PrEP and npep for HIV Prevention Harry Rosado-Santos MD, FACP Associate Professor UU School of Medicine
Case Study A 26 y/o M presents for routine asymptomatic screening for sexually transmitted infections (STIs). He had 3 high-risk possible HIV exposures in the past 8 months and took fixed-dose combination tenofovir/emtricitabine as nonoccupational postexposure prophylaxis (npep) after each episode.
Case Study (cont) He is sexually active with men exclusively He engages in both receptive and insertive anal intercourse (receptive > insertive) Prefers not to use condoms during insertive anal intercourse because of ED Tries to have insertive partners use condoms when he engages in receptive anal intercourse However, previous high-risk exposures were related to the partners not using condoms
Case Study (cont.) 3 male partners, since his last npep regimen 1 of whom was known to be HIV positive Last sexual encounter was 3 weeks ago engaged only in mutual unprotected fellatio, and the HIV-infected partner externally ejaculated His last unprotected receptive anal intercourse was 1 day prior to previous course of npep
Case Study (cont.) PAST MEDICAL HISTORY: Rectal gonorrhea 2 years ago SOCIAL HISTORY: Nonsmoker Drinks ~2 to 3 hard-liquor drinks on the weekends, sometimes a few more if he feels nervous about meeting a prospective sexual partner Denies any recreational drug use PHYSICAL EXAMINATION: unremarkable, without any signs of an STI; he is circumcised
Question Given this patient s sexual history, should PrEP be considered? A. Yes B. No 0% 0% Yes No
Question What is the most appropriate PrEP dosing interval for this patient? A. Monthly dosing B. Continuous daily dosing C. Prior to each sexual encounter D. Weekly dosing 0% 0% 0% 0% Monthly dosing Continuous daily dosing Prior to each sexual enc... Weekly dosing
PrEP-1 Although no effective vaccine protecting against HIV infection has yet been developed, oral PrEP may be effective prophylaxis for persons who engage in high-risk behaviors. The Pre-Exposure Prophylaxis Initiative (iprex) is a multinational study evaluating the efficacy of oral tenofovir/emtricitabine among men and transgendered women who have sex with men. Primary analysis of the iprex data showed a 44% decrease in new HIV infections among the participants taking the study drug compared with the participants taking the placebo. The final analysis of the data showed a 42% decrease in new infections among the participants taking the study drug. Post hoc analyses revealed that increased selfreported adherence (> 90% of days) was associated with increased benefit. (73% efficacy)[3] There was increased efficacy among tenofovir/emtricitabine-treated participants who engaged in unprotected receptive anal intercourse. Because unprotected receptive anal intercourse is the main mode of sexual transmission of HIV[23] and because its risk is surpassed only by direct inoculation into the bloodstream (either by transfusion or injection drug use), this was an important finding.[12,24]
PrEP-2 The study also found that the total number of receptive anal intercourse encounters decreased and condom use increased. This challenges one of the concerns about initiating PrEP: that if individuals have access to this type of prevention, they may increase risky behaviors, manifested as risk compensation (perceiving that one is at lower risk).[25-26] However, this randomized, placebo-controlled study was done before the efficacy of tenofovir/emtricitabine for prevention had been documented. Participants were extensively counseled on a monthly basis that there was a 50% chance they were receiving placebo, and that even if receiving the study drug, there were no data about its efficacy, so condoms should be used regularly regardless.
PrEP-3 PrEP alone is likely not sufficient to prevent HIV infection. The iprex study investigators analyzed plasma and intracellular drug concentrations and found that only 3 of the 34 participants who seroconverted had detectable intracellular concentrations of at least 1 of the 2 drugs, suggesting that improved adherence, resulting in higher intracellular drug concentrations, is required for effective prevention. There is potential variability of pharmacokinetics and pharmacodynamics within each individual, influenced by several factors such as host biology and genetics, drug-drug interactions, and tissue penetration that can interfere with the efficacy of PrEP. Modification of risky behaviors is also integral to the success of PrEP; by decreasing the number of possible exposures, the risk of acquisition also decreases. Modification may include increased use of condoms, avoiding sexual activities in the presence of an active sexually transmitted infection, and avoiding sharing injection paraphernalia. This patient recurrently engages in high-risk activities and has accessed npep 3 times in the past year. Continuous regular dosing of PrEP, rather than intermittent courses of npep, may provide more efficient coverage of unanticipated high-risk sexual events, and, if taken on a daily basis, can shorten or remove any lag time from exposure to availability of active chemoprophylaxis.
Definitions and Goals PrEP = Pre-Exposure Prophylaxis npep = Non-Occupational Post-Exposure Prophylaxis Ultimate goal of both -> reduce/prevent HIV acquisition
PEP: Prevents Infection After Isolated Exposure
PrEP Treatment before exposure to HIV
Modified from Abdool Karim, Lancet, 2011 Prevention Science Overview: Biomedical Intervention Efficacy 100 90 80 70 60 50 40 30 20 10 0
PrEP Clinical Trials: iprex: Grant RM, Lama JR, Anderson PL, et al; iprex Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363(27):2587-99. TDF2: Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012;367(5):423-34. Partners PrEP: Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367(5):399-410. Bangkok Tenofovir Study: Choopanya K, Martin M, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, doubleblind, placebo-controlled phase 3 trial. Lancet 2013;381(9883):2083-90.
Risk Behavior Assessment- Men Having Sex With Men (MSM) Address the following issues (over the past 6 months): Number of sexual partners Sex with men, women, or both Condom use Anal sex (top, bottom or versatile) HIV status of sexual partners Substance use (e.g. methamphetamines, crystal, speed etc.)
Recommended Indications for PrEP use in adult MSM Without acute or established HIV infection Male sex partner(s) in past 6 months (if also has sex with women) Not in a monogamous partnership with a recently tested, HIV-negative man AND at least one of the following : Any anal sex without condoms (receptive or insertive) in past 6 months Any STI diagnosed or reported in past 6 months Is in an ongoing sexual relationship with an HIV-positive male partner
Risk Behavior Assessment- Heterosexual Men AND Women Address the following issues (over the past 6 months): Number of sexual partners Sex with men women, or both? Condom use HIV status of sexual partnerships
Recommended Indications for PrEP use in Heterosexually Active Men AND Women Without acute or established HIV infection Any sex with opposite sex partners in past 6 months Not in a monogamous partnership with a recently tested HIV-negative partner AND at least one of the following: Is a man who has sex with both women and men (behaviorally bisexual) Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV infection (IDU or bisexual male partner) Is in an ongoing sexual relationship with an HIV-positive partner
Risk Behavior Assessment for Injections Drug Users Address the following issues: History of IV drug use Time and date of last use Needle/syringe sharing Drug preparation by others Methadone use in past 6 months Participation in medication-based drug treatment program in past 6 months
Recommended Indications for PrEP Use in Injection Drug Users Without acute or established HIV infection Any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following : Any sharing of injection or drug preparation equipment in past 6 months Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months Remember to assess risk of sexual acquisition!
Laboratory Tests and Other Diagnostic HIV TESTING Procedures MUST be done before starting PrEP Should be repeated at least every 3 months At a minimum, clinicians should document a negative antibody test result within the week before initiating (or reinitiating) PrEP medications Oral rapid tests should NOT be used to screen for HIV infection when considering PrEP.
Laboratory Tests and Other Diagnostic Procedures RENAL FUNCTION TESTING PrEP and HBV decrease renal function Active HBV infection is a potential safety issue when using TDF/FTC for PrEP. Any person with an ecrcl of <60 ml/min should NOT be prescribed PrEP with TDF/FTC. HEPATITIS SEROLOGY HBV and HCV infection status should be documented by screening serology before TDF/FTC is prescribed as PrEP Patients determined to be susceptible to HBV infection should be vaccinated.
Recommended Oral PrEP Medications Tenofovir disoproxil fumarate (TDF) Viread 300 mg once a day Nausea, flatulence Emtricitabine (FTC)- Emtriva 200 mg once a day Rash, headache TDF + FTC -Truvada 300mg/200 mg once a day D-D interactions
Time to Achieving Protection The time to achieve maximal protection against HIV infection with PrEP is unknown. Lack of scientific consensus regarding protective intracellular concentrations Data suggests maximum intracellular concentrations of TFV-DP are reached as follows: Blood ~ 20 days after daily oral dosing Rectal tissue ~7 days after daily oral dosing Cervico-vaginal tissues ~20 days after daily oral dosing No data for penile tissues
Discontinuing PrEP Patients may discontinue PrEP medications for the following: Personal choice Lifestyle changes resulting in decreased risk of HIV acquisition Intolerable toxicities Chronic non-adherence Acquisition of HIV infection
Clinical Follow-up & Monitoring- 3 months Repeat HIV testing and assess for signs or symptoms of acute HIV Infection Repeat pregnancy testing for women who may become pregnant Prescription or refill authorization of daily TDF/FTC for no more than 90 days (until the next HIV test) Assess side effects, adherence, and HIV acquisition risk behaviors Provide support for medication adherence and riskreduction behaviors Respond to new questions Provide any new information about PrEP use
Clinical Follow-Up & Monitoring- 6 months Monitor ecrcl Rise in serum creatinine is not a reason to withhold treatment if ecrcl remains 60 ml/min. If ecrcl is declining steadily (but still 60 ml/min), consultation with a nephrologist or other evaluation of possible threats to renal health may be indicated. Conduct STI testing recommended for sexually active adolescents and adults (i.e., syphilis, gonorrhea, chlamydia)
Clinical Follow-up & Monitoring- 12 Months Evaluate the need to continue PrEP as a component of HIV prevention strategy
Women Who Become Pregnant or Breastfeed While Taking PrEP Medication PrEP use periconception and during pregnancy by the uninfected partner may reduce risk of sexual HIV acquisition. Both the FDA labeling information and the perinatal antiretroviral treatment guidelines permit this use. Data on pregnancy outcomes in the Antiretroviral Pregnancy Registry provide no evidence of adverse effects among fetuses exposed to these medications
Women Who Become Pregnant or Breastfeed While Taking PrEP Medication Whether or not PrEP is elected, the HIVinfected partner should be prescribed effective antiretroviral therapy before conception attempts: if the infected partner is male to reduce the risk of transmission-related viral load in semen; and in both sexes for the benefit of their own health.
Women Who Become Pregnant or Breastfeed While Taking PrEP Medication The safety of PrEP with TDF/FTC or TDF alone for infants exposed during lactation has not been adequately studied. However, data from studies of infants born to HIVinfected mothers and exposed to TDF or FTC through breast milk suggest limited drug exposure
Patients with Chronic Active Hepatitis B Virus Infection Both TDF & FTC are active against HIV infection and HBV infection All persons screened for PrEP who test positive for hepatitis B surface antigen (HBsAg) should be evaluated by a clinician experienced in the treatment of HBV infection. Patients should be tested for HBV DNA by the use of a quantitative assay to determine the level of HBV replication before PrEP is prescribed and every 6-12 months while taking PrEP.
Medication Adherence Counseling Establish trust and bidirectional communication Provide simple explanations and education Medication dosage and schedule Management of common side effect Relationship of adherence to the efficacy of PrEP Signs & symptoms of acute HIV infection and
Medication Adherence Counseling Monitor medication adherence in a nonjudgmental manner Normalize occasional missed doses, Ensure patient understands importance of daily dosing for optimal protection Reinforce success Identify factors interfering with adherence and plan with patient to address them Assess side effects and plan how to manage them
Financial Case-Management Issues for PrEP For patients who do not have health insurance, whose insurance does not cover PrEP medication, and whose personal resources are inadequate to pay out-ofpocket, Gilead Sciences has established a PrEP medication assistance program In addition to providing Truvada to providers for eligible patients and access to free HIV testing, the program provides co-pay assistance for medical care visits and free condoms to patients on request. Providers may obtain applications for their patients at https://start.truvada.com/.
PEP Prevents HIV acquisition after an isolated exposure
Estimated Per-Act Probability of Acquiring HIV from an Infected Source, by Exposure Act Type of Exposure Risk per 100,00 Parenteral Sexual Blood Transfusion 9,250 Needle-sharing during injection drug use 63 Percutaneous (needle-stick) 23 Receptive anal intercourse 138 Insertive anal intercourse 11 Receptive penile-vaginal intercourse 8 Insertive penile-vaginal intercourse 4 Receptive oral intercourse Insertive oral intercourse low low
Estimated HIV transmission risk per exposure for specific activities and events Activity Mother-to-child, mother takes at least two weeks antiretroviral therapy Mother-to-child, mother takes combination therapy, viral load below 50 Injecting drug use Risk-per-exposure 0.8% (1:125) 0.1% (1:1000) Estimates range from 0.63% (1:158) to 2.4% (1:41) Needlestick injury, no other risk factors 0.13% (1:769) Blood transfusion with contaminated blood 92.5% (9:10)
Estimated Per-Act Probability of Acquiring HIV from an Infected Source, by Exposure Act Type of Exposure Risk per 100,00 Other Biting* Spitting* Throwing body fluids (including semen or saliva)* Sharing sex toys* Negligible Negligible Negligible Negligible *HIV transmission through these exposure routes is technically possible but unlikely and not well documented
Estimated Per-Act Probability of Acquiring HIV from an Infected Source, by Exposure Act Factors that may increase risk of HIV transmission: sexually transmitted diseases acute and late-stage HIV infection high viral load. Factors that may decrease risk include: condom use male circumcision antiretroviral treatment pre-exposure prophylaxis None of these factors are accounted for in the estimates presented in the table
npep Considerations Plasma HIV RNA testing of the source person is recommended in addition to HIV serologic screening in the following settings npep should be initiated and continued until results of the plasma HIV RNA assay are available Baseline STI testing for sexual exposures that do not occur as a result of sexual assault PEP regimens for sexual assault are the same as PEP regimens for other types of non-occupational and occupational exposures.
Recommended Regimen for HIV PEP Following Non-Occupational Exposure Tenofovir* 300 mg PO daily + Emtricitabine* 200 mg PO daily Plus Raltegravir 400 mg PO twice daily or Dolutegravir 50 mg PO daily *Dosing adjustments for renal insufficiency
Timing of Initiation of PEP for All Non-Occupation Every effort should be made to initiate PEP as soon as possible, ideally within 2 hours. > 36 hours post exposure, the decision to initiate npep is made on a case-by-case basis PEP is generally not offered if exposure > 72 hours
Duration of npep Regimen Recommended duration of npep = 28 days Discontinue npep regimen when source patient is confirmed to be HIV-negative Continue npep if the exposed person s baseline test shows evidence of HIV infection acquired before exposure and initiation of npep npep regimen should not be discontinued until the positive result is repeated with a confirmatory assay
Follow-up & Monitoring Following Non-Occupational Exposure Re-evaluate patients receiving PEP within 3 days of exposure to: Clarify the nature of the exposure Review available data Evaluate adherence Monitor for toxicities Weekly evaluations while receiving PEP to assess: Treatment adherence Side effects Interval physical complaints Emotional Status
Sequential HIV Testing Sequential confidential HIV testing (laboratorybased tests) should be obtained at: baseline week 4 week 12 HIV testing at 6 months post-exposure is no longer recommended If patient declines PEP, when PEP is indicated, serial testing should still be obtained.
Other Considerations HIV-Exposed Women Who Are Pregnant HIV-Exposed Women Who Are Breastfeeding Non-Occupational Exposures to Hepatitis B and C Hepatitis B Virus Post-Exposure Management Hepatitis C Virus Post-Exposure Management Victims of Sexual Assault
When to Seek Consultation for npep Delayed (>72 hours) exposure report Known or suspected pregnancy in the exposed person Breast-feeding in the exposed person Known or suspected resistance Toxicity of the initial PEP regimen
Consultation Resources University of Utah Division of Infectious Diseases, Clinic 1A at 801-585-2031 National Clinicians Post-Exposure Prophylaxis Hotline (PEPline) at 888-448-4911
Training and technical assistance in providing components of PrEP-related services, medications, and counseling are available at the following Web sites: -AIDS Info (http://www.aidsinfo.nih.gov) -The National Network of STD/HIV Prevention Training Centers ( http://nnptc.org/), -The AIDS Education Training Centers National Resource Center (http://www.aids-ed.org) -The Addiction Technology Transfer Center Network (http://www.attcnetwork.org); - The National HIV/AIDS Clinicians Consultation Service (http://www.nccc.ucsf.edu).