A Single CD4 Test with 250 Cells/Mm Threshold Predicts Viral Suppression in HIV-Infected Adults Failing First-Line Therapy by Clinical Criteria
ABSTRACT 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. 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.
3316 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/mm(3)) were reviewed in 361 LCM, 314 CDM participants who switched over median 5 years follow-up. Retrospective VLs were available in 368 (55%) participants.
Overall, 265/361 (73%) LCM participants failed with CD4<100 cells/mm(3); only 7 (2%) switched with CD4≥250 cells/mm(3), 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/mm(3) (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/mm(3) only 11/133 (8%) had VL<400copies/ml, compared with 38/48 (79%) with CD4≥250 cells/mm(3) (p<0.0001).
Multiple, but not single, WHO 3 events predicted first-line ART failure. A CD4 threshold 'tiebreaker' of ≥250 cells/mm(3) 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.
Full-textDOI: · Available from: Diana M Gibb, Aug 13, 2015
- SourceAvailable from: Reuben GranichThe Lancet Infectious Diseases 04/2013; 13(7). DOI:10.1016/S1473-3099(13)70105-1 · 19.45 Impact Factor
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ABSTRACT: Background No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). Methods In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. This trial is registered, ISRCTN24791884. Findings 1206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1.13, 95% CI 0.73-1.73, p=0.59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1.3 vs 0.4 per 100 child-years, difference 0.99, 0.37-1.60, p=0.002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0.98, 0.83-1.16, p=0.83). Mean CD4 percentage change did not differ between ART groups at week 72 (16.5% [SD 8.6] vs 17.1% [8.5] vs 17.3% [8.0], p=0.33) or week 144 (p=0.69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12.4% [7.2] vs 14.1% [7.1] vs 14.6% [7.3], p<0.0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B: A] 1.32, 1.07-1.63) and C (218 [54%] children in C; HR [C: A] 1.58, 1.29-1.94; global p=0.0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively. Interpretation NNRTI plus NRTI-based three-drug or four-drug ART can be given across childhood without routine toxicity monitoring; CD4 monitoring provided clinical benefit after the first year on ART, but event rates were very low and long-term survival high, suggesting ART rollout should take priority. CD4 benefits from four-drug induction were not durable, but three-NRTI long-term maintenance was immunologically and clinically similar to NNRTI-based ART and could be valuable during tuberculosis co-treatment.The Lancet 04/2013; 381(9875):1391-1403. DOI:10.1016/S0140-6736(12)62198-9 · 45.22 Impact Factor
- The Lancet Global Health 01/2014; 2(1):e4–e5. DOI:10.1016/S2214-109X(13)70081-0 · 10.04 Impact Factor