1. IPEC - Fundação Oswaldo Cruz Rio de Janeiro -Brazil Women and Trials in Low and Middle-income settings: the clinical investigators Perspective August 6, 2008 Beatriz Grinsztejn, MD,Ph.D

2. Background HIV disproportionately affects women in developing countries Underrepresented in poor-resource regions (McGovern et al, 1994; Allen 1994; Mills et al, 2006; Kapoor 2004; Zuniga et al, 2007; Wassenaar et al, 2007)

3. Background If women are to benefit from prevention and therapeutics interventions, they must participate in the trials in a sufficient number to allow appropriate gender-specific evaluation of efficacy and safety.

4. Background In general, there is a paucity of clinical trials going on in the RLS, where the greatest burden of the epidemic exists The majority of products in the market were developed without adequate representation of RLS population in the trials. The generalisability of trials results to these populations may be compromised This affects both men and women. Womens social inequality in these societies makes it even worse for them

5. Women in HIV Clinical Trials Willingness to participate, perceptions and concerns about clinical trials in poor-resource settings : –Studies show that women want to participate in clinical trials (qualitative analysis, interviews with women participating in prevention studies) –The two most common motivations for participating in a trial were "getting tested for HIV" and "doing something good for women's health. –Repeated, voluntary counseling and testing, knowledge of HIV status, and heightened awareness of sexual and reproductive health reshaped study participants' approaches to sexual relationships and AIDS Tharawan et al, 2001; Coulibaly-Traoré et al, 2003; Stadler et al, 2008

6. Recruitment HIV-related stigma –Studies have shown that stigma is a measurable barrier to accessing general HIV care; thus, it would be expected that it may also serve as a barrier to participating in a clinical trial. Confidentiality issues –Employment opportunities –Family relationships –Social acceptance

7. Recruitment-II Ability of women to meet the ongoing and multiple requirements of trial participation –Employment issues –Childcare –Partner health status –Disclosure –Financial resources Fertility desires Social representation of motherhood

8. Recruitment-III Investigators fear of occurrency of pregnancy during the trial Easier to end up enrolling men

9. Women enrolled in HPTN & ACTG clinical trials – international studies

10. IPEC - FIOCRUZ 1986: HIV Care service outpatient/inpatient 1996: HIV-infected women cohort –790 women enrolled –25% (197) also participate in clinical trials

17. IPEC - FIOCRUZ 1999: 34 Clinical trials –Sponsered by: Pharmaceutical industry = 27 HPTN and ACTG = 7 Patients enrolled –678 (total) –29% (197) women

18. Total of women who participated in clinical trials - IPEC Participated in clinical trials N(%) No593 (75%) Yes197 (25%) Total790 (100%)

19. Characteristics of women who participated in clinical trials – IPEC (N=197) CharacteristicsResults Type of study – n(%) ARV – naïve ARV – experienced 64 (33.2%) 129 (66.8%) Age Mean (SD) Median 38.8 (9.8) 38.0 Race White Others 95 (48.2%) 102(51.8%) Formal education >8 years <= 8 years 125(63.8%) 71(36.2%)

20. Characteristics of women who participated in clinical trials – IPEC (N=197) Characteristics Type of study ARV – naïve ARV – experienced T CD4+ count Mean (SEM) Median 242.7 (20.7) 238.0 294.9 (18.7) 254.0 Viral Load Mean (SEM) Median 423642.0 (143280.7) 110855.0 224983.2 (83767.5) 16709.0 *SEM = Standart error mean

21. Period of time Total Number of pregnancies Pregnant women n% 1996-20087641018611,3 (86/764) 1999-2008*6678477 11,5 (77/667) 1999-2008*197**44 2,0 (4/197) Pregnancy rates *Time period in which HIV clinical trials have been conducted in IPEC/FIOCRUZ. **Total of women who participated in HIV clinical trials.

22. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Objective: To evaluate the potential factors associated with womens participation in clinical trials. Outcome variable: Did the woman participate in clinical trials? Yes or No. Covariates: age, ethnicity, years of formal education, occupation, monthly familiar income, lives in her own house, lives as married//married, partner drugs abuse, partner HIV serology, receive any support, number of alive children, children with HIV/AIDS, tobacco use, alcohol use, drug abuse, sexual abuse history, domestic violence history, reason to be HIV tested (sick/HIV+ family).

23. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Statistical analysis: Univariate analysis: The χ 2 test Variables for which the significance level was 0.25 and variables of known biologic importance were considered in the initial Logistic regression model. Multivariate analysis: Logistic regression We begin with a full model containing all of the selected variables. The Wald statistic and Likelihood ratio test were used to check the importance of each variable included in the model. The following rules were used in evaluating if a variable was retained in the final model: 0.7 < Odds Ratio < 1.3 : p-value 0.1 Odds Ratio 0.7 or Odds Ratio 1.3 : p-value 0.2

24. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Univariate analysis Variables Participated in Clinical Trials No (N=565)Yes (N=102)p Age <35 36-45 >=46 55,1% 30,1% 14,8% 33,0% 50,0% 17,0% <0.05 Formal education (>8 years) 40.6%53.1%<0.05 Occupation (employed)47.9%34.3%<0.05 Lives in her own house65.4%78.0%<0.05 Living as married/married38.6%49.0%<0.10 Partner drug use No Yes Unknown 14.4% 6.4% 12.4% 6.0% 2.0% 12.0% <0.05 Partner serology Negative Positive Unknown / not tested 23.1% 40.5% 12.9% 23.2% 25.3% 18.2% <0.05

25. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Univariate analysis Variables Participated in Clinical Trials No (N=565)Yes (N=102)p Smoking No not anymore 53.9% 23.8% 22.0% 16.0% <0.25 Alcohol use59.9%67.0%<0.25 Drug use28.5%18.0%<0.05 History of sexual abuse20.6%12.1%<0.05 The reason to be HIV tested is sick/HIV+ family 39.7%32.3%<0.25

26. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Logistic regression Variables OR- CI(95%)p Age <35 36-45 >=46 0,28(0,16-0,48) 1,00 0,65(0,32-1,27) 0,000 - 0,219 Formal education >8 years <8 years 2,08(1,27-3,43) 1,00 0,004 - Occupation employed unemployed 0,46(0,27-0,76) 1,00 0,003 - Lives in her own house Yes No 1,71(1,00-3,01) 1,00 0,057 - Living as married/married Yes No 1,89(1,11-3,24) 1,00 0,019 -

27. Factors associated with Womens participation in clinical trials IPEC/Fiocruz (1999-2008) Logistic regression Variables OR- CI(95%)p Partner drug use No Yes Unknown Without partner 1,62(0,74-3,84) 0,96(0,28-3,05) 0,27(0,01-1,81) 1,00 0,250 0,944 0,254 - Partner serology* Negative Positive Unknown / not tested Without partner 0,65(0,29-1,46) 0,38(0,18-0,79) 0,95(0,45-2,00) 1,00 0,300 0,011 0,894 - Drug use Yes No 0,64(0,34-1,17) 1,00 0,160 - Sexual abuse history * Yes No 0,64(0,31-1,26) 1,00 0,215 - *Likelihood ratio test for partner serology and sexual abuse history was 0.05 and 0.20, respectively.

28. Conclusion Women with more years of formal education, who live in their own home, in marital relationship and those who have a non drug use partner are more prone to participate in HIV clinical trials. Younger women, those who are employed and who have a HIV positive partner have a lower chance to participate in HIV clinical trials, as well as that women who reported drug use and sexual abuse history.

29. Final Remarks More research is needed in order to improve the understanding of individual and system barriers to clinical trials participation of women in RLS Investigators directly involved on the recruitment must be sensitized about the importance of womens participation in clinical trials and potential strategies to overcome this barriers must be discussed with the team before the start of each study

30. Final Remarks Strategies of recruitment and retention must be individualized considering social and cultural aspects of each context Involvement of the affected communities since the beginning is crucial

32. Thank you.