Women and clinical trials in HIV

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2. Contents. Introduction. Overview of women and HIV. Responses to therapy: differences between men and women. Women in clinical trials. The importance of women in clinical trials. Enrolling and retaining women in clinical trials. Alternatives to standard clinical trials. Case studies. . . . . . . .

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Women and clinical trials in HIV

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1. Women and clinical trials in HIV This presentation has been produced as part of the Women for Positive Action initiative. Women for Positive Action aims to empower, educate and support women with HIV and the healthcare providers who treat them The slides overview the differential responses to therapy and uptake of clinical trials between men and women. The factors behind the under-representation of women in clinical trials and the importance of enrolling and retaining women in clinical trials are discussed The Women for Positive Action educational slide kits are intended for use by healthcare professionals, community representatives and patients who want to create or participate in learning opportunities relating to improving the care of women living with HIV. If you have any questions about WFPA and sponsorship please email the WFPA secretariat: [email protected] This kit contains a PowerPoint presentation and a learning guide in Word format for use in any non-commercial setting. These files are provided by the Women for Positive Action initiative. By requesting these materials, you are agreeing to use them as provided. However, if you choose to significantly adapt or edit these slides, change the meaning or context of the information, or use them for a purpose other than that outlined above, you accept responsibility for the content of your presentation and agree to use a different slide template. Accuracy of Information and Disclaimer We do our best to ensure that all information and material on the slides is accurate as at 8 July 2009, and if you find anything that is inaccurate let us know and we will correct it as soon as practicable. We provide use of these resources free of charge and do so on the basis that we have no liability for their use. Women for Positive Action is supported by a grant from Abbott. This presentation has been produced as part of the Women for Positive Action initiative. Women for Positive Action aims to empower, educate and support women with HIV and the healthcare providers who treat them The slides overview the differential responses to therapy and uptake of clinical trials between men and women. The factors behind the under-representation of women in clinical trials and the importance of enrolling and retaining women in clinical trials are discussed The Women for Positive Action educational slide kits are intended for use by healthcare professionals, community representatives and patients who want to create or participate in learning opportunities relating to improving the care of women living with HIV. If you have any questions about WFPA and sponsorship please email the WFPA secretariat: [email protected] This kit contains a PowerPoint presentation and a learning guide in Word format for use in any non-commercial setting. These files are provided by the Women for Positive Action initiative. By requesting these materials, you are agreeing to use them as provided. However, if you choose to significantly adapt or edit these slides, change the meaning or context of the information, or use them for a purpose other than that outlined above, you accept responsibility for the content of your presentation and agree to use a different slide template. Accuracy of Information and Disclaimer We do our best to ensure that all information and material on the slides is accurate as at 8 July 2009, and if you find anything that is inaccurate let us know and we will correct it as soon as practicable. We provide use of these resources free of charge and do so on the basis that we have no liability for their use. Women for Positive Action is supported by a grant from Abbott.

2. 2 Contents

3. 3 Introduction In 2007 an estimated 33 million people were living with HIV1 The proportion of global HIV cases that are women is about 50%1 Women make up a higher proportion of new diagnoses, meaning the share of infections among women is increasing in several countries2 It is important to note that the number of cases of HIV infection in women are increasing in all parts of the world, albeit at different rates, and not just in the developing world. Most women with HIV are of childbearing potential2 Half of all new infections – over 7000 daily – are occurring among young people, and two-thirds of all new infections are among young women The proportion of women among people newly diagnosed with HIV in Western Europe increased from 25% in 1997 to 38% in 2002: 27.8% of newly registered Canadian HIV cases in 2006 were women3 32–33% of all newly diagnosed HIV/AIDS cases in North America acquired the infection through heterosexual intercourse2 References UNAIDS/ WHO. AIDS epidemic update. 2007;UNAIDS/07.27E / JC1322E UNAIDS. Report on the Global AIDS Epidemic. 2008; UNAIDS/08.25E / JC1510E Public Health Agency of Canada. HIV/AIDS. Epi Updates November 2007 In 2007 an estimated 33 million people were living with HIV1 The proportion of global HIV cases that are women is about 50%1 Women make up a higher proportion of new diagnoses, meaning the share of infections among women is increasing in several countries2 It is important to note that the number of cases of HIV infection in women are increasing in all parts of the world, albeit at different rates, and not just in the developing world. Most women with HIV are of childbearing potential2 Half of all new infections – over 7000 daily – are occurring among young people, and two-thirds of all new infections are among young women The proportion of women among people newly diagnosed with HIV in Western Europe increased from 25% in 1997 to 38% in 2002: 27.8% of newly registered Canadian HIV cases in 2006 were women3 32–33% of all newly diagnosed HIV/AIDS cases in North America acquired the infection through heterosexual intercourse2 References UNAIDS/ WHO. AIDS epidemic update. 2007;UNAIDS/07.27E / JC1322E UNAIDS. Report on the Global AIDS Epidemic. 2008; UNAIDS/08.25E / JC1510E Public Health Agency of Canada. HIV/AIDS. Epi Updates November 2007

4. Overview of women and HIV

5. 5 Biological differences between men and women: effect on HIV Biological factors are responsible for women being 2-4 times more susceptible to HIV infection than men1,2, 3 Women tend to be diagnosed with HIV later than men1,2 Viral loads tend to be lower in women, especially when CD4 count is high4 The rate of decline in CD4 count in women may be faster despite their generally lower viral load5,6 Recurrent vaginal yeast infections, severe PID and increased risk of precancerous changes to the cervix can occur in addition to most manifestations also seen in men Women are physiologically 2-4 times more susceptible to HIV:1,2,3 Women have a more delicate larger mucosal surface area and the female sexual organs are more vulnerable to tears and micro-lesions; a direct transmission route Untreated STIs increase women’s risk of HIV infection Ejaculate is released in greater quantities and contains a higher viral content than vaginal secretions Women tend to present later than men, often diagnosed while pregnant, or as older women seeking treatment for an opportunistic infection Viral loads tend to be lower in women, especially when CD4 count is high4 A meta-analysis several studies of gender effects on viral load showed that HIV-infected women consistently have a 2-6-fold lower viral load than men. Possible biological explanations are variations in viral load and CD4 count throughout the menstrual cycle. These findings are significant as viral loads are used to guide initiation and modification of ART The rate of decline in CD4 count in women may be faster in spite of their generally lower viral load5,6 References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003. Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 Ghandi M et al. Does patient sex affect Human Immunodeficiency Virus levels? Clinical Infectious Diseases 2002;35:313-322 Hubert JB et al. Gender, disease progression and response to HAART. Abstract presented at XIV International AIDS Conference, Barcelona, Spain 2002;ThOrC1448. Patterson K et al. Effects of Age and Sex on Immunological and Virological Responses to Initial HAART. HIV Medicine 2007;8:406-410.Women are physiologically 2-4 times more susceptible to HIV:1,2,3 Women have a more delicate larger mucosal surface area and the female sexual organs are more vulnerable to tears and micro-lesions; a direct transmission route Untreated STIs increase women’s risk of HIV infection Ejaculate is released in greater quantities and contains a higher viral content than vaginal secretions Women tend to present later than men, often diagnosed while pregnant, or as older women seeking treatment for an opportunistic infection Viral loads tend to be lower in women, especially when CD4 count is high4 A meta-analysis several studies of gender effects on viral load showed that HIV-infected women consistently have a 2-6-fold lower viral load than men. Possible biological explanations are variations in viral load and CD4 count throughout the menstrual cycle. These findings are significant as viral loads are used to guide initiation and modification of ART The rate of decline in CD4 count in women may be faster in spite of their generally lower viral load5,6 References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003. Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 Ghandi M et al. Does patient sex affect Human Immunodeficiency Virus levels? Clinical Infectious Diseases 2002;35:313-322 Hubert JB et al. Gender, disease progression and response to HAART. Abstract presented at XIV International AIDS Conference, Barcelona, Spain 2002;ThOrC1448. Patterson K et al. Effects of Age and Sex on Immunological and Virological Responses to Initial HAART. HIV Medicine 2007;8:406-410.

6. 6 Social and cultural differences affect how women manage HIV A number of psychosocial factors increase the risk of HIV infection in women: Limited control over the means to practice low-risk sexual behaviour, such as condom use Social standing and inability to negotiate frequency of and nature of sexual interactions Violence may increase a woman’s vulnerability to HIV because: Forced sex may result in tears and lacerations that contribute to virus transmission Violence can prevent women from safe-sex negotiations and access to treatment Fear of violence may prevent women from getting tested for HIV and/or disclosing their HIV status to others References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008 A number of psychosocial factors increase the risk of HIV infection in women: Limited control over the means to practice low-risk sexual behaviour, such as condom use Social standing and inability to negotiate frequency of and nature of sexual interactions Violence may increase a woman’s vulnerability to HIV because: Forced sex may result in tears and lacerations that contribute to virus transmission Violence can prevent women from safe-sex negotiations and access to treatment Fear of violence may prevent women from getting tested for HIV and/or disclosing their HIV status to others References WHO. Gender inequalities in HIV. Available at: http://www.who.int/gender/hiv_aids/en/. Accessed January 2008 Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008. Available at: http://www.paho.org/English/AD/GE/HIV.htm. Accessed January 2008

7. Response to therapy: differences between men and women

8. 8 Gender differences to therapeutic interventions Gender differences are found throughout medicine, due to a number of factors

9. 9 Pharmacokinetic factors in women There have been variable data reporting gender differences in disease outcome in women versus men with HIV Due to weight and fat distribution differences, standard doses for men may not be equivalent in women Administration of concomitant medications can affect the pharmacokinetic profile – the extent of the differences and the type of concomitant medication may differ between men and women. For example, hormonal contraceptives or hormone replacement therapies may alter the metabolic action of some drugs A 20% increase in the AUC has been reported for women taking nevirapine (an NNRTI) vs men, although the clinical significance of this finding is not clear. Body size and metabolic differences are possible determining factors of differences in pharmacokinetics between men and women. However, psychosocial, behavioural and attitudinal differences such as accessing treatment or delays in initiating therapy until pregnant explain most differences between men and women with HIV References Bacon MC et al. The Women’s Interagency HIV Study: an Observational Cohort Brings Clinical Studies to the Bench. Clinical and Diagnostic Laboratory Immunology 2005;12:1013-1019. UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study. HIV Medicine 2004;5:115-124 Rezza G et al. Plasma Viral Load Concentrations in Women and Men From Different Exposure Categories and With Known Duration of HIV Infection. JAIDS 2000;25:56-62. Moore AI et al. Gender differences in response to HAART. JAIDS 2003;1(3):188 Fletcher CV et al. Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in AIDS Clinical Trials Group Study. Journal of Infectious Diseases 2004;189:1176-1184 Patterson K et al. Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. HIV Medicine 2007;8:406-410There have been variable data reporting gender differences in disease outcome in women versus men with HIV Due to weight and fat distribution differences, standard doses for men may not be equivalent in women Administration of concomitant medications can affect the pharmacokinetic profile – the extent of the differences and the type of concomitant medication may differ between men and women. For example, hormonal contraceptives or hormone replacement therapies may alter the metabolic action of some drugs A 20% increase in the AUC has been reported for women taking nevirapine (an NNRTI) vs men, although the clinical significance of this finding is not clear. Body size and metabolic differences are possible determining factors of differences in pharmacokinetics between men and women. However, psychosocial, behavioural and attitudinal differences such as accessing treatment or delays in initiating therapy until pregnant explain most differences between men and women with HIV References Bacon MC et al. The Women’s Interagency HIV Study: an Observational Cohort Brings Clinical Studies to the Bench. Clinical and Diagnostic Laboratory Immunology 2005;12:1013-1019. UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study. HIV Medicine 2004;5:115-124 Rezza G et al. Plasma Viral Load Concentrations in Women and Men From Different Exposure Categories and With Known Duration of HIV Infection. JAIDS 2000;25:56-62. Moore AI et al. Gender differences in response to HAART. JAIDS 2003;1(3):188 Fletcher CV et al. Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in AIDS Clinical Trials Group Study. Journal of Infectious Diseases 2004;189:1176-1184 Patterson K et al. Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. HIV Medicine 2007;8:406-410

10. Women in clinical trials

11. 11 Our knowledge is limited

12. 12 Relatively few studies and few women enrolled in HIV trials This literature study, conducted in 2007, included data which met the following criteria: written in English, involved human subjects, involved adults and reported data on sex differences in the viroimmunological and clinical parameters during HAART. Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732This literature study, conducted in 2007, included data which met the following criteria: written in English, involved human subjects, involved adults and reported data on sex differences in the viroimmunological and clinical parameters during HAART. Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732

13. 13 Relatively few studies with more than 50% women: recent examples Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Reference Nicastri EN et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. Journal of Antimicrobial Chemotherapy 2007;60:724-732

14. 14 Differences between men and women: initiation of HAART The median time to HAART initiation was longer in women than in men; 28 vs 17 weeks (from date of study enrollment)1 Women had twice the odds of having difficulties in openly taking medication at home than homo/bisexual men2 Women having difficulties in taking medication at home had a substantially lower probability of being on HAART2 Female sex is an independent predictor of not receiving HAART3,4 A study investigating ART-naïve patients (2323 men and 1335 women) found that the median time to commencing ART from enrollment to the study was 28 weeks for women and 17 weeks for men (P = 0.0003 by logrank test). However, when adjusted for CD4 count and viral load at the point of enrollment this difference was no longer statistically significant1 A survey of 2864 people receiving treatment for HIV found that women had twice the odds of having difficulties in openly taking medication at home than homo/bisexual men2 women having difficulties taking medication openly at home had a substantially lower probability of being on HAART (0.59 compared to 0.78) even after adjusting for confounding factors2 Female sex is an independent predictor of not receiving HAART3,4 References Murri R et al. Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study. JAIDS 2003;34:184–90 Sayles JN, Wong MD, Cunningham WE. The inability to take medications openly at home: does it help explain gender disparities in HAART use? Journal of Women’s Health 2006;15:173–81 McNaghten AD et al. Adult/Adolescent Spectrum of HIV Disease Group. Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients. JAIDS 2003;32:499–505 Giordano TP, White AC Jr, Sajja P et al. Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. JAIDS 2003;32:399–405A study investigating ART-naïve patients (2323 men and 1335 women) found that the median time to commencing ART from enrollment to the study was 28 weeks for women and 17 weeks for men (P = 0.0003 by logrank test). However, when adjusted for CD4 count and viral load at the point of enrollment this difference was no longer statistically significant1 A survey of 2864 people receiving treatment for HIV found that women had twice the odds of having difficulties in openly taking medication at home than homo/bisexual men2 women having difficulties taking medication openly at home had a substantially lower probability of being on HAART (0.59 compared to 0.78) even after adjusting for confounding factors2 Female sex is an independent predictor of not receiving HAART3,4 References Murri R et al. Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study. JAIDS 2003;34:184–90 Sayles JN, Wong MD, Cunningham WE. The inability to take medications openly at home: does it help explain gender disparities in HAART use? Journal of Women’s Health 2006;15:173–81 McNaghten AD et al. Adult/Adolescent Spectrum of HIV Disease Group. Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients. JAIDS 2003;32:499–505 Giordano TP, White AC Jr, Sajja P et al. Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. JAIDS 2003;32:399–405

15. 15 Differences between men and women: HAART adherence and treatment discontinuation The findings on adherence are unclear and some reviews have found no differences between the sexes1 However, some studies have found that women are less adherent than men (18% vs 25%)2 Women are more likely to be diagnosed with depression than men (34% vs 29%)2 Women are more likely to have an interruption in treatment than men in the same exposure group 35.8% vs 24.4% among drug users 22.1% vs 13.3% among heterosexuals3 A literature review showed no difference in adherence between the sexes1 However, there are individual reports of differences: A retrospective cohort study reported that women are less adherent (18% vs 25%) and more likely to be diagnosed with depression (34% vs 29%)2 Women are more likely to have an interruption than men in the same exposure group (35.8% vs 24.4% among drug users; 22.1% vs 13.3% among heterosexuals)3 Women with HIV are known to be particularly vulnerable to experiencing depressive symptoms, and persistent depression has been associated with reduced adherence to HAART and significantly poorer survival rates. The relationship of gender, depression, medical care, and mental health care with adherence in 1,827 female and 3,246 male drug users on combination antiretroviral therapy was investigated. While women had lower adherence and an increased chance of being diagnosed with depression, there was a slightly stronger association between mental health care and adherence in women than in men. Women with a diagnosis of depression who received psychiatric care in combination with antidepressant therapy had nearly 2-fold greater adjusted odds of adherence than depressed women without either care However, it was also thought that men were more likely to take advantage of mental health services available through drug-treatment programs than women were. This correlates to other evidence which indicates that women are less likely to receive care from an HIV specialty provider, or receive antiretroviral therapy4 References Ammassari A et al. Relationship between HAART adherence and adipose tissue alterations. JAIDS 2002;31:S140–4 Turner BJ et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV –infected drug users. Journal of General Internal Medicine 2003;18:248-257 Touloumi et al. CASCADE Collaboration. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Shapiro MF et al. Variations in the care of HIV infected adults in the United States: results from the HIV Cost and Services Utilisation Study. Journal of the American Medical Association 1999;281:2305-15 A literature review showed no difference in adherence between the sexes1 However, there are individual reports of differences: A retrospective cohort study reported that women are less adherent (18% vs 25%) and more likely to be diagnosed with depression (34% vs 29%)2 Women are more likely to have an interruption than men in the same exposure group (35.8% vs 24.4% among drug users; 22.1% vs 13.3% among heterosexuals)3 Women with HIV are known to be particularly vulnerable to experiencing depressive symptoms, and persistent depression has been associated with reduced adherence to HAART and significantly poorer survival rates. The relationship of gender, depression, medical care, and mental health care with adherence in 1,827 female and 3,246 male drug users on combination antiretroviral therapy was investigated. While women had lower adherence and an increased chance of being diagnosed with depression, there was a slightly stronger association between mental health care and adherence in women than in men. Women with a diagnosis of depression who received psychiatric care in combination with antidepressant therapy had nearly 2-fold greater adjusted odds of adherence than depressed women without either care However, it was also thought that men were more likely to take advantage of mental health services available through drug-treatment programs than women were. This correlates to other evidence which indicates that women are less likely to receive care from an HIV specialty provider, or receive antiretroviral therapy4 References Ammassari A et al. Relationship between HAART adherence and adipose tissue alterations. JAIDS 2002;31:S140–4 Turner BJ et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV –infected drug users. Journal of General Internal Medicine 2003;18:248-257 Touloumi et al. CASCADE Collaboration. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. Journal of Antimicrobial Chemotherapy 2007;60:724-732 Shapiro MF et al. Variations in the care of HIV infected adults in the United States: results from the HIV Cost and Services Utilisation Study. Journal of the American Medical Association 1999;281:2305-15

16. 16 Differences between men and women: adverse events during HAART In an observational study in HIV patients receiving stavudine (d4t) treatment in South Africa, all 14 cases of lactic acidosis were in females, with a mortality rate of 29%1 In Canada, a large population-based study confirmed the significantly greater risk of developing lactic acidosis in women compared with men2 There is conflicting data over whether Nevirapine poses a greater risk for liver toxicity in women3 The nucleoside drug classes (still widely used in the developing world) are associated with a number of adverse events that are greater in women vs men: AZT-associated anaemia and d4T-associated hyperlactataemia and lipodystrophy References Geddes R et al. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. South African Medical Journal 2006;96:722–4. Boulassel MR et al. Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons. Journals of Medical Virology 2006;78:1158–63. De Lazzari E at al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. 46th ICAAC, San Francisco 2006;Abstract H-1064 In an observational study in HIV patients receiving stavudine (d4t) treatment in South Africa, all 14 cases of lactic acidosis were in females, with a mortality rate of 29%1 In Canada, a large population-based study confirmed the significantly greater risk of developing lactic acidosis in women compared with men2 There is conflicting data over whether Nevirapine poses a greater risk for liver toxicity in women3 The nucleoside drug classes (still widely used in the developing world) are associated with a number of adverse events that are greater in women vs men: AZT-associated anaemia and d4T-associated hyperlactataemia and lipodystrophy References Geddes R et al. A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. South African Medical Journal 2006;96:722–4. Boulassel MR et al. Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons. Journals of Medical Virology 2006;78:1158–63. De Lazzari E at al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. 46th ICAAC, San Francisco 2006;Abstract H-1064

17. The importance of women in clinical trials

18. 18 Women use more pharmaceutical resources, but are under represented in clinical trials

19. 19 Women are under-represented in clinical trials of new ARTs Women are under-represented in the majority of clinical studies, such that effective gender comparisons are not possible References Derived from a slide of John Bartlett, CROI 2006, from Abbott Virology slide deck: “Improving the lives of women with HIV”Women are under-represented in the majority of clinical studies, such that effective gender comparisons are not possible References Derived from a slide of John Bartlett, CROI 2006, from Abbott Virology slide deck: “Improving the lives of women with HIV”

20. 20 Guidelines for the inclusion of women in clinical studies

21. 21 Importance of women in clinical trials

22. 22 Pregnancy is now a fact of life for women with HIV References Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Finer LB et al. Disparities in Rates of Unintended Pregnancy In the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health, 2006,38(2):90–96 Koenig LJ et al. Young, seropositive, and pregnant: epidemiologic and psychosocial perspectives on pregnant adolescents with human immunodeficiency virus infection. American Journal of Obstetrics and Gynecology 2007;S123-S131 References Stratton SE and Watstein SB. The encyclopedia of HIV and AIDS. 2nd ed. New York: Facts on File. 2003 Finer LB et al. Disparities in Rates of Unintended Pregnancy In the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health, 2006,38(2):90–96 Koenig LJ et al. Young, seropositive, and pregnant: epidemiologic and psychosocial perspectives on pregnant adolescents with human immunodeficiency virus infection. American Journal of Obstetrics and Gynecology 2007;S123-S131

23. 23 Significant proportion of pregnancies among women with HIV are not planned Among 334 women receiving ART, less than half reported their current pregnancy as planned The ART regimen at conception is frequently only suitable for non-pregnant woman Many different regimens were prescribed to women of childbearing age, including: ddI+d4T-based regimens (9.6%) EFV-based regimens (13.5%) Once pregnant, patients receiving EFV or ddI often had to change ART (OR 13.2 P<0.001; 1.8 P=0.033, respectively) Physicians should consider the child-bearing potential of this patient group when initiating ART Women with HIV infection, like other women, may wish to plan pregnancy to start a family, control the size of their family, or avoid pregnancy Anticipating for the possibility of pregnancy, whether planned or unplanned, is an important component of care Health professionals should enable women to make reproductive choices by counselling, education and provision of contraception at the time of HIV diagnosis and during follow up With access to optimal management, becoming pregnant and giving birth to a healthy, HIV negative baby is possible for the vast majority of women of childbearing age References Floridia M et al. Short communication: Antiretroviral therapy at conception in pregnant women with HIV in Italy: wide range of variability and frequent exposure to contraindicated drugs. Antiviral Therapy 2006;11:941-946Women with HIV infection, like other women, may wish to plan pregnancy to start a family, control the size of their family, or avoid pregnancy Anticipating for the possibility of pregnancy, whether planned or unplanned, is an important component of care Health professionals should enable women to make reproductive choices by counselling, education and provision of contraception at the time of HIV diagnosis and during follow up With access to optimal management, becoming pregnant and giving birth to a healthy, HIV negative baby is possible for the vast majority of women of childbearing age References Floridia M et al. Short communication: Antiretroviral therapy at conception in pregnant women with HIV in Italy: wide range of variability and frequent exposure to contraindicated drugs. Antiviral Therapy 2006;11:941-946

24. Enrolling and retaining women in clinical trials

25. 25 Social, logistic and scientific factors affect women’s participation in trials The barriers are not well understood or defined Thalidomide and diethylstilbestrol (DES) were used in the 1950s and 60s Since then, all women between the time of first menstruation until menopause were defined as “potentially pregnant” A policy of exclusion prohibited all such women from pharmaceutical research for fear of causing foetal harm Thalidomide and diethylstilbestrol (DES) were used in the 1950s and 60s Since then, all women between the time of first menstruation until menopause were defined as “potentially pregnant” A policy of exclusion prohibited all such women from pharmaceutical research for fear of causing foetal harm

26. 26 Balancing ethical implications Exposure in the first trimester of pregnancy raises a number of ethical considerations

27. 27 Understanding drivers and barriers to trial participation

28. 28 Informing women and anticipating barriers and drivers to trial participation Any attempt to put pressure on an individual to take part in research is unethical Patients must make their own fully-informed decisions, knowing all the potential risks and benefits of enrolling in the study Information and support should anticipate issues that are likely to impact women e.g. additional clinic visits and impact on work and family life Treatment advocacy groups may play a key role in: promoting trials, supporting women in trials to make informed choices Providing more support for women while they are in the trials (emotional/peer support) : this could reduce drop out. Disseminating findings to PLHIV Any attempt to put pressure on an individual to take part in research is unethical Patients must make their own fully-informed decisions, knowing all the potential risks and benefits of enrolling in the study Information and support should anticipate issues that are likely to impact women e.g. additional clinic visits and impact on work and family life Treatment advocacy groups may play a key role in: promoting trials, supporting women in trials to make informed choices Providing more support for women while they are in the trials (emotional/peer support) : this could reduce drop out. Disseminating findings to PLHIV

29. 29 Can study protocols be made more woman-friendly? Modify requirements for contraception Include an open phase / follow-up for women who become pregnant Avoid ‘judgmental’ language e.g. woman don’t ‘drop out’ due to pregnancy, they convert to another phase of the protocol Develop networks of centres that care for large numbers of women

30. 30 Can study protocols be made more woman-friendly? Provide referrers, centres and investigators with guidance on how to make visits and studies more accessible and woman-friendly Childcare Transport costs Confidentiality Compensation for loss of earnings Communicate findings to participants in an appropriate way to promote further engagement in clinical trials

31. 31 What happens if a woman becomes pregnant while part of a clinical trial?

32. Alternatives to clinical trials

33. 33 Randomized controlled trials RCTs give the highest level of evidence when seeking to answer a specific clinical questions with statistical significance They have their limitations: usually enrol a less diverse population of subjects than is commonly seen in everyday clinical practice (e.g. fewer women, less complicated patients) do not always reflect the common clinical settings in which many people receive treatment often expensive and time-consuming good for answering specific questions, but not for generating new hypotheses or exploring broad questions

34. 34 Alternatives to randomized controlled trials Post-hoc analyses, retrospective studies and chart reviews are ways to study data that has already been collected or looking at completed studies in a new way. Case-control studies look at patients who already have HIV or their condition and look back to see if there are characteristics of these patients that differ from a control group. If the evidence found from these alternatives to randomized controlled trials is convincing enough, then resources can be allocated to more comprehensive studies. Regulatory authorities, drug manufacturers and clinicians are increasingly recognising the benefits of data from registries and observational studies, while still accepting their limitations.Post-hoc analyses, retrospective studies and chart reviews are ways to study data that has already been collected or looking at completed studies in a new way. Case-control studies look at patients who already have HIV or their condition and look back to see if there are characteristics of these patients that differ from a control group. If the evidence found from these alternatives to randomized controlled trials is convincing enough, then resources can be allocated to more comprehensive studies. Regulatory authorities, drug manufacturers and clinicians are increasingly recognising the benefits of data from registries and observational studies, while still accepting their limitations.

35. 35 Patient registries Randomized Controlled Trials (RCTs) are considered the ‘gold standard’ when testing the efficacy and effectiveness of healthcare interventions. They involve splitting the trial participants into a randomly allocated intervention group and a control group. The outcomes of these two groups are then compared to measure the effectiveness of the intervention. If done correctly this form of clinical trial compares like for like and therefore eliminates the effects of confounding factors on the data. Randomized Controlled Trials (RCTs) are considered the ‘gold standard’ when testing the efficacy and effectiveness of healthcare interventions. They involve splitting the trial participants into a randomly allocated intervention group and a control group. The outcomes of these two groups are then compared to measure the effectiveness of the intervention. If done correctly this form of clinical trial compares like for like and therefore eliminates the effects of confounding factors on the data.

36. 36 Women’s HIV registries Example: Antiretroviral Pregnancy Registry (APR) www.apregistry.com International, prospective, exposure-registration study established in 1989 Collects data on birth outcomes, primarily birth defects, following pregnancy exposures to antiretroviral therapy Registries are beneficial especially when patient numbers are large Several limitations to registries e.g.: Passive reporting may over-represent abnormalities It may be difficult to determine which drug is the root of the problem when a combination is prescribed

37. Case studies

38. 38 Case study 1: a potential candidate for enrolment in a clinical trial Standard information about what a clinical trial involves in order for the woman to make a fully informed choice Information about childcare, what to do if she can’t make a clinic visit, etc Contraception inclusion criteria, what this means and what she should do if she becomes pregnant Implications for the unborn child Implications for her Implications for the clinical trial Details where she can get more information and advice as required

39. 39 Case study 2: potential drop-out from a clinical trial Her specific problems and needs avoiding any impression of blame or disappointment for dropping out Explore whether the centre or sponsor can provide support to help her make the clinic visits Provide information and support using language that is relevant to her and her needs Discuss her continuing treatment options should she leave the study Reassurance that many patients do not complete a whole study but that their participation is still valuable

40. 40 Case study 3: pregnancy during a clinical trial Answer questions about any effects that the trial drug might have on her pregnancy Discuss the options of continuing with the trial, e.g. converting to an open phase of the protocol if allowed Follow up during and after the pregnancy Continuing treatment options Avoid any impression of blame or disappointment for dropping out Reassurance that patients often do not complete a whole study but that their participation is still valuable

41. Thank you for your attention Any questions?

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