New data shows high benefit from HIV-related diarrhea treatment
By Gary Blick, MD, and Jeannie Wraight
HIV-related diarrhea is a damaging condition that can greatly affect quality of life, as well as increase the risk of mortality in people living with HIV and AIDS (PLHWA), both receiving antiretroviral therapy (ART) and those not on ART. New data, released at the IAS 2017 conference, shows an FDA-approved medication for HIV-related diarrhea is more effective than previously believed.
In the early HAART days prior to 2005, as many as sixty percent of PLWHA in the developed world experienced diarrhea. Currently, in the developing world, it is estimated that close to 100 percent of PLWHA have experienced chronic diarrhea either from infectious or noninfectious causes.
Although AIDS-related diarrhea has decreased significantly with the global use of ART, the incidence of noninfectious diarrhea (NID) has increased. HIV enteropathy—or gastrointestinal damage related to HIV infection—as well as the use of ART are the main causes of NID in PLWHA. Over 750,000 newborns, infants and children die annually from potentially treatable HIV-associated infectious diarrhea.
New data from the ADVENT study, which analyzed Mytesi (formally known as crofelemer), shows a potential treatment that can significantly decrease incidents of noninfectious HIV-related diarrhea. Mytesi is an anti-secretory agent that is the only FDA-approved therapy in the U.S. for treatment of noninfectious diarrhea in PLWHA on ART. It is also currently available on formulary in Zimbabwe. Although the source of crofelemer, which is extracted and purified from a tree in the Amazon rainforest, is a timely and expensive process, its manufacture is currently working on processes that could make Mytesi more cost-effective for African countries where, many can argue, it is needed most.
Researchers for the ADVENT study evaluated Mytesi or placebo in 272 PLWHA for a four-week period, after which, all of the participants were offered the opportunity to take Mytesi for an additional twenty weeks. This study, which ultimately led to the FDA-approval of crofelemer, showed that significantly more PLWHA who received Mytesi achieved a clinical response verses those on placebo. Clinical response was defined as a reduction in watery stools from an average of twenty per week at study entry, to less than two watery stools per week during the four-week placebo-controlled phase.
However, the original analysis of the ADVENT study only included results from the four-week placebo controlled study and not the entire twenty to twenty-four weeks that participants took crofelemer. Since the results do not characterize the reduction in diarrhea among all of the participants in the study over the entire duration of the study, and as there is a substantial benefit from a fifty percent or greater reduction in watery stools, a supplemental analysis was performed to review the long-term efficacy of crofelemer. This analysis was presented at the 9th IAS Conference on HIV Science in Paris.
In this analysis of ADVENT, researchers reviewed the entirety of data in study participants. The endpoints analyzed included:
• average change in watery stools over four to twenty-four weeks in crofelemer-treated patients
• proportion of study participants with greater than a fifty percent, seventy-five percent, and 100 percent reduction in the number of watery stools
Participants in the study had NID for at least one month while taking a stable ART regimen and had CD4 cell counts over 100. Almost eighty percent had evaluable stool diary data and completed the placebo-free extension phase.
Of the participants, the average age was forty-five years, sixteen percent were female, and sixty percent were non-Caucasian (thirty-eight percent Blacks/African-Americans, twenty percent Hispanics/Latinos). On average, participants had had diarrhea for six years and reported an average of twenty watery stools per week. Additionally, fifty-nine percent had used at least one antidiarrheal medication.
The proportion of people with ≥50%, ≥75%, and 100% reduction in number of watery stools was forty-eight, thirty-five, and fifteen percent by week 4; seventy-two, sixty, and forty-one percent by week 12; and seventy-three, sixty-three, and fifty percent by week 20, respectively.
The proportion of people achieving clinically relevant reductions in watery stools at any time point was not significantly different whether analyzed by concomitant protease inhibitor use (sixty-six percent were taking protease inhibitors) or by diarrhea etiology (seventy-five percent attributed diarrhea to ART while twenty-five percent to HIV infection and/or other causes).
None of the participants on the study reported serious adverse events attributed to crofelemer. Mytesi has no clinically relevant drug-drug interactions, and does not affect CD4 counts or viral load.
In the supplemental analysis, the researchers concluded that Mytesi was associated with clinically relevant and sustained reductions in NID that were not apparent from the ADVENT trial primary responder analysis.
Mytesi represents a therapy which is direly needed throughout both the industrial world and developing nations to reduce HIV-related noninfectious diarrhea. A reduction in incidences of diarrhea has been found to have an important impact on a person’s quality of life, their physical health and the absorption of ARVs. With HIV ARVs, as well as HIV itself, known to cause diarrhea in a large number of PLWHA, Mytesi should be considered an obvious adjunct therapy for those prescribed ARVs throughout the world.