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Virologic Failure and Drug Resistance After Programmatic Switching to Dolutegravir-based First-line Antiretroviral Therapy in Malawi and Zambia
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Download the PDF here
Download the PDF here
Clinical Infectious Diseases 07 June 2024
In conclusion, this large longitudinal study of treatment-experienced, INSTI-naïve PWH transitioning to DTG-based ART in 2 different settings in Malawi and Zambia highlights the infrequency of viremia postswitch. Still, it underscores the heightened risk of treatment failure in individuals with viremia at switch. The Zambian approach of switching only PWH with evidence of virologic suppression may have reduced the risk of viremia and the potential for drug resistance but the observational nature of the data preclude firm conclusions. Our findings emphasize the necessity of VL monitoring and resistance testing to maintain ART effectiveness, especially in settings with a known high prevalence of preexisting NRTI resistance. Monitoring the emergence of DTG resistance mutations is essential to prevent resistance at the individual and the population level and ensure ART's long-term sustainability.
We report the results from the DTG SWITCH study (Clinicaltrials.gov NCT04612452), which examined viremia and antiretroviral resistance among adult PWH programmatically switched to DTG-based first-line ART in 2 countries: Malawi, where PWH were switched regardless of their VL and Zambia, where only PWH whose last VL was <1000 copies/mL were transferred to DTG-based ART.
Indeed, at all time points, the proportion of participants with suppressed viral replication was around 95% or higher.
Being viremic at switch was nevertheless associated with a substantial increase in the risk of viremia later on, and 7% of participants with sequence data harbored major or accessory drug resistance mutations in the integrase gene. For 2 PWH, the Stanford algorithm predicted high-level DTG resistance.
"The low prevalence of resistance mutations indicates that nonadherence to ART often explained viremia at switch and during follow-up."
"The sensitivity analyses showed similar results for viremia at switch with cutoff of 1000 copies/mL (see Supplementary Table 1, Supplementary Figure 1). When modeled continuously, a 10-fold increase in baseline VL resulted in an adjusted OR of 1.92 (95% CI, 1.58-2.31) (model S2, Supplementary Figure 2). The inclusion of an interaction term between baseline VL and country (model S3, Supplementary Figure 2) indicates that the dose-response relationship was weaker in Zambia than in Malawi by factor 0.74 (95% CI, 0.43-1.15) but the interaction did not reach conventional levels of statistical significance (P = .22).
Viremia at switch was associated with viremia at 1 year (adjusted odds ratio (OR), 6.15; 95% confidence interval [CI], 3.13-11.4) and 2 years (7.0; 95% CI, 3.73-12.6).
Viremia was less likely in Zambia than in Malawi at 1 year (OR, 0.55; 0.32-0.94) and 2 years (OR, 0.33; 0.18-0.57).
Drug resistance mutations in the integrase gene were observed in 5 PWH (6.9%). "
Abstract
Background
People with human immunodeficiency virus (PWH) on first-line, nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART) were routinely switched to tenofovir-lamivudine-dolutegravir. We examined virologic outcomes and drug resistance in ART programs in Malawi, where switching was irrespective of viral load, and Zambia, where switching depended on a viral load <1000 copies/mL in the past year.
Methods
We compared the risk of viremia (≥400 copies/mL) at 1 and 2 years by viral load at switch and between countries using exact methods and logistic regression adjusted for age and sex. We performed HIV-1 pol Sanger sequencing on plasma samples with viral load ≥1000 copies/mL.
Conclusions
Restricting switching to dolutegravir-based ART to PWH with a viral load <1000 copies/mL may reduce subsequent viremia and, consequently, the emergence of dolutegravir drug resistance mutations.
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