Dr Karris: I’d like to amplify Dr Gianella’s statements. Unfortunately we will not be able to answer these questions if women do not participate in HIV cure studies.

Along those lines, Dr Gianella and I also would love to see greater inclusion and involvement of HIV-infected trans women and men in HIV cure studies. Transgender men and women, especially those who use hormones, may have different biologic barriers to HIV cure than cisgender men and women. HIV interventions, including HIV cure strategies, need to be safe, culturally and socially appropriate, and effective for all affected populations.


Continue Reading

Conclusion/Clinical Implication

Dr Karris: The care for women living with HIV is complex from both a biologic and socioeconomic standpoint.  As providers, we should remember the unique challenges that women face so that we can intervene in small but impactful ways to improve linkage, engagement, and retention in care, as well as medication adherence.  For example, making a waiting room more kid-friendly, prioritizing regimen simplification, or referring a female or transgender patient to HIV research can positively impact outcomes for all women.

Dr Gianella: Specifically with regard to HIV research, sex-based analyses are imperative to understand the biological differences in HIV treatment, cure, and prevention.2 Clinical trial protocols should be written to include sex-based comparisons so that necessary information can be collected as trials are conducted. While it is not realistic to enforce a 50% recruitment of women into every HIV study (depending on epidemic characteristics and geographic location), a rate that matches the local population demographics should be a bare minimum. Specific efforts are needed to balance female and male participation at all phases of research (including basic research, cell cultures, and animal models). This will likely require adapting outreach procedures and commitment from funding agencies and sponsors to address the unique barriers to women’s participation.

Acknowledgements

Thank you to Katy Godfrey, Constance Benson, Jonathan Karn, and Liz Barr for their continuous support and inspiring dedication to this important topic.

Related Articles

References

  1. Statistics: Women and HIV/AIDS. The Foundation for AIDS Research (amfAR). http://www.amfar.org/about-hiv-and-aids/facts-and-stats/statistics–women-and-hiv-aids/. Updated July 2015. Accessed January 17, 2017.
  2. Gianella S, Tsibris A, Barr L, Godfrey C. Barriers to a cure for HIV in women. J Int AIDS Soc. 2016;19:20706. doi: 10.7448/IAS.19.1.20706
  3. Johnston RE, Heitzeg MM. Sex, age, race and intervention type in clinical studies of HIV cure: a systematic review. AIDS Res Hum Retroviruses. 2015;31:85-97. doi: 10.1089/AID.2014.0205
  4. Delmas MC, Jadand C, De Vincenzi I, et al. Gender difference in CD4+ cell counts persist after HIV-1 infection. SEROCO Study Group. AIDS. 1997;11:1071-1073.
  5. Addo MM, Altfeld M. Sex-based differences in HIV type 1 pathogenesis. J Infect Dis. 2014;209 Suppl 3:S86-92. doi: 10.1093/infdis/jiu175
  6. Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med. 2001;344:720-725. doi: 10.1056/NEJM200103083441003
  7. Farzadegan H, Hoover DR, Astemborski J, et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 1998;352:1510-1514. doi: 10.1016/S0140-6736(98)02372-1
  8. Maki PM, Martin-Thormeyer E. HIV, cognition and women. Neuropsychol Rev. 2009;19:204-214. doi:  10.1007/s11065-009-9093-2
  9. Curno MJ, Rossi S, Hodges-Mameletzis I, Johnston R, Price MA, Heidari S. A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies. J Acquir Immune Defic Syndr. 2016;71:181-188. doi: 10.1097/QAI.0000000000000842
  10. Ofotokun I, Chuck SK, Hitti JE. Antiretroviral pharmacokinetic profile: a review of sex differences. Gend Med. 2007;4:106-119. doi: 10.1016/S1550-8579(07)80025-8
  11. Clark R. Sex differences in antiretroviral therapy-associated intolerance and adverse events. Drug Saf. 2005;28:1075-1083. doi: 10.2165/00002018-200528120-00003
  12. Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434. doi: 10.1056/NEJMoa1110711
  13. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410. doi: 10.1056/NEJMoa1108524
  14. Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422. doi: 10.1056/NEJMoa1202614
  15. Marrazzo JM, Ramjee G, Richardson BA, et al; VOICE Study Team. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372:509-518. doi: 10.1056/NEJMoa1402269.
  16. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599. doi: 10.1056/NEJMoa1011205
  17. Hendrix CW, Andrade A, Bumpus NN, et al. Dose frequency ranging pharmacokinetic study of tenofovir-emtricitabine after directly observed dosing in healthy volunteers to establish adherence benchmarks (HPTN 066). AIDS Res Hum Retroviruses. 2016;32:32-43. doi: 10.1089/AID.2015.0182
  18. Cottrell ML, Yang KH, Prince HM, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214:55-64. doi: 10.1093/infdis/jiw077
  19. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499-523. doi: 10.1146/annurev.pharmtox.44.101802.121453
  20. Berg KM, Demas PA, Howard AA, Schoenbaum EE, Gourevitch MN, Arnsten JH. Gender differences in factors associated with adherence to antiretroviral therapy. J Gen Intern Med. 2004;19:1111-1117. doi: 10.1111/j.1525-1497.2004.30445.x
  21. Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;28:47-58. doi: 10.1097/00042560-200109010-00008
  22. Kempf MC, Pisu M, Dumcheva A, Westfall AO, Kilby JM, Saag MS. Gender differences in discontinuation of antiretroviral treatment regimens. J Acquir Immune Defic Syndr. 2009;52:336-341. doi: 10.1097/QAI.0b013e3181b628be
  23. Roberts KJ, Mann T. Barriers to antiretroviral medication adherence in HIV-infected women. AIDS Care. 2000;12:377-386. doi: 10.1080/09540120050123774
  24. Mills EJ, Nachega JB, Bangsberg DR, et al. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Med. 2006;3:e438. doi: 10.1371/journal.pmed.0030438
  25. Kempf MC, McLeod J, Boehme AK, et al. A qualitative study of the barriers and facilitators to retention-in-care among HIV-positive women in the rural southeastern United States: implications for targeted interventions. AIDS Patient Care STDS. 2010;24:515-520. doi: 10.1089/apc.2010.0065
  26. Logie C, James L, Tharao W, Loutfy M. Associations between HIV-related stigma, racial discrimination, gender discrimination, and depression among HIV-positive African, Caribbean, and Black women in Ontario, Canada. AIDS Patient Care STDS. 2013 Feb;27(2):114-22. doi: 10.1089/apc.2012.0296
  27. Gielen AC, McDonnell KA, Burke JG, O’Campo P. Women’s lives after an HIV-positive diagnosis: disclosure and violence. Matern Child Health J. 2000;4:111-120. doi: 10.1023/A:1009522321240
  28. Colombini M, James C, Ndwiga C; Integra team, Mayhew SH. The risks of partner violence following HIV status disclosure, and health service responses: narratives of women attending reproductive health services in Kenya. J Int AIDS Soc. 2016;19:20766. doi: 10.7448/IAS.19.1.20766
  29. Hare AQ, Ordóñez CE, Johnson BA, et al. Gender-specific risk factors for virologic failure in KwaZulu-Natal: automobile ownership and financial insecurity. AIDS Behav. 2014;18:2219-2229. doi: 10.1007/s10461-014-0849-1
  30. Wood SA, Tobias C, McCree. Medication adherence for HIV positive women caring for children: in their own words. AIDS Care. 2004;16:909-913. doi: 10.1080/09540120412331290158
  31. Mellins CA, Chu C, Malee K, et al. Adherence to antiretroviral treatment among pregnant and postpartum HIV-infected women. AIDS Care. 2008;20:958-968. doi: 10.1080/09540120701767208
  32. Nachega JB, Uthman OA, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. AIDS. 2012;26:2039-2052. doi: 10.1097/QAD.0b013e328359590f
  33. McKinney O, Modeste NN, Lee JW, Gleason PC, Maynard-Tucker G. Determinants of antiretroviral therapy adherence among women in southern Malawi: healthcare providers’ perspectives. AIDS Res Treat. 2014;2014:489370. doi: 10.1155/2014/489370
  34. Marston M, Nakiyingi-Miiro J, Kusemererwa S, et al; on behalf of the ALPHA network. The effects of HIV on fertility by infection duration: evidence from African population cohorts before ART availability: fertility by duration of HIV infection. AIDS. 2016. doi: 10.1097/QAD.0000000000001305
  35. Marston M, Nakiyingi-Miiro J, Hosegood V, Lutalo T, Mtenga B, Zaba B; on behalf of the ALPHA network. Measuring the impact of antiretroviral therapy roll-out on population level fertility in three African countries. PLoS One. 2016;11:e0151877. doi: 10.1371/journal.pone.0151877
  36. AIDS Education & Training Center Program. Guide for HIV/AIDS Clinical Care. Antiretroviral Medications and Hormonal Contraceptive Agents. https://aidsetc.org/guide/antiretroviral-medications-and-hormonal-contraceptive-agents. Published April 2014. Accessed January 4, 2016.
  37. Robinson JA, Jamshidi R, Burke AE. Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy. Infect Dis Obstet Gynecol. 2012;2012:890160. doi: 10.1155/2012/890160
  38. Mitchell HS, Stephens E. Contraception choice for HIV positive women. Sex Transm Infect. 2004;80:167-173. doi:10.1136/sti.2003.008441
  39. Wira CR, Fahey JV. A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle. AIDS. 2008;22:1909-1917. doi: 10.1097/QAD.0b013e3283060ea4
  40. Harper KN. Two recent studies find Depo-Provera use increases HIV risk. AIDS. 2015;29:N1. doi: 10.1097/QAD.0000000000000660
  41. Byrne EH, Anahtar MN, Cohen KE, et al. Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study. Lancet Infect Dis. 2016;16:441-448. doi: 10.1016/S1473-3099(15)00429-6
  42. Cuzin L, Pugliese P, Sauné K, et al; for the Dat’AIDS study group. Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy. AIDS. 2015;29:1665-1671. doi: 10.1097/QAD.0000000000000723
  43. Couturier J, Suliburk JW, Brown JM, et al. Human adipose tissue as a reservoir for memory CD4+ T cells and HIV. AIDS. 2015;29:667-674. doi: 10.1097/QAD.0000000000000599
  44. Karn J. Estrogen blocks HIV re-emergence from latency and points to gender-specific differences in HIV reservoirs. Presented at: 8th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment, and Prevention; July 19-22, 2015; Vancouver, Canada.
  45. Deeks SG. HIV: shock and kill. Nature. 2012;487:439-440. doi: 10.1038/487439a