Introduction
More than 2.1 million people were infected with HIV in 2013 [1]. Randomized trials have shown that daily use of tenofovir disoproxil fumarate (tenofovir)-emtricitabine as preexposure prophylaxis (PrEP) can reduce HIV incidence 44% among MSM [2], 62% among heterosexual men and women [3], and 75% among HIV-serodiscordant heterosexual couples [4] and that tenofovir alone can reduce HIV transmission 67% among HIV-serodiscordant heterosexual couples [4] and 49% among people who inject drugs (PWID) [5]. Based on these results, the US Public Health Service published guidelines for the use of PrEP to prevent HIV infection [6].
Adherence is required for PrEP to be effective [7–9]. During the Partners PrEP study among HIV-serodiscordant heterosexual couples, researchers provided additional counseling to a subgroup of 1147 participants if their adherence dropped below 80% [9]. In this subgroup, no incident HIV infections occurred in the treatment arms resulting in a PrEP effectiveness of 100% [95% confidence interval (CI), 84–100%] [4,9]. In contrast, in two PrEP trials, wherein drug level testing suggested poor adherence, effectiveness was not shown [10,11].
Unique among the PrEP trials, the Bangkok Tenofovir Study (BTS) offered participants daily follow-up and staff watched participants swallow study drug [5]. In this study, we describe participant adherence, examine demographic and risk factors associated with adherence, and estimate tenofovir effectiveness based on overall adherence.
Methods
The BTS was a randomized, double-blind, placebo-controlled, endpoint-driven study conducted in 17 Bangkok Metropolitan Administration (BMA) drug-treatment clinics that offer clients an HIV-prevention package, social services, and medical care [5]. Participants chose daily visits or monthly visits and could change from daily to monthly visits or vice versa at monthly visits. At daily visits, study nurses observed participants swallow study drug, both initialed the adherence diary, and participants received 70 baht (about 1.8 US dollars) to compensate for time and travel. At monthly visits, all participants (daily and monthly) received individualized adherence counseling and 350 baht (about 9.2 US dollars) compensation and staff reviewed the diary, did a pill count, and worked with participants to resolve discrepancies. Staff gave participants appointment cards, phoned them before monthly visits, and contacted participants who missed monthly visits by phone or, if they could not contact them by phone, with a home visit.
We defined adherence as the proportion of days, recorded in the diary, that the participant took study drug. We examined adherence by age group and sex and used Wilcoxon or Kruskal–Wallis tests to assess group differences [12], adjusting for age with van Elteren's test [13]. We used Spearman's correlation to assess the association between days in daily follow-up and adherence [12], and Cox regression for the adherence-based effectiveness analysis [14]. We used logistic regression to evaluate demographics and risk behaviors during the 3 months before enrollment as predictors of less than 95% adherence [12]. We chose 95% because data from PrEP trials suggest a high level of adherence is associated with protection from HIV infection [2,4,5,9,15]. Variables associated with poor adherence in bivariable analysis (P ≤ 0.1) were evaluated in a multivariable model and retained in the final model if the P value was 0.05 or less. We included treatment group in all models and censored data at the last HIV test. We used SAS version 9.3 (SAS Institute, Cary, North Carolina, USA) for statistical analyses.
The ethical review committees of the BMA, Thailand Ministry of Public Health, and US Centers for Disease Control and Prevention approved the protocol.
Results
We described BTS results in previous publications [5,16,17]. Briefly, during 2005–2012, 2413 HIV-negative individuals who injected drugs the previous year enrolled and were randomly assigned to receive daily tenofovir or placebo. Exit visits were completed in June 2012 and participants contributed 9665 person-years (mean 4.0 years; maximum 6.9 years) of follow-up; 355 (14.7%) were lost to follow-up during the 7-year study. Fifty participants became HIV-infected: 17 in the tenofovir group (incidence, 0.35 per 100 person-years) and 33 in the placebo group (incidence, 0.68 per 100 person-years) indicating a 48.9% reduction in HIV incidence (95% CI, 9.6–72.2; P = 0.01) among participants randomized to tenofovir.
Participant's median age at enrollment was 31 years (range 20–59), 1924 (79.7%) were men, 1507 (62.5%) reported injecting drugs during the 3 months before enrollment: 801 (53.2%) injected methamphetamine, 559 (37.1%) midazolam, and 527 (35.0%) heroin, and 1239 (51.4%) participants received methadone during the study. At enrollment, 2231 (92.5%) participants chose daily visits [i.e. 500 (95.4%) of those in the daily methadone programme at baseline and 1723 (91.6%) of those not in the programme (P = 0.004); methadone use data were missing from eight participants]; 628 (26.0%) remained in daily follow-up, 1711 (70.9%) switched between daily and monthly visits, and 74 (3.1%) were in monthly follow-up throughout the study. Overall, participants were in daily follow-up an average of 86.9% of the time: 1534 (63.6%) were in daily follow-up at least 95% of the time, 1742 (72.3%) at least 90% of the time, 225 (9.3%) 80–89% of the time, and less than 4.5% in each decile below 80%.
Participants took study drug an average of 83.8% of days; 84.4% while in daily follow-up and 88.9% while in monthly follow-up: 1132 (46.9%) took study drug at least 95% of the time, 1462 (60.6%) at least 90% of the time, 320 (13.3%) 80–89% of the time, 175 (7.3%) 70–79% of the time, and the number of participants ranged from 31–129 (1.3–5.4%) in each decile below 70%. Adherence did not differ by treatment group (P = 0.16) or by time in study (P = 0.22). There was a modest positive correlation between the number of days in daily follow-up and adherence of 0.32 (95% CI, 0.29–0.36).
Adherence was higher among participants 40–59 years old [median 98.2%, interquartile range (IQR) 93.5–99.5%] than participants 30–39 years old (median 94.2%, IQR 82.2–98.6%) and 20–29 years old (median 90.0%, IQR 68.9–97.5%) (P < 0.001). Controlling for age, women were more adherent (median 95.6%, IQR 81.1–98.9%) than men (median 93.8%, IQR 78.8–98.7%) (P = 0.04). Adherence, adjusted for age, did not differ significantly among participants reporting abdominal pain (P = 0.15), nausea (P = 0.32), diarrhea (P = 0.14), or any adverse event (P = 0.09) compared with participants who did not have these events.
Among placebo recipients, adherence of the 33 participants who became HIV-infected (median 94.0%, IQR 65.0–98.8%) was similar to the 1174 who remained HIV-uninfected (median 94.3%, IQR 81.2–98.8%; P = 0.45). However, among tenofovir recipients, median adherence of the 17 participants who became HIV-infected was 76.6% (IQR 65.3–94.1%), whereas median adherence of the 1187 who remained uninfected was 94.1% (IQR 77.8–98.6%; P = 0.01).
An adherence-based analysis, limited to participants coming daily who met adherence criteria (i.e., took study drug ≥71% of days with no more than 2 consecutive days off study drug) during a 2–3 month period before incident HIV infections occurred, showed a 55.9% (95% CI, −18.8 to 86.0; P = 0.11) reduction in HIV risk associated with PrEP [5]. We repeated the analysis including all participants (i.e. those coming daily and monthly) and found a similar 55.9% (95% CI, −9.8 to 84.4; P = 0.08) reduction in HIV risk, suggesting the visit schedule, daily versus monthly, did not alter the adherence-based estimate of PrEP effectiveness. Thus, using Cox regression to analyze adherence data from all participants, we found that as adherence improved, the effectiveness of PrEP increased; from 48.9% overall to 58.0% for participants with at least 75% adherence, and to 83.5% for those with at least 97.5% adherence (Fig. 1).
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Fig. 1: Estimated reduction in the risk of HIV infection (effectiveness) among 2413 participants in the Bangkok Tenofovir Study by level of adherence, 2005–2012.aEffectiveness was estimated using Cox regression.
In multivariable analysis, men were more likely to report less than 95% adherence than women (P = 0.006) and participants 20–29 years old (P < 0.001) and 30–39 years old (P = 0.01) were more likely to report less than 95% adherence than older participants (Table 1). Other factors associated with less than 95% adherence included incarceration in prison (P = 0.02), injecting methamphetamine (P = 0.04), and having sex with a casual partner (P < 0.001) in the 3 months before enrollment. Participants in a methadone programme at enrollment were more likely to report at least 95% adherence (P = 0.003).
Table 1: Results of bivariable and multivariable analysis using logistic regression to evaluate baseline demographic characteristics and risk factors as predictors of poor (<95%) adherence among people who inject drugs in the Bangkok Tenofovir Study, 2005–2012.
Discussion
In this HIV PrEP trial among PWID, we found that increasing levels of adherence were associated with a reduction in the risk of HIV infection; from a 48.9% reduction overall to 83.5% among participants with at least 97.5% adherence. This is consistent with trials among MSM [2] and HIV-discordant heterosexual couples [4] and suggests that PrEP can provide high levels of protection from HIV infection if adherence is maintained. We found better adherence among older participants (P < 0.001) and, controlling for age, among women (P = 0.04). Interestingly, although the trial was not powered to assess effectiveness among subgroups, we found statistically significant effectiveness among women (78.6%; P = 0.03) and participants at least 40 years old (88.9%; P = 0.01) [5]. Participants who were incarcerated or injected methamphetamine before enrollment were more likely to report less than 95% adherence, suggesting poor adherence among some at-risk participants.
In May 2014, the US Public Health Service issued guidelines advocating the use of PrEP for adults at substantial risk of HIV infection [6]; however, PrEP has stirred debate because of concerns about increased risk behavior, drug resistance, and adherence [18,19]. It is reassuring that in four large randomized PrEP studies risk behaviors declined and drug resistance was not detected among participants with incident HIV infections [2–5]. The BTS and Partners PrEP trials also showed that, with support and modest compensation, high levels of adherence can be achieved and maintained [5,9].
A PrEP trial among MSM, the Preexposure Prophylaxis Initiative (iPrEx) trial used participant tenofovir–emtricitabine blood concentrations and data from a separate direct-dosing study to estimate that two doses of tenofovir–emtricitabine per week corresponded with a 76% reduction in HIV risk and four doses with a 96% reduction [15] and assessment of dried blood spots in the postiPrEx study found that drug concentrations consistent with two or three tablets of tenofovir–emtricitabine per week were associated with a 90% reduction in HIV incidence [20]. These estimates of HIV risk reduction are similar but higher than our findings in BTS participants. Studies among macaques suggest that tenofovir–emtricitabine may provide better protection from HIV infection than tenofovir alone [21,22], but two large randomized trials among humans found no statistical difference in HIV incidence among participants receiving tenofovir alone or tenofovir–emtricitabine [4,23,24]. Oral dosing of tenofovir, however, has been shown to achieve higher drug levels in rectal tissue than in blood or vaginal tissue [25] and higher drug levels at the site of infection could be associated with more effective reduction in HIV risk among MSM than other populations including PWID.
The study has several limitations. Participants were allowed to change from daily to monthly visits and vice versa, complicating the adherence analysis. We did not systematically ask participants why they decided to come to the clinics daily or monthly; factors that may have encouraged participants to come daily include participating in the methadone programme that requires daily attendance, the compensation for daily visits (70 baht, about 1.8 US dollars), the relationship with study staff, and peer activities at the clinics. There were relatively few incident HIV infections (n = 50) and only 17 among tenofovir recipients limiting subgroup analyses and the precision of the adherence-based effectiveness estimates. The study was conducted in drug-treatment clinics offering a package of HIV prevention tools and daily follow-up with compensation; adherence to PrEP may differ in other settings.
Directly observed antiretroviral treatment for HIV has been successfully implemented in prisons [26] and drug treatment clinics [27] and could be adapted for PrEP. Other innovative strategies have been used to improve adherence including reminder tools, dose scheduling, and care for substance use and mental health issues [28]. Targeted PrEP dosing and long-acting antiretrovirals are being evaluated and may provide future options [29–31]. PrEP, with adherence support [32–34], provides a valuable new tool in the fight to end the HIV epidemic.
Acknowledgements
We wish to thank the 2413 study participants, many of whom came daily to the study clinics, and their community representatives for their dedication and consistent support. We also want to thank the doctors, nurses, counselors, social workers, research nurses, research assistants, and staff of the 17 Bangkok Metropolitan Administration Drug-Treatment Clinics who worked with enthusiasm and grace to make the trial a success and the members of the Bangkok Tenofovir Study Group who made the trial possible.
Authors’ contribution: All authors were involved in the conception of the study and study design. K.C. was the principal investigator. M.M. drafted the protocol, consent forms, and manuscript with input from the other authors. S.V., P.S., U.S., and K.C. managed staff in the study clinics. P.A.M. was responsible for data management and P.A.M., R.J.G., and M.M. for statistical analysis and interpretation. J.M.M., M.E.C., and M.M. were responsible for laboratory testing, analysis, and interpretation. All authors contributed to the manuscript and read and approved the final version.
Bangkok tenofovir study group: Principal Investigator: K.C.; Advisory Group: Sompob Snidvongs Na Ayudhya, S.C., Kraichack Kaewnil, Praphan Kitisin, Malinee Kukavejworakit, M.L., Pitinan Natrujirote, Saengchai Simakajorn, Wonchat Subhachaturas
Study Clinic Coordination Team: Lead: S.V.; Members: Boonrawd Prasittipol, U.S., P.S.; Bangkok Metropolitan Administration: Rapeepan Anekvorapong, Chanchai Khoomphong, Surin Koocharoenprasit, Parnrudee Manomaipiboon, Siriwat Manotham, Pirapong Saicheua, Piyathida Smutraprapoot, Sravudthi Sonthikaew, La-Ong Srisuwanvilai, Samart Tanariyakul, Montira Thongsari, Wantanee Wattana, Kovit Yongvanitjit.
Thailand Ministry of Public Health: Sumet Angwandee, S.K.; Thailand Ministry of Public Health – U.S. Centers for Disease Control and Prevention Collaboration: Wichuda Aueaksorn, Baranee Balmongkol, Benjamaporn Chaipung, Nartlada Chantharojwong, Thanyanan Chaowanachan, Thitima Cherdtrakulkiat, Wannee Chonwattana, Rutt Chuachoowong, M.E.C., Pitthaya Disprayoon, Kanjana Kamkong, Chonticha Kittinunvorakoon, Wanna Leelawiwat, Robert Linkins, M.M., J.M.M., P.A.M., S.N., Tanarak Plipat, Anchala Sa-nguansat, Panurassamee Sittidech, Pairote Tararut, Rungtiva Thongtew, Dararat Worrajittanon, Chariya Utenpitak, A.W., Punneeporn Wasinrapee; U.S. Centers for Disease Control and Prevention: Jennifer Brannon, Monique Baseer, R.J.G., Lisa Harper, L.A.P., Charles Rose; Johns Hopkins University: Craig Hendrix, Mark Marzinke.
Source of funding: The study was supported by the U.S. Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration. Study drug was donated by Gilead Sciences.
Disclaimer: The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
Trial Registration ClinicalTrials.gov, number NCT00119106.
Conflicts of interest
There are no conflicts of interest.
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