Effectiveness of a Triple-NRTI Regimen in HIV Positive African Adults

By Liz Highleyman

After years of advocacy, access to antiretroviral therapy in resource-poor countries is now becoming a reality. In Africa, the most commonly used first-line regimens consist of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI).

While NNRTI-based regimens typically offer good efficacy and simplicity, and preserve the protease inhibitor (PI) class for future use, they do have limitations. These include toxicity -- notably an increased risk of liver toxicity with nevirapine (Viramune) in women with higher CD4 cell counts -- interactions between NNRTIs and anti-tuberculosis medications, and contraindications to the use of efavirenz (Sustiva) during pregnancy.

As such, regimens that consist of three NRTIs are also sometimes used as first-line or substitution therapy. However, several studies in developed countries indicate that for many patients, NRTI-only regimens are not sufficiently potent to suppress HIV over the long term.
The DART Virology Group and Trial Team assessed virological response using a triple-NRTI regimen consisting of AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir), and tenofovir (Viread) in 300 treatment-naïve HIV positive adults in Uganda and Zimbabwe with CD4 cell counts below 200 cells/mm3. Virological suppression was determined at 48 weeks, and HIV drug-resistance mutations were assessed at 24 weeks.

Results

The median baseline CD4 cell count was 101 cells/mm3 and the median HIV viral load was 279,910 copies/mL (mean 5.4 log copies/mL).

At 48 weeks, 61% of patients (165 out of 272) had HIV RNA levels below 50 copies/mL, and 72% (196 out of 272) had viral load below 400 copies/mL.

At 24 weeks, the corresponding percentages were 59% (167 out of 281) and 79% (221 out of 281).

At 24 and 48 weeks, 15% and 24%, respectively, had HIV RNA levels above 1,000 copies/mL; 6% and 17%, respectively, had levels above 10,000 copies/mL.

Mean CD4 cell count increases were 103 cells mm3 at 24 weeks and 127 cells/mm3 at 48 weeks.

Higher baseline CD4 cell count was the most important predictor of virological suppression at 48 weeks.

Baseline viral load had little effect on HIV suppression at 48 weeks.

At 24 weeks, 18 out of 20 genotypic tests in patients with viral loads above 1,000 copies/mL showed key resistance mutations in the HIV reverse transcriptase enzyme:

- 14 had the M184V mutation

- 10 with M184V had 1-4 additional NRTI mutations (NAMs);

- 1 had three NAMs only;

- 3 had the K65R mutation.

- 1 participant with M184V also had major NNRTI mutations, despite no reported prior use of this class.

Conclusion
The authors concluded that a regimen of AZT/3TC/tenofovir "has good virological efficacy in advanced HIV disease." They added that in this group of patients, who were infected with HIV-1 subtypes A, C, or D, "M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often."

7/28/06

Reference
DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS 20(10): 1391-1399. June 26, 2006.