Growing HIV Drug Resistance Justifies Treatment Change

Resistance to antiretroviral therapy (ART) has always been low enough in sub-Saharan Africa to mostly forgo viral load monitoring, but a new study from Uganda indicates that rising resistance may necessitate more blood tests and the purchase of more costly therapies for third-line treatment.

Investigators enrolled 953 individuals with the human immunodeficiency virus (HIV) between July 2013 and August 2014. Blood tests found HIV RNA levels of at least 1,000 copies per milliliter in 119 (12.5%) of those patients. Further tests successfully genotyped the HIV of 110 of those patients—74 of whom (67.3%) were on first-line ART regimens and 36 of whom (32.7%) were on second-line ART regimens.

The most commonly found mutations known to create resistance to nucleoside reverse transcriptase inhibitors (NRTIs) were the non-thymidine analogue mutations M184V (20.7%) and K65R (8%) and the thymidine analogue mutations M41L and K70R (both 8%). The most commonly found mutations known to create resistance to non-NRTIs were K103N (19%), G190A (7%), and Y181C (6%).

Among the 36 patients on second-line ART, seven had at least one major protease inhibitor-associated drug resistance mutation such as V82A (7%), I54V, M46I, and L33I (all 5%). Other mutations associated with protease inhibitor-response included L10I (27%), L10V (12%), and L10F (5%). All but two of the seven patients with major protease inhibitor-associated mutations had a high level of resistance to ritonavir, boosted lopinavir, and atazanavir.

“Although HIV care programs in resource limited settings have hitherto concentrated on expanding ART access, the emergence of HIV drug resistance is a challenge,” the study authors wrote. “We found that nearly half of our patients with virological failure had resistance to both NRTIs and non-NRTIs, about a fifth had resistance to the three classes of ARVs commonly used in Uganda while a small proportion had no Drug Resistance Mutations.”

Earlier studies had typically found that very few HIV-positive patients in sub-Saharan Africa exhibited significant drug resistance. A systematic review published in 2010 by Lancet Infectious Diseases estimated drug resistance rates there at just 2.8%, far less than the estimated rate of 11.5% in North America. Such numbers made frequent blood testing unnecessary, particularly when it cost money that could otherwise be used to distribute treatments that were still in short supply.

The new study is not the first to find evidence of increasing drug resistance among HIV-positive patients in southern Africa. The authors of the new study, however, think their findings are significant enough to justify changes to HIV treatment protocols in sub-Saharan Africa.

“The observed PI (protease inhibitor) resistance mutations (V82A, V82F, V82S, M46I, M46L, and I54V) are clinically significant because they are associated with highest levels of phenotypic resistance and/or strongest evidence for interfering with successful PI therapy,” the team wrote. “ART programs in these settings should avail routine HIV viral load monitoring for prompt detection of virological failures, targeted HIV drug resistance testing to detect HIV drug resistance among ART failure as well as access to third-line ARV drugs like darunavir.”

The study, “From antiretroviral therapy access to provision of third line regimens: evidence of HIV Drug resistance mutations to first and second line regimens among Ugandan adults,” appears in BMC Research Notes.

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