The EXPLORE cohort provided an opportunity to evaluate HIV drug resistance, HIV-1 co-receptor tropism, and HIV-1 subtype in recent infections of MSM in major US cities. Evidence of antiretroviral drug resistance was found in 15.9% of the men studied. This most likely reflects the transmission of antiretroviral drug-resistant strains, since the men were tested using samples collected at or near the time of documented seroconversion. It is important to note that the EXPLORE study population was recruited using behavioral eligibility criteria that specifically identified men who were at high risk of HIV infection. Thus the seroconverters in this study do not necessarily represent all HIV-infected MSM. Other studies of recently infected individuals found resistance rates of 22.7% (1999–2000 in North America, n = 88) , 27.4% (2000–2001 in San Francisco, n = 91) , and 8.3% (1997–2001 in 10 US cities, n = 1082) . In the latter study, the rate of resistance among 482 MSM was similar to what we observed in the EXPLORE cohort (11.6 versus 15.9% in this study) . The resistance rates detected in recently infected individuals may be higher than those detected in individuals with chronic HIV infection. In the SPREAD study in Europe, drug resistance mutations were detected more frequently among drug-naive individuals with recent rather than chronic HIV infection . A similar trend was observed, both among MSM and among all study subjects, in a large surveillance study from the US .
In the EXPLORE cohort, 6.7% of the 195 men had resistance to an NNRTI, 8.7% had resistance to an NRTI, and 5.6% had resistance to a PI. Multi-class resistance was detected in seven (3.6%) of the men, including four (2.1%) with two-class resistance and three (1.5%) with resistance to all three antiretroviral drug classes. In the studies cited above, multi-class resistance (two- or three-class resistance) was found at rates of 1.3% , 10.2% , and 13.2% . One study reported three-class resistance in one (1.2%) of 91 subjects identified between 2000 and 2001 .
Few studies have examined associations between antiretroviral drug resistance and risk factors for HIV-1 infection. In a study from the US, antiretroviral drug resistance was more frequently detected among MSM (11.6%) than either women (6.1%) or heterosexual men (4.7%) . In Italy, a higher rate of resistance was also seen among MSM (21.6%), than among heterosexuals, intravenous drug users and others, however the difference was not statistically significant . In Canada, a similar rate of antiretroviral drug resistance was seen among individuals recently infected by intravenous drug use or sexual transmission . A preliminary report of 214 recently infected MSM in California found an association between antiretroviral drug resistance and methamphetamine use [odds ratio (OR), 4.29: P = 0.01), but not with use of other substances or with income level . In that study, methamphetamine use was reported in 19.5% of men with resistance versus 9.5% of men without resistance. Methamphetamine use was more frequent in the EXPLORE study (32% of men) than in the cohort described above (approximately 10% of men) , but there was no association between antiretroviral drug resistance and methamphetamine use among the men in EXPLORE (Table 2).
In the US, a higher rate of resistance has been noted among whites, compared to African Americans and Hispanics . We did not find an association between race/ethnicity and resistance in the EXPLORE cohort, which may reflect the smaller sample size of our study (195 seroconverters) compared to the sample size of the previous study (n > 1000). We also did not find any association of antiretroviral drug resistance with age, city, number or HIV status of sexual partners, sexual practices, self-reported STIs, or use of antiretroviral drug post-exposure prophylaxis. All of the men analyzed had subtype B HIV infection, indicating a low incidence of non-subtype B among MSM in major US cities who were recently infected with HIV-1.
HIV-1 tropism data were available for 126 men, providing the first large-scale descriptive analysis of HIV-1 tropism in recent HIV-1 seroconverters. We identified four men, each enrolled at a different study site, who were infected with dual or mixed tropic HIV-1 strains. None of those men had multi-class antiretroviral drug resistance, but one had resistance to all three NNRTIs. Two of the four men reported methamphetamine use. Only one of the men reported using intravenous drugs. Therefore, the CXCR4-using strains were likely to have been sexually transmitted in the other three men. Men in the EXPLORE study were not followed after documentation of seroconversion, so we do not have data on disease progression in the four men with CXCR4-using strains.
We identified seven groups of two or three men who were infected with genetically similar HIV-1 strains. One pair of men was infected with a nearly identical strain that had two-class resistance. The 16 men in these groups represented 8.2% of those tested. In each case, the group of two or three men may have become infected from contact with a single individual, or may have passed the infection from one to another. This finding was not surprising, since 31% of EXPLORE subjects at one study site reported having sex with another study participant .
In summary, 31 (15.9%) of 195 MSM with recent HIV-1 infection had drug resistance, including seven (3.6%) with multi-class resistance, and three (1.5%) with resistance to all three drug classes. We found no association of antiretroviral drug resistance with demographic factors, clinical factors, or specific risk behaviors. Four (3.2%) of 126 men tested had CXCR4-using HIV-1 strains, including one man with NNRTI resistance. All 195 men had HIV-1 subtype B. The frequent detection of antiretroviral drug resistant HIV-1 strains in recently infected MSM emphasizes the importance of antiretroviral drug resistance testing in similar patient populations prior to initiation of antiretroviral drug therapy. Identification of CXCR4-using strains in some men emphasizes the need for further studies defining the prevalence of mixed or dual tropic HIV-stains in individuals with recent HIV-1 infection, and for studies investigating the relationship between acquisition of CXCR4-using strains and HIV-1 disease progression.
The authors thank the EXPLORE study team and study subjects. The team also acknowledges Kayla Stratton (SCHARP) and Rufeng Xu-Friedman (Frontier Science Foundation) for assistance with data management. The authors thank Neil Parkin (Monogram Biosciences) for critical review of the manuscript.
Role of the funding source: The sponsor (HPTN) supported the original EXPLORE Study (HPTN 015) and provided support for the individuals responsible for design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, and approval of the manuscript. The sponsor also provided support for HIV genotyping and subtyping, which was performed at the HPTN Central Laboratory under the direction of S.H.E.
Authors’ contributions: This manuscript has more than 10 authors. Each author contributed to the manuscript, helped to write and review the manuscript, and approved the final version. Individual roles of the authors are described as follows: S.H.E. designed and coordinated the study, drafted the original manuscript, handled all revisions and was responsible for HIV genotyping studies. M.H. was the lead data analyst for the EXPLORE study. S.H. performed HIV genotyping and analyzed genotyping results. D.D. was the lead statistician for the EXPLORE study and was responsible for the statistical analysis for this study. Y.H. assisted with the statistical analysis. W.H. performed the HIV tropism assays and reviewed all tropism results. S.H. performed the phylogenetic analysis of HIV subtypes and linked infections. J.B.J. was the HPTN Network Laboratory Representative for the EXPLORE study and helped draft the original study plan. T.C., M.C. and B.K. were EXPLORE study Protocol Co-Chairs and B.K. assisted with the study design and data presentation.
Sponsorship: This work was supported by the HIV Network for Prevention Trials and sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute on Alcohol Abuse and Alcoholism, of the National Institutes of Health (NIH), U.S. Department of Health and Human Services (DHHS), through contract N01 AI35176 with Abt Associates Inc; contract N01 AI45200 with the Fred Hutchinson Cancer Research Center; and subcontracts with the Denver Public Health, the Fenway Community Health Center, the Howard Brown Health Center, the New York Blood Center, the Public Health Foundation Inc., and the Univ. of Washington. In addition, this work was supported by the HIV Prevention Trials Network (HPTN) and sponsored by the NIAID, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research, of the NIH, DHHS, through a cooperative agreement with Family Health International (cooperative agreement 5 U01 AI46749) with a subsequent subcontract to Abt Associates Inc. with subcontracts to the Howard Brown Health Center and Denver Public Health; cooperative agreement U01 AI48040 to the Fenway Community Health Center, cooperative agreement U01 AI48016 to Columbia Univ. (including a sub-agreement with the New York Blood Center); cooperative agreement U01 AI47981 to the Univ. of Washington; and cooperative agreement U01 AI47995 to the Univ. of California, San Francisco; as well as HPTN contracts U01-AI-46745 and U01-AI-068613 with Johns Hopkins University.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
HIV; seroconverter; resistance; tropism; men who have sex with men; United States; recent infection; subtype