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Guidance on Pre-Exposure Oral Prophylaxis (PrEP) for Serodiscordant Couples, Men and Transgender Women Who Have Sex with Men at High Risk of HIV: Recommendations for Use in the Context of Demonstration Projects. Geneva: World Health Organization; 2012 Jul.

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Guidance on Pre-Exposure Oral Prophylaxis (PrEP) for Serodiscordant Couples, Men and Transgender Women Who Have Sex with Men at High Risk of HIV: Recommendations for Use in the Context of Demonstration Projects.

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Annex 1Pre-exposure prophylaxis (PrEP) for HIV serodiscordant couples: a systematic review

Background

More than 34 million people globally are living with HIV. A number of prevention methods are available, from condoms to male circumcision, PMTCT or clean needles, but to date these have not been sufficient to stop the epidemic. In 2009 alone, an estimated 2.7 million people became newly infected. Additional safe and effective approaches to HIV prevention are urgently needed.

PrEP is the use of an antiretroviral drug to block the acquisition of HIV infection by uninfected people. Proof of concept has long been established in the laboratory by animal studies and in real world application by the prevention of mother-to-child transmission and post-exposure prophylaxis. The safety of the drugs being considered for PrEP, tenofovir and emtricitabine, has been established through their use for treatment and in safety trials in uninfected people (Peterson et al., 2007). Five trials of effectiveness of oral PrEP (Phase IIb and Phase III) have been conducted since 2005. These focus on effectiveness of PrEP among injection drug users, serodiscordant couples, heterosexual women and high risk men who have sex with men.

The first trial to produce results was the iPrex trial (Grant et al., 2010). This multi-site Phase III clinical trial tested whether a daily combination of tenofovir and emtricitabine could safely and effectively prevent HIV infection among men who have sex with men and transgendered women who have sex with men. The iPrex study demonstrated a 44% reduction in HIV transmission using a modified intention-to-treat analysis. Adherence to the recommended regimen was lower than expected, though it varied by country. For those men who reported taking the pills on 90% or more days, however, the efficacy of PrEP was 73%. Resistance was only found in two participants who had an existing acute HIV infection undetected at baseline and who were randomized to active drug. Few concerns about safety were detected. A marked trend toward risk reduction, specifically increased condom use and decreased number of partners, was reported in both arms and all sites.

The second study to produce results was a trial of daily oral emtricitabine and tenofovir among high-risk African women (FHI, 2011). This trial was terminated early due to lack of efficacy, with an equal number of infections in the PrEP and placebo arms.

The third trial to produce results, the TDF2 study conducted by the U.S. Centers for Disease Control and Prevention and the Botswana Ministry of Health, was a trial of daily oral emtricitabine and tenofovir for heterosexual men and women in Botswana (CDC, 2011). This study showed that PrEP reduced the risk of acquiring HIV infection by roughly 63 per cent overall.

The fourth trial to produce results, Partners PrEP, was a trial of daily oral tenofovir and daily oral emtricitabine and tenofovir among HIV-1 serodiscordant couples in Kenya and Uganda (Mujugira et al., 2011). This trial found that those who received tenofovir alone had an average of 62% fewer HIV infections (95% CI 34 to 78%, p=0.0003) and those who received emtricitabine and tenofovir had 73% fewer HIV infections (95% CI 49 to 85%, p<0.0001) than those who received placebo (University of Washington, 2011).

This systematic review examined evidence for the following PICO question: Should daily tenofovir (TDF) or daily tenofovir (TDF) plus emtricitabine (FTC) be used as pre-exposure prophylaxis for HIV prevention for the uninfected partner in heterosexual HIV serodiscordant couples?

Methods

PICO question

PICO 1:

Should daily tenofovir (TDF) or daily tenofovir (TDF) plus emtricitabine (FTC) be used as pre-exposure prophylaxis for HIV prevention for the uninfected partner in heterosexual HIV serodiscordant couples?

P: Heterosexual HIV serodiscordant couples

I: Oral tenofovir alone or oral emtricitabine (FTC) and tenofovir (TDF) or the HIV-negative partner

C: Placebo

O: (1) HIV infection, (2) any adverse event, (3) any stage 3 or 4 adverse event, (4) condom use, and 5) number of sexual partners

Inclusion criteria

To be included in the review, an article had to meet the following criteria:

  1. Randomized controlled trial evaluating the use of oral emtricitabine (FTC) and/or tenofovir (TDF) for the HIV-negative partner to prevent HIV infection among heterosexual HIV serodiscordant couples.
  2. Measured one or more of the following key outcomes: (1) HIV infection, (2) any adverse event, (3) any stage 3 or 4 adverse event, 4) condom use, and 5) number of sexual partners.
  3. Published in a peer-reviewed journal, or presented as an abstract at a scientific conference, between January 1, 1990 and November 1, 2011.

No restrictions were placed based on location of the intervention. No language restrictions were used on the search. Articles in languages other than English were translated where necessary.

Following the GRADE approach, when direct evidence from heterosexual HIV serodiscordant couples was not available for one or more of the key outcomes, indirect evidence from other populations (high-risk heterosexual adults, men who have sex with men, etc.) was used instead, but downgraded for indirectness. If evidence from other populations was not available, evidence from non-randomized but controlled studies was used instead, but also downgraded for directness.

Search strategy

The following electronic databases were searched using the date ranges January 1, 1990 to November 1, 2011: Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and EMBASE. Secondary reference searching was conducted on all studies included in the review. Further, selected experts in the field were contacted to identify additional articles not identified through other search methods.

Abstracts from the following conferences were searched from January 1, 1990 to November 1, 2011: International AIDS Conference (IAC), IAS Conference on HIV Pathogenesis, Treatment, and Prevention (IAS), and Conference on Retroviruses and Opportunistic Infections (CROI).

Search terms

The following terms were entered into all computer databases:

(“sero-discordant” or serodiscordant or discordant or couple) AND (“pre-exposure prophylaxis” or PrEP or emtricitabine or tenofovir or Truvada or FTC or TDF) AND (HIV OR AIDS)

Screening abstracts

Titles, abstracts, citation information, and descriptor terms of citations identified through the search strategy were screened by two members of the study staff. Full text articles were obtained for all selected abstracts and both reviewers independently assessed all full-text articles for eligibility to determine final study selection. Differences were resolved through consensus.

Articles not meeting the inclusion criteria for the review, but presenting potentially interesting background information relevant to PrEP among heterosexual HIV serodiscordant couples, including review articles, qualitative studies, cost or cost-effectiveness analyses, or descriptions of interventions without an evaluation component, were included in an annotated bibliography of additional articles.

Data extraction and management

Data were extracted independently by two reviewers using standardized data extraction forms. Differences in data extraction were resolved through consensus and referral to a senior team member from WHO when necessary. Study authors were contacted when additional information or data were needed.

The following information was gathered from each included study:

  • Study identification: Author(s); type of citation; year of publication
  • Study description: Study objectives; location; population characteristics; description of the intervention; study design; sample size; follow-up periods and loss to follow-up
  • Outcomes: Analytic approach; outcome measures; comparison groups; effect sizes; confidence intervals; significance levels; conclusions; limitations

Risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias (Cochrane Handbook, chapter 8.5 – Higgins & Green, 2011). This tool assesses random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data addressed (attrition bias), incomplete outcome data, and selective reporting (reporting bias). Methodological components of the studies were assessed and classified as high, low, or uncertain risk of bias.

Data analysis

Data were analyzed according to the data extraction categories and outcomes listed above. If multiple studies reported the same outcome, meta-analysis would have been conducted using random-effects models to combine odds ratios with the program Comprehensive Meta-Analysis (CMA). Data were summarized in GRADE evidence profiles, summary of finding tables, and risk/benefit tables.

Results

Our initial database search yielded 82 citations and 292 conference abstracts; two additional studies were identified through other means, such as searching through the reference lists of relevant articles (Figure 1). One randomized trial was deemed eligible for inclusion in our review.

Figure 1. Disposition of citations during the search and screening process.

Figure 1

Disposition of citations during the search and screening process.

The one study that met all inclusion criteria was the Partners PrEP trial (Baeten et al., 2012). This study was a three arm, randomized controlled trial to evaluate the efficacy of oral PrEP (TDF and/or FTC/TDF) for HIV prevention among HIV serodiscordant heterosexual couples. The trial was conducted in 9 clinical sites in Kenya and Uganda.

Baseline characteristics of participants were equal across study arms (Mujugira et al., 2011). For 62% of enrolled couples, the HIV-1 seronegative partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. For HIV-1 seropositive participants, the median CD4 count was 495 cells/mm3 (IQR 375-662), 80% had CD4 counts >= 350 cells/mm3, and median plasma HIV-1 RNA level was 3.9 log10 copies/mL (IQR 3.2-4.5).

Using the Cochrane Risk of Bias tool, the study was judged to have low risk of bias across all of the following categories: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data addressed (attrition bias), selective reporting (reporting bias), and other biases. The study was stopped early for evidence of benefit, which may overestimate treatment effects; however, as this was a multi-country study judged to have low risk of bias on all other criteria, it was not downgraded for this reason, and was considered high quality.

The study measured all five key outcomes for this review: 1) HIV infection, 2) Any adverse event, 3) Any stage 3 or 4 adverse event, 4) Condom use, and 5) Number of sexual partners.

HIV infection

Incident HIV infection was significantly reduced among participants in both the TDF and the FTC/TDF study arms as compared to the control arm using a modified intention-to-treat analysis excluding participants who had HIV RNA detected at baseline. There were 96 serconversions in total; 82 were post-randomization conversions. In the TDF arm, there were 17 incident cases of HIV infection out of 1579 participants (HIV incidence rate: 0.65 per 100 person years (py)) compared to 52 incident HIV infections out of 1578 participants in the control group (HIV incidence rate: 1.99 per 100 py), resulting in a hazard ratio of 0.33 (95% CI 0.19-0.56, p<0.001), thus showing a 67% reduction in HIV acquisition (95% CI 44-81%, p<0.001). In the FTC/TDF arm, there were 13 incidence cases of HIV infection out of 1576 participants (HIV incidence rate: 0.25 per 100 py), resulting in a hazard ratio (compared to placebo) of 0.25 (95% CI 0.13-0.45, p<0.001), thus showing a 75% reduction in HIV acquisition. The HIV-1 protective effects of FTC/TDF and TDF were not significantly different.

These results were further stratified by gender. Among women, TDF efficacy was 71% (p=0.002) and FTC/TDF was 66% (p=0.005); among men, TDF efficacy was 63% (p=0.01) and FTC/TDF was 84% (p<0.001). The HIV-1 protective effects of TDF and FTC/TDF were not statistically different by sex.

Any adverse event

There was no statistically significant difference in reported adverse events between study arms. In the TDF arm, 1350 out of 1584 patients (82.5%) reported having any adverse event compared to 1350 out of 1584 patients (85.2%) in the control group, which was not statistically significant (p=1.00). In the FTC/TDF arm, 1362 out of 1579 patients (86.3%) reported having any adverse event, which was not statistically significant compared to the control group (p=0.42).

Any stage 3 or 4 adverse event

All three study arms also reported similar rates of stage 3 and 4 adverse events.

For stage 3 adverse events, in the TDF study arm, 289 out of 1584 patients (18.2%) reported having a grade 3 adverse event compared to 268 out of 1584 patients (16.9%) in the control arm, which was not statistically significant (p=0.35). In the FTC/TDF study arm, 293 out of 1579 patients (18.6%) reported having a grade 3 adverse event, which was not statistically significant compared to the control group (p=0.24).

For stage 4 adverse events, in the TDF study arm, 34 out of 1584 patients (2.1%) reported having a grade 4 adverse event compared to 39 out of 1584 patients (2.5%) in the control arm, which was not statistically significant (p=0.64). In the FTC/TDF study arm, 44 out of 1579 patients (2.8%) reported having a grade 4 adverse event, which was not statistically significant compared to the control group (p=0.58).

Condom use

The study found that all groups reported reduced sex without condoms over the course of the intervention, but there were no significant differences in condom use rates between the TDF, FTC/TDF, and control arms. At enrollment, 27% of HIV seronegative partners reported sex without condoms with their HIV seropositive partner during the prior month. This percentage decreased throughout the study (to 13% and 9% at 12 and 24 months) , though appeared to increase to pre-intervention levels at the end of the trial among a small number of participants who completed 36 months of follow-up. The difference across arms was not statistically significant using generalized estimating equations analysis (GEE) to assess trends over time (TDF vs. placebo: p=0.32; FTC/TDF vs. placebo: p=0.66).

Number of sexual partners

There was no difference in reported outside sexual partners across the three study arms. In the TDF arm, 468 out of 1584 participants (29.7%) reported an outside partner at any follow-up visit, compared with 459 out of 1584 participants (29.1%) in the control group (p=0.74). In the FTC/TDF arm, 469 out of 1579 participants (29.9%), which was also not a statistically significant difference compared to the control group (p=0.67).

Table 1Risk-benefit table

FactorExplanation / EvidenceJudgment
Quality of EvidenceOne multi-country RCT without serious limitations. Additional studies from other populations at various stages of completion.High
Balance of Benefits vs. HarmsHIV infection
Oral PrEP was associated with reduced risk of HIV-1 compared to placebo. This reduction was 67% for TDF [Hazard ratio (HR): 0.33, 95% CI 0.19-0.56, p<0.001) and 75% for FTC/TDF (HR: 0.25, 95% CI 0.13-0.45, p<0.001). These HIV-1 protective effects of TDF and FTC/TDF were not statistically different by sex.

Adverse events
There was no significant difference in reported adverse events between the TDF or FTC/TDF and control arms. This was the case for any adverse event (TDF vs. control: 82.5% vs. 85.2%, p=1.00; FTC/TDF vs. control: 86.3% vs. 85.2%, p=0.42), for grade 3 adverse events (TDF vs. control: 18.2% vs. 16.9%, p=0.35; FTC/TDF vs. control: 18.6% vs. 16.9%, p=0.24), and for grade 4 adverse events (TDF vs. control: 2.1% vs. 2.5%, p=0.64; FTC/TDF vs. control: 2.8% vs. 2.5%, p=0.58).

Condom use
All groups reported reduced sex without condoms over the course of the intervention, but there were no significant differences in condom use rates between the TDF, FTC/TDF, and control arms. Rates across arms dropped from 27% at baseline to 13% at 12 months and 9% at 24 months.

Number of sexual partners
There was no difference in reported outside sexual partners across the three study arms (TDF vs. control: 29.7% vs. 29.1%, p=0.74; FTC/TDF vs. control: 29.9% vs. 29.1%, p=0.67).
Benefits outweigh harms
Values and PreferencesAlthough few studies have examined values and preferences around PrEP for serodiscordant couples, existing research indicates acceptability.Acceptable
Resource UseIn mathematical modeling (Hallett et. al., 2011), although the cost of PrEP was high, the cost per infection averted was significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, PrEP could be cost-saving overall.

Using Partners in Prevention data:
-

Cost per infection averted was between US$6,000 and $66,000 when PrEP was always used

-

Cost per QALY saved was $260-$4,900

Using “more typical” data on risk behavior
-

Cost per infection averted was between ∼$0 (breakeven) and $26,000 when PrEP was always used

-

Cost per QALY saved was -$200 (cost-saving) to $1,900

Although the cost of PrEP may be high, the cost per infection averted may be offset by future savings in lifelong treatment. In some situations, PrEP could be cost-saving overall.
Consideration in certain settings
FeasibilityOral PrEP for heterosexual HIV serodiscordant couples has proven feasible in various trial settings. Adherence to daily oral medication may prove challenging over longer periods of time.Consideration in certain settings

References for Annex 1: systematic review of serodiscordant couples

  1. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV-1 prevention in heterosexual men and women. New England Journal of Medicine. In Press. [PMC free article: PMC3770474] [PubMed: 22784037]
  2. CDC website. CDC trial and another major study find PrEP can reduce risk of HIV infection among heterosexuals. 2011. [2 November 2011]. Available from: http://www​.cdc.gov/nchhstp​/newsroom/PrEPHeterosexuals.html.
  3. FHI website. FHI to initiate orderly closure of FEM-PrEP. 2011. [2 November 2011]. Available from: http://www​.fhi.org/en​/AboutFHI/Media/Releases​/FEM-PrEP_statement041811.htm.
  4. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 2010;363(27):2587–99. [PMC free article: PMC3079639] [PubMed: 21091279]
  5. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2011. [June 10, 2011]. Version 5.1.0. Available from: http://www​.cochrane-handbook.org/
  6. Mujugira A, Baeten JM, Donnell D, Ndase P, Mugo NR, Barnes L, et al. Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention. PLoS One. 2011;6(10):e25828. [PMC free article: PMC3187805] [PubMed: 21998703]
  7. Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clinical Trials. 2007;2(5):e27. [PMC free article: PMC1876601] [PubMed: 17525796]
  8. University of Washington website. Pivotal study finds that HIV medications are highly effective as prophylaxis against HIV infection in men and women in Africa. 2011. [2 November 2011]. Available from: http://depts​.washington​.edu/uwicrc/research​/studies/files/PrEP​_PressRelease-UW_13Jul2011.pdf.
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