Christopher B. Hurt

Pre-Exposure Prophylaxis and Antiretroviral Resistance: HIV Prevention at a Cost?

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)-uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance.

Sex with older partners is associated with primary HIV infection among men who have sex with men in North Carolina

Background:Studies from the 1990s suggested sex with older partners was associated with HIV infection. We evaluated the hypothesized association between primary HIV infection (PHI) and having older sexual partners among men who have sex with men (MSM). Methods:MSM with PHI and HIV-uninfected MSM completed audio computer-assisted self-interviews exploring behaviors involving their 3 most recent sexual partners before enrollment (if uninfected) or diagnosis (if PHI). Results:Of 74 men reporting any lifetime sex with men, 20 had PHI (27%). Demographics (including age) were similar between groups; 39% were non-white and 74% identified as gay. The mean age of sex partners differed significantly: men with PHI had partners on average 6 years older than themselves, whereas uninfected mens partners were 4 months their junior (P < 0.001). After adjusting for race, sex while intoxicated, and having a serodiscordant/serostatus unknown partner, a participant had twice the odds of PHI if his sex partner was 5 years his senior (odds ratio 2.0, 95% confidence interval: 1.2 to 3.3). Conclusions:Among a sample of young MSM, the odds of HIV infection increased significantly as the age of sexual partners increased. These findings can inform behavioral interventions in communities of at-risk MSM and secondary prevention efforts among those already living with HIV.

Investigating A Sexual Network of Black Men Who Have Sex with Men: Implications for Transmission and Prevention of HIV Infection in the United States

Background:HIV infections increased 48% among young Black men who have sex with men (MSM) in the United States between 2006 and 2009. Incomplete understanding of this trend undermines prevention strategy development. We investigated a sexual network to characterize the risk environment in which young Black MSM acquire HIV. Methods:Persons reported to the state after diagnosis of HIV or syphilis were included, along with sexual partners. We used network mapping alongside descriptive and bivariate statistics to characterize network connections. Generalized linear models assessed predictors of having untraceable sex partners. Results:The network included 398 individuals and 419 sexual relationships. Three-quarters were Black (n = 299); 92% were MSM. Median age at first network appearance was 26 years and decreased over time (P < 0.001). HIV prevalence was at least 29% (n = 117); serostatus was unknown for 47% of the network, either because they were untraceable (n = 150) or refused HIV testing (n = 39). One in 5 network members diagnosed with HIV had a subsequent incident sexually transmitted infection. In multivariable models, one-time encounters increased the risk of having an untraceable partner (risk ratio = 4.51, 95% CI: 2.27 to 8.97), whereas being acutely HIV infected at diagnosis reduced it (risk ratio = 0.27, 95% CI: 0.08 to 0.89). Conclusions:HIV prevalence in this sexual network of young Black MSM rivals that of sub-Saharan Africa, reflecting dramatically increased risk of acquiring HIV from the moment one entered the network. Prevention efforts for this population must consider the effect of sexual networks on HIV risk and find ways of leveraging network structure to reduce transmission.

Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients.

Abstract:The associations of acute HIV infection (AHI) and other predictors with transmitted drug resistance (TDR) prevalence were assessed in a cohort of HIV-infected, antiretroviral-naïve patients. AHI was defined as being seronegative with detectable HIV RNA. Binomial regression was used to estimate prevalence ratios and 95% confidence intervals for associations with TDR. Among 43 AHI patients, TDR prevalence was 20.9%, whereas prevalence was 8.6% among 677 chronically infected patients. AHI was associated with 1.9 times the prevalence of TDR (95% confidence intervals: 1.0 to 3.6) in multivariable analysis. AHI patients may represent a vanguard group that portends increasing TDR in the future.

Phylogenetic insights into regional HIV transmission.

Objectives:Despite prevention efforts, new HIV diagnoses continue in the southern United States, where the epidemic is characterized by significant racial/ethnic disparities. We integrated phylogenetic analyses with clinical data to reveal trends in local HIV transmission. Design:Cross-sectional analysis of 1671 HIV-infected individuals each with one B-subtype pol sequence obtained during chronic (82%; UNC Center for AIDS Research Clinical Cohort) or acute/recent (18%; Duke/UNC Acute HIV Consortium) infection. Methods:Phylogenies were inferred using neighbor joining to select related sequences then confirmed with Bayesian methods. We characterized transmission clusters (clades n ≥ 3 sequences supported by posterior probabilities = 1) by factors including race/ethnicity and transmission risk. Factors associated with cluster membership were evaluated for newly diagnosed patients. Results:Overall, 72% were men, 59% black and 39% men who have sex with men (MSM). A total of 557 (33%) sequences grouped in either 108 pairs (n = 216) or 67 clusters (n = 341). Clusters ranged from three to 36 (median 4) members. Composition was delineated primarily by race, with 28% exclusively black, and to a lesser extent by risk group. Both MSM and heterosexuals formed discrete clusters, although substantial mixing was observed. In multivariable analysis, patients with age 30 years or less (P = 0.009), acute infection (P = 0.02), local residence (P = 0.002) and transmitted drug resistance (P = 0.02) were more likely to be cluster members, whereas Latinos were less likely (P < 0.001). Conclusion:Integration of molecular, clinical and demographic data offers a unique view into the structure of local transmission networks. Clustering by black race, youth and transmitted drug resistance and inability to identify Latino clusters will inform prevention, testing and linkage to care strategies.

Barriers and Facilitators to HIV Testing and Linkage to Primary Care: Narratives of People with Advanced HIV in the Southeast

Abstract Persons with unrecognized HIV infection forgo timely clinical intervention and may unknowingly transmit HIV to partners. However, in the USA, unrecognized infection and late diagnosis are common. To understand barriers and facilitators to HIV testing and care, we conducted a qualitative study of 24 HIV infected persons attending a Southeastern HIV clinic who presented with clinically advanced illness. The primary barrier to HIV testing prior to diagnosis was perception of risk; consequently, most participants were diagnosed after the onset of clinical symptoms. While most patients were anxious to initiate care rapidly after diagnosis, some felt frustrated by the passive process of connecting to specialty care. The first visit with an HIV care provider was identified as critical in the coping process for many patients. Implications for the implementation of Centers for Disease Control and Prevention HIV routine screening guidelines are discussed.

HIV-1 Protease, Reverse Transcriptase, and Integrase Variation.

ABSTRACT HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ≥1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ≥0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ≥0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS. IMPORTANCE Most antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.

Transmitted resistance to HIV integrase strand-transfer inhibitors: right on schedule

Transmitted drug resistance (TDR), the primary acquisition of an HIV variant already resistant to antiretrovirals, affects approximately 15% of all new infections in the United States. Historically, from the time initial agents in the reverse transcriptase, protease and entry inhibitor classes were introduced, it took 3-5 years before the first case reports of TDR appeared. With the description of the first two cases of transmitted integrase stand-transfer inhibitor resistance, it is only a matter of time before the prevalence of TDR affecting this newest antiretroviral class reaches a level warranting baseline resistance testing for all patients entering care.

Transmitted HIV-1 Drug Resistance Among Young Men of Color Who Have Sex With Men: A Multicenter Cohort Analysis

BACKGROUND Given the elevated potential for primary or transmitted drug resistance (TDR) among newly HIV-infected individuals, there is a need for a deeper understanding of the baseline resistance patterns present in young men of color who have sex with men. METHODS Genotypic data were collected for participants aged 13-24 who were enrolled from seven sites. Univariate and bivariate methods were used to describe the prevalence of TDR and characteristics associated with TDR. RESULTS Of the 296 individuals participating in the substudy, 145 (49%) had baseline genotypes. The majority of the individuals were African American (65%) and gay-identified (70%). There was significant variation in genotype availability by site (p < .001). Major surveillance drug resistance mutations were present in 28 subjects (19.3%); the majority were non-nucleoside reverse transcriptase inhibitor mutations (12.4%). Subjects with TDR were less likely to have used alcohol on 1 or more days in the prior 2 weeks. Location was not associated with acquisition of TDR. CONCLUSIONS There was a high rate of TDR in a geographically and racially diverse sample of HIV-infected young men of color who have sex with men. This represents a serious public health concern given the young age of this sample and the potential need for long-term antiretroviral therapy. These findings underscore the critical roles of both early case identification and secondary prevention.

Self-testing for HIV and its impact on public health.

The Centers for Disease Control and Prevention (CDC) estimate that 18% of the 1.15 million persons living with HIV in the United States (U.S.) are unaware of their infection.1 Without the individual and public health benefits afforded by linkage to care and provision of antiretroviral therapy (ART),2 these infected-but-unaware individuals are the source for approximately half of all new sexually transmitted HIV infections in the U.S.3 Minimizing the number of undiagnosed HIV-infected Americans requires expanded coverage of HIV testing and increased testing frequency among those at greatest risk of infection – both of which are important elements of the National HIV/AIDS Strategy’s prevention goals.4