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HIV-Related Diarrhea

Author: Jeannie Wraight and Maria Mejia

For many, having a positive attitude and a good perspective can minimize the effect we let HIV have on our daily lives. Living with HIV often makes us stronger people who learn to prioritize what's important, value those we love, navigate the bumps in the road and not sweat the small stuff. But what happens when HIV does affect our lives day to day? Specifically, what if the medications that keep us from getting sick, actually make us sick?

Although newer antiretrovirals (ARVs) like Triumeq have reduced its occurrence, approximately 20–24% (statistics vary) of people living with HIV (PLHIV) in the U.S. experience chronic diarrhea, either as a side effect of ARVs or from HIV itself. Recent global statistics are scarce however, it’s estimated that nearly 90% of PLWHA’s in the developing world suffer with diarrhea periodically throughout their lifetime. It's not an issue we like to talk about and most people find it embarrassing to admit. For those living with this condition, it can make our days and nights difficult. How do you hold on to a steady job if you have to keep running to the bathroom and take longer than normal while there? How do you make plans to go out when you never know when you'll have to stay close to home? How can you be physically close to someone when you don't feel confident?

Chronic diarrhea can have profound and serious consequences to the way a person thinks, feels and lives. It can make us feel as though we have no control of our lives or bodies, feel ashamed or 'dirty', and be afraid of what these reoccurring bouts of diarrhea are doing to our bodies and health. Some fear that it's a sign that they have or are progressing towards AIDS. All of these thoughts can lead to depression, social isolation, anxiety and shying away from intimacy.

It has also been shown that PLWHA’s who believe their diarrhea is related to their antivirals (ARVs) are much less adherent in taking them as prescribed. Poor drug adherence puts them at risk for becoming drug resistant which can lead to illness and the ability of potentially transmit HIV to a sexual partner. It also makes them less likely to see their doctors regularly due to the discomfort of discussing adherence.

Most doctors, even HIV specialists, have little to offer in terms of treatment for HIV-related diarrhea. Most often, Imodium, an over the counter medication, or a change in diet is the given advice. As such, most people don't complain about diarrhea and have accepted chronic diarrhea as a part of living with HIV. Fortunately, as a new study shows, there is an option for many with this condition.

A drug called Mytesi (generic name crofelemer) was approved by the US FDA for relieving the symptoms of non-infectious, HV-related diarrhea. That is diarrhea that is caused either by ARVs or by HIV itself (e.g. from enteropathy). To determine if diarrhea is non- infectious, a doctor must first rule out other causes such as a parasitic or bacterial infection or a side effect of other antibiotics or another non- HIV-related medication(s).

Although Mytesi is the only treatment approved for HIV-related diarrhea, most doctors aren’t familiar with the drug or don't prescribe it, often because the results of the study (The ADVENT study) that led to the FDA approving Mytesi, although good enough for the FDA, showed that Mytesi appeared to be only mildly effective.

However, this perception of mild effectiveness of the drug didn't match the actual patient experience for those who have used it and with a lack of alternative treatments, a review of this study was conducted. What the review or 'secondary analysis' demonstrated was that the original results, simply did not show the whole picture of the study.

According to Patrick G. Clay, PharmD, AAHIVP, CPI, Professor, Pharmacotherapy, UNT System College of Pharmacy, one of the authors of the study, "The bar set by the FDA was very high. It translated to a 90% reduction in diarrhea within 2 weeks. The FDA doesn't even hold antiretrovirals to 90% improvement in 2 weeks. In other words, patients who had been living with 20 watery stools per week for nearly 6 years had to drop to 2 or less per week to be called 'successful'. When we looked more closely at the results, we found that within 1 month, 61% of crofelemer patients went from 20 down to 10 loose stools per week. This continued through week 24 when 86% of patients had 50% fewer loose stools per week. To me, that is a success."

To enroll in the study, participants had to be experiencing chronic, non-infectious HIV-related diarrhea (defined as daily watery stools) for at least a month. All of the participants had an average of 20 watery stool episodes per week and had chronic HIV-related diarrhea for an average of nearly six years. There were 2 actual parts of the study – the stage I portion of the study and a stage II 'roll-over phase'.

The stage I portion was over a 4 week-period where everyone who was enrolled were randomly given either Mytesi or placebo. Once the four-week period was completed, those who had been given placebo (that wished to remain in the study), were randomized ('rolled-over') to the stage II, which was a blinded 20-week continuation from the stage I portion. Most participants who completed the initial 4-week stage I study decided to continue onto the 20-week portion.

Now here’s where the problem lies. Because of the way the study was set up, as per the FDA, the final results on the label reflected only the first 4-week stage I portion of the study. They looked at those who 'responded' to therapy. People who were considered 'responders' were those who at the end of the 4 weeks had less than 2 episodes of [watery] diarrhea per week and that was only 18% of those who took Mytesi compared to 8% of those who were on placebo. Clearly, that's not much of a difference and when doctors looked at whether they should prescribe Mytesi to their patients, most decided not to, based on that snap shot of the study. But when researchers considered the entire 24 weeks that participants took Mytesi – the results were dramatically different. In the original results, since everyone on the study had an average of 20 episodes of diarrhea a week (which is approximately 3 times a day) and in order to be considered a 'responder' to Mytesi, participants had to have 2 or less episodes of diarrhea per week within the first 4 weeks of initiation of treatment, anyone who’s diarrhea reduced from 20 to as little as three times a week or more (a substantial reduction) – was not considered a 'responder'. However, it’s easily apparent that even a 50% reduction, which would be 10 episodes a week dropped from 20 a week, would make taking this drug worthwhile for someone plagued with chronic diarrhea. When looking at the entire study, researchers found that a 100% reduction in diarrhea (i.e. zero watery stools) in those taking Mytesi was seen in 19% of participants by week 4, 41% by week 12 and 56% by week 20. That means by the end of the study, diarrhea was completely eliminated for more than half of the participants. Greater than a 75% reduction was seen in 45% by week 4, 60% by week 12 and 72% by week 20. And greater than a 50% reduction was seen in 61% by week 4, 72% by week 12 and 83% by week 20.

"GI issues are a significant comorbidity for many HIV patients, most of whom have learned to live with abdominal discomfort and loose stools. Patients do not mention diarrhea to their doctors, as they are unaware that a therapy, aside from using anti-motility agents, is available. When questioned; many patients feel that diarrhea is bothersome and impacts their daily activities. Having an effective therapy available may have a very beneficial effect for these patients. With results such as these for a condition that effects quality of life to the extreme that chronic diarrhea does, PLWHA's need to be aware that there is a treatment their doctors can prescribe that could significantly reduce the occurrence of diarrhea and for some, even eliminate it," stated Dr. Laveeza Bhatti, an HIV and Infectious Disease specialist in Los Angeles affiliated with Cedars-Sinai Medical Center.

As with any medical condition, chronic diarrhea can be difficult and can affect the way we think, feel and live life. But by knowing the facts and what treatments are available, we can initiate discussions with our care providers, and advocate for our best treatment options. The results of this show that there is hope for PLWHA's who struggle with the ongoing issue of chronic HIV-related diarrhea and that this condition is not something they simply have to 'live with'.

Currently, Mytesi is only available in the U.S. and advocacy is essential for country-to-country access. As with all aspects of living with HIV, knowledge is key to living a healthy, empowered, productive and happy life.

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