- Preexposure prophylaxis (PrEP) is the use of antiretroviral (ARV) drugs by HIV-negative individuals to prevent acquisition of HIV.
- Preexposure Prophylaxis Initiative (iPrEX) study of daily oral TDF/FTC in 2499 high-risk men who have sex with men (MSM) reduced HIV incidence by 44%. 
- Partners PrEP Study of 4747 serodiscordant heterosexual couples in Kenya and Uganda found 67% HIV reduction for TDF and 75% reduction for TDF/FTC. 
- TDF2 study of 1203 couples in Botswana found 63% reduction. 
- Vaginal and Oral Interventions to Control the Epidemic (VOICE) at sites in Uganda, South Africa and Zimbabwe included 5029 sexually active women assigned to oral TDF, oral TDF/FTC or TDF vaginal gel. Adherence rates based on drug levels were too low to allow for detectable treatment effect. 
- FEM-PrEP study of 2120 women in Kenya, South Africa, and Tanzania found that TDF-FTC did not reduce HIV acquisition. Adherence rates were < 40% as determined by drug blood levels. 
- Bangkok Tenofovir Study showed 49% reduction in HIV incidence among 2413 injection drug users (IDUs) taking daily TDF vs placebo. 
- As per CDC interim guidelines for PrEP in MSM , IDUs, and heterosexual men and women:
- Determine eligibility, document negative HIV Ab test immediately before PrEP initiation.
- Test for acute HIV (HIV RNA or 4th generation Ag/Ab test) if symptoms support Dx.
- Confirm high-risk for HIV acquisition.
- Confirm creatinine clearance (CrCl) is ≥60 ml/min with Cockcroft-Gault formula.
- CrCl=([140-age] X weight [kg])/(serum creatinine x72), x 0.85 in women.
- Screen and vaccinate for hepatitis B; screen for and treat STDs.
- Prescribe TDF/FTC 300/200mg combined formulation (Truvada) 1 tablet PO once-daily.
- Give 90-day supply, renewable after confirmation of negative HIV test.
- Follow-up CrCl, at 3 mos after initiation then yearly while on PrEP.
- Check HIV Ab test and document negative result every 2-3 mos.
- For women, document negative pregnancy test at baseline, retest q2-3 mos.
Selected Drug Comments
- Adherence critical to effectiveness; greatest efficacy (92% risk reduction) associated with highest adherence.
- Use of PrEP AND condoms associated with greatest risk reduction.
- TDF linked with decreased proximal renal tubular function, trial data suggests most creatinine elevations self-limited.
- Loss of bone mineral density (up to 1%) seen with TDF. Not progressive, not associated with increased fracture rate.
- ARV resistance, 
- Resistance in iPrEX seen only in patients subsequently found to have acute HIV infection at enrollment, emphasizing importance of excluding acute infection before starting PrEP.
- In TDF2 study, of 601 participants assigned to receive TDF-FTC, 9 acquired HIV during the study with no resistance identified. 
- TDF resistance mutations: K65R confers intermediate level of resistance to TDF, ABC, ddI, 3TC and FTC; increases susceptibility to AZT; and is more likely to develop in subtype C. K70E/G confers moderately reduced susceptibility to TDF, ddI and ABC and slight reduction in susceptibility to 3TC and FTC.
- FTC resistance mutations: M184V and M184I confer high-level resistance to FTC and 3TC.
- Time to development of resistance is 2-12 wks.
- If active hepatitis B infection, consider using TDF/FTC as treatment for hepatitis B and HIV prevention. Avoid interruption due to risk of hepatitis flares.
- Risk-reduction interventions include PrEP and condoms.
- CDC recomends q2-3 mos HIV antibody testing, some endorse monthly check with sensitive fourth generation Ab/Ag assay or nucleic acid amplification testing.
Basis for recommendation
- Baeten JM et al: Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 367:399, 2012 [PMID:22784037]
Comment: Partners PrEP followed 4747 individuals with serodiscordant partners in Kenya and Uganda treated with TDF or TDF/FTC versus placebo. HIV seroconversion detected during prophylaxis seen in 82 participants with 75% risk reduction (95%CI, 55-87%). No participants who acquired HIV-1 after randomization harbored the K65R or M184V mutation.
- Centers for Disease Control and Prevention (CDC): Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep 61:586, 2012 [PMID:22874836]
Comment: CDC issued interim guidance expands use of PrEP in heterosexually active adults with "ongoing, very high risk for acquiring HIV infection." Pregnancy testing prior to initiation and at regular intervals is recommended.
- Centers for Disease Control and Prevention (CDC): Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep 60:65, 2011 [PMID:21270743]
Comment: CDC guidelines detail best practices for use of PrEP in MSM. Includes screening guidelines to determine eligibility for PrEP and hepatitis B vaccination or treatment, and provides testing intervals (i.e., HIV Ab, CrCl≥60 ml/min) for follow-up and discontinuation of PrEP.
- Centers for Disease Control and Prevention (CDC): Update to Interim Guidance for Preexposure Prophylaxis (PrEP) for the Prevention of HIV Infection: PrEP for injecting drug users. MMWR Morb Mortal Wkly Rep 62:463, 2013 [PMID:23760186]
Comment: CDC interim guidance for PrEP in injection drug-users is based on HIV incidence in Bangkok Tenofovir Study of 2,413 randomized to TDF (0.35 per 100 PY) vs placebo (0.68 per 100 PY) or a 49% reduction (95%CI, 9.6-72.2%). Very high risk practices include sharing injection equipment, injecting at least once daily, injecting cocaine or methamphetamine. Recommendations include daily TDF/FTC delivered as part of comprehensive prevention services including prior testing to rule out pre-existing HIV infection and estimated creatinine clearance < 60 ml/min.
- Thigpen MC et al: Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 367:423, 2012 [PMID:22784038]
Comment: Among 1203 sexually active heterosexual adults enrolled in the TDF2 study, 9 of 33 who seroconverted during the study were assigned to receive daily TDF-FTC. TDF-FTC efficacy was 62.2% (95%CI, 21.5-83.4%; P=0.03). A significant decline in bone mineral density was noted in participants who received TDF-FTC vs placebo (Table 3). Ninety percent of participants were 21-29 yrs, >90% were single, 67% reported 1 partner in the prior 1 month, and 78% denied sex with a known HIV+ partner.
- Chirwa LI et al: CD4+ cell count, viral load, and drug resistance patterns among heterosexual breakthrough HIV infections in a study of oral preexposure prophylaxis. AIDS Dec 19 [PMID:24361682]
Comment: Report of 9 TDF2 trial participants assigned to daily TDF/FTC who were evaluated for breakthrough HIV infections found no detectable resistance to these ART. Authors address the concern for initiating PrEP in individuals with undiagnosed acute HIV infection as one individua,l who was nonreactive at baseline and randomized to TDF/FTC, developed M184V at 1 month and A62V and K65R between 4 and 7 mos after study entry.
- Gupta RK et al: Oral antiretroviral drugs as public health tools for HIV prevention: global implications for adherence, drug resistance, and the success of HIV treatment programs. J Infect Dis 207 Suppl 2:S101, 2013 [PMID:23687287]
Comment: Report summarizes data on ART for prevention of HIV acquistion and emphasizes importance of adherence. Available data supports limited drug resistance development in those using TDF/FTC as preexposure prophylaxis. Authors endorse consideration of maraviroc for PrEP, as is ongoing in HPTN 069. MVC is unlikely to be used as first-line therapy in resource-limited settings and almost all transmitted viruses are R5 tropic.
- Marcus JL et al: No Evidence of Sexual Risk Compensation in the iPrEx Trial of Daily Oral HIV Preexposure Prophylaxis. PLoS One 8:, 2013 [PMID:24367497]
Comment: iPrEx study of 2499 high risk MSM found higher report of receptive anal intercourse prior to PrEP initation (12.8 vs. 7.7, P = 0.04). Reduction of behaviors associated with HIV transmission supported by decrease in acute HIV infection and syphilis during follow-up.
- Marrazzo J, Ramjee G, Nair G, Palanee T, Mkhize B, Nakabiito Taljaard M, Piper J, Gomez Feliciano K, Chirenje M. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine or vaginal tenofovir gel in the VOICE study (MTN 003). Presented March 4, 2013 at the 20th CROI, Atlanta, GA.
Comment: Oral Abstract 26LBVOICE study found no detectable drug levels in 58% , 50%, and 55% of samples for those assigned to oral TDF, oral TDF/FTC, and vaginal TDF gel, respectively.
- Parikh UM, Mellors JW: HIV-1 Drug Resistance Resulting from Antiretroviral Therapy Far Exceeds That From Pre-exposure Prophylaxis. Clin Infect Dis May 4 [PMID:22491333]
Comment: Letter to the Editor in reply to Hurt et al. challenges the concern for drug resistance as a result of PrEP when compared to the extent of ARV resistance occurring as a result of first-line ART (22% viral failure with 95% attributable to drug resistance).
- Van Damme L et al: Preexposure prophylaxis for HIV infection among African women. N Engl J Med 367:411, 2012 [PMID:22784040]
Comment: FEM-PrEP study of 2120 women in Kenya, South Africa and Tanzania found no effect of preexposure prophylaxis. Adherence rates were < 40% as determined by drug blood levels (Table S2) and 13% of participants were lost to follow-up. Ninety percent of the women were 21-29 yrs, >90% were single, 67% reported 1 partner in the prior 1 month, and 78% denied sex with a known HIV+ partner.
- van der Straten A et al: Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention. AIDS 26:F13, 2012 [PMID:22333749]
Comment: Review of 7 HIV PrEP trials with available endpoints describes differences in adherence behavior, drug concentrations at exposure site, integrity of vaginal epithelium, and stage of infection of index partner to account for divergent PrEP trial results. Authors call for determination of "the minimum level of adeherence to achieve adequate drug levels in the female genital tract or rectum for reliable protection."
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