ANRS IPERGAY
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Clinical Question
Among men who have sex with men and are at high risk for HIV transmission, does on-demand pre-exposure prophylaxis around the time of sex reduce the transmission of HIV?
Bottom Line
Among men who have sex with men who are at high risk for HIV transmission, on-demand pre-exposure prophylaxis with antiretrovirals reduces the transmission of HIV.
Major Points
Previously, the 2010 IPrEx trial demonstrated that emtricitabine-tenofovir (TDF-FTC, brand name Truvada) taken daily reduces the incidence of new HIV infections among seronegative men who have sex with men (MSM) at high risk of HIV infection.[1] The drawbacks of daily use — including cost and the risk of renal insufficiency and Fanconi syndrome — drove investigators to evaluate the efficacy of as-needed pre-exposure prophylaxis.
Published in 2015, the France Recherche Nord & Sud Sida-HIV et Hépatites Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (ANRS IPERGAY) trial randomized 400 high-risk MSM who engaged in unprotected anal sex with men either to PrEP with TDF-FTC or to placebo. Individuals were instructed to take 1-2 tablets 2-24 hours before sexual encounter then daily for several days following. The trial was stopped early with a median follow-up of 9.3 months, when an interim analysis determined that on-demand PrEP significantly reduced the rate of HIV seroconversion when compared to placebo (0.91 vs. 6.60 per 100 person-years; P=0.002). The therapy was generally well tolerated, except for higher rates of nausea and increased incidence of elevated creatinine in the TDF-FTC arm. The benefit in this trial is somewhat surprising as most patients either didn't take the medication or didn't follow the protocol.
Guidelines
As of December 2015, no guidelines have been published that reflect the results of this trial.
Design
- Multicenter randomized, placebo controlled trial
- N=400 high-risk MSM
- TDF-FTC (n=199)
- Placebo (n=201)
- Setting: Seven centers in France and Canada
- Enrollment: 2012-2014
- Median follow-up: 9.3 months (stopped early)
- Analysis: Modified intention-to-treat
- Primary outcome: HIV-1 infection
Population
Inclusion Criteria
- Male sex (any gender), age ≥18, HIV-1 & 2 negative
- Anal sex with ≥2 partners in prior 6 months without consistent condom use
- CrCl >60 mL/min
- ALT <2.5x ULN
- Neutrophils ≥1,000/mm3, Hgb ≥10 g/dL, platelets ≥150,000/mm3
Exclusion Criteria
- Hep B or hep C infection
- Routine condom use
- Glucosuria, proteinuria, hematuria, or pyuria
- CKD or long-term use of potentially nephrotoxic agent
- Osteoporosis, osteopenia, or pathologic bone fracture
- Treatment with IFN, an interleukin, corticosteroids, or antiretrovirals
- IV drug use
- GI disease that reduces absorption
- Likely to be noncompliant
- Life-threatening disease
Baseline Characteristics
From the TDF-FTC group.
- Demographics: Male sex 100%, age 35 years (18-24 years 16%, 25-29 years 13%, 30-39 years 36%, 40-49 years 25%, ≥50 years 10%), white race 94%, post-secondary or greater education 73%, site:
- France: 89%
- Montreal: 11%
- Risk factors:
- Median number of sexual partners in prior 2 months: 8
- Median number of sexual intercourse in past month: 10
- Circumcision: 19%
- Relationship: Single 72%, HIV-1 serodiscordant couple 10%, other 18%
- >5 daily EtOH drinks in prior month: 25%
- Recreational drug use: 43%
- STI at screening: 25%
- HBV status: Susceptible 23%, immune from infection 9%, immune from vaccination 68%
Interventions
- Randomized to a group:
- TDF-FTC - Tenofovir-emtricitabine 300-200 mg
- Placebo
- Participants were instructed to take a loading dose (2 tablets) with food 2-24 hours before sex, a 3rd pill 24 hours after the first tablet, and a 4th tablet 24 hours after that
- If multiple sexual encounters, they were instructed to take a daily tablet until the last sexual encounter, followed by two final tablets
- If reinitiation of the intervention, users were advised to take a loading dose if their last dose was >1 week prior and a single tablet if <1 week prior
- All participants received risk-reduction counseling, condoms, vaccinations against hep A&E
- Participants received routine STI screening
- Pill counts occurred at each visit
Outcomes
Comparisons are TDF-FTC vs. placebo. P-Y is person-years. RR is relative reduction.
Primary Outcome
- HIV-1 infection
- 0.91 vs. 6.60/100 P-Y (RR 86%; 95% CI 40-98%; P=0.002)
- 2 vs. 14 individuals
- The authors note that the two individuals in the intervention group that acquired infection took at most 2 pills during the study.
- 2 vs. 14 individuals
Secondary Outcomes
- Adherence
- Followed protocol: 45% vs. 40%
- Suboptimal use: 27% vs. 31%
- None used: 27% vs. 29%
- Monthly pills taken (median)
- 15 vs. 15 (P=0.57)
- Post-exposure prophyaxis during the study
- 31 vs. 25 people (P=0.37)
- Changes in sexual habits from baseline
- The authors note that there were no differences in the number of sexual encounters in the prior 4 weeks (P=0.07), proportion of receptive anal intercourse without condoms (P=0.40)
- New STIs
- Both groups combined.
- Chlamydia: 20%
- Gonorrhea: 22%
- Syphilis: 10%
- HCV: 1%
- HBV: None
Adverse Events
- Any
- 93 vs. 90%
- Elevated creatinine
- 18% vs. 10% (P=0.03)
- Most events were grade 1
- Nausea
- 8% vs. 1%
Criticisms
- Its unclear if it was ethically sound to conduct a PrEP trial involving placebo with enrollment beginning >2 years after publication of the iPrEx study. Perhaps a better comparator than placebo would be continuous PrEP.
- Unclear long-term risks of TDF-FTC given its increased risk for kidney disease and Fanconi's syndrome
- Unclear if PrEP will select for more transmission of more resistant HIV viruses
- The trial was stopped early
Funding
- ANRS
- Canadian HIV Trials Network
- Fonds de Dotation Pierre Berge pour la Prevention
- Bill and Melinda Gates Foundation
- Gilead Sciences (makers of Truvada, the brand name of TDF-FTC, who provided study medication and placebo and funded the pharmacokinetic analysis)