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Drug resistance in human immunodeficiency virus type-1 infected Zambian children using adult fixed dose combination stavudine, lamivudine, and nevirapine
Global Health Sciences Literature Digest
Published October 18, 2010
Journal Article

Gupta RK, Ford D, Mulenga V, Walker AS, Kabamba D, Kalumbi M, Grant PR, Ferrier A, Pillay D, Gibb DM, Chintu C. .Drug resistance in human immunodeficiency virus type-1 infected Zambian children using adult fixed dose combination stavudine, lamivudine, and nevirapine. Pediatr Infect Dis J. 2010; 29:e57-62.

In Context

Fixed-dose combination (FDC) antiretroviral therapy (ART) has the benefits of reducing the complexity of antiretroviral therapy (ART), reducing pill burden and increasing adherence. Triomune (an FDC containing stavudine [d4T], lamivudine [3TC] and nevirapine [NVP]) is the most widely used FDC in sub-Saharan Africa for first-line ART. Children have been dosed using quartered tablets. However, the amount of NVP in the adult formulation of Triomune has been associated with subtherapeutic concentrations of NVP in young children <15 kg because of their more rapid metabolism of NVP,(1, 2) which in turn could be associated with increased risk of virologic failure and drug resistance.

Objective

To evaluate antiretroviral resistance in a cohort of children and adolescents being treated with the adult formulation of Triomune.

Setting/Population

The Children with HIV Antibiotic Prophylaxis (CHAP2) study is a prospective cohort study of HIV-infected Zambian children who participated in an earlier trial of cotrimoxazole prophylaxis prior to the introduction of ART.

Methods

Children eligible for ART received either a half or a whole Triomune 30 tablet and were followed every 6 months. Genotypic resistance was determined in stored serum samples for the pol gene and classified by the IAS-USA system.(3)

Results

A total of 114 children began ART between June 2003 and December 2005. Twenty-one (18%) had some prior use of ART. Follow up was through February 2008. Eight children died, and 3 were lost to follow-up in the first 6 months of treatment; in general these children had more severe disease at ART initiation. At 24 months, 84 (82%) of the remaining 103 children were still attending the clinic, 17 had stopped attending, and 2 had died. Of the 74 children with viral loads at 24 months, 51 (69%) had <50 copies/mL, and at 36 months, 37 (59%) had <50 copies/mL. Overall of the 103 children surviving at least 6 months, 27 (26%) had virologic failure by 24 months; 26 of these children were successfully genotyped. Twenty-five had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, and 22 (84%) had 3TC resistance (M184V); 8 (31%) had ≥1 thymidine analogue mutation and 4 (15%) had ≥2. Overall 21% of 103 children followed for >6 months had high-level resistance to NNRTI and 3TC by two years (no difference between those with and without prior ART histories).

Conclusions

Sixty-nine percent of children attending clinic at 24 months had achieved virologic suppression, but 21% had high-level resistance to NNRTI and 3TC.

Study Quality

Using the Newcastle Ottawa scale for cohort studies, this was a high quality study with losses to follow up clearly reported.

Programmatic Implications

The implication of this study is in order to reap the benefits of generic, inexpensive NNRI-containing ART, access to frequent, low-cost plasma viral load testing is needed to limit emergence of extensive resistance when appropriate second- and third-line regimens are available.

References

  1. Ellis JC, L'Homme RF, Ewings FM, et al. Nevirapine concentrations in HIV-infected children treated with divided fixed-dose combination antiretroviral tablets in Malawi and Zambia. Antivir Ther. 2007; 12:253-260.
  2. Corbett AH, Hosseinipour MC, Nyirenda J, et al. Pharmacokinetics of generic and trade formulations of lamivudine, stavudine, and nevirapine in HIV-infected Malawian children. Antivir Ther 2010; 15:83-90.
  3. International AIDS Society-USA. HIV Drug Resistance Mutations. Accessed 22 September 2010.