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The Importance of Treatment Adherence in HIV
Kenneth L. Schaecher, MD, FACP, CPC
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Management of Noninfectious Diarrhea Associated With HIV and Highly Active Antiretroviral Therapy
Rodger D. MacArthur, MD

Management of Noninfectious Diarrhea Associated With HIV and Highly Active Antiretroviral Therapy

Rodger D. MacArthur, MD
In geographic locations where highly active antiretroviral therapy (HAART) is widely available, the nature of HIV-related diarrhea has shifted from being predominantly a consequence of opportunistic infection to being largely a side effect of HAART agents. With this shift has come a smaller risk for the life-threatening wasting and weight loss, although serious instances of noninfectious diarrhea remain a concern. While estimates vary, in part due to the lack of a standard diarrhea definition, over a quarter of patients receiving HAART experience diarrhea. The negative effect on quality-of-life in patients with HAART-related diarrhea is profound; diarrhea may also increase the risk of poor adherence to treatment, with potentially serious effects on viral suppression and increased risk of drug resistance. Diagnosis of HAART-related diarrhea largely involves ruling out pathogen involvement, which, in addition to laboratory testing, may require endoscopic examination. Treatment was, until recently, mainly supportive in nature. The recent US Food and Drug Administration approval of crofelemer offers the first reliably effective treatment for HAART-related diarrhea.

Am J Manag Care. 2013;19(11 suppl):S238-S245
 
Introduction

Prior to the advent of highly active antiretroviral therapy (HAART; also referred to as combination antiretroviral therapy), diarrhea in patients with HIV was primarily a result of opportunistic infections that often manifested with devastating effects. Malabsorption and maldigestion exacerbated weight loss and wasting, contributing, in turn, to high rates of mortality. Gastrointestinal (GI) disease, in fact, was the primary cause of morbidity and mortality among patients with AIDS in the pre-HAART era.1 The emergence of, and continuous improvements to, HAART have considerably reduced mortality and morbidity in the HIV/AIDS populations, including a significant reduction in GI disease. Despite these improvements, diarrhea is still very common, but the nature of the diarrhea and the degree of risk associated with diarrhea in patients receiving HAART has changed. While the prevalence of infectious diarrhea has diminished considerably, there has been a corresponding rise in noninfectious, often chronic, diarrhea in patients being treated with HAART.2 The primary cause of noninfectious diarrhea in HIV-positive patients receiving HAART is the treatment itself, of which diarrhea is a fairly common side effect, although certain antiretroviral (ART) agents are more likely to cause diarrhea than others.3 Noninfectious diarrhea can also derive from the pathological effects of HIV on cells and on the immune system in the GI tract, while HIV enteropathy can also produce a noninfectious form of diarrhea at almost any stage of HIV/AIDS.3,4

A precise estimation of the current rate of chronic diarrhea in HIV is problematic because of the multiple ways of defining diarrhea. With regard to the terminology and definitions used in clinical trials of diarrhea in HIV, there exists no widespread agreement as to whether acute diarrhea should be measured together with or separately from chronic diarrhea; what minimum level of stool frequency is definitive, what form the stool should take, and what descriptive terms should be used (“watery,” “loose,” “unformed,” etc); and, at a global level, whether a given patient population has access to HAART. Nevertheless, while diarrhea may be delineated in multiple ways, the Division of AIDS of the National Institute of Allergy and Infectious Diseases has defined 4 grades of diarrhea severity as shown in Table 1.5,6

Three studies of diarrhea in the HAART era offer a sense of its range of prevalence. A study conducted by Siddiqui et al in New York City (Bellevue Hospital and Veterans Affairs Harbor Healthcare System) included 163 consecutive HIV-positive patients, 150 of them (92.0%) receiving HAART, and 253 HIV-negative patients who served as controls. The authors found that 28.2% of patients infected with HIV had experienced diarrhea, defined as 3 or more bowel movements per day over the previous 7 days, compared with 7.1% of HIV-negative subjects, a nearly 4-fold difference (P <.001). Patients with HIV were also more likely to experience diarrhea if they were older or had received treatment with a protease inhibitor (PI).7

Zingmond et al evaluated the prevalence and characteristics of diarrhea in HIV-positive patients participating in 2 Veteran’s Affairs studies: the HIV Cost and Service Utilization Study (HCSUS), which included 2864 patients, and the Veterans Aging Cohort 3 Site Study (VACS 3), which included 881 patients. Participants in the VACS 3 study were largely non-white (67%), and 42% were aged 50 years or over. Patients in the HCSUS study were approximately 50% non-white, with 10% aged 50 years or over. More than 85% of patients in the VACS 3 study were receiving antiretroviral therapy (ART) compared with more than 80% in the HCSUS study. Diarrhea was observed in 53% of the HCSUS patients under the age of 50 years and 37% of those aged 50 years or over (P <.01). In the VACS 3 study, 60% of those under 50 years experienced diarrhea compared with 55% of those aged 50 years or over (P = NS).8

Finally, a study from the United Kingdom evaluated 778 patients with HIV in the London area, 67% of whom were receiving ART and 20% of whom were treatment naïve. Similar to the HCSUS and VACS 3 studies, the authors found that 54% of patients had experienced diarrhea in the previous 7 days.9

It is, of course, difficult to clearly identify exactly why rates of diarrhea varied among studies. Numerous possible causes may be identified, including the definition of diarrhea applied and the time frame of its measurement. Differences between study populations are also plausible confounding factors, including such variables as differences in ART regimens, baseline health, stage of infection, diet, and patient age. Indeed, the relationship between patient age and diarrhea risk is an important one, particularly in light of the aging of the HIV patient population.

Patient Burden of HIV-Related Diarrhea

As with any serious side effect caused by a medication, there always exists a risk of diminished adherence to therapy. It is widely assumed that the diarrhea associated with HAART reduces adherence. The available data are ambiguous on the relationship between diarrhea and adherence with HAART. Rather than seeing an independent association of diarrhea with poor treatment adherence, the medical literature suggests that diarrhea, in combination with other treatmentrelated symptoms, exerts a negative effect on adherence.9-11 That said, the relationship between gastrointestinal adverse events (AEs), such as diarrhea, and discontinuation of ART has been better established. A retrospective cohort study, published in 2012, assessed the key factors in treatment discontinuation in 1096 HIV-positive patients who had initiated first-line ART. The authors found that among AEs, gastrointestinal AEs constituted the largest factor, comprising nearly 29% of AE-related ART discontinuations.12

Poor adherence in HIV is of concern not only because it lessens the likelihood of optimal viral suppression, but also because irregular administration of HAART increases the risk of the development of HIV drug-limiting mutations.13,14 A study published in 2012 found that HIV-positive children in Ethiopia who experienced diarrhea after the initiation of first-line HAART had a significantly increased risk of treatment failure.15 Cadosch et al determined that the risk of treatment failure, and of developing drug resistance, due to poor adherence is contingent on both the particular drug being taken, specifically with regard to its half-life, and the duration of a patient’s “drug holiday.” Brief and repeated dose skipping was shown, in the case of drugs with shorter half-lives, to be associated with a greater risk for emerging drug resistance than a longer uninterrupted period of nonadherence.13

In addition to the risk of poor adherence, diarrhea in HIV has a considerable and adverse effect on quality-of-life (QoL). Diarrhea at its most severe, including diarrhea secondary to HAART, can be life-threatening.16 In the Siddiqui study, the authors sought to determine the effect of diarrhea in HIV on health-related QoL (HRQoL) by comparing HIV-infected patients with and without diarrhea using the Medical Outcomes Study HIV (MOS-HIV) Health Survey. Compared with patients who did not experience diarrhea, patients who did experience diarrhea scored significantly worse on 9 out of 11 domains of the MOS-HIV instrument, including measures of physical health, social function, health distress, and pain (Table 2).7

The Palladio Study Group undertook an evaluation of HIV-related diarrhea on HRQoL using data from a multicenter prospective observational study of 100 HIV-positive patients at 11 AIDS clinics in Italy who were receiving HAART. A total of 271 patients with HIV who had participated in an earlier prospective observational study, none of whom had experienced diarrhea, served as individually matched controls for the initial 100 patients; all of these had also been receiving HAART and were matched by CDC disease stage. The MOS-HIV instrument was used to measure HRQoL. In this study, HRQoOL was found to be significantly worse in all 11 MOS-HIV domains, with notably larger gaps in scores for social function, role function, energy/fatigue, and health transition for those patients who experienced diarrheal symptoms.17

Diagnosis

Diagnosis of diarrhea in HIV can be thought of as progressing through 1 to 4 stages. The first stage seeks to determine whether or not a pathogen is the cause of the diarrhea. If a pathogen is not the cause, the second stage involves examination of the GI tract to ascertain whether one of a number observable causes of the diarrhea can be perceived. This evaluation is particularly important in cases of acute or subacute diarrhea, and for the evaluation of diarrhea in HIV-infected persons with CD4+ lymphocyte counts less than 100 cells per microliter. The third stage is an evaluation of the patient’s HAART regimen to discern whether the diarrhea is a treatment side effect. If none of these approaches yields a diagnosis, and if the diarrhea has persisted for at least 1 month, an HIV enteropathy diagnosis should be considered.3

Prior to the first stage, however, the clinician must determine whether the patient does, in fact, have diarrhea as opposed to fecal incontinence. A functional definition of diarrhea involves passing 3 or more abnormal stools in a 24-hour period or liquid stools in excess of 200 grams over the same time period. If diarrhea is confirmed, the duration of the diarrhea should be established to distinguish between acute and chronic diarrhea, with diarrhea in excess of 4 weeks duration being considered chronic.3

Stage 1: Evaluation for Pathogen Involvement3,4
  1. Physical examination, patient/HIV history, treatment history, determination of possibility of exposure to pathogen
  2. Stool examination; requires up to 3 stool samples taken over a period of 10 days. Specimens should be over 2 g and transported to the testing lab without delay. Microbiologic examination for ova, cysts, and parasites (eg, cryptosporidia); culture for enteric pathogens; depending on evidence, tests for: Salmonella sp, Shigella sp, Campylobacter sp, Clostridium difficile, mycobacterium avium complex (MAC); assay for stool protozoa (polymerase chain reaction analysis or an antigen detection test)
  3. Plasma CD4+ count to measure degree of immunosuppression and establish spectrum of possible opportunistic infection
  4. HIV viral load to determine response to ART. An increase in viral load is the earliest sign of nonadherence, treatment failure, or resistance; viral load increases occur before reductions in CD4+ count


Stage 2: Examination of Gastrointestinal Tract

 
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