Pre-exposure Prophylaxis

Lisa A. Spacek, M.D., Ph.D.

DEFINITION

  • Preexposure prophylaxis (PrEP) is the use of antiretroviral (ARV) drugs by HIV-negative individuals to prevent acquisition of HIV.
  • Consider PrEP for:
    • Anyone from a population whose HIV incidence is at least 2% per year; or
    • HIV-seronegative partners of HIV-infected person whose viral load is not suppressed.[2]

INDICATIONS

  • iPrEx study: Daily oral TDF/FTC in 2499 men and transgender women who have sex with men reduced HIV incidence by 44%. In the TDF/FTC group, relative reduction of HIV risk was 92% (95% CI, 40-99%) for those with detectable study drug level compared to those without.[6]
  • Partners PrEP study: 4747 serodiscordant heterosexual couples in Kenya and Uganda. 67% HIV reduction for TDF and 75% reduction for TDF/FTC.[23] In substudy that measured TDF levels, 90% risk reduction with detectable TDF.
  • TDF2 study: 63% reduction in 1203 heterosexual couples in Botswana in those randomized to daily, oral TDF/FTC versus placebo.
  • VOICE study: 5029 sexually active women in Uganda, South Africa and Zimbabwe randomized to oral TDF, oral TDF/FTC or TDF vaginal gel. Drug levels were too low to allow for detectable treatment effect.[20]
  • FEM-PrEP study: TDF-FTC did not reduce HIV acquisition in 2120 women in Kenya, South Africa, and Tanzania.
  • Bangkok Tenofovir study: 49% reduction in HIV incidence among 2413 IDUs taking daily TDF vs placebo.
  • IPERGAY study: On-demand dosing of 2 tablets 2-24 hours before sex, a third pill 24 hours after first dose, and a fourth pill 24 hours later, reduced HIV infection by 86%.[4] However, number of sex acts (and therefore doses) was high, so efficacy may reflect the equivalent of continuous dosing.
  • PROUD study: O[23]pen-label randomized trial compared immediate versus deferred daily oral PrEP reduced risk of incident HIV infection by 86% (95%CI, 64-96%). Number needed to treat is 13 men for 1 year.[3]

CLINICAL RECOMMENDATION

  • IAS-USA Guidelines detail recommendations for prevention of HIV acquisition.[2]
  • CDC Clinical Practice Guidelines review evidence for safety and efficacy and include data from clinical trials in different segments of populations including MSM, heterosexuals and IDUs.[7] Available at: https://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf
    • HIV Risk Reduction Tool allows user to customize content and input scenarios to generate risk of HIV transmission and acquisition. Available at: https://wwwn.cdc.gov/hivrisk/
  • Daily oral PrEP with fixed dose combination pill, TDF/FTC, is recommended for individuals who are sexually active with HIV+ partners and partners with unknown serostatus and IDUs.
    • Determine risk for HIV acquisition: number of partners; men, women, or both; use of condoms; receptive or insertive anal sex; use of drugs such as methamphetamines; known HIV+ partner without viral suppression.
  • HIV testing, preferably with a combination antigen-antibody assay. For high-incidence populations, i.e., those with a history of recent exposure, consider HIV RNA assay to exclude acute HIV infection prior to PrEP.[2]
    • Evaluate for signs/symptoms of acute HIV infection: fever, myalgias, rash, headache, pharyngitis, cervical adenopathy
  • 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 for hepatitis B[14] and vaccinate if non-immune. Also consider hepatitis A screening and vaccination and HPV vaccination in appropriate age strata.
  • Screen and treat for sexually-transmitted infections (STIs).[11] For MSM, pharyngeal and rectal STI testing is recommended.[7]
  • 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 q6 mos while on PrEP and perhaps more frequently for those aged >50 years, exposed to potential nephrotoxins, with baseline eGFR < 90 ml/min or declining eGFRs.[1][17]
    • HIV testing at least q3 mos by antigen-antibody assay unless symptoms or signs of acute HIV infection are present, in which case HIV RNA testing should be ordered.[2]
    • For women, document negative pregnancy test at baseline, retest q2-3 mos.
    • For IDUs, connect to drug treatment services and clean needles and syringes.
    • Regular STI screening based on risk. Combine PrEP with STI testing and management for those seeking sexual health services.

Selected Drug Comments

  • Effectiveness is determined by adherence and may also depend on route of HIV acquisition. Colorectal and vaginal tissue concentrations of active intracellular metabolite, tenofovir diphosphate, may differ.[10]
  • TDF can cause proximal renal tubular dysfunction, trial data suggest that most creatinine elevations self-limited.[1][16]
    • iPrEx-OLE data show association of decline in renal function with age ≥50 yrs and baseline CrCl < 90.[1]
  • Loss of bone mineral density seen with TDF. In iPrEX, those on PrEP with measured drug levels experienced mean BMD loss of 1.42% at spine and 0.85% at hip.[21] Most rapid decline seen in first 24 weeks. TDF effect on bone may be direct, associated with proximal tubule dysfunction, or related to PTH/vitamin D metabolism.[13]
    • DEXA scan not routinely recommended, but could be considered based on risk (e.g., age, chronic steroid exposure) and counseling on bone health (e.g., limit use of alcohol and tobacco, increase weight-bearing exercise and dietary intake of calcium and vitamin D.
  • If active hepatitis B infection, consider using TDF/FTC as both treatment for hepatitis B and HIV prevention. Limited data on those with chronic HBV, check for cirrhosis and transaminase elevation.[14] If discontinuing PrEP in those with chronic active HBV, recognize potential for reactivation.
  • Side effects uncommon but may include headache, nausea, and flatulance, which usually resolve within first month.
  • 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.[22] One participant with acute wild-type infection, who tested falsely negative at entry screening and received TDF/FTC, developed M184V one month after study entry and A62V and K65R mutations 4 to 7 months after study entry.
    • In Partners PrEP, no participants who acquired HIV after randomization harbored K65R or M184V mutation.[23]

OTHER INFORMATION

  • PrEP use periconception and during pregnancy in uninfected partner may reduce HIV acquisition.[7] Infected partner’s viral load should be suppressed before attempting conception. Assessment of pregnant and postpartum women who may benefit from PrEP includes those with partner of unknown HIV serostatus.[9]
  • Safety and acceptability phase 2 study of tenofovir topical gel, rectally applied (CONRAD, Arlington, VA) was safe, and adherence with intermittant gel was similar to daily oral TDF/FTC.[8]
  • Studies evaluating the efficacy of TAF or TAF/FTC for PrEP are ongoing.
    • TAF/FTC treated macaques rectally exposed to simian/human immunodeficiency virus (SHIV) were protected (n=6), whereas all controls (n=6) were infected.[12]
    • TAFsingle-dose pharmacokinetics in healthy women (n=8) showed that the majority of female genital tract and lower gastrointestinal tract tissue tenofovir diphosphate concentrations were unquantifiable and could not be quantified in any samples collected after 72h.[10]
    • Oral TAF/FTC as PrEP (NCT02842086) Phase 3, randomized, double-blind study to evaluate the safety and efficacy of daily TAF/TFC for PrEP in men and transgender women who have sex with men and are at risk of HIV-1 infection, DISCOVER, sponsored by Gilead.
    • TAF for subcutaneous delivery via a thin-film polymer device (TFPD) is under development.[15]
  • Phase 3 study of dapivirine-containing vaginal ring found 27% reduction (95%CI, 1-46%) in incidence of HIV in the dapirivine group versus placebo.[18] Protection for women ≥ 25 years was 61% (95%CI, 32-77%) compared to 10% (95%CI, -41-43%) in women < 25 years.
  • Phase 2 studies of cabotegravir, long-acting injectable IM formulation, include ECLAIR and HPTN 077, HPTN 083. (Long-acting nanoparticle injection.)[19]

Basis for recommendation

  1. Gandhi M, Glidden DV, Mayer K, et al. Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV. 2016;3(11):e521-e528.  [PMID:27658870]

    Comment: Subanalysis of iPrEx OLE (N=1224) and hair substudy (N=220) evaluated association of decline in CrCl with (1) age ≥ 50 years, (2) baseline CrCl < 90, and (3) estimated number of TDF doses taken per week based on hair analysis. Authors suggest that risk stratification for anticipated decline in renal function may be based on older age and reduced CrCl at initiation of TDF.

  2. Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016;316(2):191-210.  [PMID:27404187]

    Comment: Guidelines detail recommendations for prevention of HIV acquisition: PrEP should be considered for anyone from a population whose HIV incidence is at least 2% per year or HIV-seronegative partners of HIV-infected persons who do not have viral suppression.

  3. McCormack S, Dunn DT, Desai M, et al. 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. 2016;387(10013):53-60.  [PMID:26364263]

    Comment: Open-label randomized trial compared immediate versus deferred daily PrEP in 540 men (median, 35 yrs; majority were white, employed with university degree) found 1.2 versus 9.0 per 100 person-years incident HIV infections (3 versus 20), respectively. Over one-third of each group reported use of post-exposure prophylaxis in prior 12 months. Calculated number needed to treat is 13 men (95%CI, 9-23%) with 1 year of PrEP.

  4. Molina JM, Capitant C, Spire B, et al. On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. N Engl J Med. 2015;373(23):2237-46.  [PMID:26624850]

    Comment: RCT of TDF/FTC versus placebo in 400 men with HIV infection incidence of 0.91 versus 6.60 per 100 person-years (2 versus 14), respectively. Unlike current CDC guidelines, this investigation incorporated on-demand dosing of 2 tablets with food 2-24 hours before sex, a third pill 24 hours after first drug intake, and a fourth pill 24 hours later. Incidence rates generate number needed to treat of 18.

  5. Grohskopf LA, Chillag KL, Gvetadze R, et al. 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. 2013;64(1):79-86.  [PMID:23466649]

    Comment: US-based safety study of daily oral tenofovir in San Francisco, Atlanta, and Boston (2005-2007) included 400 men (median, 37 yrs, majority were white and college graduates). There were no grade ≥3 creatinine elevations; grades 1 and 2 creatinine increases were not associated with TDF receipt.

  6. 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.  [PMID:21091279]

    Comment: Multinational (n=6 countries) RTC of daily, oral TDF/FTC in 2499 men and transgender women who have sex with men found relative risk reduction of 44% (95%CI, 15-63%). Evidence for risk of acquisition of HIV infection included any of the following in the 6 months prior to screening: anal sex with 4 or more male partners, STI diagnosis, transactional sex, or condomless anal sex with HIV infected partner or partner of unknown serostatus.

  7. Centers for Disease Control. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States - 2014 Clinical Practice Guideline.

    Comment: Guidelines review indications and implementation of PrEP. Available at https://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf. Accessed 4/4/2017.

References

  1. Cranston RD, Lama JR, Richardson BA, et al. MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel. Clin Infect Dis. 2017;64(5):614-620.  [PMID:27986684]

    Comment: Multi-site (USA, Thailand, Peru, and South Africa) phase 2 open-label study compared rectally applied topical tenofovir (daily and intermittant) and daily oral TDF/FTC in MSM and transgender women. Rectal application was safe, but efficacy of less than single daily doses of tenofovir 1% gel to prevent HIV acquisition has not been tested.
    Rating: Important

  2. Pintye J, Drake AL, Kinuthia J, et al. A Risk Assessment Tool for Identifying Pregnant and Postpartum Women Who May Benefit From Preexposure Prophylaxis. Clin Infect Dis. 2017;64(6):751-758.  [PMID:28034882]

    Comment: Risk score for maternal HIV acquisition developed and validated from longitudinal cohort, the Mama Salama Study, in western Kenya identified number of lifetime sex partners (1 pt per partner), HIV status of male partner (6 pts if unknown status), and syphilis (5 pts if RPR reactive). Score > 6 predicted 56% of HIV acquisition and 16% of women had scores > 6. In full cohort (N=1304), those with score > 6 had HIV incidence of 7 per 100PY (95%CI, 4-12) and those with score ≤ 6 had HIV incidence of 1 per PY (95%CI, 1-2).
    Rating: Important

  3. Cottrell ML, Garrett KL, Prince HM, et al. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother. 2017.  [PMID:28369415]

    Comment: TAF single-dose pharmacokinetics in healthy women (n=8) showed that the majority of female genital tract (95%) and lower gastrointestinal tract (81%) tissue tenofovir diphosphate concentrations were unquantifiable and could not be quantified in any samples collected after 72h.
    Rating: Important

  4. Kojima N, Davey DJ, Klausner JD. Pre-exposure prophylaxis for HIV infection and new sexually transmitted infections among men who have sex with men. AIDS. 2016;30(14):2251-2.  [PMID:27314179]

    Comment: Meta-analysis compared MSM using and not using PrEP and calculated incidence rate ratios for syphilis of 45 (95%CI, 39-51), for N. gonorrhoeae of 25 (95%CI, 23-28), and for C. trachomatis of 11 (95%CI, 10-12). STI testing is an important aspect of PrEP administration.
    Rating: Important

  5. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis With Oral Emtricitabine and Tenofovir Alafenamide Combination Protects Macaques From Rectal Simian/Human Immunodeficiency Virus Infection. J Infect Dis. 2016;214(7):1058-62.  [PMID:27465645]

    Comment: Macaque study supporting TAF/FTC for prevention of rectal acquisition of HIV infection. Repeat, low-virus-dose rectal simian/human immunodeficiency virus (SHIV) challenges served as model for populations at high risk of infection. Macaques rectally exposed to SHIV were protected by TAF/FTC (n=6) whereas all controls (n=6) were infected.
    Rating: Important

  6. Grant PM, Cotter AG. Tenofovir and bone health. Curr Opin HIV AIDS. 2016;11(3):326-32.  [PMID:26859637]

    Comment: Review of studies that document bone mineral density loss associated with TDF and switch studies that document BMD increase after TDF switched to different antiretroviral. Pathophysiology of TDF bone toxicity reviewed and clinical data supporting TAF as more ’bone-friendly’ replacement especially for those at higher risk of fracture or for children who have not reached peak bone mass.

  7. Solomon MM, Schechter M, Liu AY, et al. The Safety of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active Hepatitis B. J Acquir Immune Defic Syndr. 2016;71(3):281-6.  [PMID:26413853]

    Comment: Six of 12 iPrEx participants with chronic HBV were randomized to FTC/TDF arm, and 5 had follow-up LFTs. All were in normal range except for a grade 1 elevation in 1 participant at post-stop week 12 (ALT= 90, AST= 61). There was no evidence of hepatic flares. Authors conclude that PrEP can be safely provided to individuals with HBV infection if there is no evidence of cirrhosis or substantial transaminase elevation.

  8. Schlesinger E, Johengen D, Luecke E, et al. A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis. Pharm Res. 2016;33(7):1649-56.  [PMID:26975357]

    Comment: Development of tunable, biodegradable implant uses thin-film polycaprolactone membrane to control release of TAF with PEG300 as a solubilizing excipient, by altering membrane thickness and/or surface area.
    Rating: Important

  9. Marcus JL, Hurley LB, Hare CB, et al. Preexposure Prophylaxis for HIV Prevention in a Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation. J Acquir Immune Defic Syndr. 2016;73(5):540-546.  [PMID:27851714]

    Comment: Observational study of 972 individuals (98% men, 38 yo, SD 10 yrs) receiving primary care at Kaiser Permanente from 2012-2015 found 92% adherence by pharmay refills. Risk of eGFR < 70 associated with age > 50 yo and baseline eGFR < 90.

  10. Casado JL, Del Rey JM, Bañón S, et al. Changes in Kidney Function and in the Rate of Tubular Dysfunction After Tenofovir Withdrawal or Continuation in HIV-Infected Patients. J Acquir Immune Defic Syndr. 2016;72(4):416-22.  [PMID:26962850]

    Comment: Longitudinal observational study of 228 HIV+ patients receiving ART which includes TDF followed for 60 months found small, significant, and progressive decline in eGFR and increased prevalence of tubular dysfunction. Thirty-five (15%) discontinued TDF. Authors cite time on TDF, intensity of exposure, and severity of tubular alteration as contributors to development of TDF toxicity. Severity of tubulointerstitial involvement is a determinant of progression and leads to decline in eGFR.
    Rating: Important

  11. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. N Engl J Med. 2016;375(22):2121-2132.  [PMID:26900902]

    Comment: Phase 3 RCT of monthly dapirivine-containing vaginal ring enrolled 2629 African women aged 18-45 years. Of 168 incident HIV-1 infections, 71 occurred in the dapirivine group (3.3/100 PY) and 97 occurred in the placebo group (4.5/100 PY) for 27% reduction (95%CI, 1-46%, p=0.046). Higher rates of protection were seen in post-hoc analysis for women older than 21 years.
    Rating: Important

  12. Whitfield T, Torkington A, van Halsema C. Profile of cabotegravir and its potential in the treatment and prevention of HIV-1 infection: evidence to date. HIV AIDS (Auckl). 2016;8:157-164.  [PMID:27799824]

    Comment: Cabotegravir, analog of dolutegravir, can be formulated into a long-acting suspension. Models of intravaginal, rectal, and intravenous acquisition of HIV infection are reviewed.

  13. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509-18.  [PMID:25651245]

    Comment: RCT of 5,029 young (25 yrs), unmarried (80%) women in South Africa, Uganda, and Zimbabwe documented 312 incident HIV-1 infections (5.7 per 100 PY) with efficacy of TDF (HR, 1.49; 95%CI, 0.97-2.29), of TDF-FTC (HR, 1.04; 95%CI, 0.73-1.49), and of TFV gel (HR, 0.85; 95%CI, 0.61-1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively.

  14. Mulligan K, Glidden DV, Anderson PL, et al. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial. Clin Infect Dis. 2015;61(4):572-80.  [PMID:25908682]

    Comment: iPrEx substudy of 498 compared BMD in those with tenofovir diphosphate levels consistent with adherence versus placebo. Net mean BMD loss was -1.42% for spine and -0.85% for hip by week 24. No difference detected in fractures.
    Rating: Important

  15. Chirwa LI, Johnson JA, Niska RW, et al. CD4(+) cell count, viral load, and drug resistance patterns among heterosexual breakthrough HIV infections in a study of oral preexposure prophylaxis. AIDS. 2014;28(2):223-6.  [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 individual 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.

  16. 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.  [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.
    Rating: Important

Pre-exposure Prophylaxisis the Johns Hopkins Guides Word of the day!

Last updated: June 3, 2017