Global impact of antiretroviral therapy-associated diarrhea.

Side effects of antiretroviral therapy (ART) still remain a formidable issue for patients globally. In resource-limited settings, side effects are a major risk for lack of treatment adherence. Diarrhea remains one of the leading side effects seen in ART, and it contributes significantly to lack of treatment adherence in patients experiencing it. Historically, diarrhea in HIV-positive patients was due to opportunistic infections or HIV itself. However, since the advent of highly active antiretroviral therapy (HAART), diarrhea is now thought to be primarily due to antiretrovirals. It is noted that among the major classes of antiretrovirals, protease inhibitors (and in particular ritonavir) seem to carry the greatest risk of for ART-induced diarrhea. Two recent reviews highlight the importance of ART-associated diarrhea in HIV-infected patients, and focus on data regarding ritonavir-associated diarrhea. Macarthur and DuPont found that up to 18% (range, 2–18%) of patients on ritonavir-boosted protease inhibitor regimens experience grade 2–4 diarrhea (grade 1=mild; grade 2 =moderate; grade 3 = severe; grade 4= life threatening). Wegzyn et al. reported a diarrhea incidence of 15.5% in patients taking ritonavir-boosted lopinavir as part of their ART. These results mimic a previous review that demonstrated up to 19% (range, 2–19%) of patients experience diarrhea on similar regimens. Given that none of the current recommended therapies for first-line treatment of ART-naı̈ve patients by the World Health Organization (WHO) include protease inhibitors or ritonavir-boosted regimens, the global impact of ART-associated diarrhea remains unclear. We conducted a review of published manuscripts in PubMed to assess the rate of diarrhea associated with the six WHOrecommended HIV regimens for ART-naı̈ve patients. A literature search on August 1, 2012 produced 235 article titles. Search strategies used in PubMed were as follows: (‘‘azt’’ or ‘‘azidothymidine’’ or ‘‘ZDV’’ or ‘‘zidovudine’’) and (‘‘3TC’’ or ‘‘lamivudine’’) and (‘‘EFV’’ or ‘‘efavirenz’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’); (‘‘azt’’ or ‘‘azidothymidine’’ or ‘‘ZDV’’ or ‘‘zidovudine’’) and (‘‘3TC’’ or ‘‘lamivudine’’) and (‘‘NVP’’ or ‘‘nevirapine’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’); (‘‘TDF’’ or ‘‘tenofovir’’) and (‘‘3TC’’ or ‘‘lamivudine’’) and (‘‘EFV’’ or ‘‘efavirenz’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’); (‘‘TDF’’ or ‘‘tenofovir’’) and (‘‘FTC’’ or ‘‘emtricitabine’’) and (‘‘EFV’’ or ‘‘efavirenz’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’); (‘‘TDF’’ or ‘‘tenofovir’’) and (‘‘FTC’’ or ‘‘emtricitabine’’) and (‘‘NVP’’ or ‘‘nevirapine’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’); (‘‘TDF’’ or ‘‘tenofovir’’) and (‘‘3TC’’ or ‘‘lamivudine’’) and (‘‘NVP’’ or ‘‘nevirapine’’) and (‘‘adverse events’’ or ‘‘side effects’’ or ‘‘diarrhea’’). An initial screen for English and relevance of titles resulted in 133 abstracts, for which articles were retrieved and assessed for inclusion and exclusion criteria. This resulted in 13 unique articles to be included in our study. Manuscripts were excluded for the following reasons: diarrhea-specific data not provided (71), data provided as an aggregate of several treatment regimens (23), selected treatment regimens were not assessed (10), treatment regimen included additional ART drugs (5), duplicate data/ article (4), time extension of previous study (4), fewer than 10 patients (1), regimen altered because of policy change (1), and article not retrievable (1). Comparative and noncomparative trials were included in the review, as were prospective and retrospective studies. All diarrheal definitions were considered. Diarrhea was assessed by physician or self-reported by patients. Authors were not contacted for additional data. Up to 38% of subjects (range, 0–38%, weighted mean 11%, n= 3649) receiving one of the six WHO regimens experienced diarrhea. Regimen-specific data are as follows: zidovudine (AZT) + lamivudine (3TC) + efavirenz (EFV) (range, 4–18%, weighted mean 8%, n = 1627), AZT + 3TC +nevirapine (NVP) (range, 0–38%, weighted mean 7%, n = 146), tenofovir (TDF) + emtricitabine (FTC) +EFV (range, 3–33%, weighted mean 12%, n = 1466), TDF + 3TC +EFV (range, 5–11%, weighted mean 6%, n = 410), TDF + 3TC +NVP (no data available), TDF + FTC +NVP (no data available; Table 1). When reported, study duration varied from 12 to 168 weeks. Only one study was conducted in a pediatric population with the remainder conducted in adults. One study was a postexposure prophylaxis study while the others were treatment studies. The majority of study sites were in resource-wealthy settings. Six articles reported grade 1–4 diarrhea or mild to severe diarrhea (no life-threatening diarrhea emerged in the study), 4 articles reported grade 2–4 diarrhea or moderate to severe diarrhea (no life-threatening diarrhea emerged in the study), and 3 articles did not indicate what grade of diarrhea was reported. The range of ART-associated diarrhea among the four WHO-recommended first-line regimens for which data were