This analysis of data from a large HIV vaccine efficacy trial in U.S. MSM provides important information about the national HIV epidemic. Although a largely white population, over 70% of participants were enrolled from cities lacking substantial epidemiologic information derived from MSM HIV seroincidence cohorts 
. It is noteworthy how consistent MSM HIV seroincidence was across U.S. cities.
From 1998–2002, HIV seroincidence was 2.7/100 py among this U.S. MSM cohort. It remained relatively constant over each year of observation despite intensive ongoing HIV counseling and testing and reported decreases in HIV sexual risk behaviors 
. HIV seroincidence was not associated with geographic region, race/ethnicity, education level, and calendar year, but substantially higher incidence was observed among younger men and men who reported risky sexual behaviors, recreational drug use, or a STI history at baseline. Many of these items were confirmed in the time varying multivariate model which indicated that younger age, having a positive male partner, UAI with an HIV-infected or unknown serostatus male partner, multiple male sex partners, and amphetamine and popper use were all independently predictive of HIV infection.
Since this trial excluded men who reported current IDU, few reported its use, and it was not incorporated into the multivariate model. However, non-injection recreational drug use was extremely high. Over 60% of MSM reported recreational drug use at enrollment, and high HIV seroincidence was seen among those MSM. Amphetamine and popper use were significantly linked to higher risks of seroconversion. Although, this study did not collect data on circumstances of drug use, other studies have demonstrated sexual situation-specific use of recreational drugs among MSM 
. The popularity of these drugs is attributed to their reported abilities to facilitate access to certain types of sexual partners, specific types of sexual exchange, and to improve sexual performance 
. Amphetamines, methamphetamine in particular, have been associated with unprotected intercourse among both HIV negative and HIV positive MSM 
, condom failure 
and HIV infection 
. Given these findings, it was concerning that amphetamine use increased over the course of the trial, suggesting concurrent and continued expansion in MSM populations outside the trial and subsequent increases in HIV incidence, especially among young users.
Seroincidence among young men was much higher compared to older MSM, and younger age was a significant predictor of HIV seroconversion. These data confirm results from other studies that young MSM are at greater risk for HIV seroconversion 
perhaps due to riskier sexual activities 
, partner choice 
, internet-facilitated higher risk sexual encounters 
and psychosocial attitudes 
. Without targeted prevention activities directed at this group, HIV seroincidence will continue to remain elevated among young MSM.
This analysis had several limitations. The study sample, although regionally diverse, was not representative of MSM at the state or national level and was not a population-based cohort. Generalizability is limited since minority men, younger men, and less educated men, made up smaller components of the study population, and were also less likely to be retained in follow-up. The study population also reflects only MSM interested in participating in an HIV vaccine trial. Study eligibility criteria were based on vaccine preparedness studies designed to enroll a high-risk HIV-negative MSM population sufficiently powered to detect a vaccine efficacy against sexual transmission and excluded men with a history of IDU or in monogamous relationships with HIV-negative men. Behavioral data were collected via an interviewer-administered questionnaire, thus socially undesirable drug using and sexual behaviors may have been underreported. Lastly, the lack of data regarding frequency, type, and circumstances of recreational drug use or the presence of primary or casual partners prevented in depth analysis of their contribution to seroconversion.
MSM have been a population long-affected by HIV and targeted for interventions by numerous prevention programs. However, despite awareness of their risk for HIV infection, HIV seroincidence continues to be elevated nationally among this group, especially among young men 
. Although unsafe sexual risk behaviors were important predictors of HIV seroconversion and should be highlighted in any MSM prevention activity, our data and that of others reveal that drug use, in particular amphetamines and poppers, are also strongly associated with HIV infection. Most HIV risk reduction strategies concentrate largely on reducing sexual risk by encouraging condom use, reducing the number of sexual partners, promoting safer sexual practices, and stopping injection drug use 
. Alcohol and other substance use which may be addressed in the overall safer sex guidelines may not be stressed as specific risk factors. The consistent drug use over the course of the study in the face of declining sexual risk behaviors 
suggests that prevention messages delivered in the HIV counseling and testing of MSM may not adequately acknowledge or address all risk behaviors that place them at risk for HIV infection. Continuing development of promising new HIV prevention strategies 
and intensification of existing effective interventions (e.g. frequent repeat HIV testing and early linkage to care and treatment 
) will be necessary to reduce the rate of HIV, especially among drug using young MSM.