Hard to Digest

Current_Research_and_Opinions_200Why HIV-associated Enteropathy is So Often Left Undiagnosed, Unaddressed and The Potential of Nutritional Management.

HIV-associated enteropathy remains a substantial problem for both HIV patients on HAART and those who are not receiving treatment. It is estimated that about 15-30% of HIV+ people, even when on antiretroviral therapy, continue to live with this persistent and debilitating condition for which there is currently no effective marketed intervention. HIV-associated enteropathy, first described in 1984, is a change in intestinal structure and function in HIV-infected persons. There is a lack of research not only on potential treatments, but also on the role of this condition in HIV disease progression and its effects on HAART and treatment for co-infections.

Gut associated lymphoid tissue (GALT) harbors a majority of the body’s immune system and is an important mucosal target of HIV for acute, primary and chronic infection. The massive and rapid depletion of CD4+ T cells from GALT that occurs with HIV infection is predictably a cause of the progressive deterioration of intestinal immune and digestive functions, which is collectively termed “enteropathy.” After prolonged viral suppression by antiretroviral therapy, there may be partial restoration of the HIV-associated intestinal mucosal barrier defect despite persisting alterations of the mucosal immune system. Chronic diarrhea is the most common clinical manifestation of HIV-associated enteropathy, which is diagnosed via endoscopy and is also characterized by increased GI inflammation, increased intestinal permeability and results in malabsorption and subsequently malnutrition, significantly impacting clinical outcomes, as well as the quality of life, in people living with HIV. Immunologically, it is hypothesized that the loss of CD4+ T helper cell function in GALT contributes to HIV-associated enteropathy via the disruption of the homeostasis between adaptive and innate immune responses. It is now well-established that HIV infection transforms the intestinal mucosa from a balanced system to one of chronically activated inflammation leading to disruption of epithelial barrier integrity and microbial translocation with subsequent inflammation and co-infection.

HIV-associated enteropathy is under diagnosed and not given the attention that it previously received when it caused life-threatening conditions such as wasting syndrome. The incidence of this condition is still higher than expected even with the advent of and increased access to HAART. Rising costs of treating HIV patients who are living longer due to the initial success of HAART are now being driven by manifestations of consequences driven by chronic immune activation and subsequent inflammation and the long-term consequences of ARVs, such as lypodystrophy, which is suspected to contribute to cardiovascular disease. Studies on nutritional interventions in people living with HIV to address HIV-associated enteropathy, immune restoration, reductions in diarrhea, metabolic complications and patterns of drug resistance have shown that aggressively improving the quality of life in people living with HIV during the fourth decade of the epidemic improves clinical outcomes and reduces associated costs.

Data from a pilot study presented at both the XIX International AIDS Conference (AIDS 2012) and CROI 2013 illustrates how nutritional address of this condition can be achieved utilizing a specific protein source. Researchers led by Dr. David Asmuth studied the effects of EnteraGam™ (serum bovine-derived immunoglobulin/protein isolate or SBI) on gastrointestinal (GI) symptoms, mucosal immunity, bacterial translocation and the impact on imbalances in the gut microbiota. In an initial 8-week study of 8 patients with HIV-associated enteropathy and in a 48-week extension in 5 patients, EnteraGam was found to increase duodenal CD4+ cell density and CD4/CD8 ratios as well as improve nutrient absorption. A significant and dramatic decrease in diarrhea plus an improvement in stool frequency and consistency was maintained throughout the study and there were notable positive changes in gut microbiota.

Dr. David Asmuth, lead author of an article reported the results of an open-label pilot study of EnteraGam published in the May 22, 2013 issue of the journal AIDS, a leading HIV/AIDS peer-reviewed publication. In addition to effects on HIV-associated enteropathy, the corresponding reduction in intestinal inflammation and restoration of mucosal immunity further validate the continuing dialogue regarding the effects of HIV infection on the gut and the need to restore mucosal immune function to pre-infection levels.

A larger randomized, blinded study testing SBI as distinct nutrition for management of HIV-associated enteropathy is currently underway to confirm these results (www.clinicaltrials.gov, NCT01828593). This study on EnteraGam is the only clinical trial currently being performed nationwide on patients suffering with HIV-associated enteropathy.

EnteraGam™, a medical food, is being developed for the management of HIV-associated enteropathy in patients who have impaired capacity to absorb nutrients from food. Patients with HIV-associated enteropathy suffer from malnutrition due to this impaired absorption. These patients also face persistent bouts of chronic diarrhea, which predictably provokes the development of drug resistance.

The question of the impact of HIV-associated enteropathy on a case study presented at the 14th International Workshop on the Clinical Pharmacology of HIV Therapy in Amsterdam, the Netherlands in April of this year spurred discussion of the effect of this condition on the pharmacology of HIV and Hepatitis C treatments as it affects the level of medication and drug-interactions. HIV-associated enteropathy was also the topic of a presentation at the 30 Years of HIV Science: Imagine the Future meeting that took place at Institut Pasteur from May 21-23, 2013 in Paris, France. The historic meeting brought together 500 leading world-renowned scientists, clinicians and community activists in the very place where HIV was discovered, for which the conference organizer, Francoise Barre-Sinoussi, won the Nobel Prize in 2008. It was suggested that addressing HIV-associated enteropathy will reduce microbial translocation in the gut and thus the chronic inflammation that plagues HIV patients, even those chronically, successfully suppressed on HAART.

It is obvious from discussions at these recent meetings that despite the current issues of budgetary convolutions due to sequestration in the U.S. and austerity measures in Europe, public research dollars are going to be necessary for further studies on HIV-associated enteropathy. Some community leaders are hoping to provoke the development and circulation of concept sheets by leading Principal Investigators for the ACTG and other HIV research networks at the upcoming 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) taking place from June 30-July 3, 2013 in Kuala Lumpur. This will be the largest scientific meeting focused on HIV this year and represent our best chance of seeing HIV-associated enteropathy studies move forward.

A clinical investigation of EnteraGam™ as a nutritional therapy along with HAART on HIV-associated enteropathy by publicly facilitated HIV research networks could further validate the data presented at AIDS 2012 and CROI and reported in the May 22, 2013 issue of AIDS and translate to tens of millions of dollars saved in public health costs. Continuing to ignore HIV-associated enteropathy comes at too high a price both for patients and our global efforts to change the course of the epidemic.

It is hard to digest that persistent and debilitating HIV-associated enteropathy is still the state of affairs given the advancements made over the past 15 years in the treatment of HIV. HIV-associated enteropathy is affecting the pharmacology and efficacy of HAART, Hepatitis C treatment, psychotropic medications and impairs mucosal integrity in the gut, which studies indicate is a fundamental mechanism of the chronic inflammation in HIV infection and persists despite durable viral suppression in patients on HAAART.

These are hard times with dozens of agendas pushing equally important clinical priorities in public health systems and scientific investigation programs, while competing for dwindling funding dollars. We learned at the beginning of the AIDS crisis that innovative approaches often yield disproportionately beneficial results that translate to unexpected advances across the field of public health. HIV-associated enteropathy is but one example where advances can be made that will yield more sustainable patient outcomes for the long haul ahead, as the agenda for the XX International AIDS Conference is being set.

Written by David Miller and Mariel Selbovitz, MPH

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