Skip to main content
NCBI home page
Frontiers in Pharmacology logoLink to Frontiers in Pharmacology
. 2018 Sep 4;9:799. doi: 10.3389/fphar.2018.00799

Efficacy and Safety of Oral TDF-Based Pre-exposure Prophylaxis for Men Who Have Sex With Men: A Systematic Review and Meta-Analysis

Xiaojie Huang 1,†, Jianhua Hou 1,†, Aixin Song 1, Xinchao Liu 2, Xiaodong Yang 1, Junjie Xu 3, Jing Zhang 3, Qinghai Hu 3, Hui Chen 4, Yaokai Chen 5, Kathrine Meyers 6,*, Hao Wu 1,*
PMCID: PMC6131617  PMID: 30233355

Abstract

Background: Pre-exposure prophylaxis (PrEP) is used as an HIV prevention method by people at substantial risk of HIV infection. This systematic review and meta-analysis evaluates current clinical evidence for use of oral TDF-based PrEP among men who have sex with men.

Methods: A comprehensive literature search in PubMed, web of science, Google Scholar and ClinicalTrials.gov was performed. A random-effects meta-analysis was conducted using the event rate (ER) for estimation of the incidence of HIV and grade 3 or 4 adverse events (AE) among PrEP arm and using risk ratio (RR) for comparison of incidence of HIV and grade 3 or 4 AE between PrEP recipients and PrEP non-users. Blood-based adherence levels were also divided into three categories with reference to previous meta-analysis. Subgroup meta-analysis was also performed to evaluate whether blood-based adherence levels moderated the effect of TDF-based PrEP on HIV incidence. Narrative review was used due to inconsistent measurements of risk behavior and drug resistance. This review is registered on the PROSPERO database (CRD42017077965).

Results: Fourteen studies were included in the review. Oral TDF-based PrEP significantly reduced HIV incidence with minimum drug resistance and tolerable safety risks (HIV incidence, ER = 1.1%, 95% CI 0.6–2.0%, p < 0.001, RR = 0.244, 95% CI 0.111–0.537, p < 0.001 and grade 3 or 4 AEs, ER = 13.0%, 95% CI 9.9–16.9%, p < 0.001, RR = 1.059, 95% CI 0.824–1.362, p = 0.653). Oral TDF-based PrEP was more effective in reducing HIV incidence with high levels of blood-based PrEP adherence (ER, 0.4%) compared to moderate adherence (2.9%; p < 0.001). Most studies found no association between PrEP use and self-reported sexual behavior.

Conclusion: Oral TDF-based PrEP is an effective intervention to prevent against HIV infection among MSM. Well-designed implementation science studies that integrate sociobehavioral and biomedical interventions are needed to identify optimal PrEP delivery models in different populations to translate biomedical efficacy into real-world efficacy.

Keywords: HIV, pre-exposure prophylaxis, TDF, men who have sex with men, meta-analysis

Introduction

Around 1.8 million people became newly infected with HIV in 2016 globally, according to the Joint United Nations Program on HIV/AIDS (UNAIDS, 2016), indicating that tremendous efforts are needed to slow down the AIDS epidemic. Globally there continue to be rising rates of HIV incidence among men who have sex with men (i.e., gay and bisexual men) (Prejean et al., 2011; Phillips et al., 2013; Reback and Fletcher, 2014; Newsum et al., 2017), with the highest HIV incidence rates observed among MSM in countries such as China, Kenya, Thailand, and among young and minority MSM in the US (Beyrer et al., 2016).

Although the promotion of regular HIV testing and encouragement of condom use will remain essential preventative strategies for HIV infection, additional approaches for people who are unwilling or unable to use condoms consistently are needed. In 2012, WHO first published a PrEP guidance, which recommended the use of tenofovir (TDF) and emtritabine (FTC) for people who are at substantial risk for HIV (such as serodiscordant couples and MSM). In recent years, daily use of PrEP by populations at high risk of HIV infection has been recommended in guidelines from United States, Europe, Australia and South Africa. Previous meta-analyses and systematic reviews have indicated that while TDF/FTC-based oral PrEP protects (Fonner et al., 2016; Desai et al., 2017), the efficacy of PrEP may vary across populations.

Thus we conducted this systematic review and meta-analysis to specify the efficacy and safety of TDF/FTC-based oral PrEP specifically among MSM.

Methods

The review was registered in the in the International Prospective Register of Systematic Reviews (PROSPERO, https://www.crd.york.ac.uk/PROSPERO/): CRD42017077965. The work was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (Moher et al., 2009). Detailed information of PRISMA checklist is included in Supplementary Table 1.

Search strategy

A comprehensive literature search in PubMed, web of science, Google Scholar and ClinicalTrials.gov was performed. Search terms were intersections of PrEP related terms (pre-exposure prophylaxis OR preexposure prophylaxis OR antiretroviral prophylaxis OR preexposure chemoprophylaxis OR chemoprevention OR PrEP OR Truvada), disease terms (HIV OR AIDS) and target population terms (MSM OR gay OR men have sex with men). Reference lists of selected articles and related review articles were further screened. Additional searches in Google Scholar and ClinicalTrials.gov were also performed. The search was limited to English-written journal articles and conference abstracts. The full search strategy is shown in Supplementary Table 2.

Selection criteria

To be included in the meta-analysis, the study had to (1) focus on MSM and transgender women; (2) evaluate the efficacy or safety of TDF-based PrEP; (3) provide sufficient data on at least one outcome of interest. Outcomes of interest included: HIV infection, grade 3 or 4 AEs and behavior (condom use, STI and number of sexual partners) and drug resistance. Studies were excluded if they were (1) case reports; (2) review articles or theoretical articles; (3) thesis, dissertation or book chapters. Two reviewers (JHH and AXS) initially selected search results based on titles and abstracts. The remaining articles were further selected by full-text assessment by JHH and AXS. Disagreements between reviewers about eligibility were resolved by discussion with XJH. The procedure of study selection and numbers of included and excluded studies is shown in Figure 1.

Figure 1.

Figure 1

Open in a new tab

Flow diagram of this systematic review and meta-analysis.

Data extraction and code

Coding of outcome measures was done by two reviewers (JHH and AXS) based on previous meta-analysis reviews. Outcomes of interest included: HIV infection, grade 3 or 4 AEs, behavior (condom use, STI and number of sexual partners) and drug resistance mutation. Other information was also extracted from articles including article author, year of publication, study location, age of participants, sample size, study design, PrEP regimen, PrEP dose, and adherence. The results of quality assessment are also shown in Table 1.

Table 1.

Study characteristic.

Study name Year of publication Number of participants Study Design PrEP regimen Dose Comparison Adherence Location
CDC Safety Study (Grohskopf et al., 2013) 2013 400 RCT TDF Daily PrEP vs. placebo 94% United States
NCT01632995 (Liu et al., 2016) 2016 557 Demonstration FTC/TDF Daily PrEP group 80–86% from wk 4 to 48 San Francisco, California, and Miami, Florida and Washington DC United States
HPTN-069 (Gulick et al., 2017) 2016 406 RCT FTC/TDF Daily Four PrEP arms (TDF/FTC arm used in the analysis) 83%,74% at wk 24,48 United States
Ipergay (Molina et al., 2015) 2015 400 Real world RCT FTC/TDF On demand PrEP vs. placebo Not reported France and Canada
Ipergay OLE (Molina et al., 2017) 2017 361 Real world Cohort FTC/TDF On demand Only PrEP group Not reported France and Canada
iPrEx (Grant et al., 2010) 2010 2499 RCT FTC/TDF Daily PrEP vs. placebo 51% Peru, Ecuador, South Africa, Brazil, Thailand, and United States
iPrEx OLE (Grant et al., 2014)@ 2014 1603 Cohort FTC/TDF Daily PrEP vs. no PrEP 71% Peru, Ecuador, South Africa, Brazil, Thailand, and United States
KPSF (Volk et al., 2015) 2015 657 Real world Cohort FTC/TDF Daily Only PrEP group Not Reported San Francisco, United States
PATH-PrEP (Landovitz et al., 2017) 2017 297 Cohort FTC/TDF Daily PrEP and PEP cohorts: only PrEP cohort was analyzed 65.5%-83.4% from wk 4 to 48 Los Angeles, California
ATN082 Project PrEPare (Hosek et al., 2013) 2013 58 RCT FTC/TDF Daily PrEP vs. placebo vs. no Pill 63.2% (wk 4) to 20% (wk 24) United States
PROUD-pilot phase (I) (McCormack et al., 2016) 2016 545 Real world RCT FTC/TDF Daily Immediate PrEP to delayed PrEP Not reported England
PROUD-Second phase (II)$ 2017 255 Real world Second phase of PROUD FTC/TDF Daily Delayed with PrEP (second phase) vs. Delayed without PrEP (first phase) Not reported England
ATN110 YSMS (Hosek et al., 2017)& 2017 200 Demonstration FTC/TDF Daily PrEP group Not reported United States
HPTN073BSMS (Wheeler et al., 2016) 2016 226 Demonstration FTC/TDF Daily PrEP vs. No PrEP Not reported Washington DC, Los Angeles and Chapel Hill, NC United States
Open in a new tab

BSMS, black men who have sex with men; CDC, Center for Disease Control and Prevention; FTC, emtrictabine; KPSF, Kaiser Permanent Medical Center; OLE, open label extension; NA, not available, RAI, receptive anal intercourse; RG, reduced-glycerin; wk, week; YSMS, young men who have sex with men.

$

For PROUD-second phase: the deferred PrEP group in the second phase (PrEP use) was self-compared to the first phase (No PrEP).(with reference to 9th International AIDS Society Conference on HIV Science).

&

In this study, DBS results were translated into dosing categories previously used in PrEP trials with adult MSM. The proportion of daily use of PrEP ranges from 4.6 to 21.4% during 48 weeks follow-up. But in our meta-analysis, we do not use this translated data.

@

In this study, most participants were recruited from iPrEx (68 participants in ATN082, 2499 participants in iPrEx and 279 participants from US safety study;1603 participants in this cohort meet the criteria for PrEP), so we use iPrEx OLE to name this cohort study.

Data analysis

We adopted Comprehensive Meta-Analysis (CMA) Version 2.0 (Biostat, Englewood, New Jersey) to conduct a quantitative analysis. First, combined event rate (ER) was calculated using number of events and sample size of PrEP arms. A random-effects meta-analysis was conducted using the event rate (ER) for estimation of the incidence of HIV and grade 3 or 4 AEs among oral TDF-based PrEP arm and using risk ratio (RR) for comparison of incidence of HIV and grade 3 or 4 AEs between oral TDF-based PrEP users and non-users. For open label extensions (OLEs) of previous RCTs, narrative review was used in order to avoid calculating the results based on the same sample. The variation in effect sizes across studies was assessed by the homogeneity statistics, Q. I2 statistic was also used to estimate the observed proportion of the heterogeneity in observed variance (Higgins and Thompson, 2002). Begg rank correlation test was adopted to assess publication bias across studies when more than three comparisons were in the analysis (Begg and Mazumdar, 1994). In some cases, narrative review was also used due to inconsistent measurements of some outcomes of interest including condom use, STI and drug resistance. Blood-based adherence levels were also divided into three categories with high adherence, >70%; moderate, 40–70%; and low, <40% according to arithmetic average of each time point with reference to previous meta-analysis (Fonner et al., 2016). Subgroup meta-analysis was performed to assess the difference among different blood-based adherence levels on HIV incidence.

Role of the funding resource

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Characteristic of included studies

Overall we identified 14 eligible studies in this review, whose sample size ranged from 58 to 2,499. We included six RCTs and eight OLEs or demonstration projects. All participants were adults over 18. The most commonly-used PrEP regimen was TDF in combination with FTC. Seven studies reported detectable blood-based drug component with a range from 51 to 94% of all populations. Thirteen studies examined daily oral PrEP, but Ipergay and its OLE examined non-daily dosing strategy (on demand: two pills taken 2–24 h before sex act and one pill taken 24 h after sexual intercourse and one pill taken 48 h after sex act). These studies reported a variety of outcomes including HIV incidence, grade 3 or 4 AEs, self-reported risk behavior and number of sex partners, STI and drug resistance. Detailed information for included studies is shown in Table 1.

HIV incidence

Eleven studies with 11 PrEP arms reported the effect of PrEP on HIV incidence, so ER of each study could be analyzed. Begg rank correlation test showed no significant publication bias (Kendall's tau = −0.309, p = 0.09). As shown in Figure 2, the combined ER of HIV incidence in PrEP arm was 1.1% (95% CI 0.6–2.0%, p < 0.001). Results revealed significant heterogeneity across studies [Q(10) = 24,524, p = 0.006, I2 = 59.2%].

Figure 2.

Figure 2

Open in a new tab

Forest plot for overall analysis of PrEP and HIV incidence (ER).

Among eleven studies, six studies compare PrEP with no PrEP or placebo, so RR of each study could be analyzed. All consistently reported a decreased HIV incidence rate. Begg rank correlation test showed no significant publication bias (Kendall's tau = −0.33, p > 0.05). The combined RR of PrEP on HIV incidence was 0.244 (95% CI 0.111–0.537, p < 0.001, Figure 3). Results revealed significant heterogeneity across studies [Q(5) = 11.236, p = 0.047, I2 = 55.5%].

Figure 3.

Figure 3

Open in a new tab

Forest plot for overall analysis of PrEP and HIV incidence (RR).

Regarding open label extensions, results from iPrEx US-based OLE cohorts showed that PrEP use was associated with reductions in HIV incidence when comparing PrEP recipients (1.8 infections per 100 person, 95% CI 1.5–4.5) to PrEP non-recipients (2.6 infections per 100 persons, 95% CI 1.3–2.6). Results from Ipergay OLE showed that the overall HIV incidence in this follow-up phase was 0.19 per 100 person-years of follow-up (95% CI 0.01–1.08).

When stratified by blood-based adherence, there were four studies classified as high-adherence group, one study as moderate-adherence group and no studies as low-adherence group. Adherence significantly moderated the efficacy of PrEP [Q(1) = 14.939, p < 0.001]. The ER for HIV incidence for high adherence was 0.4% (95% CI 0.1–1.0%) and 2.9% (95% CI 2.1–4%) for moderate adherence.

Detailed information of HIV infection is also shown in Table 2.

Table 2.

Effects of PrEP on HIV infection.

Study Outcome Risk reduction#
PrEP arm (TDF-based regimen) Control
CDC safety study 0 infections among 101 persons (PrEP immediate arm) 3 infection among 99 persons (placebo immediate arm)
NCT01632995 2 infections among 557 persons during follow-up
HPTN-069 0 infections among 100 persons (PrEP immediate arm)
Ipergay 2 infection among 199 persons 14 infection among 201 persons 86% in relative reduction (95% CI 40–98, p = 0.002)
Ipergay OLE 0.19 per 100 person-year 6.6 per 100 person-years 97% in relative reduction (95% CI 81–100)
iPrEx 36 infections among 1251 persons 64 infection among 1225 persons 44% in relative reduction (95% CI 15–63, p = 0.005)
iPrEx OLE 1.8 infections per 100 person-year 2.6 infection per 100 person-year
KPSF 0 infections among 657 initiating PrEP
PATH-PrEP 1 infection among 297 persons
PROUD-pilot phase 3 infections among 275 persons 20 infections among 269 persons 86% in relative reduction (95%CI 64–96, p = 0.001)
PROUD-second phase 1 infection among 206 persons 20 infections among 269 persons
ATN110 YSMS 4 infections among 200 persons
HPTN073BSMS 5 infections among 178 persons
Open in a new tab
#

We reported risk reduction based on original papers.

Grade 3 or 4 adverse events

Six studies with six PrEP arms reported the effect of PrEP on grade 3 or 4 AE, allowing us to calculate the ER of each study. Begg rank correlation test showed no significant publication bias (Kendall's tau = −0.2, p = 0.286). As shown in Figure 4, the combined ER of grade 3 or 4 AEs in PrEP arm was 13.0% (ER, 95% CI 9.9–16.9%, p < 0.001). Results revealed significant heterogeneity across studies [Q(5) = 15,579, p = 0.008, I2 = 67.9%].

Figure 4.

Figure 4

Open in a new tab

Forest plot for overall analysis of PrEP and any AEs (ER).

Four RCT studies reported the effect of PrEP on grade 3 or 4 AEs. All consistently reported a comparable AE rate in the PrEP and control arms. Begg rank correlation test showed no significant publication bias (Kendall's tau = 0.333, p = 0.497). The combined effect size of PrEP on grade 3 or 4 AEs was 1.059 (RR, 95% CI 0.824–1.362, p = 0.653, Figure 5). Results revealed no significant heterogeneity across studies [Q(3) = 3.654, p = 0.301, I2 = 17.9%].

Figure 5.

Figure 5

Open in a new tab

Forest plot for overall analysis of PrEP and grade 3 or 4 AEs (RR).

Regarding open label extensions, results from Ipergay OLE showed that the grade 3 or 4 AE rate in this follow-up phase was 11% (40/361; 40 of the total participants have grade 3 or 4 AEs during OLE). The iPrEx OLE cohorts did not provide specific data on grade 3 or 4 AEs.

Summary of grade 3 or 4 AEs in each study is also shown in Supplementary Table 3.

Behavior change

Condom use, STI, and number of sex partners were summarized in this review as indices of behavior change. Quantitative synthesis was improper due to inconsistent measurements of condom use, STI and number of sex partners in these studies. Thus narrative description of each outcomes is included in this review.

Condom use was reported in five RCTs (iPrEx, Ipergay, CDC safety study, PROUD, and Project PrEPare), and six longitudinal observational studies (iPrEx OLE, Ipergay OLE, PATH-PrEP, KPSF, ANT110YSMS, and NCT01632995). Among RCT studies comparing PrEP and no-PrEP, results from these studies showed similar change between different arms and for observational studies, condom use was stable or slightly decreased in PrEP arms (Grant et al., 2010, 2014; Hosek et al., 2013; Liu et al., 2013; Molina et al., 2015; McCormack et al., 2016). One observational study (Ipergay OLE) reported a significant rise in condomless anal sex at the last sexual intercourse.

Incidence of STIs was recorded in seven studies (iPrEx OLE, Ipergay OLE, KPSF, NCT01632995, PATH-PrEP, PROUD-pilot phase, ATN110YSMS). Inconsistent results were reported across studies. Two studies reported comparable rates of STIs between PrEP users and non-users (iPrEx OLE and PROUD-pilot phase). Three studies reported stable or decreased STI incidence rates during follow-up (Ipergay OLE, NCT01632995, and ATN110YSMS). One study demonstrated a parabolic distribution over the follow-up phase (PATH-PrEP). One study showed a slightly increase trend during follow-up (KPSF).

Number of sex partners was reported in four RCTs (iPrEx, Ipergay, CDC safety study, and PROUD) and four longitudinal observational studies (iPrEx OLE, Ipergay OLE, NCT01632995, and KPSF). Number of sex partners was stable or slightly decreased over time in the PrEP arms and similar between PrEP users and PrEP non-users despite different study designs and measurements of outcome (Grant et al., 2010, 2014; Liu et al., 2013; Molina et al., 2015; McCormack et al., 2016).

Detailed information of condom use, STI and number of sexual partners is recorded in Tables 3–5 respectively.

Table 3.

Effects of PrEP on condom use.

Study name Outcome Description
RCTS: PrEP vs. NO PrEP
CDC safety study CAS CASPU

  • CAS: no statistical difference between immediate vs. delayed arms during months 3–9 (p = 0.10) and no significant change when delayed group initiated study drug 0.42)

  • CASPU: remained stable or decreased [2.02 at baseline vs. 1.51 during months 3–9 (p = 0.22) and 2.02 at baseline vs. 1.37 during months 12–24 (p = 0.05)]
iPrEx study Percent of receptive anal partners with which condoms used

  • No significant treatment by visit interaction (p = 0.36) with 50.38% in TDF-FTC and 51.04% in placebo at baseline plus 73.98% in TDF-FTC and 83.64% in placebo at follow-up
Project PrEPare CAS

  • No significant differences among the 3 treatment groups across visits; Insignificant trend from baseline to week 24 of decreasing condomless anal sex across all treatment arms.
Ipergay CAS

  • No significant differences in the total number of episodes of sexual intercourse in the 4 weeks before visits (p = 0.07), in the proportion of episodes of CRAS (p = 0.40), or in the proportion of episodes of CAS during the most recent sexual intercourse (p = 0.90) across groups.
OBSERVATIONAL STUDIES: CHANGE DURING PrEP USE or COMPARISON BETWEEN PRE/POST PrEP
iPrEx OLE CAS

  • Decreased from 34% (377/1115) to 25% (232/926) among PrEP recipients (p = 0.006), and from 27 (101/369) to 20% (61/304) among non-recipients (p = 0.03).

  • Decreases in CRAS and CIAS were similar across groups (p = 0.95 and p = 0.56).
Ipergay OLE CAS at the last sexual intercourse

  • CAS: significant increase from 77%(136/176) at baseline to 86%(66/76) at 18 months' follow-up (p = 0.004)
KPSF Condom use

  • Condom use: unchange in 56% of PrEP users, decrease in 41% of PrEP users, and increase in 3% of PrEP users
NCT01632995 CAS

  • CAS:baseline:165/557(65.5%);remained stable (65.6%) during follow-up (p = 0.99)
PATH-PrEP CAS

  • CAS: decreased over the first 24 weeks of study, and then were stable thereafter
Open in a new tab

CAS, condomless anal sex; CASPU, condomless anal sex with HIV positive/unknown status partner; CRAS, condomless receptive anal intercourse; CIAS, condomless insertive anal intercourse; PY, person-years.

Table 5.

Effects of PrEP on number of sexual partners.

Study name Outcome Description
RCTS: PrEP vs. NO PrEP
CDC safety study Mean number of male sex partners in past 3 months

  • Decreased significantly from 7.25 at baseline to 6.02 during months 3–9 and 5.71 during months 12–24 (P < 0.001). Declines were similar between the immediate vs. delayed arms during months 3–9 (P value for interaction = 0.67)

  • Mean number did not differ in months 12–24 vs. months 3–9 with initiation of study drug in delayed arm (p = 0.22) or drug continuation in immediate arm (IRR = 0.96, P = 0.56).

  • Mean number of positive or unknown HIV-status partners declined from 4.17 at baseline to 3.51 during months 3–9 (P = 0.04) and 3.37 during months 12–24 (P = 0.01).
iPrEx study Mean number of receptive anal partners

  • Baseline: FTC-TDF: 12.21 (SE = 0.81); Placebo: 11.21 (SE = 0.81) Follow-up (132 weeks): FTC-TDF: 3.47 (SE = 0.81); Placebo: 5.71 (SE = 1.59) Wald test of the treatment by visit interaction: p = 0.97
Ipergay Number of sexual partners in the past 2 months

  • There was a slight but significant decrease in the number of sexual partners within the past 2 months in the placebo group as compared with the TDF-FTC group
OBSERVATIONAL STUDIES: CHANGE DURING PrEP USE OR COMPARISON BETWEEN PRE/POST PrEP
iPrEx OLE Number of sexual partners

  • Numbers of sexual partners were much the same in the each groups (p = 0.64)
Ipergay Number of sexual partners in the past 2 months

  • There was a slight but significant decrease in the number of sexual partners within the past 2 months in the placebo group as compared with the TDF-FTC grou
Ipergay OLE Number of sexual partners during the 2 months before visit Total number of sexual intercourses in the 4 weeks before visits

  • No significant change during the 2 months before visits (p = 0.42)and the total number of sexual intercourses in the 4 weeks before visits (p = 0.12)
KPSF Number of sexual partners every 1–3 months after PrEP initiation

  • Unchange:74% of PrEP users, decrease:15% of PrEP users, and increase:11% of PrEP users after 6 months
NCT01632995 Number of anal sex partners in the past three months

  • Declined from 10.9 at baseline to 9.3 at week 48 (p = 0.04)
PROUD-pilot phase Number of anal sex partners in last 90 day

  • At baseline: immediate arm: 10.5 (5–20); delayed arm: 10 (4–20) and at month 12: immediate arm: 10 (3–24); delayed arm: 8 (3–15)
Open in a new tab

Table 4.

Effects of PrEP on STIs.

Study name Outcome Description
RCTS: PrEP vs. No PrEP
PROUD-pilot phase STI

  • Proportion with confirmed rectal chlamydia/gonorrhea was similar in immediate (29%) and delayed (27%) (p = 0.50) arms.
OBSERVATIONAL STUDIES: CHANGE DURING PrEP USE or COMPARISON BETWEEN PRE/POST PrEP
iPrEx OLE Syphilis incidence

  • Syphilis incidence was similar among PrEP users and non-users (HR 1.35, 95 CI 0.83–2.19). PrEP no-user:7.2 infections per 100 PY, PrEP no-user:5.4 infections per 100 PY
Ipergay OLE Incidence of first bacterial STIs

  • Remain stable from 49.1 per 100 PY (95% CI 41.6–57.6) at RCT phase to 59.0 per 100 PY0 (95% CI 50.1–69.0) at open phase (p = 0.11)
KPSF Multiple STIs

  • STIs: 187/657 PrEP initiators: at least 1 STI during follow-up; 78/657 PrEP initiators: multiple STIs (range 2–10); after 6 months of PrEP use, 30% of PrEP users with any STI (95% CI 26–35%), after 12 months of PrEP use, 50% of PrEP users with any STI (95% CI 43–56%)
NCT01632995 Multiple STIs

  • Overall STI incidence:90 per 100 PY (81–99); incidence remain stable across quarterly (p > 0.1)
PATH-PrEP STI

  • STI:177(46.4%) participants with 175 STIs over 48 weeks follow-up, with a parabolic distribution over the follow-up phase (Baseline = 20.3%, 24 weeks = 17.7%,48 weeks = 28%)
ATN110YSMS STI

  • Decreased from 76.48/100 PY at first 24 weeks to 60.99/100 PY in the latter 24 weeks
Open in a new tab

STI, sexual transmitted infection, PY, person years.

Drug resistance

Drug resistance was reported in six studies (CDC safety study, iPrEx study, iPrEx OLE, PROUD-pilot phase, NCT01632995, and ATN110YSMS). No drug resistance was found to be associated with TDF at enrollment or during the trial or follow-up phase. FTC-related mutation was observed at enrollment or during the trial phase in four studies with minimum event rate. Specifically, FTC-related drug resistance was found at enrollment in one studies (iPrEx study) and after enrollment in two studies (iPrEx OLE and NCT01632995). For PROUD-Pilot phase study, FTC- related mutation was found in two of the three participants who initiated TDF/FTC PrEP with a reactive test at enrolment or at the 4-week visit. Detailed information is recorded in Table 6.

Table 6.

Effects of PrEP on drug resistance.

Study name PrEP regimen Drug resistance Event rate
TDF-related FTC-related
ATN110YSMS TDF/FTC No No 0
CDC safety study TDF No No 0
iPrEx study TDF/FTC No Enrollment phase: n = 3 (2 in PrEP group and one in placebo group) Trial phase: No 0.12%
iPrEx OLE TDF/FTC No Met184Val (n = 1) 0.06%
NCT01632995 TDF/FTC No M184MI (n = 1) 0.17%
PROUD-pilot phase TDF/FTC No At enrolment or the 4-week visit (n = 2): Met184Ile/Met, Met184Ile/Val/Met 0.36%
Open in a new tab

Discussion

This systematic review provides synthesized estimates of HIV incidence, grade 3 or 4 AEs, self-reported risk behavior, STI and drug resistance among MSM using TDF-based PrEP. The overall estimates are useful for targeted prevention efforts among key population.

Our systematic review shows that PrEP significantly reduced HIV incidence, with low rates of HIV incidence among PrEP users, indicating the utility of this biomedical HIV prevention intervention in curbing HIV transmission among MSM. The findings in this meta-analysis are consistent with a previous review that evaluated the efficacy of PrEP across all populations (Fonner et al., 2016). As would be expected, PrEP was most effective in reducing HIV incidence among users with high levels of PrEP adherence. Adherence-support interventions for PrEP should be designed, building on the experience of HIV treatment studies that adopted multiple behavioral interventions to help improve and maintain treatment adherence (Popeleches et al., 2011; Ingersoll et al., 2015). Psychological counseling which focus on the development of coping strategies (i.e., Life Steps counseling in Partners PrEP Ancillary Adherence Study and Project PrEPARE and Next Step counseling in iPrEx OLE) should also be tested as strategies to increase adherence to PrEP medication (R Amico et al., 2012; Psaros et al., 2014; Taylor et al., 2017). Moreover, studies have demonstrated that some MSMprefer long-acting injectable formulation, which might also be beneficial for improving PrEP adherence (Meyers et al., 2017). Thus future studies are needed to evaluate the efficacy of PrEP in combination with suitable behavioral and psychological intervention or different PrEP formulations among MSM.

Regarding grade 3 or 4 AEs, no significant difference was detected between PrEP users and placebo/PrEP non-users. Common AEs of TDF-based regimen were nausea, diarrhea, back pain, headache, creatinine elevation, depression, potential bone and renal toxicity (Grant et al., 2010; Liu et al., 2011; Grohskopf et al., 2013; McCormack et al., 2016). Future PrEP studies should monitor these side effects and clinicians should treat these side effects immediately, which is likely to promote adherence to PrEP, both during future trials and in clinical practice.

With respect to changes in self-reported risk behavior associated to PrEP use, no significant difference was detected between PrEP users and placebo/PrEP non-users. In our meta-analysis, PrEP did not cause risk compensation in self-reported sex acts, either in the form of decreased condom use or increased number of sex partners. These results are consistent with a recent systematic review which includes both qualitative and quantitative survey studies (Freeborn and Portillo, 2017). But these results should be treated with caution, because self-report is often influenced by social desirability, which means individuals tend to report fewer risk behaviors in order to maintain a good social impression (Zenilman et al., 1995; Difranceisco et al., 1998). Mixed methods including the use of social desirability scales, the rating of item desirability, the use of forced-choice items and the randomized response technique to evaluate and decrease social desirability should be used in future studies (Nederhof, 1985). Selection bias might be a reason for the heterogeneity of STI incidence across studies (Jenness et al., 2017). For example, some studies reported PrEP users may be at higher risk for STIs prior to PrEP initiation and continue high risk behavior during PrEP use (Montano et al., 2017). In fact, the reduction of HIV incidence in the presence of stable or increased STI incidence suggests that these TDF-based PrEP studies in fact enrolled exactly the right population to benefit from biomedical HIV prevention. The relationship between PrEP and STI infection is unclear and further studies are needed to determine the potential effects of selection bias and risk compensation.

Regarding drug resistance, no drug resistance was found to be associated with TDF at enrollment or during the trial, supporting the evidence that TDF is a safe component in PrEP. In our review, we found FTC-related drug resistance might be more easily detected at enrollment and during the trial. Two special cases should not be ignored: one case was infected with multidrug resistance despite long-term use of PrEP and another acquired wild-type HIV virus despite consistent detectable drug levels (Knox et al., 2016; Elske and Godelieve, 2017). Overall drug resistance has rarely occurred among PrEP users, which indicates oral TDF in combination with FTC offers safe prevention for key populations. Moreover drug resistance due to daily PrEP might be associated with adherence. While such real world data does not exist, in one study using mathematic modeling, results have suggested 17–23% infected participants could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence (Dimitrov et al., 2016). Whether real world experience will bear out this model remains to be seen. Nevertheless, effective methods to support adherence should be provided and adherence should be monitored by researchers during PrEP demonstration studies in order to both reduce HIV infection and drug resistance. A urine-based drug detection assay currently under development as a point of care test could be useful tool to monitor PrEP adherence and identify PrEP users who require additional adherence support (Koenig et al., 2017). While a baseline HIV RNA test to rule out acute infection should be included in a clinical trial in order to decrease the risk of secondary resistance, the high cost of HIV RNA test may make the adoption of HIV RNA test before initiation of PrEP difficult to achieve in real world clinical practice. New testing algorithms may be needed in the PrEP era to minimize PrEP initiation during acute infection and to correctly diagnosis HIV in the context of PrEP-use.

Several limitations in the analysis should also be addressed. First, the limited number of studies included for some results could limit the ability to generalize the results to other settings. Future studies should thus adopt comprehensive evaluations including HIV infection, AE monitoring, risk behavior and drug resistance. Secondly, measurement for some outcomes (i.e., risk behavior) is inconsistent across studies, making it difficult to quantitatively analyze the effect of PrEP on risk compensation and drug resistance. Agreement to and use of a common set of behavioral measures would greatly enhance the field's ability to make meaningful comparisons across studies.

In summary, the results of our global meta-analysis suggest that oral TDF-based PrEP is effective at reducing HIV infection among MSM at substantial risk of HIV infection. Moreover, self-reported behavioral measurements indicate no significant risk compensation occurred in PrEP group. According to our results, clinicians should carefully monitor PrEP adherence and high risk sexual behaviors by self-reported questionnaires and blood-based laboratory tests. In resource limited countries, it might be an efficient and useful social health policy to integrate PrEP into medical insurance. Minimum drug resistance is associated with PrEP use. But results should be cautiously interpreted because of limited comparisons for some outcomes. Well-designed studies with large sample size are needed to optimize oral PrEP delivery and plan for other PrEP formulations. Consistent and reliable measurements of key outcomes (such as condom use and number of sexual partners) should also be used in the future studies.

Author contributions

HW, XH, and JH conceptualized the study, and developed the research protocol. JH and AS identified articles for full-test review and extracted data that matched inclusion criteria. JH did the statistical analyses with input from XL and XY. All authors contributed to the writing of the manuscript. KM, XH, and JH polished and revised the manuscript.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by the Chinese Government 13th Five-Year Plan (2017ZX10201101), Major Project of Beijing Municipal Science and Technology Committee (D161100000416003, D171100000517003), the National Natural Science Foundation of China (No. 81571973), the NSFC-NIH Biomedical collaborative research program (81761128001), The Capital Health Research and Development of Special Fund (2016-1-2182), and Beijing Key Laboratory (No. BZ0089).

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2018.00799/full#supplementary-material

Click here for additional data file. (27.2KB, DOCX)

References

  1. Begg C. B., Mazumdar M. (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics. 50, 1088–1101. [PubMed] [Google Scholar]
  2. Beyrer C., Baral S. D., Collins C., Richardson E. T., Sullivan P. S., Sanchez J., et al. (2016). The global response to HIV in men who have sex with men. Lancet 388, 198–206. 10.1016/S0140-6736(16)30781-4 [DOI] [PubMed] [Google Scholar]
  3. Desai M., Field N., Grant R., Mccormack S. (2017). Recent advances in pre-exposure prophylaxis for HIV. BMJ 359:j5011. 10.1136/bmj.j5011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Difranceisco W., Mcauliffe T. L., Sikkema K. J. (1998). Influences of survey instrument format and social desirability on the reliability of self-reported high risk sexual behavior. Aids Behav. 2, 329–337. [Google Scholar]
  5. Dimitrov D. T., Boily M. C., Hallett T. B., Albert J., Boucher C., Mellors J. W., et al. (2016). How much do we know about drug resistance due to PrEP use? analysis of experts' opinion and its influence on the projected public health impact. PLoS ONE 11:e0158620. 10.1371/journal.pone.0158620 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Elske H., Godelieve J. (2017). Acute infection with a wild-type HIV-1 virus in PrEP user with high TDF levels, in Lessons From Seroconversion on Prep and Microbicides (Seattle, WA: CROI; ). [Google Scholar]
  7. Fonner V. A., Dalglish S. L., Kennedy C. E., Baggaley R., O'Reilly K. R., Koechlin F. M., et al. (2016). Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS 30, 1973–1983. 10.1097/QAD.0000000000001145 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Freeborn K., Portillo C. J. (2017). Does pre-exposure prophylaxis (PrEP) for HIV prevention in men who have sex with men (MSM) change risk behavior? A systematic review. J. Clin. Nurs. [Epub ahead of print]. 10.1111/jocn.13990 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grant R. M., Anderson P. L., McMahan V., Liu A., Amico K. R., Mehrotra M., et al. (2014). Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect. Dis. 14, 820–829. 10.1016/S1473-3099(14)70847-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grant R. M., Lama J. R., Anderson P. L., McMahan V., Liu A. Y., Vargas L., et al. (2010). Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Eng. J. Med. 363, 2587–2599. 10.1056/NEJMoa1011205 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grohskopf L. A., Chillag K. L., Gvetadze R., Liu A. Y., Thompson M., Mayer K. H., et al. (2013). Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J. Acquir. Immune Defic. Syndr. 64, 79–86. 10.1097/QAI.0b013e31828ece33 [DOI] [PubMed] [Google Scholar]
  12. Gulick R. M., Wilkin T. J., Chen Y. Q., Landovitz R. J., Amico K. R., Young A. M., et al. (2017). Phase 2 study of the safety and tolerability of maraviroc-containing regimens to prevent HIV infection in men who have sex with men (HPTN 069/ACTG A5305). J. Infect. Dis. 215, 238–246. 10.1093/infdis/jiw525 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Higgins J. P., Thompson S. G. (2002). Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558. 10.1002/sim.1186 [DOI] [PubMed] [Google Scholar]
  14. Hosek S. G., Rudy B., Landovitz R., Kapogiannis B., Siberry G., Rutledge B., et al. (2017). An HIV preexposure prophylaxis demonstration project and safety study for young, MSM. J. Acquir. Immune Defic. Syndr. 74, 21–29. 10.1097/QAI.0000000000001179 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hosek S., Siberry G., Bell M., Lally M., Kapogiannis B., Green K., et al. (2013). Project PrEPare (ATN082): the acceptability and feasibility of an HIV pre-exposure prophylaxis (PrEP) trial with young men who have sex with men (YMSM). J. Acquir. Immune Defic. Syndr. 62, 447–456. 10.1097/QAI.0b013e3182801081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ingersoll K. S., Dillingham R. A., Hettema J. E., Conaway M., Freeman J., Reynolds G., et al. (2015). Pilot RCT of bidirectional text messaging for ART adherence among nonurban substance users with HIV. Health Psychol. 34 S, 1305–1315. 10.1037/hea0000295 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jenness S. M., Weiss K. M., Goodreau S. M., Gift T., Chesson H., Hoover K. W., et al. (2017). Incidence of gonorrhea and chlamydia following HIV preexposure prophylaxis among men who have sex with men: a modeling study. Clin. Infect. Dis. 65, 712–718. 10.1093/cid/cix439 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Knox D. C., Tan D. H., Harrigan P. R., Anderson P. L. (2016). HIV-1 infection with multiclass resistance despite preexposure prophylaxis (PrEP), in Lessons From Seroconversion On Prep And Microbicides (Boston, MA: CROI; ). [Google Scholar]
  19. Koenig H. C., Mounzer K., Daughtridge G. W., Sloan C. E., Lalley-Chareczko L., Moorthy G. S., et al. (2017). Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis. HIV Med. 18, 412–418. 10.1111/hiv.12518 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Landovitz R. J., Beymer M., Kofron R., Amico K. R., Psaros C., Bushman L., et al. (2017). Plasma tenofovir-levels to support adherence to TDF/FTC pre-exposure prophylaxis for HIV prevention in MSM in Los Angeles, California. J. Acquir. Immune Defic. Syndr. 76, 501–511 10.1097/QAI.0000000000001538 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liu A. Y., Cohen S. E., Vittinghoff E., Anderson P. L., Dobleckilewis S., Bacon O., et al. (2016). Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern. Med. 176:75–84. 10.1001/jamainternmed.2015.4683 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu A. Y., Vittinghoff E., Chillag K., Mayer K., Thompson M., Grohskopf L., et al. (2013). Sexual risk behavior among HIV-uninfected men who have sex with men participating in a tenofovir preexposure prophylaxis randomized trial in the United States. J. Acquir. Immune Defic. Syndr. 64, 87–94. 10.1097/QAI.0b013e31828f097a [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liu A. Y., Vittinghoff E., Sellmeyer D. E., Irvin R., Mulligan K., Mayer K., et al. (2011). Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS ONE 6:e23688. 10.1371/journal.pone.0023688 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McCormack S., Dunn D. T., Desai M., Dolling D. I., Gafos M., Gilson R., et al. (2016). Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 387, 53–60. 10.1016/S0140-6736(15)00056-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Meyers K., Wu Y., Qian H., Sandfort T., Huang X., Xu J., et al. (2017). Interest in long-acting injectable PrEP in a cohort of men who have sex with men in china. AIDS Behav. 22, 1217–1227. 10.1007/s10461-017-1845-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moher D., Liberati A., Tetzlaff J., Altman D. G., Group P. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 6:e1000097 10.1371/journal.pmed.1000097 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Molina J. M., Capitant C., Spire B., Pialoux G., Cotte L., Charreau I., et al. (2015). On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N. Eng. J. Med. 373, 2237–2246. 10.1056/NEJMoa1506273 [DOI] [PubMed] [Google Scholar]
  28. Molina J.-M., Charreau I., Spire B., Cotte L., Chas J., Capitant C., et al. (2017). Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. Lancet HIV 4, e402–e410. 10.1016/S2352-3018(17)30089-9 [DOI] [PubMed] [Google Scholar]
  29. Montano M. A., Dombrowski J. C., Barbee L. A., Golden M. R., Khosropour C. M. (2017). Changes in sexual behavior and STI diagnosis among MSM Using PrEP in Seattle, WA, in Prep Persistence, Adherence, and Outcomes (Seattle, WA: CROI; ). [Google Scholar]
  30. Nederhof A. J. (1985). Methods of coping with social desirability bias: a review. Eur. J. Soc. Psychol. 15, 263–280. 10.1002/ejsp.2420150303 [DOI] [Google Scholar]
  31. Newsum A. M., Stolte I. G., van der Meer J. T., Schinkel J., Van der Valk M., Vanhommerig J. W., et al. (2017). Development and validation of the HCV-MOSAIC risk score to assist testing for acute hepatitis C virus (HCV) infection in HIV-infected men who have sex with men (MSM). Euro Surveill. 22:30540. 10.2807/1560-7917.ES.2017.22.21.30540 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Phillips A. N., Cambiano V., Nakagawa F., Brown A. E., Lampe F., Rodger A., et al. (2013). Increased HIV incidence in men who have sex with men despite high levels of ART-induced viral suppression: analysis of an extensively documented epidemic. PLoS ONE 8:e55312. 10.1371/journal.pone.0055312 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Popeleches C., Thirumurthy H., Habyarimana J., Zivin J. G., Goldstein M., Walque D. D., et al. (2011). Mobile phone technologies improve adherence to antiretroviral treatment in resource-limited settings: a randomized controlled trial of text message reminders. AIDS 25, 825–834. 10.1097/QAD.0b013e32834380c1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Prejean J., Song R., Hernandez A., Ziebell R., Green T., Walker F., et al. (2011). Estimated HIV incidence in the United States, 2006-2009. PLoS ONE 6:e17502. 10.1371/journal.pone.0017502 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Psaros C., Haberer J. E., Katabira E., Ronald A., Tumwesigye E., Campbell J. D., et al. (2014). An intervention to support HIV preexposure prophylaxis adherence in HIV-serodiscordant couples in Uganda. J. Acquir. Immune Defic. Syndr. 66, 522–529. 10.1097/QAI.0000000000000212 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. R Amico K., McMahan V., Goicochea P., Vargas L., Marcus J. L., Grant R. M., et al. (2012). Supporting study product use and accuracy in self-report in the iPrEx study: next step counseling and neutral assessment. AIDS Behav. 16, 1243–1259. 10.1007/s10461-012-0182-5 [DOI] [PubMed] [Google Scholar]
  37. Reback C. J., Fletcher J. B. (2014). HIV prevalence, substance use, and sexual risk behaviors among transgender women recruited through outreach. AIDS Behav. 18, 1359–1367. 10.1007/s10461-013-0657-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Taylor S. W., Psaros C., Pantalone D. W., Tinsley J., Elsesser S. A., Mayer K. H., et al. (2017). “Life-Steps” for PrEP adherence: demonstration of a CBT-based intervention to increase adherence to preexposure prophylaxis (PrEP) medication among sexual-minority men at high risk for HIV acquisition. Cogn. Behav. Pract. 24, 38–49. 10.1016/j.cbpra.2016.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. UNAIDS (2016). Global Factsheets.
  40. Volk J. E., Marcus J. L., Phengrasamy T., Blechinger D., Nguyen D. P., Follansbee S., et al. (2015). No new HIV infections with increasing use of HIV preexposure prophylaxis in a clinical practice setting. Clin. Infect. Dis. 61, 1601–1603. 10.1093/cid/civ778 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wheeler D. P., Fields S., Nelson L. E., Wilton L., Hightow-Weidman L., Shoptaw S., et al. (2016). HPTN 073: PrEP uptake and use by black men who have sex with men in 3 US cities, in Conference on Retroviruses and Opportunistic Infections (Boston, MA: ). [Google Scholar]
  42. Zenilman J. M., Weisman C. S., Rompalo A. M., Ellish N., Upchurch D. M., Celentano D. (1995). Condom use to prevent incident STDs: the validity of self-reported condom use. Sex. Transm. Dis. 22:15–21. 10.1097/00007435-199501000-00003 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Click here for additional data file. (27.2KB, DOCX)

Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA

RESOURCES