Women and HIV Piotr Budnik MBBCh FCP(SA) Medical Lead HIV Southern - PowerPoint PPT Presentation

Women and HIV Piotr Budnik MBBCh FCP(SA) Medical Lead HIV Southern Africa - GSK VIIV/DGR/0002/16a August 2016

Half of the global HIV-infected adult population are women and the majority are living in Sub-Saharan Africa 17.8 million ~ 2,491 15% women worldwide new HIV infections per DAY of women living were living with among women (≥15 years old) with HIV are aged HIV in 2015 15 – 24 years 59% 50% 80% of adults living with HIV of these young of adults living with in Sub-Saharan Africa women live in HIV globally are are women Sub-Saharan Africa women 5 – 7 years x2 Young women (15-24 years) In Sub-Saharan in Sub-Saharan Africa are more Africa, women acquire likely to be living with HIV* HIV earlier than men *Versus young men UNAIDS GAP Report 2014: http://www.unaids.org/en/resources/publications/2014 Accessed May 2016

There are significant regional differences in the proportions* women constitute of adults living with HIV 36% 22% 22% 39% 38% 50% 58% 30% The proportion of HIV-infected women as compared to men is highest in Africa , the Caribbean , Asia and Eastern Europe *Proportions calculated from the unrounded 2013 HIV estimates published in UNAIDS, 2014, The Gap Report, p. A30-A35 See slide notes for reference

There is a strong link between sociological factors and the HIV-epidemic in young women Young women are facing a HIV epidemic 60% of all new HIV infections HIV/AIDS is the leading cause of among young people aged death worldwide for women aged 15 – 44 1 15 – 24 , occurred among adolescent #1 girls and young women 1 HIV prevalence among adolescent girls and young women is 7x that of males 2 Key drivers and challenges of the epidemic in young women 3 Poverty Unemployment Lack of education 80% Lack of access to healthcare services Inability to advocate for safe sex See slide notes for reference

Living with HIV: Considerations specific to women WOMEN OF CHILD MENOPAUSE BEARING POTENTIAL AND OLD AGE Increased barriers to accessing treatment in some Increased barriers to accessing treatment in some populations 1 populations 1 Choice of contraceptive when partner is serodiscordant 1 Barriers to adherence in older women 1 DDIs with hormonal contraception 1,2 Impact of side effects in older women 2 Concerns around conception and the HIV status of Potential early onset of menopause 2 partner and baby 3 DDIs with HRT 1,2 Safety of mother and baby during pregnancy and breasfeeding 3 – 5 Elevated symptom burden in menopause and beyond 1,2 Potential early onset of menopause 2 1. Greig JM, Anderson J. Curr Opin Infect Dis 2014;27:46 – 52; 2. Cejtin H. Am J Obstet Gynecol 2012;207:87 – 93 3. SHE Programme: Women and HIV; Fertility. Available from: http://www.shetoshe.org/living-well-with-hiv/sexual-and- reproductive-health/fertility/#.V3ze0vkrJD8 4. SHE Programme: HIV and breastfeeding. Available from: http://www.shetoshe.org/living-well-with-hiv/sexual-and-reproductive-health/hiv-and-breastfeeding/#.V3zfAPkrJD8 5. AVERT: Pregnancy, childbirth and breastfeeding. Available from: http://www.avert.org/hiv-transmission-prevention/pregnancy-childbirth-breastfeeding

There is a lack of data regarding the efficacy and safety of ARV drugs during pregnancy as most clinical trials exclude pregnant women Pregnant women are excluded from the vast majority of clinical trials 1,2 Very few drugs are approved for use during pregnancy; most drug labels provide little pregnancy data 1 The relatively low percentage of women living with HIV who are pregnant at any given time 2 and the length of the gestation period result in slow generation of pregnancy data HIV studies involving pregnant women typically concentrate on outcomes for infants 2 1. Blehar M, et al. Womens Health Issues 2013 23(1) e39 – e45 2. Westreich D, et al. PLoS ONE 2013;8(8):e73398

Physiological changes during pregnancy alter drug metabolism and distribution A variety of physiological changes during pregnancy can alter the PKs of ARV drugs at all stages of drug metabolism and may lead to lower plasma levels of drugs Changes in digestive processes, nausea and vomiting lead to decreased C max , Absorption increased T max and reduced absorption/bioavailability Alterations to vascular volume and reduced protein concentrations lower C max Distribution and increase the free fraction of drug Hormonal alterations to enzyme and biliary functions lead to variable effects on drug Metabolism metabolism and reduce biliary drug secretion Enhanced renal activity increases clearance of renally eliminated drugs and Excretion decreased steady-state drug concentrations For HIV-infected women, pregnancy and the associated physiological alterations may have an impact on their ARV regimens and necessitate increased dosages, more frequent dosing, or boosting, especially of PIs 2 1. Gilbert EM, et al. Pharmacotherapy 2015;35:838 – 55 2. DHHS. Guidelines for pregnant HIV-1-infected women. August 2015. https://aidsinfo.nih.gov/guidelines Accessed Oct 2015

From evidence to policy: Evolution of WHO MTCT and ART recommendations 2002 1 2004 2 2006 3 2010 4 2013 5 2016 6  MATERNAL ART FOR PREVENTION OF MTCT AZT or AZT from AZT from Option A Options Option B+ AZT + 3TC Week 28 Week 28 + AZT from Week 14 Lifelong triple ART, B and B+ or SD NVP + SD NVP SD NVP + SD NVP + Triple ART irrespective of CD4+ + 7 days’ 7 days’ AZT + 3TC cell count AZT + 3TC Option B Triple ART from Week 14  INITIATION OF LIFELONG MATERNAL ART No specific CD4+ CD4+ CD4+ N/A For B guidance <200 cells/mm 3 <200 cells/mm 3 ≤350 cells/mm 3 CD4+ ≤500 cells/mm 3 Evolution towards more efficacious treatment schedules and lifelong treatment for all See slide notes for references

Impact of ageing is amplified in women living with HIV particularly due to physiological changes during menopause Possible early onset of 1 General menopause factors Burden of Burden HIV of HIV infection treatment Elevated Cervical burden of cancer menopausal screening symptoms Co-morbid Ageing conditions 2 Women-specific Osteoporosis factors Cejtin H. Am J Obstet Gynecol 2012;207:87 – 93

Key considerations for choice of ART during menopause in women with HIV GENERAL CONSIDERATIONS HRT CONSIDERATIONS PK and Increased plasma drug concentrations Hepatic and renal functions DDIs in elderly patients 1 may be affected 3 Post-menopausal women may respond DDIs, e.g. PIs/NNRTIs 1 differently to ART as oestrogen deficiency Efficacy and could affect CD4 cell recovery and immunologic Concerns regarding worsening of HIV HIV replication 2 response status under hormonal treatment 1 Lower CD4 cell count in previously untreated menopausal women 1 Concerns regarding toxicity 1 Menopause can lead to metabolic Safety and Increased pill burden 1 complications, including osteoporosis, tolerability lipid and glucose disturbances 1,3 Depressive symptoms are more likely during menopause 1 Convenience Similarity of menopausal symptoms and ART side effects 3 In the era of cART, women with HIV live longer and go through menopausal changes leading to a continuous increase in complexity in the management of HIV infection 2 1. Andany N, et al. Int J Womens Health 2016;8:1 – 22; 2. Imai K, et al. Obstet Gynecol Int 2013;2013:340309 3. Loutfy M, et al. J Int AIDS Soc 2013 Oct 1;16:18509

Women are under-represented in treatment-naïve, registrational ART clinical trials 1 ART clinical trials since 2005 have recruited on average ~18% women 1 Proportion of women recruited (%) Third agent RPV RAL LPV/r EFV ATV/r DTG ATV DRV/r EVG Time (by start date) 2005 2013 1. Soon GG, et al. AIDS Patient Care STDs 2012;26:444 – 53; 2. Daar E, et al. Ann Intern Med 2011;154:445 – 56; 3. Ortiz R, et al. AIDS 2008;22:1389 – 1397; 4. Molina JM, et al. Lancet 2008;372:646 – 55; 5. Rockstroh J, et al. J Acquir Immune Defic Syndr 2013;63:77 – 85. Supplementary file; 6. Molina JM, et al. Lancet 2011;378:238 – 46; 7. Cohen CJ, et al. Lancet 2011;378:229 – 37; 8. Landovitz RJ, et al. *or ATV/r (24%) CROI 2014. Abstract 85; 9. Sax PE, et al. Lancet 2012;379:2439 – 48; 10. Dejesus E, et al. Lancet 2012;379:2429 – 38; 11. Raffi F, et al. CROI 2014. †DRV/r + RAL (12%) or DRV/r +TDF/FTC (11%) Abstract 84LB; 12. Raffi F, et al. Lancet 2013;381:735 – 43; 13. Cahn P, et al. EACS 2013. Abstract LBPS7/6; 14. Cohen C, et al. HIV Therapy Glasgow ‡LPV/r + 3TC (16%) or LPV/r + ABC/3TC (17%) 2012. Abstract O425; 15. Walmsley S, et al. N Engl J Med 2013;369:1807 – 18. Supplementary appendix; § EVG/c/FTC/TDF vs EVG/c/FTC/TAF 16. Clotet B, et al. Lancet 2014;383:2222 – 31; 17. Sax PE, et al. Lancet 2015;385:2606 – 15

Importance of women in clinical trials SCIENTIFIC RATIONALE Biological and hormonal gender differences Bodyweight/fat distribution differences and their effects on drug absorption, distribution, metabolism and excretion Drugs should be tested in populations that reflect the end-users (including age, gender, ethnicity) More biologically susceptible of the HIV population 50% to HIV transmission are women Different ARV toxicity profiles reported SOCIAL RATIONALE Understanding and addressing the barriers to inclusion Ensuring equal access to treatment More vulnerable due to gender-based power relationships Access to testing, counselling, prevention and treatment programmes Heidari S, et al. J Int AIDs Soc 2011;14:11