Background:  HIV RNA viral load testing is costly and is generally unavailable in resource limited settings. Patients with viral failure may progress to drug resistance despite clinical well-being and/or immunologic recovery. We identified predictors of viral failure and documented genotypic mutations in a sub-set of patients with viral failure after 12 months on ART.

Methods:  From January 2004 to June 2005, consecutive treatment-naïve patients beginning ART at a university clinic in Uganda were enrolled into a prospective cohort (children aged 0 to 18 years, and adults ≥19 years). A clinical data collection form was completed for each patient at baseline and every 3 months and CD4⁺ count and plasma HIV RNA level every 6 months. Viral failure was defined as a change to second-line ART or a detectable viral load 12 months on ART. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with detectable viral loads at 12 months was measured at baseline, 6 and 12 months.

Results:  We started 526 adults and 250 children on first-line ART regimens and followed for 12-months. Outcomes could not be assessed in 14% of adults (63 died, 9 withdrew) and 11% of children (12 died, 16 withdrew). Children were almost twice as likely to have viral failure compared with adults (26% vs 14%, p = 0.0001). In adults, independent predictors of viral failure included younger age (OR = 0.67 per 10-year increase in age, 95%CI 0.45 to 0.99) and treatment with stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) versus branded zidovudine (ZDV) + 3TC + efavirenz (EFV) (OR = 2.54, 95%CI 1.18 to 5.44). In children, independent predictors of viral failure included male gender (OR = 2.45, 95%CI 1.07 to 5.57), having a baseline CD4% <5 (OR = 3.99, 95%CI 1.75 to 9.07) and treatment with d4T+3TC+NVP vs ZDV+3TC+EFV (OR = 3.33, 95%CI 1.51 to 7.36). Of the 120 participants (58 children and 62 adults) with detectable viral loads 12 months after ART, 8 genotypic drug-resistance results were completed. None of 4 patients with available genotypic testing at baseline had detectable antecedent resistant mutations. All 8 patients with viral breakthrough had non-nucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations. Of the 8 patients, 2 already had thymidine analog mutations.

Conclusions:  Children and patients with d4T-based regimens were more likely to experience viral failure. Future efforts should be focused on developing affordable methods for early detection of viral failure. These data indicate that nearly all patients with viral failure 6 or more months after starting these common ART regimens will have NNRTI- and 3TC-resistant virus.