Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings.

BACKGROUND: One of the critical clinical decisions made in antiretroviral therapy (ART) is when to switch from an initial regimen to another due to treatment failure. This complex process requires consideration of multiple factors including: (1) what type of monitoring (e.g. clinical, immunologic, virologic) is available to guide switching; (2) establishing criteria for treatment failure (e.g. viral load >10,000 copies/mL); (3) integrating data from different types of monitoring; (4) making a decision; and, if possible, (5) follow-up and monitoring to determine patient outcomes. The initial step in this model of deciding when to switch is determining what type of monitoring for guiding when to switch is available and appropriate. This review seeks to find and summarize evidence on optimal monitoring strategies for guiding when to switch first-line regimens due to treatment failure among adults and adolescents living with HIV in low-resource settings. This review was one of a series of reviews prepared in 2009 at the request of the World Health Organization to inform the development of new guidelines on ART for adults and adolescents. OBJECTIVES: To assess optimal monitoring strategies for guiding when to switch antiretroviral therapy regimens for first-line treatment failure among adults and adolescents living with HIV in low-resource settings. SEARCH STRATEGY: We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status. In July 2009, we search the following electronic journal and trial databases: MEDLINE, EMBASE, CENTRAL. We also searched conference databases using NLM Gateway (for HIV/AIDS conference abstracts before 2005), abstract databases from the Conferences on Retroviruses and Opportunistic Infections, International AIDS Conferences, and International AIDS Society Conferences on HIV Pathogenesis, Treatment, and Prevention from 2005 to 2009, and the trials registers ClinicalTrials.gov, Current Controlled Trials, and Pan-African Clinical Trials Registry. We contacted researchers and relevant organizations and checked reference lists for all included studies. SELECTION CRITERIA: We selected studies which evaluated a monitoring intervention/strategy that helps guide when to switch ART. Study types included randomized controlled trials and observational studies (cohort and case-control) which included comparators. DATA COLLECTION AND ANALYSIS: One author performed an initial screening. Two authors performed a detailed screening. Two authors independently assessed study eligibility, extracted data, and graded methodological quality. Differences were resolved by a third reviewer. Heterogeneity was assessed, and meta-analyses were performed where appropriate. MAIN RESULTS: Two randomized trials were identified which were in abstract form only. Two cohort studies (both published) with comparators were identified. Of the evidence available, three comparisons were studied: clinical versus immunologic and clinical monitoring; clinical versus virologic, immunologic, and clinical monitoring; and immunologic and clinical monitoring versus virologic, immunologic, and clinical monitoring. Clinical vs. Immunologic and Clinical Monitoring: Based upon two randomized trials, clinical monitoring alone results in increased mortality (low-quality evidence), increased AIDS-defining illnesses and mortality as a composite endpoint (moderate), no difference in serious adverse events (low), increased numbers of unnecessary switches (low), and no difference in switches to second-line (low) compared to immunological and clinical monitoring. Clinical vs. Virologic, Immunologic, and Clinical Monitoring: Based upon a single randomized trial, clinical monitoring alone results in a trend toward increased mortality (low), increased AIDS-defining illnesses and mortality as a composite endpoint (low), increased unnecessary switches (low), no difference in virologic treatment failures (low), and a trend toward increased switches to second-line (low) compared to virologic, immunologic, and clinical monitoring. Immunologic and Clinical vs. Virologic, Immunologic, and Clinical Monitoring: Based upon a single randomized trial, immunologic and clinical monitoring results in no difference in mortality (low), no difference in AIDS-defining illnesses and mortality as a composite endpoint (low), no difference in unnecessary switches (very low), no difference in virologic treatment failures (low), and no difference in switches to second-line (low) compared to virologic, immunologic, and clinical monitoring. Observational studies appear to demonstrate that programs with virologic, immunologic, and clinical monitoring switch therapy more frequently (very low), earlier (very low), and at higher CD4 counts (very low) compared with programs that have immunologic and clinical monitoring alone. AUTHORS' CONCLUSIONS: A limited number of studies were available to address this topic, and, of the two randomized trials identified, both were in abstract form only. Observational studies also were limited in number and were of lesser quality. Although the quality of the evidence varied from the randomized trials, ranging from very low to moderate, there appeared to be substantial benefits for key outcomes (e.g. mortality, AIDS-defining illness and mortality as a composite endpoint, and unnecessary switches) favoring both immunologic and clinical monitoring or virologic, immunologic, and clinical monitoring versus clinical monitoring alone. Very low-quality evidence from observational studies suggested that virologic, immunologic, and clinical monitoring led to more frequent switching, earlier switching, and switching at higher CD4 counts compared with immunologic and clinical monitoring. Further information on the studies currently reported in abstract form will provide insight. Ongoing studies addressing this topic likely will provide information to further clarify optimal monitoring strategies for guiding when to switch first-line therapy. Additionally, studies looking at different virologic monitoring frequencies and/or virologic monitoring at different times after ART initiation (e.g. after 2-3 years) would be informative. Finally, cost-analysis studies will lend further insights into the applicability of these findings to low-resource settings.

Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy has reduced the morbidity and mortality of patients with HIV/AIDS. A common first-line ART regimen in low-resource settings includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary. OBJECTIVES: This systematic review aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with a recommended World Health Organization (WHO) first-line regimen. SEARCH STRATEGY: Electronic databases and conference proceedings were searched with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials of HIV-infected adolescent and adult patients administered second-line ART after virologic failure of a first-line regimen were included. Observational studies were included given the insufficient number of trials identified. The primary outcome measure included mortality. Secondary outcome measures included rate of adverse events, change in mean CD4 cell count, clinical resolution of symptoms, proportion of patients achieving undetectable viral load (VL) and acquisition of genotypic mutations. DATA COLLECTION AND ANALYSIS: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. Risk of bias was assessed for individual studies and the GRADE approach for assessing the quality of evidence across a body of evidence was also applied. MAIN RESULTS: One randomised trial in 136 patients studied maintaining lamivudine in second-line regimens or not. There was no difference in virological outcomes in the group who maintained lamivudine and those who did not in their subsequent regimens. Two other small observational studies reported in abstract form also did not report a difference in the proportion of those with viral suppression after six months and time to HIV-1 RNA suppression among those on a lamivudine (3TC) or emtricitabine (FTC) regimen compared to those on a 3TC/FTC-sparing second-line regimen. There were no trials identified comparing boosted protease inhibitors (PIs) or nucleoside backbone combinations after first-line failure on non-thymidine analog combinations. Observational studies of populations starting ART in resource-limited settings suggest that short-term response on boosted PI-based regimens is encouraging. AUTHORS' CONCLUSIONS: There is limited evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with a WHO-recommended regimen. One randomised trial in 136 patients and two observational studies (both of low quality) suggest no difference in virological suppression whether or not lamivudine is maintained in a second-line regimen. While outcomes of second-line regimens with boosted PIs are favourable in general, there are no studies comparing boosted PIs directly in populations starting second-line regimens. Current recommendations are based on available resources and patient- and public-health-level considerations.

Prevention of diarrhoea in children with HIV infection or exposure to maternal HIV infection.

BACKGROUND: Diarrhoea is a major cause of morbidity and mortality among infants and children worldwide, especially in low- and middle-income countries. Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a condition that similarly disproportionately affects low- and middle-income countries; of the nearly 2.1 million children under age 15 years living with HIV/AIDS, the large majority reside in sub-Saharan Africa. Infants and children with HIV infection have more frequent and more severe diarrhoea than children without HIV. Interventions including vitamin A, zinc and cotrimoxazole may contribute substantially to preventing diarrhoea in children with HIV infection or exposure to HIV. OBJECTIVES: We perform a systematic review of randomised controlled trials and nonrandomised studies that examine the effectiveness of vitamin A, zinc and cotrimoxazole on mortality and morbidity from diarrhoea in HIV-infected and -exposed infants and children. SEARCH STRATEGY: Electronic databases including Pubmed, Central and EMBASE were searched without limits to language from 1980 to April 2010. Conference database searches were performed, experts were contacted and bibliographies were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs) and nonrandomised studies (NRSs) that examined the effectiveness of the three interventions were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed citations for eligibility and double-extracted included studies. Assessment of bias of individual studies was performed independently by both reviewers. Only two summary estimates were performed due to heterogeneity in study design and interventions. MAIN RESULTS: Four RCTs were identified for vitamin A. One RCT was identified for zinc. One RCT and two NRSs were identified for cotrimoxazole. Vitamin A reduced mortality overall in children with HIV infection (four studies). A pooled estimate of three studies for reduction in mortality from vitamin A compared to placebo had a relative risk (DerSimonian and Laird method, random effects) of 0.50 (95% confidence interval (CI): 0.31 to 0.79) in 267 patients. Diarrheoa-specific mortality did not reach statistical significance and diarrhoeal morbidity outcomes were variable in three trials. Zinc supplementation reduced the number of physician visits for watery diarrhoea in one trial. Cotrimoxazole reduced mortality and hospitalisations compared to placebo in one RCT, although diarrhoea-specific morbidities were not significant. AUTHORS' CONCLUSIONS: Vitamin A shows benefits in reduction of mortality in HIV-infected children. The effect of vitamin A on children with HIV exposure is not clear and needs further review. Zinc and combination vitamin A, zinc and micronutrient supplementation did not show an effect compared to vitamin A alone in children with HIV infection. Cotrimoxazole reduced mortality and some morbidity in children with HIV infection. Further research may clarify the effects of these interventions on morbidity from diarrhoea and in the population of children with HIV exposure.

Treatment interventions for diarrhoea in HIV-infected and HIV-exposed children: a systematic review.

INTRODUCTION: Seventy percent of an estimated 10 million children less than five years of age in developing countries die each year of acute respiratory infections, diarrhoea, measles, malaria, malnutrition or a combination of these conditions. Children living with Human immunodeficiency virus (HIV) are at risk of diarrhoea because of drug interactions with antiretroviral therapy and bottle feeding. This may be aggravated by malnutrition and other infectious diseases which are frequent in children living with HIV. Objective: to evaluate treatment interventions for diarrhoea in HIV infected and exposed children. METHODS: A comprehensive search was conducted on 02 June 2016 to identify relevant studies for inclusion. We included randomised controlled trials of HIV infected or exposed children under 15 years of age with diarrhoea. Two authors independently selected studies for inclusion, assessed risk of bias (RoB) and extracted data using a pre-designed data extraction form. RESULTS: We included two studies (Amadi 2002 and Mda 2010) that each enrolled 50 participants. The RoB was assessed as low-risk for both included studies. There was no difference in clinical cure and all-cause mortality between nitazoxanide and placebo for cryptosporidial diarrhoea in Amadi 2002. In Mda 2010, there was a reduction in duration of hospitalisation in the micronutrient supplement group (P < 0.005) although there was no difference in all-cause mortality. CONCLUSION: There is low certainty evidence on the effectiveness of nitazoxanide for treating cryptosporidial diarrhoea and micronutrient supplementation in children with diarrhoea. Adequately powered trials are needed to assess micronutrients and nitazoxanide, as well as other interventions, for diarrhoea in HIV-infected and-exposed children.