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Better mind the gap: addressing the shortage of HIV-positive women in clinical trials

2010; Lippincott Williams & Wilkins; Volume: 24; Issue: 8 Linguagem: Inglês

10.1097/qad.0b013e3283390db3

1473-5571

Antonella d’Arminio Monforte, L. Rey González, Annette Haberl, Lorraine Sherr, Winnie Ssanyu-Sseruma, Sharon Walmsley,

Ethics in Clinical Research

Introduction Worldwide, over 50% of the people with HIV are women, and women represent a growing proportion of new diagnoses [1]. Other than for studies to evaluate mother-to-child transmission, women are poorly represented in HIV clinical trials [2]. This opinion piece aims to raise awareness of the need for women to be considered at all stages of the design, conduct, interpretation, reporting, knowledge translation, and application of clinical HIV research. Studies are usually underpowered for sex comparisons due to low rates of enrolment of women [3], and failure to report sex subanalyses has also contributed to a knowledge gap. A recent meta-analysis reported that since 2000, only 20% of participants in clinical trials of antiretroviral therapy (ART) were women and the proportion has declined in the past 8 years [4] (Fig. 1). Women are biologically different than men and in order to gain a better understanding of the potential sex influences on HIV therapies, trials need to better reflect the population living with the disease by routinely including an appropriate proportion of women [3] or by conducting concurrent, similarly powered trials in each sex.Fig. 1: Proportion of women enrolled in HIV clinical trials from 2000 to 2007. Reproduced with permission from Struble et al. [4].Why is there a gap? Historically, women have been underrepresented in many areas of clinical research, often to minimize risk to the unborn child. Consequently, efficacy and safety information from studies with a preponderance of men have often been extrapolated to women. Regulatory authorities recommend that more women should be included in HIV clinical trials [5], and this call to action has been supported by other groups, including UNAIDS and partners in the initiative ‘Make HIV Trials Work for Women and Adolescent Girls’ [6]. Despite this call, initially raised over 16 years ago, results are poor. It is, therefore, important to consider the barriers to the inclusion of adult women in clinical trials (Table 1). Although there may be compelling reasons to exclude women from certain trials, such as a desire to become pregnant, it is important that the inclusion and exclusion criteria are valid and that artificial barriers for women are not constructed.Table 1: Barriers to the recruitment and retention of women into HIV clinical trials and strategies to overcome them.Why data in women are essential Women are entitled to equal access to successful treatment and the ability to make appropriate informed choices. This starts with data regarding sex-specific efficacy and toxicity. Women have a different physical makeup to men and HIV therapies may affect them differently. Sex differences in treatments are found throughout medicine and may be mediated through metabolic, physiological, cultural, and behavioural differences. In heart failure, digoxin is associated with an increased risk of mortality among women but not among men, possibly due to sex-associated differences in drug pharmacokinetics or an interaction with hormone replacement therapy (HRT) [7]. As described below, several studies have identified potential differences between men and women in HIV therapy. Pharmacological effects of antiretroviral therapy Known pharmacokinetic and pharmacodynamic differences between sexes may affect the efficacy and tolerability of ART [2,8]. Differences in body size, composition, metabolic processes, and renal and hepatic clearance have been described [2] and may be further altered during pregnancy or by hormonal contraceptives and HRT. Mechanisms could include sex-related differences in ART absorption and distribution, the differential expression of metabolic enzymes or differences in gastric emptying time [2], or be influenced by the higher relative amount of adipose tissue, lower skeletal muscle, and blood and bone mass in women. Despite these findings, the standard ART doses recommended for men are routinely prescribed for both sexes. Response to antiretroviral therapy Preliminary observations from cohort studies suggest that women may respond better to ART than men [9]. Other studies show differential rates of virologic rebound and failure in women relative to men [10]. Due to the insufficient numbers of women enrolled in randomized clinical trials (RCTs), these findings cannot be confirmed, and data extracted from observational databases should be interpreted with caution. This was highlighted by the relationship between HRT and risk of heart disease. Initial positive data from cohort and observational studies resulted in significant changes in practice, but subsequent RCTs identified a negative impact of HRT on heart disease risk [11]. Tolerability of antiretroviral therapy Studies on ART generally report a reduced tolerability among women [2]. Adverse effects reported include increased risk of rash and hepatitis with nonnucleoside reverse transcriptase inhibitors (NNRTIs), lactic acidosis with thymidine analogues, alterations in the distribution of lipodystrophic changes, and in the patterns of dyslipidaemia [12–16]. Poor tolerability is important as it can impact adherence. Other sex differences Psychosocial, behavioural and attitudinal factors, such as access to treatment, delays in initiating therapy, increased rates of depression and suicidal behaviour, and the impact of confidentiality on adherence are potential confounders that may account for some of the sex differences observed in cohort studies [2] related to treatment outcomes. How to address the gaps Increasing the numbers of women in clinical trials will require concerted efforts from all those involved in trial development, management and reporting. The solutions are not simple and carry significant cost implications for communication, training, education, and counselling. We would argue, however, that initial costs are worth the gains for more long-term and ongoing benefits. Clinical researchers Those involved in clinical research should ensure proportional representation of women in earlier clinical studies (e.g. in phase II) with women-only trials conducted at phase III. Furthermore, protocols should be statistically powered to provide meaningful data on sex differences and designed to remove unfair barriers to the involvement of women (Table 1). Physicians Physicians should work with clinical trial investigators to develop ways to improve appropriate recruitment of women and put into place strategies to address barriers by catering for their specific needs (Table 1). Clinical trial sponsors Pharmaceutical companies and trial sponsors typically accept enrolment into studies irrespective of sex ratio to complete recruitment quickly. Trial sponsors should collaborate with investigators and centres responsible for the treatment of a high proportion of women living with HIV. Indeed, more recently, with the inclusion of many middle-income to low-income countries in phase III studies of ART, the proportion of women being recruited has increased. More balanced sex ratios can also be achieved by providing specific tools to enable recruitment of more women. Regulatory authorities and ethical committees Regulatory authorities and ethical committees can also help by recommending that pharmaceutical companies, trial sponsors and clinical trial investigators recognize and address the sex imbalance in HIV trials. Journal editors Journals that publish HIV clinical trial research must aim to encourage the reporting and publication of results for female participants in HIV clinical studies. Although the limitations of subanalyses of results are recognized, such observations could be hypotheses generating. The incorporation of a recommendation for including women in clinical trials and reporting female subanalyses in the CONSORT guidelines would encourage the transparent reporting of clinical trials [17]. CONSORT should also recommend that a minimum percentage of female participants be included in studies that are not related to sex-specific problems. Journal editors are urged to ensure that publications represent and discuss women where possible and that the use of women-specific endpoints, both non-gynaecological and gynaecological, be investigated. Discussion of any evident differences between men and women that emerge from studies should be included – a women's health specialist on journal editorial boards could facilitate this. Furthermore, guidelines for authors should recommend that, where no specific conclusions on outcomes in women can be drawn, further research is required, which may help to raise awareness of the sex imbalance. Medical societies and congress organizers Reporting of data relating to women at national and international conferences could be improved by encouraging the submission of data on women in the call for abstracts. Priority could be given to data on women when allocating scientific sessions and symposia, and organizers must ensure that they address sex-specific issues related to treatment. The number and proportion of women in the studies that are reported should be monitored. Good-quality abstracts that address sex issues should be given high priority for oral presentation. Advocacy groups Advocates should be encouraged to highlight gaps in the reporting of data during the discussion sessions of scientific symposia. Patient advocacy and knowledge translation publications should stress the importance of the adequate representation of women. The participation of advocacy group representatives in the planning and conducting of trials can enhance the patients' perspectives and help recruit female patients. Increasing the involvement of the HIV community in all aspects of management of women and HIV should be maximized in accordance with the Greater Involvement of People Living with HIV (GIPA) principles [18]. Conclusion The recruitment and retention of women into HIV clinical trials is of significant importance, as, globally, women contribute to 50% of HIV diagnoses. Factors other than eligibility criteria appear to be responsible for the gap in women's enrolment in HIV clinical trials. The education and empowerment of women living with HIV will increase awareness of the need for participation. Furthermore, awareness of the barriers to the inclusion of women and encouraging the development and implementation of appropriate strategies to target this issue will work towards enhancing clinical research in this area and ultimately improve the lives of women living with HIV. Acknowledgements Women for Positive Action is a global initiative established in response to the need to address specific concerns of women living and working with HIV. The group is made up of healthcare professionals, women living with HIV, and community group representatives from across Canada, Europe, and Latin America. Working together, the Women For Positive Action group aims to empower, educate, and support women with HIV and the healthcare professionals and community advocates/leaders involved in their treatment, to explore the issues facing women with HIV and provide meaningful educational-based support to respond to these needs, to contribute towards an enhanced quality of life for women with HIV. For further information on this initiative, please visit www.womenforpositiveaction.org. Women for Positive Action Faculty: Larissa Afonina (Russia), Adriana Ammassari (Italy), Jane Anderson (UK), Teresa Branco (Portugal), Viviam Patricia Cañon Garcia (Colombia), Ana Coromoto Carvajal (Venezuela), Isabel Cassetti (Argentina), Andrea Cipolla (Argentina), Elisabeth Crafer (UK), Antonella d'Arminio Monforte (Italy), Lorena González (Mexico), Georgina Gutierrez (Mexico), Annette Haberl (Germany), Griselda Hernandez (Mexico), Moraima Hernandez (Venezuela), Diana Irazabal (Venezuela), Margaret Johnson (UK), Anne-Mette Lebech (Denmark), Laurette Lévy (Canada), Mona Loutfy (Canada), Mariana Mărdărescu (Romania), Helaine Milanez (Brazil), Rachel Moreno (Brazil), Laura Bahamondes Moya (Chile), Fiona Mulcahy (Ireland), Angelina Namiba (UK), Ophelia Haanyama Ørum (Sweden), Maria Jesús Pérez Elías (Spain), Norma Porteiro (Argentina), Lorraine Sherr (UK), Ulrike Sonnenberg-Schwan (Germany), Winnie Ssanyu-Sseruma (UK), María Celia Trejo (Argentina), Sandra Valderrama (Colombia), Patricia Vasquez (Chile), Sharon Walmsley (Canada). We also acknowledge Louise Brady, PhD (Litmus MME Ltd) who provided medical writing support to the Faculty Women for Positive Action is funded by an educational grant from Abbott International.