AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.
Introduction Antiretroviral medication for HIV prevention are an attractive additional to existing interventions: Behavioral interventions HIV positive HIV negative HIV testing and counseling STD screening and treatment Partner notification IVDU reduction – methadone, needle exchange PMTC Male circumcision
Outline of Recent Advances Introduction Update on data on PrEP HIV negatives Efficacy in men and women Pharmacology Adverse events Future directions PrEP use guidance
Efficacy of ART for Reduced Transmission Population/ Reduction in Study Study Design Outcomes Transmissions 5021 heterosexual couples Attia 2009 Meta-analysis 92% Percent 461 transmissions 3381 heterosexual African Partners in couples Prospective 92% Prevention Observational 103 transmissions 1763 couples Multisite HPTN 052 People Living With HIV 96% New Sexual infections/Year RCT (1,039,000-1,185,000) transmissions(~32,000) 28Grant R, NEJMAIDS. 2006;20:1447-1450. Marks G. 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.
Viral Suppression among HIV infected in United States Smith PLoS 2012Marks G. AIDS. 2006;20:1447-1450.
Awareness of HIV Serostatus: Estimates of Transmission 1 ~10%?? 0.9 ~31% 0.8 0.7 Intervene ~36% with ART 0.6 and PrEP Aware (ART) Aware (no ART) 0.5 ~44% 0.4 Unaware Intervene with 0.3 HIV testing ~54% and PrEP 0.2 ~25% 0.1 0 Status New infections People Living New With HIV Infections/YearMarks G. AIDS. 2006;20:1447-1450. (~32,000)
Past and Current PrEP Trials(July 2011)Available at: www.avac.org.
Efficacy of Daily Oral FTC/TDF PrEP Trial Pop. Efficacy 95% CI iPrEx 2499 MSM 44% 15 to 63% (completed) Partners PrEP Men 83% 49 to 94% (ongoing, placebo Women 62% 19 to 82% Percent arm stopped) TDF2 Men 80% 25 to 97% (stopped early due to Women 49% -22 to 81% large loss to FU) FemPREP 6% - Not Significant - Only 26% had (stopped early due to Women detectable TDF futility) People Living With HIV TDF alone arm stopped due to futility, New Sexual infections/Year VOICE (ongoing) Women (1,039,000-1,185,000) (~32,000) continue TDF gel and TDF/FTC Marks G. AIDS. 2006;20:1447-1450.Celum 2012Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.
Important New PrEP StudiesTrial Population Study Heterosexual TDF/FTC daily vs. twice a week and oneHPTN 067 women and PEP dose vs. event-driven MSMFNARAVHPIRE MSM On demand coital TDF/FTC vs. placebo PercentG TDF/FTC vs. placebo vs. no pill withATN 082 Young MSM behavioral intervention MVC vs. MVC/TDF vs. MVC/FTC vs.HPTN 069 MSM TDF/FTC Poynten 2012
iPrEx Study Results:Cumulative Probability of HIV Infection PlaceboCumulative Probability (n=1248) P=0.005 of HIV Infection Emtricitabine/ Tenofovir DF (n=1251) 0 12 24 36 48 60 72 84 96 108 120 132 WeeksGrant RM, et al. N Engl J Med. 2010;363:2587-2599.
Efficacy of Daily Oral FTC/TDF PrEP Percent People Living With HIV New Sexual infections/Year (1,039,000-1,185,000) (~32,000)Grant R, NEJMAIDS. 2006;20:1447-1450. Marks G. 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.
Phamacology of PrEP TDF dosing in HIV-uninfected individuals Oral dosing results in 20+ higher plasma levels compared to topical gel but 10 fold less local concentrations Oral TDF results in 100x greater TFV-DP in rectal tissue compared to vaginal tissue. 20x greater in local CD4 cells. No diff. at 2 weeks. Oral TDF has a 49-64 hours terminal half life in plasma. 100-112 hours in CD4 cells. FTC dosing Oral FTC results in 10x greater FTC-TP in vaginal tissue compared to rectal tissue. Oral FTC has a 8-10 hours terminal half life in plasma. 29-56 hours in PBMCs.Hendrix 2012
Adverse Events with PrEP TDF/FTC Nausea, back pain, weight loss>5% (iPREX) 1% drop in bone density (iPREX) Resistance iPREX had 2 on drug had M184V/I that was not detectable at 6 months by ultrasensitive testing Partners in PrEP 1 M184V and 1 K65R Renal toxicity from TDF was not observed higher (2% vs. 1%, p=0.08) in iPREX. Risk Compensation?Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Sexual Behavior in PnP Celum IAS 2011Marks G. AIDS. 2006;20:1447-1450.
Sexual Behavior in iPREX Liu IAS 2011Marks G. AIDS. 2006;20:1447-1450.
Summary of PrEP TDF/FTC oral appears superior to topical TDF/FTC oral may be superior to TDF alone TDF/FTC oral is seems most effective among MSM compared to heterosexual women This could be related to tissue penetration TDF/FTC is relatively safe for HIV-uninfected Tissue penetration and long half life may be the key factor for future development of new PrEPGrant RM, et al. N Engl J Med. 2010;363:2587-2599.
Truvada Updated Monograph INDICATIONS AND USAGE of TRUVADA TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. TRUVADA is indicated in combination with safer sex practices for pre- exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Truvada Updated MonographWARNINGS LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITHSTEATOSIS, POST-TREATMENT ACUTE EXACERBATION OFHEPATITIS B, and RISK OF DRUG RESISTANCE WITH USE OFTRUVADA FOR PrEP IN UNDIAGNOSED HIV-1 INFECTION TRUVADA used for a PrEP indication must only beprescribed to individuals confirmed to be HIV-negativeimmediately prior to initial use and periodically during use. Drug-resistant HIV-1 variants have been identified with the use ofTRUVADA for a PrEP indication following undetected acute HIV-1infection. Do not initiate TRUVADA for a PrEP indication if signsor symptoms of acute HIV infection are present unless negativeinfection status is confirmed.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Truvada Updated Monograph Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g., unprotected, or condom broke during sex with an HIV-1 infected partner) that may have occurred within the last month. If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Truvada Updated MonographCONTRAINDICATIONS Do not use TRUVADA for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. TRUVADA should be used in HIV-infected patients only in combination with other antiretroviral agents.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Truvada Updated MonographWARNINGS AND PRECAUTIONSNew onset or worsening renal impairment: including ARF and Fanconi syndrome. Assesscreatinine clearance (CrCl) before initiating. Monitor CrCl and serum phosphorus inpatients at risk. Avoid with use of nephrotoxic drugs. Do not use TRUVADA for a PrEPindication with creatinine clearance below 60 mL/min.Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with ahistory of pathologic fracture or other risk factors for osteoporosis or bone loss.Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of acomprehensive prevention strategy including other prevention measures; strictly adhere todosing schedule.Management to reduce the risk of acquiring HIV-1 drug resistance: Prior to initiating for PrEP - if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.While using TRUVADA for PrEP - HIV-1 screening tests should be repeated at least every 3months.
Truvada Updated MonographADVERSE REACTIONS In HIV1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by more than 2% of TRUVADA subjects and more frequently than by placebo subjects were headache, abdominal pain and weight decreased.
Truvada Updated Monograph Comprehensive Management to Reduce the Risk of Acquiring HIV-1 Use TRUVADA for pre-exposure prophylaxis only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing the acquisition of HIV-1 Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea). ␣ Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.
CDC Interim Guidance for MSMMMWR Jan 2011 Before initiating PrEP Determine eligibility Document negative HIV antibody test(s) immediately before starting PrEP medication. Test for acute HIV infection if patient has symptoms consistent with acute HIV infection. Confirm that patient is at substantial, ongoing, high risk for acquiring HIV infection. Confirm that calculated creatinine clearance is ≥60 mL per minute (via Cockcroft-Gault formula). Other recommended actions Screen for hepatitis B infection; vaccinate against hepatitis B if susceptible, or treat if active infection exists, regardless of decision about prescribing PrEP. Screen and treat as needed for STIs.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance for MSMMMWR Jan 2011 Beginning PrEP medication regimen Prescribe 1 tablet of Truvada* (TDF [300 mg] plus FTC [200 mg]) daily. In general, prescribe no more than a 90-day supply, renewable only after HIV testing confirms that patient remains HIV-uninfected. If active hepatitis B infection is diagnosed, consider using TDF/FTC for both treatment of active hepatitis B infection and HIV prevention. Provide risk-reduction and PrEP medication adherence counseling and condoms.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance for MSMMMWR Jan 2011 Follow-up while PrEP medication is being taken Every 2--3 months, perform an HIV antibody test; document negative result. Evaluate and support PrEP medication adherence at each follow- up visit, more often if inconsistent adherence is identified. Every 2--3 months, assess risk behaviors and provide risk- reduction counseling and condoms. Assess STI symptoms and, if present, test and treat for STI as needed. Every 6 months, test for STI even if patient is asymptomatic, and treat as needed. 3 months after initiation, then yearly while on PrEP medication, check blood urea nitrogen and serum creatinine.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance for MSMMMWR Jan 2011 On discontinuing PrEP (at patient request, for safety concerns, or if HIV infection is acquired) Perform HIV test(s) to confirm whether HIV infection has occurred. If HIV positive, order and document results of resistance testing and establish linkage to HIV care. If HIV negative, establish linkage to risk-reduction support services as indicated. If active hepatitis B is diagnosed at initiation of PrEP, consider appropriate medication for continued treatment of hepatitis B.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance-Heterosexuals MMWR Aug 10 2012 Before initiating PrEP Determine eligibility Determine if women are planning to become pregnant, are currently pregnant, or are breastfeeding. Confirm that patient is at ongoing, very high risk for acquiring HIV infection. If any sexual partner is known to be HIV-infected, determine whether receiving antiretroviral therapy; assist with linkage to care if not in care or not receiving antiretroviral therapy. Other recommended actions Disclose to women that safety for infants exposed during pregnancy is not fully assessed but no harm has been reported. Do not prescribe PrEP to women who are breastfeeding.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance-Heterosexuals MMWR Aug 10 2012 Beginning PrEP medication regimen For women, ensure that pregnancy test is negative or, if pregnant, that the patient has been informed about use during pregnancy.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance-Heterosexuals MMWR Aug 10 2012 Follow-up while PrEP medication is being taken At each follow-up visit for women, conduct a pregnancy test and document results; if pregnant, discuss continued use of PrEP with patient and prenatal-care provider.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
CDC Interim Guidance-Heterosexuals MMWR Aug 10 2012 On discontinuing PrEP (at patient request, for safety concerns, or if HIV infection is acquired Inform prenatal provider of PrEP use in early pregnancy and coordinate care to maintain HIV prevention during pregnancy and breastfeeding.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Some Possible PrEP Providers • Implementation of PreP will be challenging due to the multiple needs of an effective program • Innovative programs that combine previously unlinked services may be needed Access to High HIV Longitudinal Familiar Seronegatives Incidence Care with ART Percent Testing Centers + +/- +/- - STD Clinics + + - - Community Clinics + +/- + - Partners of HIV Clinics ?* + + HIV+ Patients Prevention CBOs + + +/- - People Treatment CBOs Living With HIV - - New Sexual infections/Year + +/- (1,039,000-1,185,000) (~32,000) *Prevalence of HIV among seronegative partners of HIV+ pts is unknownGrant R, etG. 51st ICAAC; Chicago, IL; September 17-20, 2011; Abst. H2-1007. Marks al. AIDS. 2006;20:1447-1450.
Protocol Co-Chairs:Sheldon Morris M.D., M.P.H. David J. Moore, Ph.D.
PrEP Algorithm 1. Test for HIV at least Identify individuals every 3 mo. with substantial, 2. Offer STD screening as ongoing risk for HIV needed every 6 mo. acquisition 3. Provide ongoing risk reduction 4. Check creatinine at month 3 and then yearly 5. Preg. Test for women every 3 months1. Medical History2. Elicit any acute HIV symptoms3. Required lab testing: Confirm HIV status HBV status 1. Provide adherence Creatinine clearance counseling Pregnancy test for women 2. Prescribe no more4. Provide risk reduction counseling and than 3 months STD testing as needed
PrEP Study Double-Blind Randomization Truvada (n=200) Multisite Study 1:1 (UCLA, USC, UCSD) Both receive comprehensive Minimum Follow-High risk HIV-negative men who web based risk reduction Up 1 year counseling, STD testing, HIV have sex with men testing (n=400) Truvada + iTAB (n=200) Intervention ousing texting Study Outcomes reminders (iTAB) •HIV seroconversion •Risk behavior and STIs •Adherence (self report and FTC levels) •Drug resistanceDrug resistance, HIV RNA level, immunologic response, and CD4 cell count assessed in people who become HIV positive during the study.Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Why Text Reminders Might Work“ Well, I’m always aware of the importance of taking my meds but time gets lost and at the end of the week or end of the month, you realize ” you still have a lot of pills left!
iTAB Intervention Texting reminders developed and chosen by participant that will be received daily If possible, participants use their own cell phone; otherwise receive study phone All participant go through process of reminder generation
Inclusion Criteria• Man or transgender M to F who has sex with men• Age 18 years or older.• Subjects must have substantial ongoing risk of acquisition of HIV as evident by one or more of the following: • Has at least one HIV infected sexual partner for ≥4 weeks (i.e. serodiscordant couple). • No condom use during anal intercourse with ≥3 male sex partners who are HIV-positive or of unknown HIV status during the last 3 months • No condom use during anal sex with ≥1 male partner and STI diagnosis during the last 3 months
Conclusions PrEP works…Woohoo. Prescribing PrEP should be done with care: For those with substantial ongoing risk and no medical contraindication (i.e. renal disease) CONFIRM HIV negative status Routine adherence counseling, HIV testing, STD testing and risk reduction counseling
CCTG 595: TAPIR studyenrollment starting January 2013Potential subjects can call AVRC: 619-543-3196