Tackling the Issues: Caring for HIV-Positive Women Today

Tackling the Issues: Caring for HIV-Positive Women Today Anna Maria Geretti University of Liverpool 2 nd CENTRAL AND EASTERN EUROPEAN MEETING ON VIRAL HEPATITIS AND CO-INFECTION WITH HIV - BUCHAREST, ROMANIA 6-7 OCTOBER 2016

Women as Share of People Living with HIV by Region, 2014 ( 15 years of age) HIV is the leading cause of death in women aged 15-49 yrs Young women who experience partner violence 50% more likely to have HIV than women who do not report partner violence UNAIDS HOW AIDS Changed Everything 2015

UNAIDS HOW AIDS Changed Everything 2015

Proportion of Women enrolled in HIV Trials ALERT GEMINI ESS30009 ASSERT GS 934 ARIES ARTEN STARTMRK GS 903 CNA30024 THRIVE ARTEMIS ECHO HEAT MERIT ACTG 5905 AI424034 KLEAN CASTLE ACTG 384 ACTG 5202 Proportion of Women in Clinical Trials 27% women 78% women GRACE WAVES 0 10 20 30 40 50 60 70 80 90 100 Percent of Women enrolled (%) Percentage of recruited women apted from Slide courtesy Michelle Giles

Potential Impact of Gender in HIV Infection BIOLOGY TREATMENT PSYCHO-SOCIAL RESEARCH NEEDS Susceptibility, immune activation, disease progression, compartmentalization, pregnancy, hormones PK/PD, drug toxicity and tolerability, virological outcomes Testing, access to care, retention in care, mental health and well-being, internalised stigma, gender-based violence, neighbourhood, food security, housing Equity of access, support, treatment, cure Loutfy et al. AIDS Soc 2013; Rosin et al. HIV Med 2015; Gueler et al. AIDS 2015; Johnston et al. AIDS Res Human Retrovir 2015; Hatcher et al. AIDS 2015

Gender: Pre-ART Profile Women with and without HIV have higher CD4 counts than man (Main et al 1996; Delmas et al 1997) Adjusted for CD4 count, women have lower viral load than men (Sterling et al. 2001; Law et al. 2015) No difference in disease progression despite CD4 count and viral load differences (Napravnik et al. 2002; Sterling et al. 2001; Perez-Elias et al. 2014; Lee et al. 2015; Law et al. 2015) Pregnancy does not influence CD4 count or progression (Allegro et al. 1997) Women have lower serum CRP, scd14 and LPS than men (Mathad et al. J AIDS 2016)

START Study START Study Design HIV-positive ART-naïve individuals with CD4 count >500 cells/µl Immediate ART Group Initiate ART immediately following randomization N=2,326 Randomisation Stratified by clinical site Deferred ART Group Defer ART until CD4+ count declines to <350 cells/mm 3 or AIDS N=2,359 Primary composite endpoint, target = 213 Serious AIDS or death from AIDS Serious Non-AIDS Events and death not attributable to AIDS -CVD, ESRD, decompensated liver disease, & non-aids defining cancers

START Study START: Recruitment Sites START around the world Women: Recruited 12579/4/2009 (27%) to 23/12/2013 507 (11%) 1,539 (33%) 356 (8%) 1,174 (25%) 1,000 (21%) 109 (2%) 35 countries and 215 sites 2530 (54%) from low- and middle-income countries

START: Primary End-Point by Subgroup Primary End Point for Subgroups

START: Summary 1.8% of participants in the immediate vs. 4.1% in the deferred arm experienced the primary outcome Serious AIDS Events, Serious Non-AIDS Events, or Death 57% reduction in risk Evident for both AIDS and Serious Non-AIDS, greater for Serious AIDS Events, TB and cancer - most events occurred at high CD4 counts Consistent regardless of age, gender, race, region of the world, CD4 count, and viral load at entry Gender differences generally not analysed and reported apart from overall primary START outcome and a BMD sub-study Only 3% post-menopausal women in BMD analysis

Questions about Starting Treatment When to start: At the time of HIV diagnosis regardless of CD4 count and when the individual understands the goals of treatment and is ready to start

When to START Differences Gender in Differences Efficacy of ART in Efficacy between of men ART and wome Soon et al. AIDS Patient Care & STDs 2012

% with VL <50 cps/ml HIV-Positive Women in Germany 2015 vs. 2008 Multicentre analysis 100 80 77 91 88 On ART 60 40 48 Virological suppression 20 0 2008 2015 Knecht et al. 6 th International Workshop on HIV & Women 2016

UK ASTRA Cohort: Factors Associated with Virological Suppression after >6 Months of ART Women MSW MSM p=0.003 UK born/ not fluent English Non UK born/ fluent English UK Born p=0.16 Depression No Depression p<0.01 0,00 10,00 20,00 % with VL>50 copies/ml p values by Chi squared tests

ASTRA Cohort: Key Findings MSW and women compared to MSM more likely to have: detectable viral load viral load rebound after suppression Differences in virological outcomes between MSM and women largely explained by socio-economic circumstances They appear to have less impact for virological differences between MSM and MSW

Gender and ART Outcomes: Swiss Cohort 1984 men and 1941 women starting first-line ART Women had lower baseline viral load and higher CD4 counts Women more likely to switch ART or stop treatment in first year of ART, only partly pregnancy driven Lower probability of virological suppression in first 2 years of ART, abated after adjustment for HIV-related and sociodemographic factors Rosin et al. HIV Med 2015

Preferred First-Line ART Regimens EACS 2016* DHSS 2016 ABC 3TC DTG TDF FTC DTG TDF FTC RAL TDF FTC EVG/c TAF FTC EVG/c TDF FTC DRV/r TDF FTC RPV HLA-B*5701 negative Pre-treatment estimated CrCl 70 ml/min Pre-treatment estimated CrCl 30 ml/min CD4 count >200 cells and VL <100,000 cps *To be released in Autumn 2016

Questions about Selecting Treatment Does gender influence the choice of initial regimen? Does a discussion take place with women about treatment choices in accordance with different life stages and needs?

Questions about Selecting Treatment What to consider: Adverse effects of ART Child bearing potential, desire for or likelihood of pregnancy, and safety of ARVs in first trimester (or insufficient data for safety) Choice of contraception and drug-drug interactions

Toxicity in women Grade 4 anemia Gender and ART Outcomes CPCRA FIRST study: 55% used AZT, majority pre-menopausal African American women ART discontinuation or changes significantly greater in women for skin rash, neurological symptoms, constitutional symptoms, (and poor adherence) Immune activation and inflammation in women After 48 wks of ART, women have higher γifn and TNFα than men Tedaldi et al. J AIDS 2008; Mirjam-Colette et al. J AIDS 2009; Mathad et al. J AIDS 2016

Superior Efficacy of Dolutegravir/Abacavir/Lamivudine FDC Compared With Ritonavir-Boosted Atazanavir Plus Tenofovir Disoproxil Fumarate/Emtricitabine FDC in Treatment-Naive Women With HIV-1 Infection: ARIA Study C. Orrell, 1 D. Hagins, 2 E. Belonosova, 3 N. Porteiro, 4 S. Walmsley, 5 V. Falcó, 6 C. Man, 7 A. Aylott, 8 A. Buchanan, 7 B. Wynne, 9 C. Vavro, 7 M. Aboud, 10 K. Smith 7 1 Desmond Tutu HIV Foundation, Cape Town, South Africa; 2 Chatham County Health Department, Savannah, GA, USA; 3 Orel Regional Center for AIDS, Orel, Russia; 4 Fundación IDEAA, Buenos Aires, Argentina; 5 University Health Network, Toronto, Canada; 6 Hospital Vall d Hebron, Barcelona, Spain; 7,9,10 ViiV Healthcare, 7 Research Triangle Park, NC, USA; 9 Philadelphia, PA, USA; 10 Brentford, UK; 8 GlaxoSmithKline Stockley Park, UK 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

ARIA: DTG/ABC/3TC vs. ATV/r + TDF/FTC Open-label randomised non-inferiority phase 3b study Open-label, randomized 1:1 DTG/ABC/3TC FDC ATV/r +TDF/FTC FDC DTG/ABC/3TC FDC Continuation phase Randomization Week 48 primary analysis Key eligibility criteria: women, ART-naive, HLA-B*5701 negative, HIV-1 RNA >500 c/ml, hepatitis B negative Stratification: by HIV-1 RNA ( or >100,000 copies/ml), CD4+ count ( or >350 cells/mm 3 ) Women who became pregnant were withdrawn and, if possible, offered entry into a DTG/ABC/3TC pregnancy study Primary endpoint: proportion with HIV-1 RNA <50 c/ml at Week 48 using the FDA snapshot algorithm (-12% non-inferiority margin) 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa Orrell et al. AIDS 2016; Durban, South Africa.

Number of subjects Global Enrollment 160 140 134 N=499 randomized 120 100 80 60 40 20 0 66 54 50 44 40 28 25 20 16 11 9 2 Country 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

HIV-1 RNA <50 c/ml, % Snapshot Outcomes at Week 48: ITT-E and PP Populations Virologic outcomes Treatment differences (95% CI) 100 80 60 82 71 86 76 DTG/ABC/3TC (ITT-E, n=248) ATV/r+TDF/FTC (ITT-E, n=247) DTG/ABC/3TC (PP, n=230) ATV/r+TDF/FTC (PP, n=225) ATV/r+TDF/FTC DTG/ABC/3TC 3.1 10,5 17.8 ITT-E (primary) 40 2.6 9,7 16.8 PP 20 0 Virologic success 6 14 15 11 12 6 Virologic non-response 8 13 No virologic data -12-10 -8-6 -4-2 0 2 4 6 8 10 12 14 16 18 20 DTG/ABC/3TC is superior to ATV/r+TDF/FTC at Week 48, P=0.005 CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol. 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

HIV-1 RNA <50 c/ml, % Snapshot Outcomes by Baseline Randomization Strata at Week 48: ITT-E 100 DTG/ABC/3TC (n) ATV/r+TDF/FTC (n) ATV regimen 82 83 85 80 80 78 74 71 72 71 64 60 40 20 0 248 247 179 181 69 66 130 123 118 124 Overall 100,000 >100,000 350 >350 HIV-1 RNA c/ml CD4+ count cells/mm 3 ITT-E, intent-to-treat exposed. 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

Treatment Emergent Mutations in Patients with Confirmed Virologic Withdrawal The resistance analysis was performed on subjects meeting confirmed virologic withdrawal (confirmed 400 c/ml on or after Week 24) Resistance Analysis DTG/ABC/3TC (n=6) ATV/r +TDF/FTC (n=4) INSTI 0 0 NRTI 0 * 1 M184V 0 1 PI 0 0 * Two subjects receiving DTG/ABC/3TC had either K219K/Q (TAM) or E138E/G at CVW with no reduced susceptibility to DTG/ABC/3TC. K219K/Q is not selected for by ABC or 3TC nor does it affect their fold change No subject receiving DTG/ABC/3TC developed INSTI or ABC/3TC resistanceassociated mutations INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

Summary of Adverse Events: Randomized Phase (up to Week 48) DTG/ABC/3TC (n=248) ATV/r+TDF/FTC (n=247) Any adverse event, n (%) 195 (79%) 197 (80%)* Grade 2 to 4 AE 115 (46%) 137(55%) Drug-related AE (occurring 5% of subjects in either arm) 83 (33%) 121 (49%) Nausea 31 (13) 35 (14) Diarrhoea 12 (5) 18 (7) Dyspepsia 4 (2) 15 (6) Ocular icterus 0 18 (7) Headache 5 (2) 14 (6) Jaundice 0 13 (5) Serious AE 12 (5%) 20 (8%) Fatal AE 1 + 0 Drug-related SAE 0 3 (1%) Discontinuations due to AEs 10 (4%) 17 (7%) *Additional AEs identified post-hoc for two ATV+RTV+TDF/FTC subjects at one site are not included in this table. AEs were not considered to impact overall safety findings + Death certificate noted death due to natural causes. Investigator deemed event unrelated to study drug. AE, adverse event; SAE, serious adverse event. 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

Conclusions In treatment-naive women, DTG/ABC/3TC was superior to ATV/r+TDF/FTC at 48 weeks Difference driven by lower rate of virological non-response and fewer discontinuations due to AEs in DTG arm DTG/ABC/3TC had a favorable safety profile Similar to overall safety profile for DTG from previous studies No treatment-emergent primary INSTI or ABC/3TC resistance mutations in the DTG/ABC/3TC group AE, adverse event; CI, confidence interval; INSTI, integrase strand transfer inhibitor 21st International AIDS Conference, 18-22 July 2016, Durban, South Africa Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB.

WAVES: TDF/FTC/EVG/c vs. TDF/FTC + ATV/r for First-Line ART in Women International, randomized, double-blind placebo-controlled phase III trial Wk 48 ART-naïve women egfr 70 ml/min (N=575) TDF/FTC/EVG/c OD (n = 289) TDF/FTC + ATV/r OD (n = 286) Openlabel extension Patients generally well matched at baseline HIV-1 RNA >100,000 cps 24%-25% TDF= Tenofovir DF; FTC= Emtricitabine; EVG/c= Elvitegravir/cobicistat; ATV/r= Atazanavir + ritonavir Squires et al. IAS 2015

HIV-1 RNA < 50 cps (%) Virological Outcome at Week 48 TDF/FTC/EVG/c TDF/FTC + ATV/r p=0.03 Virological success Virological failure No data Overall treatment difference 6.5% (95% CI 0.4-12.6) FDA snapshot algorithm in intention-to-treat population Squires et al. IAS 2015

HIV-1 RNA < 50 cps (%) WAVES: Key Results TDF/FTC/EVG/c 100 80 60 40 20 0 87 81 86 TDF/FTC + ATV/r 82 90 78 289 286 220 214 69 72 Overall 100,000 > 100,000 HIV-1 RNA (cps/ml) Emergent Resistance EVG/c ATV/r (n = 289) (n = 286) Analysis population 7 12 Resistance mutations 1* 3** *RT D67N/D; ** RT M184V/I No difference in changes from baseline for egfr, spine or hip BMD, LDL and HDL cholesterol, total cholesterol/hdl ratio, and triglycerides Greater increase in total cholesterol with EVG/c Lower rate of discontinuation due to adverse events with EVG/c (2.4% vs. 7.0%) egfr= Estimated glomerular filtration rate BMD= Bone mineral density Squires et al. IAS 2015

Success (%) WAVES: Virological Success by Region TDF/FTC/EVG/c TDF/FTC + ATV/r Overall USA Uganda Russia Other *p=0.03; p=0.07 Squires et al. IAS 2015

Cumulative VF Probability ACTG A5257: Gender and Racial Disparities in Virological Outcomes of First-Line ART Randomised phase III trial of ATV/r vs. RAL vs. DRV/r each with TDF/FTC Week 96 Unadjusted HR Women vs. Men: 1.4 (95% CI 1.1-1.9; P= 0.026) Wk 96 Unadjusted HR Black vs. White: 2.8 (95% CI: 2.0-3.8; P <.001) Wk 96 Unadjusted HR Hispanic vs. White: 2.0 (95% CI: 1.4-2.8; P =.001) 0.5 0.5 0.4 0.4 0.3 0.2 Women Men 0.3 0.2 Black Hispanic White 0.1 0.1 0 0 0 24 48 64 80 96 112 128 144 160 176 192 Wks Since Study Entry 0 24 48 64 80 96 112 128 144 160 176 192 Wks Since Study Entry ATV/r = Atazanavir + ritonavir; RAL= Raltegravir; DRV/r= Darunavir + ritonavir TDF/FTC= Tenofovir DR/Emtricitabine; HR= Hazard Ratio Ribaudo et al. CROI 2016

ACTG A5257: Other Factors Associated with Virological Failure Additional factors associated with increased risk of failure: oyounger age orecent non-adherence o Underweight ohigh pre-art viral load olow income oless education ohistory of IDU Ribaudo et al. CROI 2016

Stigma & Adherence in Women Women's Interagency HIV Study (2013-2014) n=1168 Significant association between internalized stigma and sub-optimal selfreported adherence among ethnic minority groups (not observe with non- Hispanic whites) Depressive symptoms Internalised stigma Loneliness Low perceived social support Sub-optimal adherence Turan et al. J Acquir Immune Defic Syndr. 2016

How Does Living with HIV Impact on Women s Mental Health? Online survey of respondents from 94 countries Social disadvantages correlated with mental health issues Before diagnosis After diagnosis Depression Self-blame Feeling of rejection A strong sense of isolation Anxiety Anorexia Spiritual isolation Suicidal feelings Harmful use of drugs/alcohol Percentage 0 20 40 60 80 N= 489 Orza et al. J Int AIDS Soc 2015

Multiple Factors Influence Access, Engagement, and Treatment Outcomes in Women Experience or fear of violence Beliefs Isolation Drug dependency Depression Alcohol abuse Mental health vulnerabilities Socioeconomic circumstances Fear of blame Care responsibilities Fear of disclosure Fear of prosecution Food security

Conclusions: HIV-Positive Women Multi-faceted interventions are needed to promote access, engagement, outcomes, well-being Psycho-social support as part of comprehensive care Interventions aimed at moderating socioeconomic impact on health outcomes may improve outcomes in women a Research should strive for equity of access Clinical research should include measures of socioeconomic factors Reproductive care and beyond Prepare to address issues relevant to aging population Walcott et al. Cult Health Sex 2015; Kumar et al. J Int AIDS Soc 2015; Amin et al. J Int AIDS Soc. 2015; Loutfy et al. J Int AIDS Soc. 2015 ; Turan et al. J Acquir Immune Defic Syndr. 2016

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