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Women-Specific ART Trials
Why ART Trials Specific to Women Are Important

Released: September 28, 2016

Expiration: September 27, 2017

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For most of the US Food and Drug Administration (FDA)–approved antiretroviral therapies (ART) available today, only modest numbers of women were included in the phase III studies leading to their development. Numerous reasons contribute to that limitation, including strict restrictions regarding pregnancy and contraceptive use, but that is reality. For example, in the phase III GS-103 study demonstrating noninferiority of elvitegravir (EVG)/cobicistat (COBI)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) to atazanavir (ATV)/ritonavir (RTV) plus TDF/FTC in treatment-naive HIV-infected patients, women accounted for just 8% and 11% of the treatment arms, respectively. Furthermore, women accounted for only 16% of the trial population for the phase III SINGLE trial, which demonstrated that dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) was superior to efavirenz (EFV)/TDF/FTC for the initial treatment of HIV. However, because we know that men and women differ biologically and respond differently to drugs in various ways as demonstrated in other disease states, it is important that we understand how these drugs work specifically in women.

One Size Does Not Fit All
The overall issue is that one size does not fit all in medicine. As a classic example, studies defining heart disease have clearly demonstrated differences between men and women in the presenting signs and symptoms, as well as responses to various treatments. However, it was not until people started to evaluate heart disease in women that these differences became apparent. This example illustrates that we need to specifically ask the question, “Are there differences?” and that we should not presume a lack of differences, especially when comparing the 2 sexes. Evidence of differences in the responses of men and women to HIV treatments has been demonstrated, including sex-based differences in pharmacokinetics and relative concentrations of P450 isoenzyme systems. Furthermore, various categories of women—pregnant women vs nonpregnant women vs postmenopausal women—are each unique, necessitating the additional evaluation of how these drugs work along the continuum of a woman’s life.

ART Along the Continuum of a Woman’s Life
Pregnancy considerations are important because most women who are infected with HIV are in their childbearing years and may want to have children. Thus, it follows that ART will need to be used during pregnancy, and therefore, we need to understand how changes during pregnancy affect levels of ART. For example, we know that fluid volume and distribution as well as pharmacokinetics parameters change during pregnancy. On the other end of the continuum are postmenopausal women. In general, we know that when a woman becomes postmenopausal, there is an acceleration of bone loss and an increased risk for osteopenia and osteoporosis. We also know that some ART agents can cause bone loss. We must consider the long-term impact of ART in women knowing how aging affects bone.

It Is Imperative to Study Affected Populations
ART studies in women are also critical to ensure that we are studying and including individuals who are most affected by HIV. In the United States, one quarter of the HIV-infected population is women. In areas of the world where HIV infection has the biggest impact, for example sub-Saharan Africa, most of those populations are women. With women making up approximately one half of all HIV-infected infections on a global scale, it behooves us to understand how these drugs work in this population. Consistent with this, the FDA has clearly stated that women and minority groups should be included in clinical trials.

Landmark ART Trials in Women
The international, randomized phase III WAVES and ARIA trials were developed to address this need by specifically examining ART in women. In the WAVES trial, EVG/COBI/TDF/FTC was shown to have superior efficacy and tolerability vs ATV/RTV plus TDF/FTC, whereas the results of study GS-103 had demonstrated noninferiority. In the ARIA trial, DTG/ABC/FTC was shown to be superior to ATV/RTV plus TDF/FTC in treatment-naive HIV-infected women regarding both efficacy and safety. Not only did both of these studies serve to provide important information about ART in women, they also demonstrated that women-specific trials are feasible and even fruitful. WAVES and ARIA were large studies that accrued on time, showed superiority, which very few studies in the field have done, and are now published. Thus, clinical trials for the development of new ART medications are positioned to include women going forward.

Impact of Women-Specific ART Trials on Clinical Care
In resource-constrained settings, clinicians often do not have access to the full panoply of HIV medications. The more data available to the World Health Organization, government organizations, and health ministries in terms of what agents would be better tolerated by women or better targeted to populations that have a majority of women is very valuable information to the provider whose HIV-infected population is mostly women. In the United States and developed countries, where most HIV agents are available to choose from, I see these data being used to individualize therapy regarding tolerability in different populations of women. Regardless of context, data are necessary to inform these discussions and decisions about ART in women, and the only way to obtain these data is to generate them in trials that either include higher proportions of women or are comprised solely of women.

Your Thoughts
Do you see value in more ART trials for women? I encourage you to post your thoughts in the comments section below.

For more engaging discussion on global challenges to the treatment and prevention of HIV in women, participate in this interactive CME-certified activity featuring Catherine Hankins, MD, PhD, FRCPC, CM.

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In your opinion, what is the greatest potential benefit of higher enrollment of women in ART trials and/or more trials comprised solely of women?
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