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Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART Trial final results
P. Mugyenyi1, S. Walker2, J. Hakim3, P. Munderi4, D. Gibb2, C. Kityo1, A. Reid3, H. Grosskurth4, J. Darbyshire2, F. Ssali1, D. Bray2, E. Katabira5, A. Babiker2, C. Gilks6,7, on behalf of The DART Trial Team
1Joint Clinical Research Centre (JCRC), Kampala, Uganda, 2MRC Clinical Trials Unit, London, United Kingdom, 3University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe, 4MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda, 5Infectious Diseases Institute, Kampala, Uganda, 6UNAIDS, New Delhi, India, 7Imperial College, London, United Kingdom
Background: ART is often managed without routine laboratory monitoring in low-income countries; the clinical outcome of this strategy is unknown.
Methods: 3316 ART-naive adults (median(IQR) CD4 86(31-139)cells/mm3; WHO stage 2/3/4 20%/56%/23%) initiating ART in Uganda/Zimbabwe were randomised to Laboratory and Clinical Monitoring (LCM) versus Clinically Driven Monitoring (CDM) and followed for median 4.9 years. Participants initiated zidovudine/lamivudine plus tenofovirDF(74%), abacavir(9%) or nevirapine(16%) and switched to second-line after new/recurrent WHO stage 3/4 events or (LCM only) CD4< 100cells/mm3. Routine 3-monthly haematology and biochemistry (for toxicity) and CD4 results from participants in LCM were returned to clinicians; in CDM, only grade 4 toxicity results were returned, but tests (not CD4) could be requested if clinically indicated.
Results: 459 (28%) CDM versus 356 (22%) LCM participants had a new WHO Stage 4 event or died (event rate 6.94 versus 5.24 per 100 person-years (PY); absolute difference +1.70/100 PY (95%CI +0.87 to +2.54/100 PY); HR 1.31 [1.14-1.51],log-rank p=0.0001). Death rates per 100PY were 2.94 in CDM versus 2.18 in LCM (difference +0.77/100PY[0.25-1.28], p=0.004; 130 PY of laboratory monitoring to prevent one death). Differences between strategies occurred from the third year on ART whereas lower rates of switching to second-line ART occurred in CDM from the second year. There were no differences between strategies in time to first serious adverse event (HR=1.12[0.94-1.31];p=0.20), grade 4 toxicity (HR=1.08[0.97-1.20];p=0.18) or ART-modifying toxicity (HR=1.01[0.88-1.16];p=0.85).
Conclusions: Overall survival at 5 years (CDM:87%;LCM:90%) was excellent, strongly reinforcing WHO guidelines that ART should never be withheld due to lack of laboratory monitoring. The differences in WHO 4 event-free survival were small but suggest a role for targeted CD4 monitoring to guide switching from the second year on ART; moreover, first-line regimens used in DART can be given without need for routine toxicity laboratory monitoring, even in advanced disease. Cost-effectiveness analysis will further inform ART programme policy.
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