period 2014 to 2016 and determined to have a recent infection. These comprised 320, 138 and 197 samples from 2014, 2015 and 2016, respectively. None of the samples had major InSTI RAMs occurring at high variant frequency (≥20%). A subset (25/640, 3.9%) had major InSTI RAMs occurring only as low-frequency variants (2%-20%). In contrast, 47/588 (8.0%) had major reverse transcriptase inhibitor and PI RAMs at high frequency.Conclusions: Between 2014 and 2016, major InSTI RAMs were uncommon in adults with recent HIV-1 infection, only occurring as low-frequency variants of doubtful clinical significance. Continued surveillance of newly diagnosed patients for evidence of transmitted InSTI resistance is recommended to inform clinical practice. [ABSTRACT FROM AUTHOR]

Background Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. Methods Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. Results Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P <.00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P <.00001). Conclusions Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals. [ABSTRACT FROM AUTHOR]

Objectives: Pre-exposure prophylaxis (PrEP) is a highly effective method of HIV prevention for men who have sex with men (MSM). However, uncertainty remains around the optimal eligibility criteria for PrEP, specifically whether there are subgroups at low risk of HIV for whom PrEP might not be warranted.Methods: PROUD was an open-label waitlist trial design that randomised MSM attending participating sexual health centres in England to receive PrEP immediately (IMM) or after a deferral period of 1 year (DEF). This analysis is based on participants who were randomised to the deferred arm, when they did not have access to PrEP. HIV incidence was compared between subgroups defined by baseline characteristics.Results: Overall, 21 participants acquired HIV infection over 239.3 person-years (PY) follow-up, yielding an incidence rate of 8.8/100 PY (95% CI 5.4 to 13.4). Two highly significant predictors for HIV acquisition were identified. Men with a self-reported diagnosis of syphilis, rectal chlamydia (CT) or rectal gonorrhoea (GC) in the previous 12 months had an incidence of 17.2/100 PY (95% CI 9.7 to 28.5); those reporting receptive anal intercourse without a condom (ncRAI) with two or more partners in the previous 3 months had an incidence of 13.6/100 PY (95% CI 7.9 to 21.7). The incidence rate among participants lacking both of these risk factors was 1.1/100 PY (1/87.6, 95% CI 0.03 to 6.4).Conclusions: The high HIV incidence in PROUD suggests that most participants appropriately judged their need for PrEP. Eligibility criteria for a PrEP programme can therefore be broad, as in the current guidelines. However, a recent history of syphilis or rectal CT/GC, or multiple ncRAI partners indicates a high imminent risk of HIV infection. MSM with any of these characteristics should be offered PrEP as a matter of urgency. [ABSTRACT FROM AUTHOR]

Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.Results: Subtype B patients ( n  =   3410) were mostly MSM (78%) and those with subtype C ( n  =   810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P  <   0.001).Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated. [ABSTRACT FROM AUTHOR]

Background: Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting.Patients and methods: A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics).Results: At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18).Conclusions: Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring. [ABSTRACT FROM AUTHOR]

Background: Darunavir 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.Objectives: We examined darunavir DRMs emerging in clinical practice in the UK.Patients and Methods: Baseline 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.Results: Of 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.Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

Concern has been expressed that tenofovir-containing regimens may have reduced effectiveness in the treatment of human immunodeficiency virus type 1 (HIV-1) subtype C infections because of a propensity for these viruses to develop a key tenofovir-associated resistance mutation. We evaluated whether subtype influenced rates of virological failure in a cohort of 8746 patients from the United Kingdom who received a standard tenofovir-containing first-line regimen and were followed for a median of 3.3 years. In unadjusted analyses, the rate of failure was approximately 2-fold higher among patients infected with subtype C virus as compared to those with subtype B virus (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.50-2.31; P < .001). However, the increased risk was greatly attenuated in analyses adjusting for demographic and clinical factors (adjusted HR, 1.14; 95% CI, .83-1.58; P = .41). There were no differences between subtypes C and subtypes non-B and non-C in either univariate or multivariate analysis. These observations imply there is no intrinsic effect of viral subtype on the efficacy of tenofovir-containing regimens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.Methods: The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).Results: No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades.Conclusions: No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed. [ABSTRACT FROM AUTHOR]

Background. About 10% of new diagnoses of subtype B human immunodeficiency virus type 1 (HIV-1) in the United Kingdom are with viruses showing transmitted drug resistance (TDR). However, there is discordance between the mutation patterns observed in HIV-infected patients failing therapy and those seen in TDR. Methods. We extracted all subtype B HIV-1 pol gene sequences from treatment-naive patients within the United Kingdom HIV Drug Resistance Database sampled between 1997 and 2011 and carrying the most common protease inhibitors, nonnucleoside and nucleotide reverse transcriptase inhibitors TDR mutations, namely, L90M, K103N, and T215Y/F/rev, respectively (n = 1140). Transmission clusters (n ≤ 2 sequences) were identified by maximum-likelihood phylogeny using a genetic distance cutoff of ≥1.5%. The time of origin and the basic reproductive number (R0) of clusters were estimated by Bayesian Methods. Results.T215rev was present alone in 47% of the sequences (n = 540), K103N in 31% (n = 359), and L90M in10% (n = 109). The remaining sequences contained T215Y or combinations of L90M, K103N, and T215rev. Fifty-five percent (n = 624) of the sequences formed highly supported transmission clusters (n = 193) containing between 2 and 15 sequences. The time of origin of 10 large clusters (≤8 sequences) was estimated to be between 2000 (1999-2002; 95% highest posterior density [HPD]) and 2006 (2005-2007; 95% HPD). The oldest cluster had persisted for nearly 8 years. All 10 clusters had R0s ranging from 1.3 (0.4-2.5; 95% HPD) to 2.8 (0.6-6.5; 95% HPD). Conclusions. A high proportion of the most common TDR in subtype B infections in the United Kingdom is derived by onward transmission from treatment-naive patients. [ABSTRACT FROM AUTHOR]

: In contrast to resource-rich countries, most HIV-infected patients in resource-limited countries receive treatment without virological monitoring. There are few long-term data, in this setting, on rates of viral suppression or switch to second-line antiretroviral therapy. The DART trial compared clinically driven monitoring (CDM) versus routine laboratory (CD4/haematology/biochemistry) and clinical monitoring (LCM) in HIV-infected adults initiating therapy. There was no virological monitoring in either study group during follow-up, but viral load was measured in Ugandan participants at trial closure. Two thousand three hundred and seventeen (2317) participants from this country initiated antiretroviral therapy with zidovudine/lamivudine plus tenofovir (n = 1717), abacavir (n = 300), or nevirapine (n = 300). Of 1896 (81.8%) participants who were alive and in follow-up at trial closure (median 5.1 years after therapy initiation), 1507 (79.5%) were on first-line and 389 (20.5%) on second-line antiretroviral therapy. The overall switch rate after the first year was 5.6 per 100 person-years; the rate was substantially higher in participants with low baseline CD4 counts (<50 cells/mm3). Among 1207 (80.1%) first-line participants with viral load measured, HIV RNA was <400 copies/ml in 963 (79.8%), 400–999 copies/ml in 37 (3.1%), 1,000–9,999 copies/ml in 110 (9.1%), and ≥10,000 copies/ml in 97 (8.0%). The proportion with HIV RNA <400 copies/ml was slightly lower (difference 7.1%, 95% CI 2.5 to 11.5%) in CDM (76.3%) than in LCM (83.4%). Among 252 (64.8%) second-line participants with viral load measured (median 2.3 years after switch), HIV RNA was <400 copies/ml in 226 (89.7%), with no difference between monitoring strategies. Low switch rates and high, sustained levels of viral suppression are achievable without viral load or CD4 count monitoring in the context of high-quality clinical care. Trial Registration:: ISRCTN13968779 [ABSTRACT FROM AUTHOR]

Introduction. The CD4 count and CD4 percentage (CD4%) are both strong predictors of clinical disease progression in human immunodeficiency virus (HIV). Although individuals may show discordancy between their CD4 count and CD4%, the clinical relevance of this is unclear. Methods. Discordancy was defined where the CD4% was ≤10th percentile for a selected CD4 count range (referred to as low discordancy), within the central 80% range (concordant), or ≥90th percentile (high discordancy). Regression methods identified factors associated with low and high discordancy in untreated individuals and assessed the impact of discordancy on treatment responses to highly active antiretroviral therapy (HAART). Results. High discordancy was associated with female sex, low viral load, and white ethnicity; low discordancy was associated with black or nonwhite ethnicity, older age, and injection drug use. Clinical event rates were higher in individuals with high discordancy starting HAART, but there was no association with subsequent HIV progression by 6 months after starting HAART. CD4 count increases remained lower, by 20 cells/mm3, in individuals with low discordancy, and higher, by 27 cells/mm3, in those with high discordancy. Conclusions. Overall discrepancies between the CD4/CD4% are small, confirming the use of absolute CD4 counts as a monitoring tool. [ABSTRACT FROM AUTHOR]

Background. Many studies of sexual behavior have shown that individuals vary greatly in their number of sexual partners over time, but it has proved difficult to obtain parameter estimates relating to the dynamics of human immunodeficiency virus (HIV) transmission except in small-scale contact tracing studies. Recent developments in molecular phylodynamics have provided new routes to obtain these parameter estimates, and current clinical practice provides suitable data for entire infected populations. Methods. A phylodynamic analysis was performed on partial pol gene sequences obtained for routine clinical care from 14 560 individuals, representing approximately 60% of the HIV-positive men who have sex with men (MSM) under care in the United Kingdom Results. Among individuals linked to others in the data set, 29% are linked to only 1 individual, 41% are linked to 2-10 individuals, and 29% are linked to≤10 individuals. The right-skewed degree distribution can be approximated by a power law, but the data are best fitted by a Waring distribution for all time depths. For time depths of 5-7 years, the distribution parameter q lies within the range that indicates infinite variance. Conclusions. The transmission network among UK MSM is characterized by preferential association such that a randomly distributed intervention would not be expected to stop the epidemic [ABSTRACT FROM AUTHOR]

The article presents a study on the mutations of drug resistance to zidovudine/lamivudine/tenofovir in an antiretroviral therapy (ART) with no real-time viral load monitoring. HIV-1 RNA assaying of stored plasma and genotyping were done to explore the resistance. Results reveal that HIV RNA showed resistance to nucleutide reverse transcriptase inhibitors (NRTIs). The study concludes that the resistance tests yielded reliable data on the evolution and rate of drug resistance.

Background: Pre-exposure prophylaxis (PrEP) is a novel HIV prevention method whereby HIV-negative individuals take the drugs tenofovir and emtricitabine to prevent HIV acquisition. Optimal adherence is critical for PrEP efficacy. Chemsex describes sexual activity under the influence of psychoactive drugs, in the UK typically; crystal methamphetamine, gamma-hydroxybutyrate(GHB) and/or mephedrone. Chemsex drug use has been associated with increased HIV transmission risk among gay, bisexual and other men who have sex with men (GBM) and poor ART adherence among people living with HIV. This study assessed whether self-reported chemsex events affected self-reported daily PrEP adherence among PROUD study participants.Methods: The PROUD study was an open-label, randomised controlled trial, conducted in thirteen English sexual health clinics, assessing effectiveness of TruvadaⓇ-PrEP among 544 HIV-negative GBM. The study reported an 86% risk-reduction of HIV from daily PrEP. Participants were asked about chemsex engagement at follow-up visits. Monthly self-reports of missed PrEP tablets were aggregated to assess adherence between visits. Univariable and multivariable regression analyses were performed to test for associations between chemsex and reporting less than seven out of seven intended doses(<7/7ID) in the 7 days before and/or after last condomless anal intercourse(CAI).Results: 1479 follow-up visit forms and 2260 monthly adherence forms from 388 participants were included in the analyses, with 38.5% visit forms reporting chemsex since last visit and 29.9% follow-up periods reporting <7/7ID. No statistically significant associations were observed between reporting <7/7ID and chemsex (aOR=1.29 [95% CI 0.90-1.87], p = 0.168). Statistically significant associations were seen between reporting <7/7ID and participants perceiving that they would miss PrEP doses during the trial, Asian ethnicity, and reporting unemployment at baseline.Conclusions: These analyses suggest PrEP remains a feasible and effective HIV prevention method for GBM engaging in chemsex, a practise which is prevalent in this group and has been associated with increased HIV transmission risk. [ABSTRACT FROM AUTHOR]