Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

Abstract

OBJECTIVE We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy(ART) in accordance with World Health Organization 2010 policy and single-drug substitutions (SDS)(substituting the nucleoside reverse transcriptase inhibitor(NRTI) in first-line ART) in sub-Saharan Africa. DESIGN Prospective cohort analysis (IeDEA-Multiregional) including ART-naïve, HIV-infected patients ≥16 years initiating ART between January 2005-December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, while after tenofovir or zidovudine replaced stavudine in first-line ART. METHODS We evaluated the frequency of stavudine use and SDS by calendar year, 2004-2014. Competing risk regression was used to assess the association between NRTI use and SDS in the first 24 months on ART. RESULTS 33,441 (8.9%; 95% CI: 8.7-8.9%) SDS occurred among 377,656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20% to 95% less likely to require a SDS than patients on stavudine, while patients on zidovudine had a 75% to 85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine.

Regimen durability in HIV‐infected children and adolescents initiating first‐line antiretroviral therapy in a large public sector HIV cohort in South Africa

“…As changes in the trends of substitutions, treatment interruptions and second‐line switches for sex and age (<10 vs. >10 years) could vary by NRTI used in first‐line ART, we calculated the risk due to interdependence (R(I)). Similar to prior adult work , we here show a positive interdependence for female gender and stavudine use in first‐line ART for two of the three primary outcomes (single‐drug substitution: 6.4% [difference in RD: 0.132–0.067] and second‐line switches: 5.6% [difference in RD: 0.003 to −0.053]). Therefore, 6.4% of single‐drug substitutions in female patients on stavudine is related to the dual action of female gender and stavudine.…”

Reasons for first line ART modification over the years during the ART scale up in Uganda

“…In Uganda from 2003 to 2008 the typical ART regimens included stavudine or less frequently zidovudine, plus lamivudine plus nevirapine or efavirenz [6]. In 2008 the Uganda Ministry of Health (MoH) recommended a systematic national drug substitution from stavudine to other nucleoside/nucleotide reverse transcriptase (NRTI) regardless of the presence of toxicities [7, 8], preceding the 2010 WHO recommendation of replacing stavudine with zidovudine or tenofovir [9]. Tenofovir is an nucleotide reverse transcriptase inhibitor which has shown a better safety profile than stavudine and zidovudine [2], and several observational studies demonstrated that modifications in the first 2–3 years on ART due to toxicities are less frequent in patients started on tenofovir [5, 8, 10–13].…”

Routine data underestimates the incidence of first-line antiretroviral drug discontinuations due to adverse drug reactions: Observational study in two South African cohorts

“…As seen in previous South African studies we found a much lower rate of treatment discontinuations with tenofovir than with stavudine. [ 9 , 19 ]…”