• Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration.

      Davies, Mary-Ann; Boulle, Andrew; Eley, Brian; Moultrie, Harry; Technau, Karl; Rabie, Helena; van Cutsem, Gilles; Giddy, Janet; Wood, Robin; Egger, Matthias; et al. (2011-08-11)
      Objectives  To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART). Methods  Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment. Results  Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008). Conclusion  Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children.
    • AZT impairs immunological recovery on first-line ART: collaborative analysis of cohort studies in Southern Africa

      Wandeler, Gilles; Gsponer, Thomas; Mulenga, Lloyd; Garone, Daniela; Wood, Robin; Maskew, Mhairi; Prozesky, Hans; Hoffmann, Christopher; Ehmer, Jochen; Dickinson, Diana; et al. (Wolters Kluwer Health | Lippincott Williams & Wilkins, 2013-05-08)
      OBJECTIVES
    • CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

      Hoffmann, Christopher J; Schomaker, Michael; Fox, Matthew P; Mutevedzi, Portia; Giddy, Janet; Prozesky, Hans; Wood, Robin; Garone, Daniela B; Egger, Matthias; Boulle, Andrew; et al. (Lippincott Williams & Wilkins, 2013-05-01)
      In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information.
    • Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa.

      Egger, Matthias; Spycher, Ben D; Sidle, John; Weigel, Ralf; Geng, Elvin H; Fox, Matthew P; MacPhail, Patrick; van Cutsem, Gilles; Messou, Eugène; Wood, Robin; et al. (2011-01)
      The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART.
    • Cost-effectiveness of point-of-care viral load monitoring of antiretroviral therapy in resource-limited settings: mathematical modelling study

      Estill, Janne; Egger, Matthias; Blaser, Nello; Vizcaya, Luisa Salazar; Garone, Daniela; Wood, Robin; Campbell, Jennifer; Hallett, Timothy B; Keiser, Olivia; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. jestill@ispm.unibe.ch (Wolters Kluwer Lippincott Williams & Wilkins, 2013-06-01)
      Monitoring of HIV viral load in patients on combination antiretroviral therapy (ART) is not generally available in resource-limited settings. We examined the cost-effectiveness of qualitative point-of-care viral load tests (POC-VL) in sub-Saharan Africa.
    • Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa.

      Fenner, Lukas; Brinkhof, Martin W G; Keiser, Olivia; Weigel, Ralf; Cornell, Morna; Moultrie, Harry; Prozesky, Hans; Technau, Karl; Eley, Brian; Vaz, Paula; et al. (2010-08-15)
      BACKGROUND: Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. PATIENTS AND METHODS: Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. RESULTS: Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing > or =120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing > or =20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). CONCLUSIONS: In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.
    • Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study.

      Cornell, Morna; Schomaker, Michael; Garone, Daniela Belen; Giddy, Janet; Hoffmann, Christopher J; Lessells, Richard; Maskew, Mhairi; Prozesky, Hans; Wood, Robin; Johnson, Leigh F; et al. (2012-09)
      Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
    • Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies

      Johnson, Leigh F; Mossong, Joel; Dorrington, Rob E; Schomaker, Michael; Hoffmann, Christopher J; Keiser, Olivia; Fox, Matthew P; Wood, Robin; Prozesky, Hans; Giddy, Janet; et al. (Public Library of Science, 2013-04-09)
      Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults.
    • Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings.

      Calmy, Alexandra; Balestre, Eric; Bonnet, Fabrice; Boulle, Andrew; Sprinz, Eduardo; Wood, Robin; Delaporte, Eric; Messou, Eugène; McIntyre, James; El Filali, Kamal Marhoum; et al. (BMC, 2012-12)
      Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART.
    • Monitoring of antiretroviral therapy and mortality in HIV programmes in Malawi, South Africa and Zambia: mathematical modelling study

      Estill, Janne; Egger, Matthias; Johnson, Leigh F; Gsponer, Thomas; Wandeler, Gilles; Davies, Mary-Ann; Boulle, Andrew; Wood, Robin; Garone, Daniela; Stringer, Jeffrey S A; et al. (Public Library of Science, 2013-02-28)
      Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference.
    • Monitoring the South African National Antiretroviral Treatment Programme, 2003-2007: the IeDEA Southern Africa collaboration.

      Cornell, Morna; Technau, Karl; Fairall, Lara; Wood, Robin; Moultrie, Harry; van Cutsem, Gilles; Giddy, Janet; Mohapi, Lerato; Eley, Brian; MacPhail, Patrick; et al. (2009-09)
      OBJECTIVES: To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. DESIGN AND SETTING: Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. SUBJECTS: Adults and children (<16 years old) who initiated ART with > or =3 antiretroviral drugs before 2008. RESULTS: Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p<0.001) and for those in stage IV (39-89 cells/microl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001). CONCLUSIONS: IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.
    • Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration.

      Davies, Mary-Ann; Keiser, Olivia; Technau, Karl; Eley, Brian; Rabie, Helena; van Cutsem, Gilles; Giddy, Janet; Wood, Robin; Boulle, Andrew; Egger, Matthias; et al. (2009-10)
      OBJECTIVES: To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. DESIGN AND SETTING: Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. SUBJECTS: ART-naive children (< or = 16 years) who commenced treatment with > or = 3 antiretroviral drugs before March 2008. OUTCOME MEASURES: Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. RESULTS: The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being < 18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (< 400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1 - 82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. CONCLUSIONS: Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.
    • Provision of antiretroviral therapy in South Africa: the nuts and bolts

      Bekker, Linda-Gail; Venter, Francois; Cohen, Karen; Goemare, Eric; Van Cutsem, Gilles; Boulle, Andrew; Wood, Robin (International Medical Press, 2014-10-13)
      Public sector antiretroviral provision had a slow start in South Africa despite a raging epidemic and a World AIDS conference that shed significant public light on the disparities of therapy access globally. This was largely due to political prevarication in the midst of AIDS denialism. There has been an unprecedented expansion in the HIV treatment programme since 2008. As a result, South Africa now has the largest number of patients on antiretroviral drugs in the world, and South African life expectancy has increased by more than a decade. However, this has led to a number of fiscal, logistic and operational challenges that the country must face as the treatment programme continues to expand. Challenges include increasing detection within communities, linkage and retention in care, while strengthening operational support functions such as consistent drug supply, health staffing and infrastructure, diagnostic services, programme monitoring and sustainable financing. As a middle-income country, albeit with marked income inequality, and the heaviest HIV burden in the world, South Africa is a test case of whether a large-scale public health programme can boast of success in the face of numerous other health-system challenges.
    • 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; et al. (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.
    • Temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across South Africa, 2002-2007.

      Cornell, Morna; Grimsrud, Anna; Fairall, Lara; Fox, Matthew P; van Cutsem, Gilles; Giddy, Janet; Wood, Robin; Prozesky, Hans; Mohapi, Lerato; Graber, Claire; et al. (2010-09-10)
      OBJECTIVE: Little is known about the temporal impact of the rapid scale-up of large antiretroviral therapy (ART) services on programme outcomes. We describe patient outcomes [mortality, loss-to-follow-up (LTFU) and retention] over time in a network of South African ART cohorts. DESIGN: Cohort analysis utilizing routinely collected patient data. METHODS: Analysis included adults initiating ART in eight public sector programmes across South Africa, 2002-2007. Follow-up was censored at the end of 2008. Kaplan-Meier methods were used to estimate time to outcomes, and proportional hazards models to examine independent predictors of outcomes. RESULTS: Enrolment (n = 44 177, mean age 35 years; 68% women) increased 12-fold over 5 years, with 63% of patients enrolled in the past 2 years. Twelve-month mortality decreased from 9% to 6% over 5 years. Twelve-month LTFU increased annually from 1% (2002/2003) to 13% (2006). Cumulative LTFU increased with follow-up from 14% at 12 months to 29% at 36 months. With each additional year on ART, failure to retain participants was increasingly attributable to LTFU compared with recorded mortality. At 12 and 36 months, respectively, 80 and 64% of patients were retained. CONCLUSION: Numbers on ART have increased rapidly in South Africa, but the programme has experienced deteriorating patient retention over time, particularly due to apparent LTFU. This may represent true loss to care, but may also reflect administrative error and lack of capacity to monitor movements in and out of care. New strategies are needed for South Africa and other low-income and middle-income countries to improve monitoring of outcomes and maximize retention in care with increasing programme size.
    • Temporal Trends in the Characteristics of Children at Antiretroviral Therapy Initiation in Southern Africa: The IeDEA-SA Collaboration

      Davies, Mary-Ann; Phiri, Sam; Wood, Robin; Wellington, Maureen; Cox, Vivian; Bolton-Moore, Carolyn; Timmerman, Venessa; Moultrie, Harry; Ndirangu, James; Rabie, Helena; et al. (Public Library of Science, 2013-12-09)
    • Tenofovir in second-line ART in Zambia and South Africa: collaborative analysis of cohort studies.

      Wandeler, Gilles; Keiser, Olivia; Mulenga, Lloyd; Hoffmann, Christopher J; Wood, Robin; Chaweza, Thom; Brennan, Alana; Prozesky, Hans; Garone, Daniela; Giddy, Janet; et al. (2012-09-01)
      Tenofovir (TDF) is increasingly used in second-line antiretroviral treatment (ART) in sub-Saharan Africa. We compared outcomes of second-line ART containing and not containing TDF in cohort studies from Zambia and the Republic of South Africa (RSA).
    • Time to initiation of antiretroviral therapy among patients with HIV-associated tuberculosis in Cape Town, South Africa

      Lawn, Stephen D; Campbell, Lucy; Kaplan, Richard; Boulle, Andrew; Cornell, Morna; Kerschberger, Bernhard; Morrow, Carl; Little, Francesca; Egger, Matthias; Wood, Robin; et al. (Lippincott Williams & Wilkins, 2011-06-01)
      We studied the time interval between starting tuberculosis treatment and commencing antiretroviral treatment (ART) in HIV-infected patients (n = 1433; median CD4 count 71 cells per microliter, interquartile range: 32-132) attending 3 South African township ART services between 2002 and 2008. The overall median delay was 2.66 months (interquartile range: 1.58-4.17). In adjusted analyses, delays varied between treatment sites but were shorter for patients with lower CD4 counts and those treated in more recent calendar years. During the most recent period (2007-2008), 4.7%, 19.7%, and 51.1% of patients started ART within 2, 4, and 8 weeks of tuberculosis treatment, respectively. Operational barriers must be tackled to permit further acceleration of ART initiation as recommended by 2010 WHO ART guidelines.
    • Tuberculosis and the risk of opportunistic infections and cancers in HIV-infected patients starting ART in Southern Africa.

      Fenner, Lukas; Reid, Stewart E; Fox, Matthew P; Garone, Daniela; Wellington, Maureen; Prozesky, Hans; Zwahlen, Marcel; Schomaker, Michael; Wandeler, Gilles; Kancheya, Nzali; et al. (2013-02)
      To investigate the incidence of selected opportunistic infections (OIs) and cancers and the role of a history of tuberculosis (TB) as a risk factor for developing these conditions in HIV-infected patients starting antiretroviral treatment (ART) in Southern Africa.
    • Viral Load Monitoring of Antiretroviral Therapy, cohort viral load and HIV transmission in Southern Africa: A Mathematical Modelling Analysis

      Estill, Janne; Aubrière, Cindy; Egger, Matthias; Johnson, Leigh; Wood, Robin; Garone, Daniela; Gsponer, Thomas; Wandeler, Gilles; Boulle, Andrew; Davies, Mary-Ann; et al. (2012-03-20)
      In low-income settings, treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.