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Two-year outcomes of children on non-nucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a South African pediatric antiretroviral program
Global Health Sciences Literature Digest
Published June 15, 2009
Journal Article

Jaspan HB, Berrisford AE, Boulle AM. Two-year outcomes of children on non-nucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a South African pediatric antiretroviral program. Pediatr Infect Dis J 2008;27:993-998.

In Context

Antiretroviral therapy (ART) has become increasingly available for children with vertically-acquired HIV in resource-limited areas but information on optimal regimens has been limited.(1, 2, 3, 4)

Objective

To determine the laboratory and clinical outcomes among HIV-infected children who received ART and to compare the efficacy of protease inhibitor (PI)-based to non-nucleoside reverse transcriptase inhibitor (nNRTI)-based regimens.

Setting

Outpatient public hospital clinic, South Africa.

Study Design

Retrospective cohort.

Participants

HIV-infected children who received ART from May 2002 until June 2006.

Outcomes

CD4 percentages, CD4 count, log viral loads (VL), virologic suppression (<400 copies/mL), growth (weight for age Z score [WAZ]), loss to follow-up, and survival up to two years.

Methods

Standard treatment during 2002 and 2003 usually consisted of zidovudine (ZDV) and lamivudine (3TC) with nevirapine (NVP). Ritonavir (RTV) was an option for recipients of prevention of mother-to-child transmission (PMTCT) therapy or children who received rifampin. In 2004, first-line therapy consisted of stavudine (d4T) and 3TC and lopinavir/ritonavir (LPR/r) for children under 3 years or 10 kg and efavirenz EFV for older children. ART was initiated for children with WHO clinical stage II and stage II disease (using the older staging system) or clinical stage II or IV with the most recent staging system or CD4 percentages <15% for children under 18 months of age and <20% for older children. Change in therapy was based on WHO clinical guidelines or treatment toxicity.

PMTCT has been routinely available since 2004 and consists of ZDV and NVP prophylaxis for mother and child, pre- and postnatally. Prior to 2004, short course ZDV or NVP were provided.

All children were included in the analysis until they changed regimens or transferred out at which point they were censored. Median and ranges of parameters were compared using the Kruskal-Wallis rank sum test. The chi square test was used to compare proportions and the Kaplan-Meier method was used to calculate estimates of time to outcomes. Only HIV-related deaths were included in the survival analysis. Generalized estimating equations were used to measure the adjusted odds of virologic suppression until 24 months. The log rank test was used to examine associations between loss to follow-up and survival up to 24 months.

Results

Of the 391 children included, 202 (51.7%) initiated treatment with a PI and 189 (48.3%) started with an nNRTI. Baseline CD4 percentage was 13% and WAZ was -2.5. The two treatment groups were similar with respect to baseline CD4%, CD4 count, VL, and WAZ. The nNRTI group was older and there were more females in the PI group. Eighty-eight percent of the nNRTI group received NVP and of the children in the PI group, most received LPV/r. The median duration of follow-up was 12.9 months (interquartile range [IQR] 3.6-23.2) and 32.8 months for the nNRTI group (IQR 16.7-40.0).

Among the entire cohort, CD4% increased from 13% to 25% at 12 months and to 26% at 24 months. At 24 months WAZ was up to -0.7. Viral suppression was achieved by 54% at 12 months and 49% at 24 months. There were 28 deaths, 26 of which occurred in the first six months of treatment. Virologic suppression was more frequent among the children on PIs than among those in the nNRTI group (71% versus 41% at 12 months, and 61% versus 45% at 24 months, p<0.01.) The treatment groups did not differ with respect to CD4%, survival, or loss to follow-up. Only three changes in regimens were needed because of toxicity in the PI group and all were switched to alternative PIs. There were changes in regimen in the nNRTI group from NVP to LPV/r. Twenty children had to change treatment because of tuberculosis; 5 in the PI group and 15 in the nNRTI group.

Virologic suppression was inversely associated with nNRTI regimens (adjusted odds ratio 0.38, 95% confidence interval [CI] 0.19-0.77) and length of time on ART (adjusted OR at 12 months, 0.74, 95%CI 0.55-0.99). Older age at initiation of ART was positively associated with viral suppression (adjusted OR 1.23, 95% CI 1.09-1.39).

Conclusions

Provision of ART to children in resource-constrained areas results in clinical improvement. In this study, PI-based regimens were associated with greater viral suppression.

Quality Rating

This study was of fair quality. It was not possible to evaluate the representativeness of the cohort because such information was not provided. Selection of treatment was not random and may have biased the findings. Factors that may have resulted in the differences in the virologic suppression in the groups such as ease of administration, preparation, and storage, was not available. Information on adherence was not included - difficulties in adhering to one regimen over the other could have produced the findings of higher viral suppression in the PI group. The two treatment groups had significant differences in age and age was associated with viral suppression. The laboratory outcome measurement was acceptable but clinical outcomes were not complete (essentially only weight). Follow-up was only up to 24 months. Information on reasons for loss to follow-up was not available. The methods and completeness of death ascertainment was not provided

Programmatic Implications

This study provides additional evidence for the benefits and feasibility of providing ART to HIV-infected children in Africa and support findings from other studies.(2, 3, 4) Mortality in this cohort was lower than that reported from other studies in resource constrained areas.(5) As with other studies, deaths occurred early in life and suggest the need for early treatment intervention and careful monitoring of clinical response.

References

  1. WHO and UNAIDS. Treating 3 Million by 2005. Making it Happen: The WHO Strategy. 2003.
  2. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA. 2007;298:1888-1899.
  3. Eley B, Davies MA, Apolles P, et al. Antiretroviral treatment for children. S Afr Med J. 2006;96:988 -993.
  4. O'Brien DP, Sauvageot D, Zachariah R, Humblet P. In resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination antiretroviral therapy. AIDS. 2006;20:1955-1960.
  5. Hussey GD, Reijnhart RM, Sebens AM, Burgess J, Schaaf S, Potgeiter S. Survival of children in Cape Town known to be vertically infected with HIV-1. S Afr Med J. 1998;88:554-558.