Sexual Risk Behavior and Risk Compensation
At baseline, 41% of the participants reported UAI with another man in the past 30 days and 5% reported unprotected vaginal or anal sex with a woman in that same time period. Across all study visits, there were no statistically significant differences in the distribution of male-to-male unprotected anal sex acts among the 3 treatment groups. Although there was a trend from baseline to week 24 of decreasing unprotected anal sex acts across all treatment arms, the differences were not statistically significant (Fig. 2).
STI screening at baseline identified 5 participants with syphilis, 2 with chlamydia, 1 with genital herpes, and 1 with molluscum contagiosum. All participants were treated. During the course of the study, additional STI diagnoses included syphilis (4), chlamydia (7), anogenital human papillomavirus (3), genital herpes (1), molluscum contagiosum (1), and gonorrhea (1). There were no HIV seroconversions among enrolled participants during the study.
To assess changes in pill-taking behavior based on perceived sexual risk, participants were asked “Thinking back over the past month, did you ever change the way you were taking the study pills based on what was going on in your sex life?” Ninety-eight percent of participants reported that they did not change their pill-taking behaviors based on their sex life.
On the measure of study-related HIV risk behavior (adapted from Vanable et al18), several statistically significant differences emerged among the treatment groups. For the question “Because I am in this PrEP study, I am less concerned about becoming HIV positive,” differences were found at weeks 12 and 20. At week 12, a higher percentage of subjects in the placebo group (75%) strongly disagreed with the statement compared with the FTC/TDF (40%) and no pill (31.25%) groups. The pattern was similar at week 20, although the difference between the placebo group and FTC/TDF was smaller (79% vs. 67%). For the question “I am more willing to take a chance of getting infected now that I am in this PrEP study,” differences emerged at weeks 8 and 24. At week 8, a higher percentage of subjects in the placebo group (100%) strongly disagreed with the statement compared with the FTC/TDF (69%) and no pill (65%) groups. The pattern was similar at week 24, although the difference between the placebo group and FTC/TDF was smaller (92% vs. 80%). For the question “I am a lot less worried about ‘slipping up’ now that PrEP may be taken prior to unprotected sex,” differences were found at week 16 with a higher percentage of subjects in the placebo group (93%) strongly disagreeing with the statement compared with the FTC/TDF (54%) and no pill (43%) groups. Finally, for the question “I am less concerned about having unprotected anal sex now that I am in this PrEP study,” differences were found at week 8 with a higher percentage of subjects in the placebo group (83%) strongly disagreed with the statement compared with the FTC/TDF (47%) and no pill (35%) groups. There were no statistically significant differences between treatment groups at any of the visit weeks for the questions “The availability of PrEP makes me less worried about having unprotected sex” or “I have already risked getting infected with HIV through unsafe sex while I’ve been in this study.”
Self-reported adherence to study pill fluctuated across study visits. In the FTC/TDF arm, the median number of doses missed (out of possible 30) was 10, with a range from 5 missed doses (weeks 16 and 20) to 17 missed doses (week 24). Similar fluctuations occurred in the placebo arm, with a range from 6 missed doses (week 24) to 19 missed doses (week 16). When calculating missed doses by medication gaps in pharmacy refill dates, median doses missed was 0 across all weeks of the study. There were no statistically significant differences in self-reported adherence between the 2 study pill arms across all visits. The most common reasons reported for missing doses were: away from home (60%), simply forgot (50%), and too busy (47%).
No tenofovir was detected in the 2 randomly selected plasma samples from each participant in the placebo and no pill arms. The rates of detectable tenofovir in the plasma of participants in the FTC/TDF arm varied by study visit from 63.2% at week 4 to 20% at week 24. Figure 3 compares the percentage of self-reported doses taken to plasma tenofovir detected.
Most participants in both pill arms were unable to accurately determine their study group assignment. There were no statistically significant differences between the FTC/TDF and placebo group, with the exception of week 24 where 67% of the placebo group stated that they thought they were on placebo, whereas only 22% of the FTC/TDF group thought they were on placebo.
AEs grade 2 and above were reported to the protocol team. There were no serious AEs, and a total of 6 AEs during the course of the study were reported, 5 of which were possibly or probably related to the study drug. In the FTC/TDF arm, there were 1 increased blood bilirubin (grade 3), 1 proteinuria (grade 2), 1 migraine headache (grade 3), and 2 instances of decreased creatinine clearance (grade 3) in 1 participant. For that participant, the estimated creatinine clearance was 180 mL/min at baseline and showed considerable variability over the course of the study but never declined below 110 mL/min, despite continuation of study drug. In the placebo arm, there was 1 psychiatric hospitalization resulting from suicidal ideation (grade 4) that was not related to study participation.
All participants were asked in the audio computer-assisted self-interview to self-report possible side effects to the study drug, including headache, nausea, vomiting, diarrhea, and dizziness. The treatment groups differed at week 8 (P = 0.0389) on their reports of nausea, with a higher percentage of subjects in the FTC/TDF group (23.5%) experienced nausea than the placebo (0%) and no pill (5.9%) treatment groups. There were no other statistically significant differences among the treatment groups across all other study visits.
HIV incidence continues to rise for youth in the United States indicating that our currently available prevention tools still have room for improvement. Powerful biomedical tools, intricately linked to effective HIV risk reduction and PrEP adherence interventions, are needed to achieve a decrease in HIV incidence among adolescents and young adults. This study was an initial step toward examining the acceptability, feasibility, and safety of PrEP while also exploring adherence and risk behaviors among YMSM using PrEP.
This study demonstrated the feasibility of enrolling a young cohort of primarily racial and ethnic minority MSM into a PrEP trial and retaining them despite an intensive visit schedule. Although the recruitment team became more accurate over time at identifying productive recruitment venues, approximately 1 person was eligible for every 3 people screened. This ratio seems, however, to be consistent with large HIV prevention trials.1,19 Unfortunately, many eligible youth did not attend screening visits due primarily to changes in contact information and the inability of study staff to locate them. Participants reported high acceptability of many of the study components, including monthly HIV testing, physical examinations, group-based intervention sessions, and individual risk reduction counseling. Acceptability of random assignment to study arm and of the study pill itself was not as strong. Interestingly, a substantial number of participants indicated that they would rather not take PrEP if it were to be taken more than once per day or would take it only if they knew their partner was infected. This is consistent with results from other exploratory studies and has significant implications for the design of the next generation of PrEP studies.
Similar to most adult PrEP trials, behavioral disinhibition was not seen among this cohort and an actual decrease in sexual risk behavior was seen over time. This is not surprising given that youth received an intensive evidence-based HIV prevention intervention before randomization and individual risk reduction counseling and condom provision at every study visit. Additionally, youth consistently reported that their pill-taking behavior was not altered by events in their sex life. However, given the discrepancies between self-reported adherence and plasma drug detection, the social desirability bias of self-reported behavior must be considered. The strong acceptability of the behavioral interventions and the corresponding decreases in risk behavior from baseline continue to support the use of these types of interventions in conjunction with PrEP.
The identification of previously undiagnosed prevalent cases of HIV during screening and incident STIs in this group along with the ability to provide treatment and/or linkage to care for those diagnoses was a success of this study. The ability of a PrEP program to identify an HIV infection rate of 3%, when the range of detection for routine testing in the United States is <1%, and to hone in on incident STIs, needs to be further explored, evaluated, and considered as part of the ultimate cost-effectiveness of PrEP rollout. PrEP programs may be an effective HIV and STI (eg, syphilis) testing and care linkage strategy that could yield successful primary and secondary prevention interventions that are synergistic in decreasing risk for HIV acquisition among youth populations.
Adherence to the study pill was low, and poor concordance was seen between self-report and objective measures, with self-report being consistently higher than plasma detection. However, because of the limitations of plasma concentration testing, the low levels only demonstrate that pills were not taken in the 1–2 days before the study visit. Many participants did report that simple forgetting and changes in their daily schedules interfered with their ability to adhere to the pill regimen. These low levels of study pill adherence are consistent with the literature on youth adherence to contraception and medication for youth living with HIV or other chronic medical conditions.7–9 Because this study was not intended to measure PrEP efficacy, no structured interventions targeting adherence were offered to participants. PrEP adherence for youth, in the absence of behavioral interventions to improve it in a sustainable fashion, may be insufficient for adequate HIV prevention. Thus, youth-friendly interventions and messaging around adherence will be essential for successful PrEP implementation. Because participants demonstrated a noticeable decline in adherence toward the end of the study, behavioral interventions could incorporate adherence “boosters,” such as text messaging or check-in calls, at times when adherence seems to be waning.
PrEP appeared to be generally safe and well tolerated by the participants. Nausea was the primary side effect experienced by participants in the FTC/TDF group but seemed to resolve over several weeks. The side effects and AEs that occurred in this study were similar to other PrEP trials.1–3
This study successfully demonstrated that a cohort of young, primarily racial and ethnic minority, MSM can be successfully recruited, enrolled, and retained in a domestic PrEP study and that the HIV prevention components of such a study are highly acceptable. Future PrEP studies are needed to explore the effectiveness of PrEP among young populations. Such studies should strive to incorporate behavioral interventions aimed at improving both sexual health and adherence, particularly for disadvantaged youth who are unfamiliar with or have limited access to the health care system. Furthermore, future demonstration and safety studies should begin to consider the effectiveness of PrEP among adolescents younger than 18 years who are at high risk for acquiring HIV.
The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) is funded by grant Number U01 HD040533-06 from the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (B.K.) with supplemental funding from the National Institutes on Drug Abuse (Nicolette Borek, PhD) and National Institute of Mental Health (Susannah Allison, PhD). The authors thank Jaime Martinez, MD, PI, and Lisa Henry-Reid, MD, Co-PI of the Adolescent Trials Unit at John Stroger, Jr. Hospital of Cook County, Chicago, IL and the staff (Kelly Bojan, Christina Brakebill and Rachel Jackson) of the Ruth M. Rothstein CORE Center, Chicago, IL; Robert Garofalo, MD, PI of the Adolescent Trials Unit at Children’s Memorial Hospital and the staff at Howard Brown Health Center (Julia Brennan and Sara Flannigan), Chicago, IL; and the incredibly hardworking Research Assistants at both sites who made recruitment for this project possible (Christopher Balthazar, Ixchell Estes-Ortiz, Carlos Orengo, Pedro Serrano, Alexander Sewell, and Michael Slater). ATN 082 has been scientifically reviewed by the ATN's Community Prevention Leadership Group. The authors also thank Protocol Specialist Nancy Liu and individuals from the ATN Data and Operations Center (Westat, Inc), Rockville, MD; and individuals from the ATN Coordinating Center at the University of Alabama at Birmingham including Cindy Partlow, Jeanne Merchant, and Marcia Berck. Finally, and most importantly, the authors thank the young men who participated in this study for their willingness to share their lives and their time with us.
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pre-exposure prophylaxis; adolescents and young adults; combination HIV prevention
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