HIV This Week

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

DART Trial Team. The Lancet, Early Online Publication, 9 December 2009 [Epub ahead of print]

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving antiretroviral therapy had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, antiretroviral therapy-naive, HIV-infected adults with CD4 counts less than 200 cells per muL starting antiretroviral therapy were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the laboratory and clinical monitoring group, results were available to clinicians; in the clinically driven monitoring group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line antiretroviral therapy after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per muL (laboratory and clinical monitoring only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. Two participants assigned to clinically driven monitoring and three to laboratory and clinical monitoring were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years’ follow-up. 459 (28%) participants receiving clinically driven monitoring versus 356 (21%) laboratory and clinical monitoring had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on antiretroviral therapy, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving clinically driven monitoring versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). Antiretroviral therapy can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of antiretroviral therapy to guide the switch to second-line treatment.

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Editors’ note: These findings, presented at the International AIDS Society conference in Cape Town in July 2009 are fully described here, complementing the excellent film produced by Tom Gibb (http://www.youtube.com/MRCcomms#p/u/1/MSyFmbiR-Hc). The results of this trial, designed to determine whether clinician monitoring of signs and symptoms without knowledge of CD4 count was not inferior to similar monitoring with knowledge of CD4 test results, suggest that once eligibility for antiretroviral treatment is determined, clinically driven monitoring holds the fort well for the first 2 years of treatment, freeing up resources and allowing extension of treatment access to more remote areas with no laboratory infrastructure.

McCarthy K, Chersich MF, Vearey J, Meyer-Rath G, Jaffer A, Simpwalo S, Venter WD. Int J STD AIDS. 2009 20:858-62.

Foreigners, including displaced persons, often have limited health-care access, especially to HIV services. Outcomes of antiretroviral therapy (ART) in South Africans and foreigners were compared at a Johannesburg non-governmental clinic. Records were reviewed of 1297 adults enrolled between April 2004 and March 2007 (568 self-identified foreigners, 431 South Africans citizens and 298 with unknown origin). Compared with citizens, foreigners had fewer hospital admissions (39%, 90/303 versus 51%, 126/244; P < 0.001), less missed appointments for antiretroviral therapy initiation (20%, 39/200 versus 25%, 51/206; P < 0.001), faster median time to antiretroviral therapy initiation (14 versus 21 days, P = 0.008), better retention in care (88%, 325/369 versus 69%, 155/226; P < 0.001) and lower mortality (2.5%, 14/568 versus 10%, 44/431; P < 0.001) after 426 person-years. In logistic regression, after controlling for baseline CD4 count and tuberculosis status, foreigners were 55% less likely to fail antiretroviral therapy than citizens (95% CI = 0.23-0.87). These findings support United Nations High Commissioner for Refugees recommendations that antiretroviral therapy should not be withheld from displaced persons.

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Editors’ note: South Africa at the end of 2007 had the world’s largest number of pending asylum applications and was second only to the United States of America in annual new asylum claims. The level of undocumented migrants is much higher. The findings from this study demonstrate that foreigners were about half as likely to fail antiretroviral treatment as citizens, despite having lower baseline median CD4 cell counts and being subject to significant hurdles in accessing and staying in care. This strongly supports the argument that foreigners should be included in the ‘right to access antiretroviral treatment for all.