Population Briefs

Improving Adherence in Microbicide Clinical Trials: Lessons Learned and Recommendations

Microbicides are biomedical products being developed to protect people against sexually transmitted infections, including HIV. Some microbicides are being designed as vaginal products for women, and others would be rectal products for either men or women. Several candidate microbicides have been developed and tested over the past two decades. Yet the results of clinical trials have been largely disappointing. Just one trial provided evidence that a vaginal microbicide could protect against sexual transmission of HIV. The results of a confirmatory trial are underway. Should it provide confirmation, several years would still be needed before a product is available in sufficient quantities.

There are many reasons why most of the trials have not shown hoped-for impact. One that is extremely important, yet has little to do with the quality of a microbicide itself, is related to adherence to the microbicide regimen; that is, participants in the trial correctly following guidelines for using the microbicide. Even if a microbicide is effective, it must be used correctly and consistently if it is to prevent transmission. That expectation has not always been met, contributing to results indicating limited or non-existent effectiveness. The lack of adherence to correct and consistent use by many trial participants has been seen in post-trial analysis.

Issues regarding adherence in microbicide trials are examined in “Microbicide clinical trial adherence: Insights for introduction,” a recent paper published in the Journal of the International AIDS Society and co-authored by Population Council researcher Barbara Friedland. The authors list lessons learned regarding adherence from their review of data and observations from the six large-scale microbicide efficacy trials completed to date. Based on those lessons, they also offer recommendations for such trials in the future as well as for when microbicides are eventually available for general use.

“This article is one element of a much larger Population Council effort to improve adherence in microbicide trials,” said Friedland.

Improving Adherence: Lessons Learned and Recommendations

The authors organize their lessons learned under six categories. Some key points associated with each category are summarized below, as are some of the recommendations that followed. The need for better, and more extensive, information and support is a common theme across most of the categories.

Adherence measurement in clinical trials

Difficulties in measuring adherence have been apparent given the limitations of self-report and biological markers (such as drug levels in blood or urine). In regard to the former, for example, trial participants may intentionally or unintentionally misreport use of the product. For the latter, reliable biological markers may be adversely affected by factors such as the difficulty of measuring some drugs that are not systemically absorbed.

The authors suggest triangulation of multiple measures—i.e., using two or more evaluation methodologies and approaches— as a way to improve the accuracy of adherence measurement.

Comprehension of microbicide use/ instructions for use

Some women participating in trials misunderstood instructions on how to correctly use microbicides. In many instances, such problems have been overcome when locally appropriate illustrated materials are available in addition to adequate counseling.

The authors recommend specialized training for service providers when microbicides are eventually introduced. The goal should be to provide users with evidence-based information. Such efforts should be preceded by the development of clear instructions for users that are regularly evaluated.

Unknown efficacy and its effect on adherence/messages regarding effectiveness

Some trial participants and clinic staff, when informed that the products’ value was “uncertain,” did not understand or believe what they were told. As a result, for example, some assumed the “active” microbicide product was completely effective and that they need not take additional measures to protect themselves from HIV.

The authors recommend that thorough and easily understandable information be made available to users of such products. Such information should be explicit about the known contraceptive and protective effects of the products as demonstrated by the existing evidence.

Partner influence on use

Although microbicides have long been championed as a “female-controlled” intervention, trial participants often found it difficult to use them in secrecy or without informing their sexual partners. For some women, concern over hiding involvement in the trials, especially from partners, created problems with adherence.

The authors recommend more extensive and better-crafted up-front messages about the potential for negative consequences if use is discovered by a sexual partner. They also encourage more openness, in accordance with local norms, about a product’s effect on men’s and women’s sexual pleasure.

Retention and continuation

High rates of visit completion and retention are considered critical components for achieving adherence in microbicide trials. This is because participants who miss visits also miss the opportunity to refill products, which may result in non-adherence or non-persistent use, and ultimately can undermine the accuracy of efficacy estimates. At the same time, however, the authors observed that very high rates of retention do not appear to ensure high rates of actual product use. Thus, retention in trials is a necessary, but insufficient, condition for consistent product use.

The authors recommend regularly reassessing women’s needs and working with them as closely as possible to help maximize continuation and adherence. Women should also receive clear information about when and why to discontinue use (e.g., during pregnancy).

Generalizability of trial participants’ adherence behavior

More than 20,000 women have participated in large-scale advanced microbicide trials globally. Most have been in communities and environments where they are considered at high risk of HIV infection. However, while it makes sense to focus trials in this way, participating women may not be representative of those who will actually use microbicides. That possibility is especially great since some important population groups (pregnant women, post-menopausal women, and adolescents) have not been included in clinical trials. The authors recommend studies for populations who have not been well represented in microbicide trials to date. Such studies should seek to assess what might influence use of products as well as adherence.

The Need for Variety and Redoubling Efforts

Very few people are 100 percent adherent to any product, so it would be unrealistic to expect such behavior from all or even a majority of women who eventually use microbicides. The authors note, however, that collective adherence is likely to be greater if multiple types of products with varying use requirements are available. Variety of this sort is essential to address the issue of acceptability—whether users are able and willing to devote the time and attention to using a product as instructed.

The authors conclude by stressing the health and social importance of overcoming the challenges associated with developing safe and effective microbicides. In their view, the introduction of microbicides, and appropriate counseling on how to use them correctly and consistently, could create inroads for women’s empowerment while reducing their risk of HIV infection.


Source

Woodsong, Cynthia, Kathleen MacQueen, K Rivet Amico, Barbara Friedland, Mitzy Gafos, Leila Mansoor, Elizabeth Tolley, and Sheena McCormack. 2013. “Microbicide clinical trial adherence: Insights for introduction,” Journal of the International AIDS Society 16(1): 18505.