HIV-1 Drug Resistance and Third-Line Therapy Outcomes in Patients Failing Second-Line Therapy in Zimbabwe

Abstract

ObjectivesTo analyze the patterns and risk factors of HIV drug resistance mutations among patients failing second-line treatment and to describe early treatment responses to recommended third-line antiretroviral therapy (ART) in a national referral HIV clinic in Zimbabwe.MethodsPatients on boosted protease inhibitor (PI) regimens for more than 6 months with treatment failure confirmed by 2 viral load (VL) tests >1000 copies/mL were genotyped, and susceptibility to available antiretroviral drugs was estimated by the Stanford HIVdb program. Risk factors for major PI resistance were assessed by logistic regression. Third-line treatment was provided as Darunavir/r, Raltegravir, or Dolutegravir and Zidovudine, Abacavir Lamivudine, or Tenofovir.ResultsGenotypes were performed on 86 patients who had good adherence to treatment. The median duration of first- and second-line ART was 3.8 years (interquartile range [IQR], 2.3–5.1) and 2.6 years (IQR, 1.6–4.9), respectively. The median HIV viral load and CD4 cell count were 65 210 copies/mL (IQR, 8728–208 920 copies/mL) and 201 cells/mm3 (IQR, 49–333 cells/mm3). Major PI resistance-associated mutations (RAMs) were demonstrated in 44 (51%) non-nucleoside reverse transcriptase inhibitor RAMs in 72 patients (83%) and nucleoside reverse transcriptase inhibitors RAMs in 62 patients (72%). PI resistance was associated with age >24 years (P = .003) and CD4 cell count <200 cells/mm3 (P = .007). In multivariable analysis, only age >24 years was significantly associated (adjusted odds ratio, 4.75; 95% confidence interval, 1.69–13.38; P = .003) with major PI mutations. Third-line DRV/r- and InSTI-based therapy achieved virologic suppression in 29/36 patients (81%) after 6 months.ConclusionsThe prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective.

Predictors of Failure on Second-line Antiretroviral Therapy with Protease Inhibitor Mutations in Uganda

“…Age and failure on second-line ART with PI mutations A study by Chimbetete et al (2018) found that younger patients (< 24 years of age) were associated with lower odds of PI mutations at failure on second-line ART [20]. However, our study did not nd any statistical difference concerning age and failure on secondline ART with PI mutations.…”

“…The few studies conducted have pointed at age, and Tuberculosis treatment as factors. For example, in a small cohort of 44 patients, Chimbetete et al 2018 found age as the only factor associated with failure on second-line ART with PI mutations whereby patients above 24 years of age were at a higher risk of failing with major PI mutations [20]. Another study among children less than three years of age highlighted; timing of Tuberculosis treatment while on second-line ART and protease inhibitor dosing strategy [21].…”

Zimbabwe’s national third-line antiretroviral therapy program: Cohort description and treatment outcomes

“…Access to routine VL measurements among patients on ART is low and this leads to late diagnosis of ART treatment failure [5]. Previous studies have shown that the majority of patients failing second-line ART have not acquired protease inhibitor resistance mutations [6][7][8]. Poor adherence has been shown to be the major reason for second-line ART failure [9,10].…”

“…Due to the high costs of third-line regimens it is crucial to assess the effectiveness of these regimens to ensure optimal use of the limited resources. A few studies have reported encouraging early treatment outcomes for patients receiving third-line ART in RLS [8,[11][12][13]. Results have shown that patients who switch to third-line ART have good early treatment outcomes and are able to suppress their VL despite the high level of ART resistance observed before third-line initiation [12].…”

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial

“…However, the relatively limited availability of VL monitoring in low-income countries results in late detection of treatment failure, leading to PI mutation development [4][5][6]. The effect of continuing on a failing PI-containing regimen is largely unknown; most studies have been cross-sectional with time since failure not known [4,5,[7][8][9] or have been conducted in high-income countries, where patients spend little time on failing regimens [10,11].…”