Only a limited number of surveillance drug-resistance mutations (SDRMs) are responsible for most instances of non-nucleoside reverse transcriptase inhibitor (NNRTI)- and nucleoside reverse transcriptase inhibitor (NRTI)-associated resistance, and most strains of HIV-1 transmitted drug resistance (TDR) in sub-Saharan Africa (SSA) and south/southeast Asia (SSEA) arose independently, according to a study published this week in PLOS Medicine. The study, led by Soo-Yon Rhee of Stanford University, and colleagues, came to these conclusions after analyzing individual virus sequences from 287 published studies.
These findings have implications for TDR surveillance and control. The small number of NNRTI-resistance mutations responsible for a high percentage of high-level resistance suggests that screening for these specific high-prevalence mutations could identify most patients with TDR before they initiate therapy. The finding that most TDR strains arose independently rather than resulting from endemic strains that spread suggests that reducing the generation of new resistant strains by using antiretroviral (ARV) regimens with a high genetic barrier to resistance and improving patient adherence could have an impact on TDR prevalence.
This study is most relevant to the low- and middle-income countries of SSA and SSEA -- the regions in which most of the 15 million individuals receiving ARV therapy live. Although national treatment programs in these regions have grown dramatically since 2000, the prevalence of TDR has not increased as much as once feared.
The researchers came to these conclusions after studying individual virus sequences from 50,870 HIV-positive individuals from 111 countries. By analyzing each virus sequence for the presence of 93 SDRMs previously shown to be specific indicators of TDR, the researchers found that the overall prevalence of TDR ranged from 2.8% in SSA to 11.5% in North America. The odds of TDR increased in SSA by 1.09-fold per year following national ARV scale-up, due to increased NNRTI- and NRTI-resistance, but remained unchanged in LMICs in SSEA following ARV scale-up. The odds of NNRTI but not NRTI resistance increased in Latin America/Caribbean, North America, Europe, and upper-income Asian countries since 1995. Just four NNRTI- and 16 NRTI-SDRMs accounted for most NNRTI- and NRTI-TDR, and 89% of NNRTI-SDRMs were associated with high-level resistance to nevirapine or efavirenz. In SSA and SSEA, only 5% of transmitted drug-resistant viruses were closely related to one another, suggesting that most TDR strains in these regions arose independently.
The authors say: "This study demonstrates that sequence analysis is an important component of TDR surveillance because it yields insights into the molecular epidemiology of TDR and the specific drug-resistance mutations responsible for TDR."
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