Finding Relief

An available treatment for HIV-related non-infectious diarrhea produces beneficial results

by Jeannie Wraight

Approximately thirty to sixty percent of people living with HIV and on antiretroviral therapy (ARVs) experience diarrhea. Reoccurring and frequent diarrhea is often reluctantly accepted as a burdensome condition for which little can be done. Many HIV patients are unaware there is a medication approved by the FDA specifically to treat non-infectious diarrhea. In addition, few doctors are informing their patients of this option, despite clinical studies that show the drug’s efficacy.

During the pre-ARV era, diarrhea in people living with HIV and AIDS was most commonly the result of bacterial, viral, or protozoal pathogens such as cryptosporidium and MAC, and occurred in individuals with a suppressed immune system. During this time, seventeen percent of new AIDS cases reported to the CDC were associated with diarrhea.

Since the initiation of ARVs, studies have shown that for people on ARVs with successful viral suppression, the rate of infectious diarrhea has significantly decreased while the rate of non-infectious diarrhea has increased. The most common causes of HIV- related diarrhea are now ARV-associated diarrhea and enteropathy.

Although ARV-associated diarrhea carries a lower risk of mortality from consequences such as extreme weight loss (wasting syndrome), HIV-related diarrhea in general remains a significant problem and has been linked to increased mortality. Consistent diarrhea in conjunction with other ARV-related side effects can also lead to poor adherence to ARVs which can contribute to drug resistance and a decrease in therapeutic options to treat HIV.

When ARVs are suspected as the cause of diarrhea, switching to a new regimen or therapy could possibly eliminate the offending culprit. The decision to switch regimens must be a well thought-out decision involving both physician and patient, with options for future regimens taken into consideration.

Enteropathy is also a common cause of HIV-related diarrhea and can occur at any stage of HIV disease. It is diagnosed by episodes that last for more than one month in the absence of other detectable causes.

Treatment of HIV-associated diarrhea
Despite the high prevalence in people living with HIV and the sometimes serious physical, emotional, and quality of life issues caused by HIV-related diarrhea, few studies are exploring treatments that can reduce its occurrence and severity. As such, it’s difficult to understand why the one drug that is approved as a treatment is not being widely prescribed.

Mytesi (also called crofelemer and formerly known as Fulyzaq) is an antidiarrheal prescription medication indicated for HIV-related non-infectious diarrhea.
The ADVENT clinical trial was a placebo-controlled study, evaluating the effects of Mytesi in HIV-positive people who had non-infectious diarrhea for a minimum of four consecutive weeks and had experienced diarrhea over a 5.5–6.9-year period. Participants were on stable ARV regimens and had CD4 cells over 100 cells/ul.

The study was broken down into parts, the first being a dose-defining study which determined Mytesi’s optimal dose to be 125 mg twice a day. The second part of the study was a double-blind, randomized, controlled trial. The study included a four-week blinded phase followed by a twenty-week open-label extension where all study participants received the drug.

Prior to study launch, participants experienced a median of three watery stools per day with, on average, twenty watery bowel movements per week at baseline. The primary endpoint for the four-week blinded phase defined a responder as having no more than two watery bowel movements per week for two or more of the four weeks.

This may be difficult to understand, as a decrease from three a day to three or four a week would be considered as a non-responder; however in the life of someone suffering from diarrhea of this extent, this is a significant and noteworthy reduction. Even a decrease of a third of incidences would have a significant impact on quality of life.

Results showed the mean number of daily watery bowel movements in the study population was slightly less than three per week, with a marginally higher rate (3.04) in the placebo-treated patients versus patients receiving Mytesi.

At the end of the four-week blinded phase, the rate of response in the Mytesi-treated patients was nearly double that of the placebo group (eighteen percent vs, approximately eight percent). Response rate during the placebo portion continued to improve throughout the twenty-week open-label extension, reaching a plateau of an approximate fifty-percent response rate. An analysis of the data outcomes found a higher response rate in participants who had used antidiarrheal medications in the past 4 weeks, with CD4 counts less than 400, those diagnosed for over twelve years and participants who used PIs compared with those who used other classes of antiretrovirals.

Reported serious adverse events were low and similar in both the Mytesi arm (two) and the placebo arm (four). GI effects and infections were the most common AEs in both groups, and two cases each of the following AEs were observed in the Mytesi group: dyspepsia, flatulence, abdominal pain, hemorrhoids, and constipation. Upper respiratory tract infections were seen in five crofelemer and four placebo patients, and urinary tract infections were seen in three crofelemer patients and one placebo patient.

Over-the-counter medicines such as Imodium and Kaopectate are often used in an attempt to control the severity and frequency of diarrhea. Although some benefit may be obtained, these OTC medications will not produce lasting or consistent effects.

Studies on probiotics have shown some benefit in helping with gastrointestinal issues such as diarrhea, though conflicting results have not allowed for a definitive recommendation of probiotics to treat HIV-related diarrhea. Ongoing studies may provide a more definitive answer of their benefit.

Jeannie Wraight writes the Destination: Cure column for A&U.