Update From the 2018 Conference on Retroviruses and Opportunistic Infections (CROI)

Transcription

1 Update From the 2018 Conference on Retroviruses and Opportunistic Infections (CROI) W. David Hardy, MD Senior Director of Evidence-based Practices Whitman-Walker Health Clinical Professor of Medicine George Washington University Washington, DC Resources from CROI 2018 Searchable poster and abstract database: Webcasts: Abstract ebook, conference agenda, and more: Slide 3 of 35 Learning Objectives After attending this presentation, learners will be able to: Describe the current status of and unmet goals for PrEP for HIV in the U.S. Discuss new research for preventing and treating TB in HIV+ persons Describe data regarding new treatment approaches for HCV in HIV+ persons Slide 4 of 35

2 Preexposure Prophylaxis (PrEP) for HIV Slide 5 of 35 7 Audience Response System (ARS) Question Which of the following statements regarding PrEP for HIV is not true? 1. The CDC recently increased the estimates of how many MSM in the US are eligible for PrEP for HIV. 2. Black/African American MSM make up the largest number of persons estimated to be eligible for PrEP for HIV in the US. 3. The roll-out of PrEP for HIV in the US has followed the demographics of those persons estimated by the CDC to be at risk for HIV acquisition. 4. Potentially safer as well as longer-acting medications than tenofovir DF are currently being studied. Slide 8 of 35

3 Slide 9 of 35 CDC: Estimating Number of Persons with Indications for PrEP in Each State By Transmission Risk Group MSM with PrEP Indications # MSM in state 1, past 5 years, 18 yo # MSM in state 2, past 1 year, 18 yo * 24.7% 3 (national estimate of % of MSM with PrEP indications) # MSM with PrEP indications in state HETERO with PrEP Indications # MSM with PrEP indications in state * State HET:MSM ratio (% HET HIV dx / % MSM HIV dx) 4 # HET with PrEP indications in state PWID with PrEP Indications # MSM with PrEP indications in state * State PWID:MSM ratio (% PWID HIV dx / % MSM HIV dx) 3 # PWID with PrEP indications in state Smith D, et al, CROI Boston, MA. Poster #86. CDC: Estimated Number of Adults with PrEP Indications, US, 2015: Comparison of Results from Two Methods MSM HETERO PWID Total* Updated CDC Estimate 814, ,000 73,000 1,145,000 Previous CDC Estimate 492, , ,000 1,232,000 Slide 10 of 35 Smith D, et al, CROI Boston, MA. Poster #86. CDC: Estimated Number of Adults with PrEP Indications by Race/Ethnicity and Transmission Risk Group, US, 2015 Total Black/African American Hispanic/Latino White, non-hispanic Transmission risk group Estimated no. % of Total Estimated no. % of risk group total Estimated no. % of risk group total Estimated no. % of risk group total MSM 813, , , , HETERO 258, , , , PWID 72, , , , TOTAL 1,144, , , , Race/ethnicity data not available for New Hampshire. Estimates are rounded and may not sum to the total 2015 HIV Surveillance Data. AtlasPlus Slide 11 of 35 Smith D, et al, CROI Boston, MA. Poster #86.

4 Slide 12 of 35 CDC: Preliminary Estimate of Minimum PrEP Coverage by US Region and Race/Ethnicity, Denominator: Number of persons with indications for PrEP, 2015 Numerator: Number of persons prescribed FTC/TDF for PrEP, US Symphony Health Analytics, September 2015-August 2016 Race/ethnicity available for 66% % PrEP Coverage Northeast Midwest South West White Black Hispanic All race/ethnicities Nationwide, 14% of White, 1% of Black, 3% of Hispanic, and 8% of all persons estimated to have indications for PrEP were prescribed PrEP. 1 2 Disparities in PrEP Uptake Among Primary Care Patients Screened for HIV/STIs in San Francisco Study Design: Identify racial and age disparities in TVD for PrEP uptake in the SF DPH Primary care clinics High risk PrEP subjects were defined as HIV negative, not prescribed PrEP, and screened for rectal STD; diagnoses with syphillis in last year, or received 3 HIV tests in the last 2 years indicating provider repeatedly considered HIV risk Racial/Ethnic Disparities (Bivariate) Results: 451 patients received PrEP 2109 were identified as high risk Patients Highly or Significantly Less Likely to Be on PrEP: Latino and Black high risk patients High risk women Patients over 50 years of age Even in SF, a city with high uptake of PrEP, disparities in uptake remain and additional interventions are needed. *p<0.01 (compared with White) Slide 13 of 35 Phase II: Efficacy of FTC/TAF Against Vaginal SHIV Infection Pigtailed macaques ( 11.5 years old and 9.0 kg on average) Repeated exposures to low (50 TCID50) doses of SHIV162p3 Design identical to previous studies with FTC/TDF (-24h/+2h modality; 6/6 animals protected; Radzio et al., PLoS One 2012). FTC/TAF (20/1.5 mg/kg) administered orally by gavage Infection monitored weekly by serology and RT-PCR FTC/TAF (-24h) Treated group (n=6 pigtails) Placebo Control group (-24h) (n=6 pigtails) FTC/TAF SHIV162p3 (+2h) Placebo SHIV162p3 (+2h) Repeated once a week during 16 weeks Slide 14 of 35 Massud I, et al. CROI Boston, MA. Oral #85.

5 Slide 15 of 35 High Efficacy of FTC/TAF Against Vaginal SHIV Infection Percent survival Oral FTC/TAF Placebo controls p = (Log-rank test) Efficacy: 82% Number of virus exposures Massud I, et al. CROI Boston, MA. Oral #85. MK-8591 protects against rectal SHIV infection at very low dose Dose achievable with 250mcg weekly or 10 mcg daily in humans Slide 16 of 35 Markowitz, Abstract 89LB ART Use With TB Therapy Slide 16 of 35

6 19 Audience Response System (ARS) Question Prevention of tuberculosis disease in PLWH is of great importance. Please choose treatment regimen(s) which has/have been shown to be effective in treating latent tuberculosis infection (LTBI) in PLWH. 1. INH 300 mg daily (w/ 50 mg of Vitamin B6 daily) for 9 months 2. Rifampin 600 mg daily for 2 months 3. INH 300mg (w/ 50 mg Vitamin B6 daily) + Rifapentine mg daily for 1 month 4. Ethambutol 1200 mg daily + Rifampin 600 mg daily for 2 months 5. Both 1 and 3 Slide 20 of 35 BRIEF TB/ACTG A5279: 1 month of INH/rifapentine for treatment of Latent TB Infection (LTBI) Phase 3, open-label trial n=2996 HIV-infected adults + TST, + IGRA or high TB-incidence country 54% female median CD4+ T cells - 470/mm3 50% on ART (EFV or NVP) 80% undetectable Randomized 1:1 to: 33 vs 32 TB cases INH 300mg daily x 9 months 0.67 vs cases/100 pt years INH 300mg/RFP* daily x 1 month Both regimens were well-tolerated INH/RFP x1 month non-inferior to INH x9 months 1 mo INH/RIF arm: more hematologic toxicity (2.4% versus 1.2%) 9 mos INH arm: more liver- and neuro- toxicity (2.8% versus 1.9%) *Rifapentine 450 mg/day (<45 kg) or 600 mg/day ( 45 kg) Vitamin B6 (25 mg) with INH Slide 21 of 35 Swindells S, et al. 25 th CROI. Boston, Abstract 37LB.

7 Slide 22 of 35 INSPIRING: DTG BID + 2 NRTIs For ART-naive Patients Receiving Rifampin-based TB Therapy Interim analysis of open-label, randomized, noncomparative, active-controlled phase IIIb study Primary endpoint: Wk 48 HIV-1 RNA < 50 c/ml (modified FDA snapshot, ITT-E) Pts from South Africa, Brazil, Peru, Mexico, Russia, Argentina, and Thailand Randomization Wk 24 Wk 48 ART-naive pts with HIV-1 RNA 1000 c/ml and CD4+ cell count 50 cells/mm 3 and RIFsensitive TB coinfection (N = 113) DTG 50 mg BID + 2 NRTIs DTG 50 mg QD + 2 NRTIs (n = 69) (n = 69) EFV 600 mg QD + 2 NRTIs (n = 44) TB treatment (all pts) HRZE (2 mos)* HR (4 mos) *TB treatment containing RIF could be started up to 8 wks before randomization and no later than screening (28 to 14 days prior to randomization). DTG dose switch to occur 2 wks after TB treatment completed. Dooley KE, et al. CROI Abstract 33. INSPIRING: Efficacy and PK Outcomes Virologic Outcome at Wk 24, n (%) DTG + 2 NRTIs (n = 69) EFV + 2 NRTIs (n = 69) Week n DTG Concentration (Geometric Mean), ng/ml (90% CI, %CV) DTG 50 mg BID + RIF (TB Treatment Phase) HIV-1 RNA < 50 copies/ml HIV-1 RNA 50 copies/ml No virologic data 56 (81) 39 (89) 7 (10) 3 (7) 6 (9) 2 (5) ( , 118) ( , 276) DTG 50 mg QD (Post-TB Treatment Phase) ( , 151) ( , 359) Slide 23 of 35 Dooley KE, et al. CROI Abstract 33. Pharmacokinetic Study of Effect of Rifampin Coadministration on TAF Exposure Open-label, single-arm phase I PK study of effect of RIF co-administration on TAF PK (N = 21 evaluable healthy volunteers) Dosing: Days 1-28, FTC/TAF 200/25 mg QD; Days 29-56, FTC/TAF 200/25 mg QD + RIF 600 mg QD; Days 57-84, TDF 300 mg QD Intracellular TFV AUC higher for FTC/TAF + RIF vs TDF alone despite RIF decreasing TAF plasma and intracellular TFV AUC Geometric mean (95% CI, CV) FTC/TAF + RIF Cmax fmol*h/ ( , 69%) AUC0-24 fmol*h/ ( , 82%) Intracellular TFV-DP PK Parameters FTC/TAF 8082 ( , 64%) ( , 102%) GM Ratio (90% CI) 0.62 ( ) 0.64 ( ) TDF 1135 ( , 82%) ( , 70%) FTC/TAF + RIF 4994 ( ) ( , 82%) GM Ratio (90% CI) 0.23 ( ) 0.24 ( ) C24h fmol*h/ ( , 87%) 6138 ( , 58%) 0.57 ( ) 851 ( , 71%) 3529 ( , 87%) 0.24 ( ) Slide 24 of 35 Cerrone M, et al. CROI Abstract 28LB.

8 Slide 25 of 35 Pharmacokinetics of Twice Daily BIC/FTC/TAF Plus Rifampin Open-label, parallel-design, multiple-dose, single-center phase I study in which BIC pharmacokinetics were assessed in healthy volunteers who received BIC/FTC/ TAF* QD or BIC/FTC/TAF* BID + RIF 600 mg QD for 28 days (N = 52) Mean BIC PK (% CV) Cohort 1 BIC/FTC/TAF QD (n = 26) Coadministration of BIC/FTC/TAF BID + RIF resulted in ~ 80% reduction in BIC C trough and ~ 60% reduction in daily BIC exposure This combination is not recommended Cohort 2 BIC/FTC/TAF BID + RIF QD (n = 26) GLSM Ratio (90% CI) AUC 0-24, ng*h/ml 115,200 (21) 45,600 (23) 39.5 ( ) C max, ng/ml 8530 (16) 4560 (19) 53.2 ( ) C trough, ng/ml 3070 (28) 608 (30) 19.7 ( ) *BIC/FTC/TAF dosed 50/200/25 mg. Custodio JM, et al. CROI Abstract 34. HIV and Pregnancy Slide 24 of 35 DTG PK Analysis From DolPHIN-1: DTG vs EFV As Initial ART In Late Pregnancy Interim DTG PK analysis from a multicenter, open-label, randomized trial evaluating pharmacokinetics of and virologic suppression with DTG or EFV + 2 NRTIs* in women with HIV presenting for initial ART during the third trimester of pregnancy (planned N = 60) Primary endpoint: DTG AUC wks after initiation and 2 wks postpartum DTG (ng/ml) Plasma DTG Concentration per Pt (n = 7) rd trimester 4000 Postpartum DTG PK Parameter, Geometric Mean (95% CI) AUC 0-24, ng h/ml C max, ng/ml 3rd Trimester (n = 7) 39,415 (28,296-50,534) 2645 ( ) 2 Wks Postpartum (n = 2) Pt 1: Pt 2: 44,305 Pt 1: 4224 Pt 2: 4055 Control 53, Hr Post Dose C 24, ng/ml 778 ( ) Pt 1: 1211 Pt 2: *Dosing: DTG 50 mg QD; EFV 600 mg QD. Reference data from nonpregnant HIV-infected pts receiving DTG in SPRING-1 and -2 studies. Slide 27 of 35 Waitt C, et al. CROI Abstract 807. Reproduced with permission.

9 Slide 28 of 35 Partners Studies: Increased Risk of Female HIV Acquisition in Late Pregnancy and Postpartum N = 2751 HIV-negative women in relationship with HIV-positive ART-naive men followed until first evidence of HIV infection linked to male study partners 78 incident HIV infections occurred during follow-up; 22.4% became pregnant In adjusted model, HIV acquisition risk per sex act was increased 3-fold in late pregnancy and 4-fold postpartum RR of HIV Acquisition by Reproductive Stage Base Model* Adjusted Model RR (95% CI) P Value RR (95% CI) P Value Not pregnant or postpartum Early pregnancy through postpartum 4.97 ( ) < ( ) <.001 Early pregnancy (0-13 wks gestation) 3.20 ( ) ( ).14 Late pregnancy (14 wks to delivery/loss) 5.54 ( ) < ( ).01 Postpartum (delivery to 6 mos or less for losses) 7.80 ( ) < ( ).01 *Adjusted for condom use, reproductive stage. Adjusted for condom use, reproductive stage, female age, active PrEP use, HIV-1 RNA of male part 1. Thomson KA, et al. CROI Abstract Thomson KA, et al. J Infect Dis. 2018;[Epub ahead of print]. HIV and Co-Morbidities Slide 27 of 35 SWISS HIV Cohort Study: Antiretroviral Drugs and Subclinical Coronary Artery Disease Prospective study ( ; n=403) Coronary CT angiography 45 years of age No documented CAD or stroke GFR 60 ml/min No atrial fibrillation or other irregular heartbeat Patients with non-calcified/mixed plaque (37%) Regimens containing abacavir Only regimen with evidence for an increased risk of coronary artery non-calcified/mixed plaques Slide 30 of 35 Cumulative Exposure to Individual Drugs (per 5 years) ABC DDI FTC 3TC TDF AZT EFV ATV DRV LPV 1.5 ( ) Non-Calcified/Mixed Plaque Odds Ratio (95% CI) Kovari H, et al. 25 th CROI. Boston, Abstract 670.

10 Slide 31 of 35 D:A:D: Serious Clinical Events in Pts With HIV and CKD D:A:D analysis of Serious Clinical Events (SCE) following Chronic Kidney Disease (CKD) diagnosis Included patients with BL creatinine assessment in 2004 with available egfr data (N = 2467) Incident CKD: egfr 60 ml/min/1.73 m 2 (confirmed 3 mos apart) or 25% decrease in egfr when BL egfr 60 ml/min/1.73 m 2 Centrally validated SCE included CVD (MI, stroke, CV procedures), ESRD, ESLD, ADM, NADM, other AIDS events (excludes malignancies), death Excluded recurrent SCE when same type Patients followed to first occurrence of incident SCE, 6 mos after last visit, or February 1, 2016 Ryom L, et al. CROI Abstract O75. Serious Clinical Events in Pts With HIV and CKD: Time to Event and Incidence Kaplan-Meier Time to SCE Following CKD 30 Time Point Any-SCE Rate, % 12 mos 7.9 ( ) 36 mos 19.8 ( ) 25 Any SCE Death 20 NADM CVD 15 Other AIDS ESRD ESLD 10 ADM Pts With SCE (%) Months After CKD Slide 32 of 35 Descriptive analysis performed to determine crude SCE rates in pts followed from first egfr to SCE Parameter Pts Without CKD* (n = 34,116) Pts With CKD* (n = 2460) PYFU 272, Median f/u, yrs (IQR) Pts with any SCE, n (%) Incidence per 1000 PYFU 8.8 ( ) 2.1 ( ) 6300 (18.5) 467 (18.9) 23.0 ( ) 63.7 ( ) *Descriptive population had different inclusion and exclusion criteria than other analyses. Ryom L, et al. CROI Abstract O75. Reproduced with permission. HIV and HCV Slide 31 of 35

11 Slide 34 of 35 PROBE-C Study: Rate of Spontaneous Clearance of Acute HCV in Persons With HIV Observational European cohort ( ; n=464) Documented current or past acute HCV infection with detectable HCV RNA 12 months* 18 years of age Virologic outcome Spontaneous clearance: 12% (median 13 weeks to 1 st HCV RNA negative result) Persistent viremia: 88% SVR: 76% (reinfections: 17%) <2 log drop in HCV RNA after 4 weeks was strongly predictive of a chronic HCV course (P<0.001), allowing for early treatment *First HCV RNA positive and prior negative anti-hcv antibody or HCV RNA test OR Rise in transaminases >2.5x ULN with prior normal transaminases, OR Exclusion of other causes of acute hepatitis. Baseline Characteristics Spontaneous Persistent Clearance Viremia (n=55) (n=409) Median age (years) Male (%) Median CD4 (cells/µl) HIV RNA <200 copies/ml (%) On ART (%) Median HCV RNA (IU/mL) Median maximum ALT (U/L) >2 log decline in HCV RNA 96 3 at week 4 (%) Median time to HCV treatment initiation (weeks) Boesecke C, et al. 25 th CROI. Boston, Abstract 129. DAHHS 2 Study: Glecaprevir/Pibrentasvir for Acute HCV Genotype 1 or 4 Infection in MSM Phase 3b Open-label, single-arm 18 years of age Acute HCV genotype 1 or 4 Glecaprevir/Pibrentasvir (n=80) HIV co-infection included: No ART and CD4 500 cells/mm 3 Week 0 8 On ART and HIV RNA 400 copies/ml No cirrhosis Data available on 63 of 80 patients reaching the DAHHS: Dutch Acute HCV in HIV. SVR12 time point Primary outcome: SVR12 (ITT). Baseline demographics: Overall SVR12: 98% Age: 47 years. White: 90%. Relapse (n=1): 2% Reinfection: 24% Number of HCV episodes: 1 (76%), 2 (19%), 3 (5%). Median ALT: 139 IU/mL. Re-infection after achieving SVR12 (n=3) Median HCV RNA: 310K IU/mL. Time between estimated infection date and HCV treatment: 4.4 months. Regimen was well-tolerated HIV coinfection: 91%. On ART: 100%. No discontinuations due to adverse events, treatmentrelated serious averse events, or deaths HIV RNA <50 copies/ml: 98%. Median CD4: 606 cells/mm 3. Slide 35 of 35 Boerekamps A, et al. 25 th CROI. Boston, Abstract 128. Swiss HCVree Trial: HCV Treatment as Prevention in HIV-Positive MSM Swiss HIV Cohort (n=9128) 10/2015 to 6/2016 MSM Screened by HCV PCR (n=3722) HCV RNA Positive 4.8% (n=177) 6/2016 to 2/2017 3/2017 to 11/2017 Treated With DAA Therapy (n=132) MSM Rescreened by HCV PCR (n=3722) HCV RNA Positive 0.8% (n=28) SVR Rate: 99.5% Incident HCV (n=30) 49% Decrease Incident HCV (n=16) Chronic HCV (n=147) 93% Decrease Chronic HCV (n=12) Slide 36 of 35 Braun DL, et al. 25 th CROI. Boston, Abstract 81LB.