F/C AETC-Project ECHO™ Facilitator: Jennifer Janelle, MD University of Florida College of Medicine, Gainesville Faculty, Florida/Caribbean AETC

Case Discussants Jeffrey Beal, MD, AAHIVS Principal Investigator and Clinical Director Florida/Caribbean AETC Serenia P. Beckton, BA STD Program Manager Palm Beach County Health Department

Disclosure of Financial Relationships These speakers have no significant financial relationships with commercial entities to disclose. These speakers will not discuss off-label use or an investigational product during the program. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

Goals of F/C AETC-Project ECHO™ ECHO = Extending Community Health Outcomes Provide clinical consultations through the use of case presentations in an informal co-management setting Encourage longitudinal learning opportunities for participants by providing ongoing education and training opportunities Develop an information support system for attendees Utilize video conferencing equipment to gather clinicians and support staff in a virtual room to accomplish the goals above

F/C AETC-Project ECHO™ Educational experiences Intended for novice to expert clinicians Brief didactic presentations Case presentations Opportunity for networking CME/CEU Live audio-video-based platform

F/C AETC-Project ECHO™ Session Format Welcome and Introductions 5 minutes Overview of Important Points Brief Didactic Presentation 10 minutes Case Presentation(s) 1 hour Question/Answer Session

Didactic Presentation Pre-exposure Prophylaxis for HIV Infection

iPrEx Trial Enrolled 2499 HIV-seronegative men or transgender women who were at high risk for HIV acquisition Trial of daily emtricitabine plus tenofovir (FTC-TDF) versus placebo.

Additional Interventions During the iPrEX Trial Comprehensive prevention services Monthly HIV-1 testing Condom provision Counseling Management of other sexually transmitted infections Testing and vaccination for hepatitis B if indicated

Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population) 44% reduction in risk of HIV transmission in FTC-TDF group vs placebo Figure 2 Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population). The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P=0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10. In the FTC–TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Grant RM et al. N Engl J Med 2010;363:2587-2599.

Levels of Study-Drug Components in Blood of Subjects Receiving FTC–TDF, According to HIV Status Figure 4 Levels of Study-Drug Components in Blood of Subjects Receiving FTC–TDF, According to HIV Status. Shown are intracellular levels (Panels A and B) and plasma levels (Panels C and D) of components of emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), quantified in specimens obtained from subjects in the FTC–TDF group. FTC-TP denotes emtricitabine triphosphate, and TFV-DP tenofovir diphosphate. The horizontal lines in each panel indicate medians. Detectable blood levels strongly correlated with the prophylactic effect In the FTC–TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001) Relative reduction in risk was 44% overall but was 73% among the participants with an adherence of 90% or more (as measured by means of pill counts) and 92% among the participants with detectable tenofovir levels in the blood Grant RM et al. N Engl J Med 2010;363:2587-2599

iPrEX Trial Intensive risk reduction counseling led to decreased self-reported risk behavior Increase in condom use Decrease in number of sex partners

iPrEX Trial Conclusions Oral FTC–TDF provided protection against the acquisition of HIV infection among the subjects. Additional protection likely provided by intensive risk reduction strategies

Partners PrEP Trial Enrolled 4758 HIV-1–serodiscordant heterosexual couples in Kenya and Uganda Intervention: Daily antiretroviral prophylaxis with tenofovir (TDF) or emtricitabine–tenofovir (FTC-TDF) vs placebo in the HIV-1–negative partner

Partners PrEP Trial: Enrollment and Follow-up of the Study Participants Figure 1 Enrollment and Follow-up of the Study Participants. The most common reasons for ineligibility were HIV-1–seropositive partners' meeting national criteria for antiretroviral therapy initiation or already taking antiretroviral therapy (59%) and HIV-1–seronegative partners' being pregnant (2%), breast-feeding (0.4%), or having chronic active hepatitis B infection (10%). Less than 3% of ineligible couples met one of the exclusion criteria of creatinine elevation, glycosuria, or proteinuria in the HIV-1–seronegative partner, which were designed to minimize potential renal toxic effects from tenofovir (TDF) exposure. A total of 11 couples were enrolled and randomly assigned to one of the study groups but were later found not to meet all the eligibility criteria; they were discontinued from the study at the time their ineligibility was discovered, and their data were not included in analyses. At least 96% of HIV-1–seropositive partners remained in the study at any point during the follow-up period, and this percentage was similar across the three study groups. FTC denotes emtricitabine. Baeten JM et al. N Engl J Med 2012;367:399-410

Partners PrEP Trial Risk reduction measures HIV-1 testing with counseling before and after testing Individual and couples risk-reduction counseling Screening and treatment for sexually transmitted infections Free condoms with training Counseling and referral for male circumcision Postexposure prophylaxis according to national policies

Kaplan–Meier Estimates of the Primary End Point in the Modified Intention-to-Treat Analysis, According to Study Treatment Relative Rate Reductions vs Placebo: TDF 67% TDF-FTC 75% Figure 2 Kaplan–Meier Estimates of the Primary End Point in the Modified Intention-to-Treat Analysis, According to Study Treatment. Of 82 HIV-1 infections developing after randomization, 17 were in the TDF group, 13 were in the TDF–FTC group, and 52 were in the placebo group, indicating relative reductions in the rates of HIV-1 acquisition of 67% due to TDF (95% confidence interval[CI], 44 to 81; P<0.001) and 75% due to TDF–FTC (95% CI, 55 to 87; P<0.001), each relative to placebo (Fig. 2) Baeten JM et al. N Engl J Med 2012;367:399-410

Partners PrEP Trial Plasma drug levels measured in about 10% Risk reduction appeared greatest in subjects with detectable plasma tenofovir level Conclusion: Pre-exposure prophylaxis with TDF or FTC-TDF was effective in both men and women

FTC-TDF for PrEP FTC-TDF (Truvada®) received FDA approval for PrEP in July 2012 FDA indication: FTC-TDF 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

PrEP: Who is High Risk? Has partner known to be HIV-1 infected or Engages in sexual activity within a high prevalence area or social network plus one of the following Inconsistent or no condom use Diagnosis of sexually transmitted infections Exchanges sex for commodities (money, shelter, food, drugs) Use of illicit drugs or alcohol dependence Incarceration Partner of unknown HIV-1 status with any of the above factors

FTC-TDF for PrEP When prescribing FTC-TDF for PrEP, providers must do the following: Prescribe FTC-TDF as part of a comprehensive prevention strategy Counsel all uninfected individuals to strictly adhere to the recommended daily FTC-TDF dosing schedule

FTC-TDF for PrEP Confirm a negative HIV-1 test immediately prior to initiating PrEP. If clinical signs or symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least 1 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

FTC-TDF for PrEP HIV-1 screening tests should be repeated at least every 3 months If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection

FTC-TDF PrEP Safety Issues Can cause new onset or worsening renal impairment Assess creatinine clearance (CrCl) before prescribing FTC-TDF Do not start if CrCl < 60 mg/mL Assess risk/benefit if renal function declines Routinely monitor CrCl and serum phosphorus Avoid with concurrent or recent use of nephrotoxic drugs TRUVADA [package insert]. Foster City, CA: Gilead Sciences, Inc; 2012.

FTC-TDF PrEP Safety Issues Decreases in bone mineral density Redistribution/accumulation of body fat Hepatitis B infection Pregnancy Common adverse drug reactions in more than 2% of subjects in clinical trials Headache, abdominal pain, decreased weight TRUVADA [package insert]. Foster City, CA: Gilead Sciences, Inc; 2012.

Available Resources for FTC-TDF for PrEP Agreement form signed by healthcare provider and patient Used to document the discussion of the benefits/risks of FTC-TDF for PrEP Pharmaceutical patient assistance program More information and forms available online

http://www.univhc.com/docs/Medicaid/Forms/HIV-HEP-B_Diagnosis_Verification_Form.pdf

Case presentationS

Case – JD Patient JD is a 32 y/o white male HIV negative partnered for 12 years with your other patient DY who is his 40 y/o HIV positive male partner. JD prefers receptive anal sex and reports on a rare occasion they have had a condom break. His partner enjoys but does not wish to perform penile-anal sex for fear of infecting JD and it is a serious issue in the relationship. JD has read since DY is undetectable on HIV VL there is a marked decrease in his risk of his becoming infected.

Case – JD DY has been through multiple ARV regimens since initially infected 25 years ago. He has NRTI/NNRTI and PI resistance mutations. Currently controlled on DRV/r, ETR, and TDF/FTC FDC. In the last year DY has had 2 blips neither of which have exceeded 400 copies/mL. He always reports 100% compliance but does admit to an occasional partner outside the relationship which JD does not know and he refuses to tell. He is HBV immune and HCV negative. DY is otherwise healthy.

Case - JD JD is faithfully monogamous with DY, is immune to HBV, negative for HCV, and admits to snorting cocaine ‘at times’ and states he likes to smoke THC before sex. He convinced DY to have sex with him 2 weeks ago without a condom but DY refuses to do this again which JD finds unacceptable and inconsiderate of his needs. They cannot afford counseling services.

Identify the issues in this case Identify the issues in this case. What therapeutic options do you recommend? Issues: JD is going to have anal sex or the relationship is in peril DY has fear of infecting JD DY has multiple past drug exposures and drug resistant virus DY has VL blips Condoms have broken by history JD believes undetectable means he cannot get infected if they don’t use a condom DY has outside sexual partners and is not telling JD Risk of DY’s outside partners brining in an STD which could enhance risk of JD becoming HIV infected JD snorts cocaine and uses THC for sexual enhancement Since DY is on TDF/FTC would TDF/FTC be an effective PrEP regimen? Options: You or case manager become supportive counselor Harm reduction strategy to eliminate cocaine and decrease THC use for benefit of providing PrEP PrEP would allow closer monitoring of this couple and routinize STD screening and HIV screening PrEP can only start after HIV 4th Generation testing in 2 weeks (30 days post exposure) – education of signs and symptoms of ARV syndrome.

Case - 2 24 yo man presents to your clinic for routine healthcare. He has a history of sex with multiple female and male partners (more than 25 partners/year). His last high risk, unprotected sexual encounter was 18 days ago.

discussion

Markers of HIV Infection and Windows of Detection 1st HIV test in 1985 – 1st generation assay detected HIV-1 only, lacked sensitivity and specificity and were not able to detect the antibody response to the different HIV-1 clades 2nd generation assay – detects response to HIV-1 and HIV-2 3rd generation assay – detects HIV ½ antibodies 9-15 days after the first detection of p24 antigen, detects both IgG and IgM antibodies A positive HIV diagnosis is now possible up to 26 days prior to positive results by Western blot, the recommended confirmation test P. Patel et al. / Journal of Clinical Virology 54 (2012) 42– 47

4th Generation HIV Test Combined antibody and antigen test Detects p24 antigen which is present soon after infection and prior to the development of antibody Can detect acute HIV infection which can lead to Earlier linkage to care Earlier initiation of therapy Decreased transmission within networks

HIV Testing Algorithm J Clin Virol. 2011 Dec;52 Suppl 1:S35-40. Epub 2011 Oct 21.

Questions?