Women and clinical trials in HIV

1. Women and clinical trials in HIV Women for Positive Action is an educational program funded and initiated by AbbVie

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

3. Introduction In 2010 an estimated 34 million people were living with HIV globally, over half of whom were women1 The epidemiology and pattern of HIV spread in women differs from men1 Women aged 15–24 years are as much as eight times more likely than men to be HIV positive2 Clinical trials in HIV have tended to extrapolate findings from male subjects to women3 Women have different biological, social and behavioural factors that may impact on their HIV3 Many clinical trials pose significant barriers to the participation of women3 • 1. UNAIDS Report. Global HIV/AIDS Response 2011;2. Public Health Agency of Canada, 2010; 3. d’Arminio Monforte et al. AIDS 2010;

4. Overview of women and HIV Women for Positive Action is an educational program funded and initiated by AbbVie

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 men1-3 • 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 • Women experience more HIV-related and AIDS-defining events than men7 • 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 • In a recent Danish nationwide cohort study of people living with HIV gender had no major impact on progression to AIDS or mortality8 • WHO. www.who.int/gender/hiv_aids/en/; 2. Stratton & Watstein SB, Encyclopedia of HIV and AIDS, 2003; 3. Pan American Health Organization: www.paho.org/English/AD/GE/HIV.htm; 4. Ghandi M et al. Clinical Infectious Diseases, 2002; 5. Hubert JB et al. XIV Int AIDS Conf Abstract, 2002; 6. Patterson K et al. HIV Med, 2007; 7. Meditz AL et al. J Infect Dis, 2011; 8. Thorsteinsson K et al. Scand J Infect Dis, 2012

6. Social and cultural differences affect how women manage HIV More limited power/control to practice low-risk sexual behavior More limited scope to negotiate frequency of and nature of sexual interactions Violence may increase a woman’s vulnerability to HIV Simultaneous management of medications, jobs, families and other medical and gynecologic problems is challenging Migrant women, in particular, are often isolated and lack social support Language or cultural barriers may add to lack of support May come from ‘hard to reach’ communities Impact of religious and cultural beliefs on women Reduced access to healthcare, education and economic resources • WHO. Gender inequalities in HIV, 2008; 2. Stratton SE & Watstein SB. The encyclopedia of HIV and AIDS, 2003;3. Pan American Health Organization. Gender and HIV. Women, Health and Development Program Fact Sheets 2008, 2008

7. Response to therapy: differences between men and women Women for Positive Action is an educational program funded and initiated by AbbVie

8. Gender differences are found throughout medicine, due to a number of factors Gender differences to therapeutic interventions Pharmacodynamics and pharmacokinetics Biological differences in how medicines affect the body and the way in which it processes medicines Adverse events & toxicities Attitudes and behaviour Social reasons for delay in treatment initiation Adherence Floridia M et al. Pharm Res, 2008

9. Differences between men and women: initiation of HAART • Failure to establish outpatient treatment of HIV is more likely to occur among female patients1 • Potential barriers include distrust and stigma, lack of transportation, substance abuse, mental health and housing needs • Female sex workers often begin treatment late2 • Vancouver-based study found 49.6% of respondents reported barriers to accessing health services in the previous six months • In a US-based study of women living with HIV3 • Substance abuse decreased the likelihood of using HAART • Being Caucasian increased the likelihood of using HAART 1. Mugavero MJ. Clin Infect Dis 2007; 2. Lazarus L et al. Cult Health Sex. 2012; 3. Cohen MH et al. Am J Public Health, 2004

10. Differences between men and women: adherence to HAART • Most studies report a lower adherence rate in women1,2,3 • Occurs independently of both virological response and rate of adverse reactions Male Female 0.1 0.2 0.5 1 2 5 10 Male/female gender ratio according to discontinuation or interruption of HAART 1. Currier et al. Ann Intern Med, 2010 2. Squires, et al. CROI, 2011; 3. Nicastri, et al. J. Antimicrob. Chem, 2007

11. Differences between men and women: adherence to HAART • Women are less likely to adhere to HAART regimens if there are difficulties in taking medication openly at home1 • Lipodystrophy and poor body image can have negative effects on adherence2-3 • Medication effects on the body and body image are commonly listed reasons for non-adherence among women with HIV4 • Depression tends to be more common in women and this is also linked to poor adherence5 • In a multicentre, observational study of 135 patients with HIV, non-adherence was associated with worse depression rating scale scores6 1. Sayles JN et al. J Womens Health, 2006; 2. Ammassari A et al. JAIDS, 2002; 3. Huang JS et al. AIDS Res Ther, 2006; 4. Sansone RA et al. Gen Hosp Psychiatry, 2004; 5. Turner BJ et al. J Gen Intern Med, 2003; 6. Ammassari A et al. Psychosomatics, 2004

12. Differences between men and women: trial discontinuations and adverse events • Increased numbers of discontinuations and adverse effects in women Floridia et al. Pharm Res, 2008; Nicastri et al. J Antimicrob Chemother. 2007

13. Differences between men and women: discontinuation of HAART • Women are more likely to have an interruption in treatment than men1 • A US based retrospective cohort study reported that2 • Due to discontinuation, female sex was associated with lower rates of treatment, increased disease progression, and decreased survival • After adjustment for HAART, and for achieving an undetectable HIV-1 RNA level, the gender differences were no longer as significant • In order to overcome issues of adherence, the GRACE study utilised a flexible, female-friendly design to target recruitment of women and prevent discontinuation • Despite this, the discontinuation rate was still higher in women (32.8%) than men (23.2%) • Touloumi et al. J Antimicrob Chem, 2007; 2. Lemly DC et al. J Infect Dis, 2009; 3. Falcon R et al. J Women’s Health, 2011

14. Pharmacokinetic factors in women • Decreased acid secretion and slower gastric emptying time with oral contraceptives and pregnancy • Diet differences • No consistent differences in gut CYP or p-gp Bioavailability • Lower bodyweight • Fat distribution • Varying plasma volumes • Less organ flow • Oestrogen has effects on plasma binding proteins • AUC differences shown in some ARTs Distribution • In vitro: F>M trend • Progesterone increases CYP2A4 activity • Hepatic g-gp M>F Metabolism • Smaller organs • Hep C and liver status Elimination • Gender differences are found throughout medicine, based on a number of factors, including differences in drug metabolism and adverse events • However, there are no clear differences between the sexes regarding the clinical progression of HIV • Psychosocial, behavioural and attitudinal differences such as accessing treatment or delays in initiating therapy seem to account for most differences between men and women with HIV Floridia M et al. Pharm Res, 2008

15. Differences between men and women: efficacy of HAART • FDA review of registered trials from 2000–2008 • Results • 22,411 HIV+ subjects in 43 RCTs for 16 ARVs; 20% women • No significant gender differences in treatment response at week 48, discontinuations for AEs, lost to follow-up, or death • Higher rate of discontinuation for virologic failure in males (8.15%) than females (4.25%) • Found no statistically or clinically significant differences in outcomes by gender Favors Male (n=6) Total -100% -50% 0% 50% 100% Female and Male Response Rate Difference by Arm Soon G et al. AIDS Patient Care STDS, 2012

16. Recent studies comparing efficacy of HAART in men and women 1. Squires K et al. ICAAC, 2012; 2. Trinh R et al. BHIVA, 2012; 3. Squires K et al. J Antimicrob Chemother, 2011; 4. Currier J et al, Ann Intern Med. 2010; 5. Hermes A et al. IWHW, 2012

17. Women in clinical trials Women for Positive Action is an educational program funded and initiated by AbbVie

18. Our knowledge is limited Sex/gender-based differences in pharmacological characteristics of ARV agents have received little rigorous study1 Many clinical trials have not been powered to detect gender differences1 Women are usually under-represented in clinical trials, however this has improved in recent years2 There are conflicting results comparing virologic, immunological and clinical responses to HAART in men and women YET guidelines for initiating and changing ART are applied uniformly to women and men1 Little is known about how gender affects complications such as lipoatrophy and bone density and whether these changes are due to the treatments or the disease1 1. Meditz et al. J Infect Dis, 2011; 2. d’Arminio Monforte et al. AIDS, 2010

19. Relatively few studies and few women enrolled in HIV trials 16 14 12 10 8 6 4 2 0 <10% 10-19% 20-29% 30-39% 40-49% 50%+ % of women in trial Number of articles that assess the impact of specific sex differences of HAART on viro-immunological and clinical parameters during HAART (Mar 02-Feb 07) Nicastri et al. J Antimicrob Chem, 2007

20. Number of women participating in HIV clinical trials fell from 2000–2008 Struble et al, CROI, 2009; Soon et al. AIDS Patient Care and STDs, 2012

21. Some clinical studies include well below 50% women 1. Eron J, et al Lancet 2006; 2. Walmsley et al J Acquir Immune Defic Syndr, 2009 ; 3. Flexner et al. Clin Infect Dis. 2010 ; 4. Lathouwers et al. Antivir Ther. 2011; 5. Gathe et al. AIDS Res Hum Retroviruses. 2012; 6. Molina et al. Lancet, 2008

22. Relatively few studies with more than 50% women: recent examples 1. Nicastri et al. J Antimicrobl Chem, 2007; 2. Maman D et al. PLoS ONE, 2012; 3. Wester et al. CROI, 2012; 4. Clumeck et al. CROI, 2012

23. GRACE: The Gender, Race And Clinical Experience Study • Aim: To enrol a high proportion of women in order to investigate sex-based differences in HAART • Recruitment strategy included: Selecting study sites that focused on women Involving community consultants Subsidised child care and transportation Site grants for patient support Site-specific enrollment plans Access to other ARV drugs Site and patient toolkits Targeted public relations Study branding Falcon R et al. J Women’s Health, 2011

24. Differences between men and women: adverse events during HAART There is conflicting evidence in the literature on the difference in the incidence of adverse events between men and women during HAART Women have a significantly greater risk of developing lactic acidosis compared with men1,2 The nucleoside drug classes are associated with a number of adverse events that are greater in women vs men 1. Geddes R et al., SAMJ, 2006; 2. Boulassel MR et al., J Med Viro, 2006

25. Increasing the number of women in clinical trials d’Arminio Monforte et al. AIDS, 2010

26. Journal editorial policy on reporting gender differences in clinical trials • Journal editors, as promoters of ethical research and adequate standards of scientific reporting, should encourage inclusion of gender analyses:1 “Submitting authors are strongly encouraged to include data disaggregated by sex... If the research study was specific to one sex/gender, the reasons for this should be clearly stated.” Journal of the International AIDS Society2 "The Lancet encourages researchers to enroll more women into clinical trials of all phases, and to plan to analyse data by sex, not only when known to be scientifically appropriate, but also as a matter of routine” The Lancet3 1. Heidari et al. J Int AIDS Soc, 2012; 2. Author Guidelines, JIAS, 2012; 3. Editorial, Lancet, 2011

27. The importance of women in clinical trials Women for Positive Action is an educational program funded and initiated by AbbVie

28. Women use more pharmaceutical resources, but are under represented in clinical trials 0 0 Gender balance in terms of use of pharmaceuticals Gender balance in terms of inclusion in clinical trials of pharmaceuticals

29. Women are continually underrepresented in clinical trials • Proportion of women enrolled in 21 treatment-naïve HIV clinical trails (2001–2011) ranged from 8.8–35% Kwakwa et al, XIX International AIDS Conference, 2012

30. Women are under-represented in clinical trials of new ARTs • Women are under-represented • Studies are under-powered for gender comparison • Pregnancy is either an exclusion criterion or reason for withdrawal % Women Men Women 14% 11% 10% 3% 37% 26% 20% 19% 18% 14% 14% 100% 80% 60% 40% 20% 0% 2NN QUAD2 GS-7340 GS-903 GS-934 QUAD1 DMP-006 ACTG384 Dolutegravir ACTG5095 Abbott M98-863 1. Adapted from Bartlett J. CROI, 2006; 2. Stellbrink et al. CROI, 2012; 3. Sax et al. CROI, 2012; 4. DeJesus et al. CROI, 2012

31. Guidelines for the inclusion of women in clinical studies Regulatory authorities in Europe1 and North America2,3are seeking to involve more women and ethnic groups in clinical trials 1 • A representative number of women be included into clinical trials for therapeutic products that are intended to be used specifically by women or in heterogeneous populations that include women • Women should be included at the earliest stages of clinical trial research so that potential sex-related differences are identified and taken into consideration when planning Phase III pivotal trials Health Canada4 (1997): guidelines about the inclusion of women in clinical trials (specifically of medications) recommends: 2 The International Conference on Harmonization (ICH)5 recommends that a clinical study population should represent the target patient population 3 1. EMA 2005; 2. USFDA, 2012; 3. Pinnow E et al. Womens Health Issues, 2009; 4. Health Canada, 2012; 5. EMA/ICH, 1998

32. Importance of women in clinical trials Strong scientific rationale Strong social rationale • 50% of the HIV population are women • Biological and hormonal gender differences • Bodyweight and 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, sex, ethnicity) • Women may be more biologically susceptible to HIV transmission • Different ARV toxicity profiles have been reported • 50% of the HIV population are women • Understanding and addressing the barriers to inclusion • Ensuring that women have equal access to successful treatment • Women may be more vulnerable due to gender-based power relationships and addressing this may help improve women’s access to testing, counselling, prevention and treatment programmes Heidari et al. JIAS 2011

33. Pregnancy is now a fact of life for women with HIV • In the absence of any interventions mother-to-child transmission rates range from 15-45%1 • This rate can be reduced to levels below 5% with effective interventions • Many women – with or without HIV – do not plan their pregnancies • In 2006, 49% of pregnancies were unplanned in US2 • A Canadian study found that 56% of women with HIV who were previously pregnant, identified their last pregnancy as being unintended3 • A study of pregnant teenagers with HIV aged 13–19 years from 12 London hospitals found 82% of pregnancies were unplanned4 Concerns about harming a foetus need to be minimised and balanced with the needs to include women in clinical trials Clinical trials need to adapt 1. Mother-to-child transmission of HIV. http://www.who.int/hiv/topics/mtct/en/;2. Finer LB et al. Contraception.,2006; 3. Loufty et al. HIV Med, 2012; 4.Elgalib A et al. HIV Med, 2011

34. The incidence of pregnancy in women living with HIV is increasing • In a UK study of 7853 women who accessed HIV care from 2000–2009, there were a total of 1637 pregnancies among 1291 women • The number of pregnancies increased from 156 in 2000/01 to 450 in 2008/09 • A number of factors were associated with an increased likelihood of pregnancy: • Younger age • A CD4 count of 200–350 cells/mm3 • Black ethnicity • Women who contracted HIV via heterosexual sex • The findings reflect not only an increase in the pregnancy rate, but also an increase in the number of women accessing and remaining in care Huntington et al. AIDS, 2012

35. Significant proportion of pregnancies among women with HIV are not planned 100% 80% 58% 60% 42% 40% 20% 0% Planned Unplanned • 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 Floridia M et al. Antiviral Therapy, 2006

36. Enrolling and retaining women in clinical trials Women for Positive Action is an educational program funded and initiated by AbbVie

37. Social, logistic and scientific factors affect women’s participation in trials The barriers are not well understood or defined Contraception and conception barriers Other barriers • Study protocol criteria e.g. insisting on two forms of barrier contraception yet not providing them, thus placing additional burden on the patient • Fear of causing harm to a developing foetus • Exclusion criteria for pregnancy and lactation in the face of social pressure to bear children • Use of contraception may conflict with beliefs • Concern about drug-drug interactions with oral contraceptives • Policy of exclusion prohibiting participation of potentially pregnant women for fear of foetal harm • Blood drawing, particularly for women who already lose blood through menstruation • Competing role as primary family care giver – women may not put themselves ‘first’ • Relative lack of autonomy in decision-making • Stigma regarding disclosing status • Level of literacy required for consent forms and patient materials • Time commitment for clinic visits and the length of trial Floridia M et al. Antiviral Therapy 2006; d’Arminio Monforte et al. AIDS, 2010

38. Balancing ethical implications Exposure in the first trimester of pregnancy raises a number of ethical considerations Risk to future generations of women who will not be adequately treated Risk to the unborn child Studies may be investigating drugs which could be prescribed in practice during pregnancy, but still require the woman to withdraw from the trial if she becomes pregnant Women need to be empowered to make informed choices as to whether to stay in a trial

39. Understanding drivers and barriers to trial participation Benefits to their daily lives Wider social gain Personal benefit/gain An opportunity to discuss their condition Compensation Some of the most influential factors may be Patients are motivated by many factors Ease in participation/safety Call to action Helping to accumulate data about a treatment that could help others in their condition Site-specific benefits such as provision of childcare facilities or transport costs To fully inform women about the study, communication should be adapted to reflect the specifics of a trial and the unique drivers and challengesthat women face Individuals who make fully informed decisions about study participation are more likely to show commitment and compliance to a trial

40. Informing women and anticipating barriers and drivers to trial participation Think from a woman’s perspective Know the challenges and barriers women face Act in the interests of all patients at all times What are thepersonal driverspatients may have for involvement in a study? e.g. chance to access investigational medication What are thewider social benefitsof patient involvement in a clinical trial? e.g. helping advance treatment for others Is there a clearcall to action? e.g. why should women get involved and how can they make a difference How easy is it for women to participate? e.g. inclusion and exclusion criteria, child care, conception restrictions

41. 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 d’Arminio Monforte et al. AIDS, 2010

42. 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-friendly1 • Childcare • Transport costs • Confidentiality • Compensation for loss of earnings • Communicate findings to participants in an appropriate way to promote further engagement in clinical trials • i-Base and the Terrence Higgins Trust produce information booklets which explain to patients how clinical trials work and what issues to consider before enrolling in one2,3 1. d’Arminio Monforte et al. AIDS, 2010; 2. THT, 2012; 3. i-Base, 2009

43. What happens if a woman becomes pregnant while part of a clinical trial? Drop-out? • Empower women to make informed decisions • Stay on trial if protocol allows • Convert to open-label treatment • Treatment options if they leave the study • Keeping in touch – follow-up visits

44. Alternatives to clinical trials Women for Positive Action is an educational program funded and initiated by AbbVie

45. Randomised 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

46. Alternatives to randomised controlled trials Post-hoc analyses Retrospective studies Chart reviews Case control studies Registries Observational studies

47. Patient registries Registries allow large-scale, long-term data collection generally at a lower cost than traditional studies Registries play an increasing role in providing payers and decision-makers with information to validate the safety and efficacy of interventions reported in phase III clinical trials • There are different types of registry e.g. • Prospective • Retrospective • Observational prospective Registries Registries typically include a larger and more diverse group of patients than those studied in randomised controlled trials • Registries can be used for measuring a variety of outcomes: • Pooling data • Understanding natural history • Assessing day-to-day safety and effectiveness • Physician experience • Patient-reported outcomes: satisfaction, compliance and burden of illness • Quality of care and cost-effectiveness

48. 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 The Antiretroviral Pegnancy Registry. Available at: http://www.apregistry.com

49. Case studies Women for Positive Action is an educational program funded and initiated by AbbVie

50. 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 What issues and information might an investigator discuss with a woman potentially eligible for involvement in a study?