• A biregional survey and review of first-line treatment failure and second-line paediatric antiretroviral access and use in Asia and southern Africa

      Van Cutsem, G; Saphonn, V; Saramony, S; Vibol, U; Zhang, FJ; Han, N; Saghayam, S; Kurniati, N; Muktiarti, D; Fong, SM; Thien, M; Nik Yusoff, NK; Hai, LC; Razali, K; TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand. annette.sohn@treatasia.org (BioMed Central, 2011-04-08)
      To better understand the need for paediatric second-line antiretroviral therapy (ART), an ART management survey and a cross-sectional analysis of second-line ART use were conducted in the TREAT Asia Paediatric HIV Observational Database and the IeDEA Southern Africa (International Epidemiologic Databases to Evaluate AIDS) regional cohorts.
    • Diagnosis and management of antiretroviral-therapy failure in resource-limited settings in sub-Saharan Africa: challenges and perspectives.

      Harries, Anthony D; Zachariah, Rony; van Oosterhout, Joep J; Reid, Steven D; Hosseinipour, Mina C; Arendt, Vic; Chirwa, Zengani; Jahn, Andreas; Schouten, Erik J; Kamoto, Kelita; International Union against Tuberculosis and Lung Disease, Paris, France. adharries@theunion.org (2010-01)
      Despite the enormous progress made in scaling up antiretroviral therapy (ART) in sub-Saharan Africa, many challenges remain, not least of which are the identification and management of patients who have failed first-line therapy. Less than 3% of patients are receiving second-line treatment at present, whereas 15-25% of patients have detectable viral loads 12 months or more into treatment, of whom a substantial proportion might have virological failure. We discuss the reasons why virological ART failure is likely to be under-diagnosed in the routine health system, and address the current difficulties with standard recommended second-line ART regimens. The development of new diagnostic tools for ART failure, in particular a point-of-care HIV viral-load test, combined with simple and inexpensive second-line therapy, such as boosted protease-inhibitor monotherapy, could revolutionise the management of ART failure in resource-limited settings.
    • HIV drug resistance.

      Calmy, A; Pascual, F; Ford, N (Massachusetts Medical Society, 2004-06-24)
    • HIV Viral Load Monitoring in Resource-Limited Regions: Optional or Necessary?

      Calmy, A; Ford, N; Hirschel, B; Reynolds, S; Lynen, L; Goemaere, E; Garcia de la Vega, F; Perrin, L; Rodriguez, W; Medecins sans Frontieres, Access to Medicines Campaign, Geneva, 1211, Switzerland. acalmy@gmail.com (Published by: Infectious Diseases Society of America, 2007-01-01)
      Although it is a standard practice in high-income countries, determination of the human immunodeficiency virus (HIV) load is not recommended in developing countries because of the costs and technical constraints. As more and more countries establish capacity to provide second-line therapy, and as costs and technological constraints associated with viral load testing decrease, the question of whether determination of the viral load is necessary deserves attention. Viral load testing could increase in importance as a guide for clinical decisions on when to switch to second-line treatment and on how to optimize the duration of the first-line treatment regimen. In addition, the viral load is a particularly useful tool for monitoring adherence to treatment, performing sentinel surveillance, and diagnosing HIV infection in children aged <18 months. Rather than considering viral load data to be an unaffordable luxury, efforts should be made to ensure that viral load testing becomes affordable, simple, and easy to use in resource-limited settings.
    • Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting.

      van Zyl, Gert Uves; van Mens, Thijs E; McIlleron, Helen; Zeier, Michele; Nachega, Jean B; Decloedt, Eric; Malavazzi, Carolina; Smith, Peter; Huang, Yong; van der Merwe, Lize; Gandhi, Monica; Maartens, Gary; Division of Medical Virology, Department of Pathology, NHLS Tygerberg and Stellenbosch University, Tygerberg, South Africa. guvz@sun.ac.za (2011-04)
      In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure.
    • Outcomes After Virologic Failure of First-Line ART in South Africa

      Murphy, Richard A; Sunpath, Henry; Lu, Zhigang; Chelin, Neville; Losina, Elena; Gordon, Michelle; Ross, Douglas; Ewusi, Aba D; Matthews, Lynn T; Kuritzkes, Daniel R; Marconi, Vincent C; Operational Support Unit, Doctors Without Borders, New York, New York; McCord Hospital, Durban, South Africa; Massachusetts General Hospital, Boston, Massachusetts, USA; Nelson Mandela School of Medicine, Durban; St. Mary’s Hospital, Mariannhill, South Africa; Harvard Medical School; Division of Infectious Diseases, Beth Israel Deaconess Medical Center; Section of Retroviral Therapeutics, Brigham and Women’s Hospital, Boston, Massachusetts; Infectious Disease Service, San Antonio Military Medical Center, Fort Sam Houston, Texas; Emory University School of Medicine, Atlanta, Georgia, USA (2010-04-24)
      To determine initial 24-week outcomes among prospectively enrolled patients with failure of initial antiretroviral therapy (ART).
    • Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy

      Boulle, A; Van Cutsem, G; Cohen, K; Hilderbrand, K; Mathee, S; Abrahams, M; Goemaere, E; Coetzee, D; Maartens, G; School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; Médecins Sans Frontières, Cape Town, South Africa; Site B Community Health Centre, Department of Health, Provincial Government of the Western Cape, Cape Town, South Africa (2008-08-06)
      CONTEXT: Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described. OBJECTIVE: To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006. INTERVENTIONS: Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. MAIN OUTCOME MEASURES: Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed. RESULTS: The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7). CONCLUSION: In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.
    • Second-line antiretroviral therapy in resource-limited settings: the experience of Médecins Sans Frontières

      Pujades-Rodriguez, M; O'Brien, D; Humblet, P; Calmy, A; Epicentre, Paris, France; Médecins Sans Frontières, Paris, France; Campaign for Access to Essential Medicines, Geneva, Switzerland (2008-07-11)
      OBJECTIVES: To describe the use of second-line protease-inhibitor regimens in Médecins Sans Frontières HIV programmes, and determine switch rates, clinical outcomes, and factors associated with survival. DESIGN/METHODS: We used patient data from 62 Médecins Sans Frontières programmes and included all antiretroviral therapy-naive adults (> 15 years) at the start of antiretroviral therapy and switched to a protease inhibitor-containing regimen with at least one nucleoside reverse transcriptase inhibitor change after more than 6 months of nonnucleoside reverse transcriptase inhibitor first-line use. Cumulative switch rates and survival curves were estimated using Kaplan-Meier methods, and mortality predictors were investigated using Poisson regression. RESULTS: Of 48,338 adults followed on antiretroviral therapy, 370 switched to a second-line regimen after a median of 20 months (switch rate 4.8/1000 person-years). Median CD4 cell count at switch was 99 cells/microl (interquartile ratio 39-200; n = 244). A lopinavir/ritonavir-based regimen was given to 51% of patients and nelfinavir-based regimen to 43%; 29% changed one nucleoside reverse transcriptase inhibitor and 71% changed two nucleoside reverse transcriptase inhibitors. Median follow-up on second-line antiretroviral therapy was 8 months, and probability of remaining in care at 12 months was 0.86. Median CD4 gains were 90 at 6 months and 135 at 12 months. Death rates were higher in patients in World Health Organization stage 4 at antiretroviral therapy initiation and in those with CD4 nadir count less than 50 cells/microl. CONCLUSION: The rate of switch to second-line treatment in antiretroviral therapy-naive adults on non-nucleoside reverse transcriptase inhibitor-based first-line antiretroviral therapy was relatively low, with good early outcomes observed in protease inhibitor-based second-line regimens. Severe immunosuppression was associated with increased mortality on second-line treatment.
    • Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

      Keiser, Olivia; Tweya, Hannock; Boulle, Andrew; Braitstein, Paula; Schecter, Mauro; Brinkhof, Martin W G; Dabis, François; Tuboi, Suely; Sprinz, Eduardo; Pujades-Rodriguez, Mar; Calmy, Alexandra; Kumarasamy, Nagalingeswaran; Nash, Denis; Jahn, Andreas; MacPhail, Patrick; Lüthy, Ruedi; Wood, Robin; Egger, Matthias; Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland. (2009-09-10)
      In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia.
    • Treatment failure and mortality factors in patients receiving second-line HIV therapy in resource-limited countries.

      Pujades-Rodríguez, Mar; Balkan, Suna; Arnould, Line; Brinkhof, Martin A W; Calmy, Alexandra; Epicentre, Médecins Sans Frontières 42-bis, Bd, 8 rue Saint Sabin, 75011 Paris, France. mar.pujades@epicentre.msf.org (2010-07-21)
      CONTEXT: Long-term antiretroviral therapy (ART) use in resource-limited countries leads to increasing numbers of patients with HIV taking second-line therapy. Limited access to further therapeutic options makes essential the evaluation of second-line regimen efficacy in these settings. OBJECTIVES: To investigate failure rates in patients receiving second-line therapy and factors associated with failure and death. DESIGN, SETTING, AND PARTICIPANTS: Multicohort study of 632 patients > 14 years old receiving second-line therapy for more than 6 months in 27 ART programs in Africa and Asia between January 2001 and October 2008. MAIN OUTCOME MEASURES: Clinical, immunological, virological, and immunovirological failure (first diagnosed episode of immunological or virological failure) rates, and mortality after 6 months of second-line therapy use. Sensitivity analyses were performed using alternative CD4 cell count thresholds for immunological and immunovirological definitions of failure and for cohort attrition instead of death. RESULTS: The 632 patients provided 740.7 person-years of follow-up; 119 (18.8%) met World Health Organization failure criteria after a median 11.9 months following the start of second-line therapy (interquartile range [IQR], 8.7-17.0 months), and 34 (5.4%) died after a median 15.1 months (IQR, 11.9-25.7 months). Failure rates were lower in those who changed 2 nucleoside reverse transcriptase inhibitors (NRTIs) instead of 1 (179.2 vs 251.6 per 1000 person-years; incidence rate ratio [IRR], 0.64; 95% confidence interval [CI], 0.42-0.96), and higher in those with lowest adherence index (383.5 vs 176.0 per 1000 person-years; IRR, 3.14; 95% CI, 1.67-5.90 for < 80% vs > or = 95% [percentage adherent, as represented by percentage of appointments attended with no delay]). Failure rates increased with lower CD4 cell counts when second-line therapy was started, from 156.3 vs 96.2 per 1000 person-years; IRR, 1.59 (95% CI, 0.78-3.25) for 100 to 199/microL to 336.8 per 1000 person-years; IRR, 3.32 (95% CI, 1.81-6.08) for less than 50/microL vs 200/microL or higher; and decreased with time using second-line therapy, from 250.0 vs 123.2 per 1000 person-years; IRR, 1.90 (95% CI, 1.19-3.02) for 6 to 11 months to 212.0 per 1000 person-years; 1.71 (95% CI, 1.01-2.88) for 12 to 17 months vs 18 or more months. Mortality for those taking second-line therapy was lower in women (32.4 vs 68.3 per 1000 person-years; hazard ratio [HR], 0.45; 95% CI, 0.23-0.91); and higher in patients with treatment failure of any type (91.9 vs 28.1 per 1000 person-years; HR, 2.83; 95% CI, 1.38-5.80). Sensitivity analyses showed similar results. CONCLUSIONS: Among patients in Africa and Asia receiving second-line therapy for HIV, treatment failure was associated with low CD4 cell counts at second-line therapy start, use of suboptimal second-line regimens, and poor adherence. Mortality was associated with diagnosed treatment failure.
    • Treatment outcomes of patients on Second-line Antiretroviral Therapy in resource-limited settings: A Systematic Review and Meta-Analysis

      Ajose, Olawale; Mookerjee, Siddharth; Mills, Edward J; Boulle, Andrew; Ford, Nathan; Clinton Health Access Initiative, Dar es Salaam, Tanzania. (2012-05-15)
      A growing proportion of patients on antiretroviral therapy in resource-limited settings have switched to second-line regimens. We carried out a systematic review in order to summarize reported rates and reasons for virological failure among people on second-line therapy in resource-limited settings.
    • Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration

      Davies, Mary-Ann; Moultrie, Harry; Eley, Brian; Rabie, Helena; Van Cutsem, Gilles; Giddy, Janet; Wood, Robin; Technau, Karl; Keiser, Olivia; Egger, Matthias; Boulle, Andrew; School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; Enhancing Children's HIV Outcomes (Harriet Shezi Children's Clinic, Chris Hani Baragwanath Hospital, Soweto) and School of Public Health, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; Red Cross Children's Hospital and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa; Tygerberg Academic Hospital, University of Stellenbosch, Stellenbosch, South Africa; Médecins Sans Frontières, Khayelitsha, South Africa and Khayelitsha ART Programme; McCord Hospital, Durban, South Africa; Gugulethu Community Health Centre and Desmond Tutu HIV Centre, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Empilweni Service and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland (Lippincott Williams & Wilkins, 2011-03-01)
      With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa.