WHO-recommended second-line ART regimen is safe and effective in Africa

Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A, van Oosterhout JJ, Kiconco M, Siika A, Mwebaze R, Abwola M, Abongomera G, Mweemba A, Alima H, Atwongyeire D, Nyirenda R, Boles J, Thompson J, Tumukunde D, Chidziva E, Mambule I, Arribas JR, Easterbrook PJ, Hakim J, Walker AS, Mugyenyi P, EARNEST Trial Team. N Engl J Med. 2014 Jul 17;371(3):234-47. doi: 10.1056/NEJMoa1311274.

Background: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.

Methods: In this open-label trial in sub-Saharan Africa, we randomly assigned 1 277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10 000 copies per milliliter or 10 000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (</=4%).

Results: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).

Conclusions: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy.

Abstract  Full-text [free] access

Editor’s notes: Over the coming years, increasing numbers of individuals taking antiretroviral therapy (ART) in sub-Saharan Africa will develop treatment failure and require second-line treatment.  There is an urgent need to find the most cost-effective, tolerable and safe standardised second-line regimen for this setting.  The Europe-Africa Research Network for Evaluation of Second-Line Therapy (EARNEST) trial set out to assess whether alternative ART regimens (excluding the nucleoside reverse transcriptase inhibitor [NRTI] backbone) are more efficacious and less toxic than the WHO-recommended second-line regimen of a boosted protease inhibitor (PI) and two NRTIs.  The setting of the trial is typical of most antiretroviral programmes in Africa, with no routine viral load monitoring, and the second-line NRTI backbone selected without genotypic resistance testing. 

Participants in this study had extensive NRTI resistance. Despite this, there was substantial residual NRTI activity, and, by week  96, the WHO-recommended regimen of a boosted PI and two NRTIs was as good as the alternative regimen of a boosted PI and raltegravir, and better than PI monotherapy.  It is worth pointing out that although “good HIV disease control” was achieved in only 60% of study participants in the NRTI arm, this composite outcome required study participants to have had a CD4 count ≥250 cells per mm3 at week 96.  The 60% achieving “good HIV disease control” in the NRTI arm therefore reflects the low baseline CD4 cell counts (median CD4 count 72) at the time of switch to second-line therapy rather than treatment efficacy with regard to virologic suppression (VL<400 copies/ml), which was achieved in some 86% of people.

Further research will be needed to determine whether this second-line regimen continues to be effective in maintaining good HIV disease control through virologic suppression in the longer term.  

HIV Treatment
Africa
Kenya, Malawi, Uganda, Zambia, Zimbabwe
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