Drug-Resistance Mutations May Curb Efficacy of Dolutegravir-Based Regimens in Zimbabwe Teens With HIV

By Marilynn Larkin

July 05, 2019

NEW YORK (Reuters Health) - Implementation of dolutegravir (DTG)-containing antiretroviral therapy (ART) regimens for adolescents in Zimbabwe may require additional drugs and surveillance for drug resistance mutations (DRMs), researchers say.

"In May 2019, Zimbabwe introduced DTG in first-, second- and third-line ART regimens," Dr. Vinie Kouamou of the University of Zimbabwe in Harare told Reuters Health by email. "Public health (officials) should definitely be aware of the implications of DRMs conferring resistance to tenofovir and/or lamivudine on the activity, efficacy and durability of DTG in such a country, knowing that at present, individual- level HIV drug resistance testing in low and middle income countries (LMICs) is rare and that data are lacking on DTG use in settings with limited or no viral load monitoring."

Dr. Kouamou and colleagues sequenced plasma viral RNA from HIV-1-infected adolescents and young adults on first- and second-line ART with confirmed virologic failure (VL>1000 copies/ml) and calculated genotypic susceptibility scores (tGSS) to currently available second- and third-line DTG regimens in Zimbabwe.

As reported online June 6 in AIDS, 160 participants (median age, 18) were genotyped - 112 (70%) on first-line and 48 (30%) on second-line therapy. The median duration of ART was six years.

Major DRMs were present in 94% of first-line and 67% second-line failures. Dual class resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was detected in 96 (60%) of first-line failures.

By contrast, protease inhibitor (PI) DRMs were detected in only 10% of second-line failures.

After first-line failure, a total tGSS of two or less may risk resulting in PI monotherapy in 11% of those switching to second-line PIs and DTG monotherapy in 42% of those switching to TLD.

"Among adolescents and young adults, current PI-based second-line therapies are poorly tolerated, more expensive and adherence is poor," the authors state. "The introduction of the single-tablet regimen, TLD, with a high genetic barrier to resistance in LMICs, may optimize long term ART treatment success. However, this should be accompanied by frequent virus load monitoring to avoid DTG monotherapy and further limiting options for this vulnerable and hard-to-treat population."

Dr. Kouamou said, "I definitely think the same caution should be taken or the same awareness should be raised in all resource-limited countries in which viral load monitoring still remains a big problem, not to mention drug resistance testing at individual level."

"The need for routine surveillance for DRMs is critical in LMICs," she noted. "However, I think viral load monitoring and drug resistance testing at individual level would be more beneficial for long-term ART success, especially in key populations such as children, adolescents and young adults in this DTG era."

"Introduction of DTG in developed countries shouldn't be a concern," she added, "as we know that viral load monitoring is not a problem and HIV drug resistance genotyping is more commonly used for individual management. In addition, these countries are less likely to go through any drug stock-outs, (which are) one of the many problems encountered in LMICs."

Dr. John Zaia, director of the Center for Gene Therapy at City of Hope in Duarte, California, commented in an email to Reuters Health, "The issue of adherence to a treatment regimen, especially in teens, is universal."

"Direct observation therapy, in which a respected person in the community delivers the daily dose and watches the person take it, is a tried and true method for treatment of tuberculosis and was even used in the successful treatment of HIV in Haiti," he noted. "This might be a solution to the problem of poor adherence to the treatment regimen. It is an interesting approach that was not mentioned in the paper."

SOURCE: http://bit.ly/2Jmrtsy

AIDS 2019.