IAS 2009: Can People in Low-income Countries Benefit from Antiretroviral Therapy without Routine Laboratory Monitoring?

Antiretroviral therapy (ART) should not be withheld from HIV patients in medium- and low-income countries due to lack of laboratory monitoring, according to results of the Development of Antiretroviral Therapy (DART) in Africa trial, presented last week at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) in Cape Town, South Africa. The researchers also concluded that first-line treatment regimens can be given to people in resource-limited countries without the need for routine laboratory monitoring of toxicity.

Because of high costs, ART often is not accompanied by routine laboratory monitoring in low-income countries, and the clinical outcomes of this strategy have not been well studied. The objective of the DART trial was to discover whether the absence of routine monitoring led to poor outcomes.

The DART trial -- the largest clinical study ever conducted in sub-Saharan Africa -- enrolled 3316 previously untreated adults in Uganda and Zimbabwe with a median CD4 count of 86 cells/mm³ and World Health Organization (WHO) adverse event stages 2/3/4 (20%, 56%, and 23%, respectively).

Participants were randomized into 2 groups, the Laboratory and Clinical Monitoring (LCM) arm or the Clinically Driven Monitoring (CDM) arm, and were followed for a median of 4.9 years.

Participants started ART using 1 of 3 treatment regimens:

• Tenofovir (Viread) plus zidovudine/lamivudine (Combivir): 74%;
• Nevirapine (Viramune) plus Combivir (16%);
• Abacavir (Ziagen) plus Combivir: 9%.

Patients switched to second-line therapy after new or recurrent WHO stage 3/4 events or (in the LCM arm only) reaching a CD4 count below 100cells/mm³.

In the LCM arm, routine CD4 cell tests and hematology and biochemistry monitoring for toxicity were performed every 3 months, with results returned to patients' clinicians. In the CDM, only grade 4 toxicity results were returned, but tests other than CD4 count could be requested if clinically indicated.

Results

• 459 patients (28%) in the CDM group versus 356 participants (22%) in the LCM group experienced a new WHO stage 4 event or died.
• Death rates per 100 person years (PY) were 2.94 in the CDM group versus 2.18 in the LCM group.
• An estimated 130 PY of laboratory monitoring was needed to prevent 1 death.
• Differences between the 2 monitoring strategies occurred from the third year on ART.
• Lower likelihood of switching to second-line ART in the CDM arm occurred from the second year.
• There were no significant differences between the 2 strategies with regard to time to first serious adverse event, grade 4 toxicity, or ART-modifying toxicity.

In conclusion, the investigators stated, "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."

They noted that the differences in survival free of WHO 4 events were small, "but suggest a role for targeted CD4 monitoring to guide switching from the second year on ART."

"First-line regimens used in DART can be given without need for routine toxicity laboratory monitoring, even in advanced disease," they concluded, adding that a cost-effectiveness analysis would also help to determine ART policy in these settings.

Joint Clinical Research Centre, Kampala, Uganda; MRC Clinical Trials Unit, London, UK; University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda; Infectious Diseases Institute, Kampala, Uganda; UNAIDS, New Delhi, India; Imperial College, London, UK.

7/31/09

Reference

P Mugyeny, S Walker, J Hakim, and others (on behalf of The DART Trial Team).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. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract TuSS102.