Optimizing ARV For Women

Transcription

1 Optimizing ARV For Women Kathleen E. Squires, MD W Paul and Ida H Havens Professor of Infectious Diseases Director, Division of Infectious Diseases Sidney Kimmel Medical College of Thomas Jefferson University Medical Director, Infectious Diseases and Population Management Jefferson Health System Philadelphia, PA

2 Research grants Gilead Sciences Advisory Boards Conflicts of Interest BristolMyers Squibb, Gilead Sciences, Janssen, Merck, ViiV

3 Global Summary: People Living With HIV 46% of Cases are Women North America & Western/Central Europe 2,300,000 Caribbean 250,000 Latin America 1,600,000 North Africa & Middle East 230,000 Sub-Saharan Africa 24,700,000 Eastern Europe & Central Asia 1,100,000 Asia & the Pacific 4,800,000 UNAIDS % of Cases are Children Most via Mother-to-Child Transmission

4 UNAIDS: Adults Living With HIV Who Are Female ( ) HIV Cases (% Female) Sub-Saharan Africa Asia Eastern Europe/Central Asia Global Year UNAIDS.

5 Patient PS 60 YO AA woman History of Multiple Sclerosis; presented to outside hospital 8/3 for evaluation of signs/symptoms she thought represented a flare Admitting clinician noted leukopenia on admission lab tests and suggested HIV screen Married but no sexual relations with husband for several years; has 2 sexual partners; no need for condoms Date HIV Ag/Ab Multispot1/2 HIV RNA CD4 8/3 Reactive Negative 8/5 2,843, (50%) 8/13 6,286, (31%)

6 Patient EF 30 YO AA woman Presents to ED 9/5 requesting admission to drug rehabilitation unit PMH/SH Active IVDA G2P1; HIV screens 24 weeks pregnant, no prenatal care to date HIV-infected partner; does not use condoms Date HIV Ag/Ab Multispot 1/2 HIV RNA 9/5 Reactive Indeterminate 92,939

7 30 YO AA woman Patient EF Partner informed medical team he was taking ART up to 3 months before patient s presentation. He decided it was just not for him. The patient had noticed his pill bottle always seemed full but did not think she should ask him about this.

8 CDC: HIV-Infected Persons Engaged in Selected Stages of the Continuum of Care (2009) Incidence (%) CDC and Prevention National HIV Surveillance System 85% 81% 70% 65% 41% 35% 36% Females (n=279,200) Males (n=869,000) 32% 26% 25% Diagnosed Linked to Care Retained In Care Prescribed ART Viral Suppression n=1,148,200 HIV-infected persons, 18% of whom are unaware of their infection. Hall HI, et al. JAMA Intern Med. 2013;173:

9 Gender and HIV RNA Levels Meta-analysis results (n=12 studies) Women have lower HIV RNA levels compared to men with similar CD4 cell counts and stage of HIV disease Average difference: log 10 copies/ml Viral load may be less useful as a prognostic marker in early HIV infection in women Explanation for the sex differences in viral load remains unknown Napravnik S, et al. JAIDS. 2002;31:11-19.

10 Median CD4 Cell Count (cells/µl) Female Versus Male HIV RNA Levels by CD4 Cell Count Lower in Women Higher in Women Difference in log 10 HIV RNA 100 Gandhi M, et al. Clin Infect Dis. 2002;35: Moore 1999 (VI) (n=1173)* Sterling 1999 (n=71) Evans 1997 (n=42) Sterling 2001 (n=202) Moore 1999 (V) Farzadegan 1998 (n=527) Anastos 2000 (IV) (n=2859)* Rezza 2000 (n=415) Lyles 1999 (n=149) Moroni 1999 (n=2011) Anastos 2000 (III) Moore 1999 (IV) Katzenstein 1996 (n=391) Junghans 1999 (H) Junghans 1999 (IDU) Anastos 2000 (II) Moore 1999 (III) Bush 1996 (n=40) Anastos 2000 (I) Moore 1999 (II) Moore 1999 (I) Kalish 2000 (n=494) (n=1337)*

11 Women s Interagency HIV Study (WIHS) Cohort Women (n=4346) Seroprevalent: 3232 (74%) Seronegative: 1114 (26%) AIDS Baseline 758 (23%) AIDS-Free Baseline 2474 (77%) Sero- Converter 25 (2%) Sero- Negative 1089 (98%) AIDS 772 (36%) AIDS-Free 1352 (64%) AIDS 9 (39%) AIDS-Free 14 (61%) Dead 60% Dead 44% Dead 15% Dead 55% Dead 21% Dead 8% WIHS. October

12 WIHS: Baseline Demographics and Clinical Markers (HIV-Positive) 94/95 Cohort 01/02 Cohort Age (years) Black race (%) Exposure category (%) IDU Heterosexual contact Other Demographics Employed (%) Household income ($) No health insurance (%) Physical/sexual abuse (%) 66 9 Completed high school (%) Single mother (%) Below poverty line (%) Bacon MC, et al. Clin Diag Lab Immunol. 2005;12: CD4 (cells/mm 3 ) <50 (%) (%) (%) >350 (%) HIV RNA (copies/ml) >4000 (%) (%) (%) <80 (%) Clinical Markers 94/95 Cohort /02 Cohort AIDS ART use (%) 0 66 HBV core antibodies (%) HBV surface antigen (%) 3 1 HCV antibodies (%) 39 13

13 WIHS: Association of Race and Death From AIDS in ART Users Prospective cohort HIV-positive women on continuous ART (n=1471) Black versus white women More likely to progress to AIDS Higher cumulative incidence of AIDS death Black women were less likely to adhere to ART Black race remained an independent predictor of AIDS death after adjusting for adherence Murphy K, et al. AIDS. 2013;27: Likelihood of: AIDS death Black race (vs white) Other race (vs white) Reduced adherence Black race (vs white) Depression (vs none) AIDS-defining illness Black race (vs white) Other race (vs white) *P<0.0001; P=0.004; P=0.05; P<0.05. Adjusted Hazard Ratios 3.09* *

14 When to Start ART: Global Consensus and Diversity AIDS or HIV-Related CD4 Count (cells/mm 3 ) Symptoms < >500 United States DHHS (2015) Yes Yes Yes Yes Yes IAS-USA (2014) Yes Yes Yes Yes Yes British HIV Association (2013) Yes Yes Yes Consider Defer European AIDS Clinical Society (2014) Yes Yes Yes Consider Consider WHO (2013) Yes Yes Yes Yes Yes DHHS. Revision April 8, Günthard HF, et al. JAMA. 2014;312: EACS. Revision November BHIVA. Revision November WHO. Announcement October 2015.

15 DHHS Guidelines: Recommended Regimens Regardless of Baseline HIV RNA Level or CD4 Count PI INSTI Darunavir + ritonavir (qd) + emtricitabine/tenofovir DF or emtricitabine/tenofovir alafenamide Raltegravir + emtricitabine/tenofovir DF or emtricitabine/tenofovir alafenamide Elvitegravir/cobicistat/emtricitabine/tenofovir DF* Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide Dolutegravir /abacavir/lamivudine* Dolutegravir + emtricitabine/tenofovir DF or emtricitabine/tenofovir alafenamide *Available as a once-daily, single-tablet regimen. Notes: Lamivudine may substitute for emtricitabine or visa versa. Tenofovir DF: use with caution in patients with renal insufficiency. Elvitegravir/cobicistat/emtricitabine/tenofovir DF: only for patients with pre-art creatinine clearance >70 ml/min. Dolutegravir/abacavir/lamivudine: only for patients who are HLA-B*5701 negative. DHHS. Revision July 14, 2016.

16 FDA Analysis of Antiretroviral Registrational Studies: Gender Differences Meta-analysis of antiretroviral registrational trials ( ) Randomized controlled trials (n=40) for 18 antiretroviral agents HIV-positive patients (n=20,328) 20% women Results No significant gender differences HIV RNA <50 copies/ml at week 48 Adverse event discontinuations Death Discontinuations: virologic failure Males (8.15%) Females (4.25%) Soon G, et al. AIDS Patient Care STDS. 2012;26: Response Rate Difference by Arm Favors Male (n=6) Total: Favors Female (n=3) -100% -50% 0% 50% 100%

17 Sex/Gender Analyses: Treatment-Naïve Trials NNRTI vs NNRTI StaR Study (RLP vs EFV) NNRTI vs PI ACTG A5202 (EFV vs ATV/r) Higher rate of virologic failure in women randomized to ATV/r Higher risk of Grade 3/4 event in women randomized to ABC/3TC Brinson C, et al. 53 rd ICAAC. Denver, Abstract H-655. Smith KY, et al. Clin Infect Dis. 2014;58:

18 Fourie J, et al. HIV Clin Trials. 2011;12: Squires KE, et al. J Antimicrob Chemother. 2011;66: Squires K, et al. AIDS Res Hum Retroviruses. 2013;29: Sex/Gender Analyses: Treatment-Naïve Trials PI vs PI ARTEMIS (DRV/r vs LPV/r) CASTLE (ATV/r vs LPV/r) Virologic response rates similar Adverse events differ by gender Higher rates of nausea vomiting in women Lower rates of diarrhea INSTI in diverse population REALMRK (RAL in women, Blacks) Virologic response rates similar

19 Sex/Gender Analyses: Treatment-Experienced Trials GRACE Study Darunavir/r + OBR in a diverse population of HIVinfected patients No gender-based differences in virologic and immunologic response Most common adverse events Diarrhea, nausea, vomiting, and upper respiratory tract infection Nausea and vomiting more common in women, diarrhea in men Currier J, et al. Ann Intern Med. 2010;153:

20 WAVES Study: Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir DF in Treatment-Naïve Women Phase 3 study Treatment-naïve Double-blind HIV RNA >500 copies/ml egfr >70 ml/min Non-inferiority margin: 12% Randomization 1:1 WAVES: Women AntiretroViral Efficacy and Safety. E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir DF. Stratified by HIV RNA (<100K, >100K-<400K, >400K copies/ml) and race (black or nonblack). Squires et al. Lancet HIV 2016;3:e410-e420. E/C/F/TDF (n=289) Atazanavir + Ritonavir + Emtricitabine/Tenofovir DF (n=286) Primary Endpoint Week 48 Snapshot HIV RNA <50 Copies/mL

21 WAVES Study: Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir DF in Treatment-Naïve Women E/C/F/TDF met non-inferiority and superiority criteria versus atazanavir/r + FTC/TDF (P=0.03) Both arms had CD4 cell increases of 196 cells/mm 3 No viral isolates in women on E/C/F/TDF developed resistance Safety Fewer number of discontinuations due to adverse events in the E/C/F/TDF arm (5 versus 19) Predictable changes in egfr in the E/C/F/TDF arm Comparable changes in BMD between the 2 arms E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir DF. Squires et al. Lancet HIV 2016; 3:e Patients (%) Virologic Outcomes (Week 48) Treatment Difference: 6.5% (0.4, 12.6) 87% 81% HIV RNA <50 Copies/mL Failure E/C/F/TDF (n=289) ATV/r + FTC/TDF (n=286) 9% 12% 4% 7% No Data

22 WAVES Study: HIV RNA <50 Copies/mL by Baseline HIV RNA and CD4 Count Patients (%) HIV RNA Subgroup E/C/F/TDF Atazanavir + RTV + FTC/TDF 86% 82% 90% 78% Patients (%) E/C/F/TDF CD4 Subgroup Atazanavir + RTV + FTC/TDF 88% 86% 82% 79% <100,000 (n=220/214) Squires K, et al. Lancet HIV 2016;3:e >100,000 (n=68/72) Baseline HIV RNA (copies/ml) E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir DF. <350 (n=145/131) >350 (n=143/154) Baseline CD4 (cells/mm 3 )

23 ARIA Study: Dolutegravir Versus Atazanavir/r- Based Regimens in Treatment-Naïve Women Phase 3b Study (n=495) Treatment-naïve women HLA-B*5701 negative HIV RNA >500 copies/ml HBV negative Randomization 1:1 Abacavir/Dolutegravir/Lamivudine (n=248) Atazanavir/r + FTC/TDF (n=247) Primary outcome: proportion HIV RNA <50 copies/ml at week 48. Non-inferiority margin: -12% (based on week 48 FDA snapshot analysis of percentage of patients with HIV RNA <50 copies/ml). Stratification by baseline HIV RNA (<, >100K copies/ml) and CD4 (<, >350 cells/mm 3 ). Baseline characteristics: Median age: 37 years. Black/white/Asian race: 42%/45%/9%. HCV coinfected: 7%. AIDS: 4%. Johnson HIV RNA M, et >100K al. J Int log AIDS 10 copies/ml: Soc. 2016;19(suppl 27%. 7): Abstract P035. CD4 <350 cells/mm 3 : 51%.

24 ARIA Study: Week 48 Results in Treatment-Naïve Women Abacavir/dolutegravir/lamivudine Met non-inferior and superiority criteria versus atazanavir/r + FTC/TDF (P<0.005) Difference was driven by lower rate of virologic non-response and fewer discontinuations due to adverse events Similar results regardless of baseline HIV RNA, CD4 count, age, and geographic region No treatment-emergent primary INSTI or abacavir/lamivudine resistance in the dolutegravir arm Overall dolutegravir safety profile similar to previous studies Johnson M, et al. J Int AIDS Soc. 2016;19(suppl 7): Abstract P035. Patients (%) HIV RNA <50 Copies/mL (ITT) 82% ABC/DTG/3TC (n=248) Treatment Difference 10.5 (3.1, 17.8) 71% ATV/r + FTC/TDF (n=247)

25 PROMISE: Continuing vs Stopping ART in Postpartum, Non Breast-feeding Women Randomized trial in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand, and United States of women receiving ART (74% LPV/RTV, 19% ATV/RTV) or stopping ART following pregnancy Randomized within 42 days of delivery Pts seen 4 wks post enrollment, then every 12 wks through 84 wks after last enrollment HIV-infected, ART-naive (except PMTCT) postpartum women without guidelinespecified indication for ART, CD4+ cell count 400 cells/mm 3, not breast-feeding (N = 1652) Continue ART (n = 827) Stop ART* (n = 825) *Restarted ART if CD4+ cell count fell below 350 cells/mm 3 or was clearly indicated. Current analysis reflects median follow-up of 2.31 yrs for Continue ART arm and 2.35 yrs for Stop ART arm. Currier J, et al. AIDS Abstract THAB0103LB.

26 PROMISE: Efficacy and Safety at Median Follow-up of Approximately 2 Yrs Between treatment arms, no significant difference in primary safety or efficacy endpoints Time to first grade 3/4 sign or symptom or grade 2-4 chemistry or hematology result (P =.08) Time to AIDS-defining event, serious non-aids event, or any-cause death (P =.54) Secondary endpoints: continuing ART associated with lower HIV event rate Outcome, n (rate per 100 PY) Continue ART (n = 827) Stop ART (n = 825) HR (95% CI) Composite of HIV/AIDS-related or WHO stage 2/3 events 57 (3.09) 99 (5.49) 0.56 ( ) WHO stage 2/3 events 38 (2.02) 80 (4.36) 0.47 ( ) Currier J, et al. AIDS Abstract THAB0103LB.

27 DHHS Perinatal Guidelines HIV-infected woman who is pregnant Additional goal of therapy: prevent mother-to-child transmission Suppress HIV RNA to below the limit of detection to reduce the risk of transmission of HIV to the fetus and newborn Selection of an antiretroviral combination Take into account known safety, efficacy, and pharmacokinetic data of each agent during pregnancy If already on therapy Review therapy in terms of potential pregnancy impact Clinicians should consult the most current DHHS guidelines when designing a regimen for a pregnant patient DHHS. Revision October 26, 2016.

28 Antiretroviral Agents and Pregnancy NRTI NNRTI PI Entry Inhibitor Integrase Inhibitor Preferred Abacavir/lamivudine Emtricitabine*/tenofovir DF Atazanavir/r 3 Darunavir/r Raltegravir Alternative Zidovudine/lamivudine Efavirenz 1 Nevirapine 2 Lopinavir/r Rilpivirine Insufficient data in pregnancy Rilpivirine Fosamprenavir/r Maraviroc Dolutegravir Elvitegravir 4 Note: no data on use of cobicistat in pregnancy. *or lamivudine. 1 May be initiated after the first 8 weeks of pregnancy. Evidence of human fetal risk; Pregnancy Category D 2 Contraindicated with CD4+ counts >250/mm 3 due to potential for liver toxicity. 3 Theoretical concern for hyperbilirubinemia. 4 co-formulated with cobicistat/emtricitabine/tenofovir DF. DHHS. Revision October 26, 2016.

29 Antiretroviral Pregnancy Registry Study ( Purpose Detect any major teratogenic effects of antiretroviral drugs (ARVs) administered to HIV-infected pregnant women Maintained by an independent advisory board; all pharmaceutical companies manufacturing ARVs participate Prospective, international exposure-registration study (1989-July, 2016; n=20,833 pregnancies reported) >80% of cases are from the US 1300 cases per year (15% of 8700 births per year) APR overall findings Birth defect rate comparable to CDC population-based surveillance data (2.8% versus 2.72%) Interim Report July Available at:

30 Antiretroviral Pregnancy Registry Study NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir DF Zidovudine Defects/Live Births (>200 reported 1 st trimester exposures) 30/ /426 54/ / /811 67/ /4144 Prevalence % (95% CI) 2.91 (1.97, 4.13) 4.69 (2.89, 7.16) 2.32 ( ) 3.08 (2.60, 3.62) 2.59 (1.60, 3.94) 2.23 (1.73, 2.83) 3.21 (2.69, 3.80) PIs Atazanavir Indinavir Lopinavir Nelfinavir Ritonavir Darunavir NNRTIs Efavirenz Nevirapine Rilpivirine INSTIs Raltegravir 25/1187 7/289 29/ / / /385 22/934 32/1124 1/202 7/ (1.36, 3.10) 2.42 (0.97, 4.93) 2.10 (1.40, 3.00) 3.88 (2.86, 5.13) 2.18 (1.68, 2.77) 2.60 (1.25, 4.73) 2.36 (1.48, 3.55) 2.85 ( ) 0.50 (0.01, 2.73) 2.83 (1.14, 5.76)

31 Impact of Pregnancy on Antiretroviral Drug Distribution Pharmacokinetics not significantly altered; no change in dose indicated No studies in human pregnancy NRTI NNRTI PI Abacavir Didanosine Lamivudine Stavudine Zidovudine Nevirapine Etravirine Rilpivirine Nelfinavir 1 Saquinavir HGC/r 2 Entry Inhibitor Tenofovir DF Tipranavir Enfuvirtide Maraviroc Evidence of reduced exposure Emtricitabine 3 Efavirenz 3 Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/r 3 Ritonavir 1 Adequate levels achieved with 1250 mg twice daily. 2 Limited data suggest adequate levels achieved with 1000/100 mg twice daily. 3 No need for dose change. 4 Tablet formulation: Best BM, et al. JAIDS. 2010;54: Cobicistat: DHHS. no dosage adjustment necessary when used Revision as booster. August 6, Integrase Inhibitor Raltegravir 3 Dolutegravir Elvitegravir

32 Use Of ARVs in Women: Summary Participation of women in clinical ARV trials does not reflect the demographics of women LWHIV Post-registrational studies for the most recently approved ARVs have provided efficacy and safety data Information regarding the safety of these agents is lacking Studies suggest ARV efficacy does not differ by gender Side effects do differ by gender, at least for some ARV classes Data informing the use of ARVs during pregnancy are significantly delayed beyond the approval of the agents