Effectiveness of Prevention Strategies to Reduce the Risk of Acquiring or Transmitting HIV

Strengths and Limitations of Effectiveness Estimates:

• The Cohen, 2011 (HPTN 052) study was an RCT of providing early ART, compared to delayed ART, among mostly heterosexual HIV-discordant couples. The estimate is based on the ITT results using verified linked cases of HIV. Most subjects in the treatment group were virally suppressed (89%) by 3 months and most had high adherence via pill count (79% had at least 95% adherence).
• No published study provides subset analyses of persons with evidence of ART use based on biologic, objective measures (e.g., detectable drug), so we have selected the Cohen RCT ITT results as the best estimate to represent consistent use. Since most participants were virally suppressed and reported high adherence levels, therefore results based on evidence of drug use are likely to be similar to these results.
• Without direct empirical evidence at this time for MSM, the estimate for heterosexual men and women is the best estimate until more direct evidence is available.

Source:

• Cohen MS et al. Prevention of HIV-1 with early antiretroviral therapy. N Engl J Med 2011;365(6):493-505.

Strengths and Limitations of Effectiveness Estimates:

• The Grant, 2010 (iPrEx) study was an RCT evaluating daily PrEP use (TDF/FTC) against placebo among MSM. This effectiveness estimate comes from the case/control sub-analysis looking at new HIV infection associated with any drug detected, as measured by levels of FTC or TFV in plasma or levels of FTC-TP or TFV-DP in PBMC.
• The Baeten, 2012 (Partners PrEP) study was an RCT evaluating daily PrEP use (TDF/FTC) against placebo among heterosexual men and women. This effectiveness estimate comes from a case/control sub-analysis looking at new HIV infection associated with any drug detected, as measured by TFV plasma levels.
• The Choopanya, 2013 (Bangkok Tenofovir Study, BTS) study was an RCT evaluating daily PrEP use (TDF) against placebo among PWID. This effectiveness estimate comes from a case/control sub-analysis looking at new HIV infections associated with any drug detected, as measured by TFV plasma levels.
• All effectiveness estimates are selected from subset analyses within the larger RCTs evaluating PrEP, where PrEP use is defined as “any drug detected” and based on a biologic, objective measure for detecting the presence of drug. This is the only consistent objective measure of actual PrEP use across all populations at present. The estimates do not, however, reflect optimal adherence, which would likely yield even greater effectiveness.

Additional Estimates:

• Effectiveness Estimates (from trials, regardless of level of Prep use):
  • MSM: In an RCT, the risk of HIV acquisition was reduced by 44% among HIV-uninfected MSM assigned to daily PrEP (TDF/FTC) (mITT analysis; Grant, 2010). This estimate includes all participants assigned to take daily PrEP, regardless of actual use.
  • Heterosexual men and women: In an RTC, the risk of HIV acquisition was reduced by 75% among HIV-uninfected heterosexual men and women assigned to daily PrEP (TDF/FTC) (mITT analysis; Baeten, 2012). This estimate includes all participants assigned to take daily PrEP, regardless of actual use.
  • PWIDs: In an RTC, the risk of HIV acquisition was reduced by 49% among HIV-uninfected injecting drug users assigned to daily PrEP (TDF) (mITT analysis; Choopanya, 2013). This estimate includes all participants assigned to take daily PrEP, regardless of actual use.

• Effectiveness Estimates (based on “Optimal Use” of PrEP indicated by objective adherence measures):
  • MSM: When taking PrEP (TDF/FTC) daily, as verified by highest drug level of TFV-DP in dried blood spots (>1250 fmol/punch; ~7 pills/week), the risk of HIV acquisition is reduced by an estimated 100% among HIV-uninfected MSM (subset analysis; iPrEx OLE; Grant, 2014).
  • Heterosexual men and women: When taking PrEP (TDF/FTC), as verified by a high drug level of TFV in plasma (>40 ng/ml; unknown equivalent pills/week), the risk of HIV acquisition is reduced by 88% among HIV-uninfected heterosexual men and women (subset analysis; Partners PrEP; Donnell, 2014). It is noted that blood plasma level detects more recent use, so may not be the best objective measure for optimal use.
  • PWIDs: When taking PrEP (TDF) nearly daily, as verified by DOT (at least 70% of days were DOT, with no gaps of >2 days without DOT; equivalent to ~5 days/week) and TFV drug detected in plasma, the risk of HIV acquisition is reduced by 73.5% among HIV-uninfected injecting drug users (subset analysis; BTS; Choopanya, 2013). When taking PrEP (TDF) nearly daily, defined as 97.5% adherence based on daily diary (most often confirmed daily by staff), the risk of HIV acquisition is reduced by 83.5% (subset analysis; BTS; Martin, 2015).

Source:

• Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367(5):399-410.
• Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 2013;381:2083-90.
• Donnell D, Baeten JM, Bumpus NN, et al. HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention. J Acquir Immun Defic Syndr 2014(3);66:340.
• Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363(27):2587-99.
• Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet 2014;14:820-9.
• Martin M, Vanichseni S, Suntharasamai P, et al. The impact of adherence to preexposure prophylaxis on the risk of HIV infection among people who inject drugs. AIDS 2015;29:819-24.

Strengths and Limitations of Effectiveness Estimates:

• The Smith 2015 study combined data from 2 longitudinal studies among MSM (EXPLORE & Vax004) and compared HIV-negative MSM who reported “Always” versus “Never” using condoms during insertive and receptive anal sex with an HIV-positive partner.
• The Weller 2002 Cochrane review of 13 longitudinal cohort studies among HIV discordant heterosexual couples reported results comparing those reporting “Always” versus “Never” using condoms during vaginal sex from among 5 studies with longest follow-up. Vaginal versus anal and insertive versus receptive sex were not distinguished in these analyses.
• Estimates are based on longitudinal cohort studies because no RCTs exist. No publications report condom effectiveness based on an objective measure of condom use; instead only subjective measures (self-report) are available. Since self-report tends to overestimate actual condom use, “Always” using condoms versus “Never” using condoms is the comparison selected.
• Theoretically, based on laboratory studies, condoms can be as high as 95-98% effective, if used consistently and correctly.

Source:

• Smith DK et al. Condom effectiveness for HIV prevention by consistency of use among men who have sex with men in the United States. J Acquir Immune Defic Syndr. 2015;68(3):337-44.
• Weller SC and David-Beaty K. Condom effectiveness in reducing heterosexual HIV transmission (Review). Cochrane Database Syst Rev 1. (2002): CD003255. Available at http://apps.who.int/rhl/reviews/langs/CD003255.pdf

Serosorting is typically defined as engaging in condomless sex only with HIV-negative partners.

Strengths and Limitations of Effectiveness Estimates:

• Kennedy 2013 systematic review and meta-analysis combines 3 observational studies comparing the risk of HIV infection among MSM who self-report serosorting behavior and MSM who reported condomless anal sex with either HIV-positive or unknown status partners.
• This same review also reports that serosorting when compared to no condomless anal sex (consistent condom use during anal sex or no anal sex) has an increased risk of HIV acquisition (RR=1.80).
• Estimates are based on longitudinal cohort studies because no RCTs exist. No publications report effectiveness based on an objective measure of serosorting; instead only subjective measures (self-reported behaviors or intentions to serosort) are available.
• Given no direct empirical evidence at this time for HIV-negative heterosexual men and women, the estimate for MSM is the best estimate until more direct evidence is available.
• Serosorting, which is a known HIV-negative person having condomless sex only with a known HIV-negative partner, is theoretically 100% effective. The practice of serosorting, however, is less effective because it is difficult for both participants to know with certainty each other’s HIV serostatus.

Source:

• Kennedy CE, Bernard LJ, Muessig KE, et al. Serosorting and HIV/STI infection among HIV-negative MSM and transgender people: A systematic review and meta-analysis to inform WHO guidelines. J STD 2013; http://dx.doi.org/10.1155/2013/583627

Strengths and Limitations of Effectiveness Estimates:

• Most of the evidence is based on observational studies and circumcision status is primarily based on self-report; only some studies are based on medical exam (objective measure of exposure).
• MSM Insertive Anal Sex – A Cochrane review of 7 observational studies among MSM reporting mainly or only “insertive” sex reports a significant protective effect of circumcision on acquiring HIV through insertive anal sex, 73% risk reduction (Wiysonge 2011).  Exposure (circumcision) was primarily measured via self-report (subjective measure), although genital exams occurred in some studies. Two more recently published observational studies show non-significant effects of circumcision on HIV acquisition during insertive anal sex (Sanchez, 2011; Doerner, 2013). With conflicting results, the evidence is inconclusive and an updated meta-analysis is needed.
• MSM Receptive Anal Sex – A Cochrane review of 3 observational studies among MSM reporting primarily “receptive” sex reports a non-significant effect estimate for circumcision (of the insertive partner) on HIV acquisition during receptive anal sex, with exposure measured by self-report (Wiysonge 2011). A more recently published observational study reports a significant effect of circumcision (based on self-report) on HIV acquisition during receptive anal sex among MSM (Schneider, 2012). With conflicting results, the evidence is inconclusive, and an updated meta-analysis is needed.
• Heterosexual Men – A Cochrane review of 3 RCTs synthesizes ITT results on the effects of circumcision on risk of HIV acquisition during sex among HIV-negative heterosexual men (Siegfried, 2009). 
• Heterosexual Women – A meta-analysis (including one RCT and several observational studies) reports that there is insufficient evidence to conclude that male circumcision reduces the risk of HIV acquisition during sex among HIV-negative heterosexual women (Weiss, 2009). Two more recent reports, 1 RCT and 1 observational study, also show non-significant effects of male circumcision (confirmed by medical exam) on HIV acquisition in women among HIV-discordant heterosexual couples (Baeten, 2010; Wawer, 2009). The evidence is inconclusive, and an updated meta-analysis is needed.

Source:

• Baeten JM, Donnell D, Kapiga SH, et al. Male circumcision and risk of male-to-female HIV-1 transmission: a multinational prospective study in African HIV-1-serodiscordant couples. AIDS 2010;24(5):737-44.
• Doerner R, McKeown E, Nelson S, Anderson J, Low N, Elford J. Circumcision and HIV infection among men who have sex with men in Britain: The insertive sexual role. Archives of sexual behavior. 2013; 42:1319–1326.
• Sanchez J, Sal YRVG, Hughes JP, et al. Male circumcision and risk of HIV acquisition among MSM. AIDS 2011;25:519-23.
• Schneider JA, Michaels S, Gandham SR, et al. A protective effect of circumcision among receptive male sex partners of Indian men who have sex with men. AIDS and Behav 2012;16:(2)350-9.
• Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men (Review). Cochrane database of systematic reviews. 2009(2):CD003362.
• Wawer MJ, Makumbi F, Kigozi G, et al. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomized controlled trial. Lancet 2009;374(9685):229-37.
• Weiss HA, Hankins CA, Dickson K. Male circumcision and risk of HIV infection in women: a systematic review and meta-analysis. Lancet Infect Dis 2009;9:669–77.
• Wiysonge CS, Kongnyuy EJ, Shey M, et al. Male circumcision for prevention of homosexual acquisition of HIV in men. Cochrane database of systematic reviews. 2011(6):CD007496.