Abstract
BackgroundIn low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable.Methods3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4<100 cells/mm3) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants.ResultsOverall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm3; only 7 (2%) switched with CD4≥250 cells/mm3, four switches triggered by WHO events. Without CD4 monitoring, 207/314 (66%) CDM participants failed with WHO 4 events, and 77(25%)/30(10%) with single/multiple WHO 3 events. Failure/switching with single WHO 3 events was more likely with CD4≥250 cells/mm3 (28/77; 36%) (p = 0.0002). CD4 monitoring reduced switching with viral suppression: 23/187 (12%) LCM versus 49/181 (27%) CDM had VL<400 copies/ml at failure/switch (p<0.0001). Amongst CDM participants with CD4<250 cells/mm3 only 11/133 (8%) had VL<400copies/ml, compared with 38/48 (79%) with CD4≥250 cells/mm3 (p<0.0001).ConclusionMultiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold ‘tiebreaker’ of ≥250 cells/mm3 for clinically-monitored patients failing first-line could identify ∼80% with VL<400 copies/ml, who are unlikely to benefit from second-line. Targeting CD4s to single WHO stage 3 ‘clinical failures’ would particularly avoid premature, costly switch to second-line ART.
Highlights
Most HIV-infected individuals on antiretroviral therapy (ART) in low/middle-income countries are treated following the WHO public health approach [1]: the public sector provides one standard first-line regimen, with alternative drug substitutions for anti-tuberculosis co-therapy/toxicity; when first-line failure occurs, the patient switches to a standard boosted-protease inhibitorbased second-line regimen
Low-income countries differ in their ability to provide laboratory tests to identify first-line failure and support routine follow-up; if available at all, CD4 testing is most common with viral loads (VL) sometimes used to confirm clinical/immunological failure[2]
223(13%) clinically-driven monitoring (CDM) participants had new/recurrent WHO 4 events accepted by the ERC after 44 weeks on ART: 187/223 (84%) switched to second-line, 14(6%) died on first-line before switching and 22(10%) had not switched before trial closure
Summary
Most HIV-infected individuals on antiretroviral therapy (ART) in low/middle-income countries are treated following the WHO public health approach [1]: the public sector provides one standard first-line regimen, with alternative drug substitutions for anti-tuberculosis co-therapy/toxicity; when first-line failure occurs, the patient switches to a standard boosted-protease inhibitor (bPI)based second-line regimen. Low-income countries differ in their ability to provide laboratory tests to identify first-line failure and support routine follow-up; if available at all, CD4 testing is most common with viral loads (VL) sometimes used to confirm clinical/immunological failure[2]. Routine virological monitoring is rarely available or feasible[3] Such approaches differ markedly from individualised management in high-income countries, where routine VL monitoring is used to modify initial or subsequent therapy and many drugs are available. The aims were to investigate the characteristics of immunological/clinical failures determined without routine VL monitoring and with or without routine real-time CD4 monitoring; and to identify optimal CD4 thresholds to confirm clinical failure and switch to second-line ART when VLs are unavailable. In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable
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