Hong-Ha M. Truong

Increases in sexually transmitted infections and sexual risk behaviour without a concurrent increase in HIV incidence among men who have sex with men in San Francisco: a suggestion of HIV serosorting?

Background: Sexually transmitted infections (STI) and unprotected anal intercourse (UAI) have been increasing among men who have sex with men (MSM) in San Francisco. However, HIV incidence has stabilised. Objectives: To describe recent trends in sexual risk behaviour, STI, and HIV incidence among MSM in San Francisco and to assess whether increases in HIV serosorting (that is, selective unprotected sex with partners of the same HIV status) may contribute to preventing further expansion of the epidemic. Methods: The study applies an ecological approach and follows the principles of second generation HIV surveillance. Temporal trends in biological and behavioural measures among MSM were assessed using multiple pre-existing data sources: STI case reporting, prevention outreach programmatic data, and voluntary HIV counselling and testing data. Results: Reported STI cases among MSM rose from 1998 through 2004, although the rate of increase slowed between 2002 and 2004. Rectal gonorrhoea cases increased from 157 to 389 while early syphilis increased from nine to 492. UAI increased overall from 1998 to 2004 (p<0.001) in community based surveys; however, UAI with partners of unknown HIV serostatus decreased overall (p<0.001) among HIV negative MSM, and among HIV positive MSM it declined from 30.7% in 2001 to a low of 21.0% in 2004 (p<0.001). Any UAI, receptive UAI, and insertive UAI with a known HIV positive partner decreased overall from 1998 to 2004 (p<0.001) among MSM seeking anonymous HIV testing and at the STI clinic testing programme. HIV incidence using the serological testing algorithm for recent HIV seroconversion (STARHS) peaked in 1999 at 4.1% at the anonymous testing sites and 4.8% at the STI clinic voluntary testing programme, with rates levelling off through 2004. Conclusions: HIV incidence among MSM appears to have stabilised at a plateau following several years of resurgence. Increases in the selection of sexual partners of concordant HIV serostatus may be contributing to the stabilisation of the epidemic. However, current incidence rates of STI and HIV remain high. Moreover, a strategy of risk reduction by HIV serosorting can be severely limited by imperfect knowledge of one’s own and one’s partners’ serostatus.

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Routine surveillance for the detection of acute and recent HIV infections and transmission of antiretroviral resistance

Objective:To estimate the rate of acute and recent HIV infections and the prevalence of primary antiretroviral resistance. Design, setting, and subjects:A consecutive sample of individuals presenting for HIV testing at the San Francisco municipal sexually transmitted diseased (STD) clinic in 2004 (n = 3789). Main outcome measures:HIV antibody-positive specimens were screened by BED IgG capture enzyme immunoassay to identify recent infections. HIV antibody-negative specimens were screened by nucleic acid amplification testing (NAAT) to detect acute infections. Newly detected infections were genotyped to detect primary antiretroviral resistance. Results:There were 11 acute and 44 recent HIV infections among the total 136 newly detected cases. NAAT increased case identification by 8.08% over standard antibody testing. Acute HIV infections were associated with having a known HIV-positive partner, and a history of hepatitis B, syphilis, and chlamydia. The prevalence of primary antiretroviral resistance was 13.2%, with drug-resistant mutations detected in 17 of 129 cases genotyped. Mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) were present in 11 of 17 cases. Conclusion:The integration of HIV nucleic acid amplification, recent infection, and antiretroviral resistance testing enhanced HIV/STD surveillance. The high proportion of NNRTI mutations detected suggests they may be more common in source partners or more fit for transmission than other forms of drug-resistant HIV-1. Primary antiretroviral resistance monitoring in STD clinic patients may guide the selection of treatment and post-exposure prophylaxis regimens active against viruses being transmitted in the community, and provide health departments with surveillance data in a sentinel population at risk of HIV transmission.

HIV is hyperendemic among men who have sex with men in San Francisco: 10-year trends in HIV incidence, HIV prevalence, sexually transmitted infections and sexual risk behaviour.

Objectives: To evaluate trends in the HIV epidemic among men who have sex with men (MSM) in San Francisco and the implications for HIV prevention. Methods: An ecological approach assessed temporal trends in sexual risk behaviour, sexually transmitted infections (STI), HIV incidence and prevalence from multiple data sources between 1998 and 2007. Results: By 2007, there were over 13 000 HIV-infected MSM living in San Francisco. No consistent upward or downward temporal trends were found in HIV incidence, newly reported HIV cases, AIDS deaths, proportion of AIDS cases using antiretroviral therapy, rectal gonorrhoea or primary and secondary syphilis cases among MSM during the study period. Trends in indicators of sexual risk behaviour among MSM were mixed. Overall, unprotected anal intercourse (UAI) increased in community-based surveys. Among HIV-positive MSM, no significant trends were noted for UAI. Among HIV-negative MSM, UAI with unknown serostatus partners decreased but increased with potentially discordant serostatus partners. Among MSM seeking HIV testing, increases were noted in insertive UAI at anonymous testing sites and at the STI clinic, in receptive UAI at anonymous test sites and in receptive UAI with a known HIV-positive partner at the STI clinic. Conclusions: Temporal trends in multiple biological and behavioural indicators over the past decade describe a hyperendemic state of HIV infection among MSM in San Francisco, whereby prevalence has stabilised at a very high level. In the absence of new, effective prevention strategies this state will persist.

Sentinel Surveillance of HIV-1 Transmitted Drug Resistance, Acute Infection and Recent Infection

Background HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT) services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection. Methodology/Principal Findings A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI) clinic from 2004 to 2006 (N = 9,868) were evaluated by standard enzyme-linked immunoassays (EIA). HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) was the most common pattern detected, present in 28 cases of resistance (59.6%). Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001), unprotected anal intercourse (AOR = 2.27; p<0.001), sex with a known HIV-infected partner (AOR = 1.64; p = 0.02), and history of gonorrhea (AOR = 1.62; p = 0.03). Conclusions New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment.

Assessing subtype and drug-resistance-associated mutations among antiretroviral-treated HIV-infected patients

Background:Several studies have reported an increasing number of therapeutic failures with antiretroviral drugs in HIV-infected patients. The emergence of viral-resistant strains is a major problem for the medical management of infected individuals. The aim of this study is to determine viral subtypes and drug-resistance mutations among antiretroviral-treated HIV-infected patients. Methods:A total of 42 antiretroviral-treated but still viremic HIV-infected patients were enrolled. The HIV pol regions were amplified and sequenced to determine subtypes and antiretroviral-resistant mutations. Results:The subtype distribution was 48% A/D recombinants, 43% subtype B, 5% subtype A and 5% CRF01-AE recombinants. Drug-resistant mutations were most common in subtype B (53%) and A/D recombinant strains (44%). Virus samples from 19% of participants had no drug-resistant mutations; 2, 2 and 76% of samples carried one, two and at least three drug-resistant mutations, respectively. The prevalence of nucleoside transcriptase inhibitor mutations was 76%, with M184V and L74V present in 60 and 38% of samples, respectively. The prevalence of nonnucleoside transcriptase inhibitor mutations was 74%, with P225H present in 55% of study specimens. The prevalence of protease inhibitor mutations was 45%, with major mutation L90M seen in 33% and minor mutation A71V in 36% of samples. Of note, the P225H and A71V are ‘minor’ drug-resistance mutations conferring only minimal drug-resistance phenotypes in the absence of major mutations. Conclusion:Our study found a high prevalence of drug-resistant mutations in Iranian HIV-infected patients. Our data support the need for continued surveillance of resistance patterns to help guide therapeutic approaches and limit transmission of these variants.

Strategies Used in the Detection of Acute/Early HIV Infections. The NIMH Multisite Acute HIV Infection Study: I

Acute/early HIV infection plays a critical role in onward HIV transmission. Detection of HIV infections during this period provides an important early opportunity to offer interventions which may prevent further transmission. In six US cities, persons with acute/early HIV infection were identified using either HIV RNA testing of pooled sera from persons screened HIV antibody negative or through clinical referral of persons with acute or early infections. Fifty-one cases were identified and 34 (68%) were enrolled into the study; 28 (82%) were acute infections and 6 (18%) were early infections. Of those enrolled, 13 (38%) were identified through HIV pooled testing of 7,633 HIV antibody negative sera and 21 (62%) through referral. Both strategies identified cases that would have been missed under current HIV testing and counseling protocols. Efforts to identify newly infected persons should target specific populations and geographic areas based on knowledge of the local epidemiology of incident infections.

Lack of Understanding of Acute HIV Infection among Newly-Infected Persons—Implications for Prevention and Public Health: The NIMH Multisite Acute HIV Infection Study: II

Acute/early HIV infection is a period of high HIV transmission. Consequently, early detection of HIV infection and targeted HIV prevention could prevent a significant proportion of new transmissions. As part of an NIMH-funded multisite study, we used in-depth interviews to explore understandings of acute HIV infection (AHI) among 34 individuals diagnosed with acute/early HIV infection in six US cities. We found a marked lack of awareness of AHI-related acute retroviral symptoms and a lack of clarity about AHI testing methods. Most participants knew little about the meaning and/or consequences of AHI, particularly that it is a period of elevated infectiousness. Over time and after the acute stage of infection, many participants acquired understanding of AHI from varied sources, including the Internet, HIV-infected friends, and health clinic employees. There is a need to promote targeted education about AHI to reduce the rapid spread of HIV associated with acute/early infection within communities at risk for HIV.

Recent HIV-1 infection detection: comparison of incidence estimates derived by laboratory assays and repeat testing data.

Introduction:Advances in laboratory methods capable of detecting recent HIV infection offer the promise of quickly and efficiently measuring HIV incidence in cross-sectional surveys, thereby greatly expanding the capabilities of surveillance programs. We compared HIV-1 incidence estimates derived from 3 different methods: Vironostika-less sensitive, BED capture enzyme immuno assay (BED-CEIA), and repeat testing history. Methods:A cross-sectional analysis was performed using HIV testing data from the population of all men who have sex with men presenting for serological HIV voluntary counseling and testing at the largest testing programs in San Francisco from 2000 to 2004 (n = 15,010). Specimens were evaluated for recent HIV-1 infection using Vironostika-LS and BED-CEIA. Concordance between the 2 assays was assessed using the Kappa statistic. Results:The BED-CEIA and Vironostika-LS concurred in 90% of specimen classifications (Kappa = 0.77; “good” strength of agreement). Predictors of recent HIV-1 infection common to both methods were unprotected receptive anal intercourse (P < 0.001), sex with a known HIV-positive partner (P < 0.001), and amphetamine use (P < 0.01). Temporal trends in HIV-1 incidence were also consistent and stable. Conclusions:There was good concordance in the classification of recent HIV-1 infection between BED-CEIA and Vironostika-LS and in the correlates of acquisition of infection. The findings suggest that these incidence assays can be used for the basic epidemiological purposes of measuring HIV-1 incidence, identifying populations at risk for infection, and tracking the leading edge of the epidemic over time.

Balancing Theory and Practice in Respondent-Driven Sampling: A Case Study of Innovations Developed to Overcome Recruitment Challenges

Introduction Respondent-driven sampling (RDS) offers a recruitment strategy for hard-to-reach populations. However, RDS faces logistical and theoretical challenges that threaten efficiency and validity in settings worldwide. We present innovative adaptations to conventional RDS to overcome barriers encountered in recruiting a large, representative sample of men who have sex with men (MSM) who travel internationally. Methods Novel methodological adaptations for the “International Travel Research to Inform Prevention” or “I-TRIP” study were offering participants a choice between electronic and paper coupons referrals for recruitment and modifying the secondary incentives structure from small cash amounts to raffle entries for periodic large cash prize raffle drawings. Staged referral limit increases from 3 to 10 referrals and progressive addition of 70 seeds were also implemented. Results There were 501 participants enrolled in up to 13 waves of growth. Among participants with a choice of referral methods, 81% selected electronic referrals. Of participants who were recruited electronically, 90% chose to remain with electronic referrals when it was their turn to recruit. The mean number of enrolled referrals was 0.91 for electronic referrals compared to 0.56 for paper coupons. Median referral lag time, i.e., the time interval between when recruiters were given their referrals and when a referred individual enrolled in the study, was 20 days (IQR 10–40) for electronic referrals, 20 days (IQR 8–58) for paper coupons, 20 days (IQR 10–41) for raffle entries and 33 days (IQR 16–148) for small cash incentives. Conclusions The recruitment of MSM who travel internationally required maximizing known flexible tools of RDS while at the same time necessitating innovations to increase recruitment efficiency. Electronic referrals emerged as a major advantage in recruiting this hard-to-reach population who are of high socio-economic status, geographically diffuse and highly mobile. These enhancements may improve the performance of RDS in target populations with similar characteristics.