Factors Associated with the Development of Drug Resistance Mutations in HIV-1 Infected Children Failing Protease Inhibitor-Based Antiretroviral Therapy in South Africa

Abstract

ObjectiveLimited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors.MethodsData from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis.ResultsThe study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;-2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033).ConclusionMajor protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent protease inhibitor dosing strategy proving to be important associated factors. There is an urgent need for safe, effective, and practicable HIV/tuberculosis co-treatment in young children and the optimal timing of treatment, optimal dosing of antiretroviral therapy, and alternative tuberculosis treatment strategies should be urgently addressed.

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

“…Concomitant Tuberculosis treatment while on second-line ART was higher among cases (67%) and signi cantly associated with second-line failure with PI mutations (p=<0.001). Our ndings are in line with a study conducted by Rossouw et al 2015, which found that children on Tuberculosis treatment while on second-line ART were more likely to fail on second-line therapy with PI mutations [21]. This is attributable to factors such as higher pill burden [32,33], HIV/TB coinfection being associated with advanced HIV/AIDS [34], and the fact that Rifabutin is not readily available in the resource-limited settings as a replacement for Rifampicin which is known to reduce the pharmacookinetic levels of PIs and consequently their their e cacy [35,36].…”

“…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].…”

Appearance of Drug Resistance Mutations Among the Dominant HIV-1 Subtype, CRF01_AE in Maumere, Indonesia

“…HIV-1 drug resistance occurs rapidly among infants due to the infants' conditions, such as a higher HIV-1 viral load than that in adults, poor tolerance of ART medication, complex adherence issues, and previous exposure to ART in order to prevent MTCT [42,43,44]. In infants with co-infections such as tuberculosis, treatments may increase adverse events, including drug toxicity and the risk of significant inter-drug interactions.…”

Epidemiologic and viral predictors of antiretroviral drug resistance among persons living with HIV in a large treatment program in Nigeria

“…It is important to understand the interplay of factors associated with HIV drug resistance, especially in low to middle-income countries (LMICs) where there is limited access to viral load testing [17]. In this study we used data collected from the AIDS Prevention Initiative in Nigeria (APIN) program, a comprehensive HIV care and treatment program in the country, to evaluate sociodemographic, socioeconomic and other factors that could be associated or predict ADR in Nigeria.…”