High Levels of Dual-Class Drug Resistance in HIV-Infected Children Failing First-Line Antiretroviral Therapy in Southern Ethiopia

Abstract

Clinical monitoring of pediatric HIV treatment remains a major challenge in settings where drug resistance genotyping is not routinely available. As a result, our understanding of drug resistance, and its impact on subsequent therapeutic regimens available in these settings, remains limited. We investigate the prevalence and correlates of HIV-1 drug resistance among 94 participants of the Ethiopia Pediatric HIV Cohort failing first-line combination antiretroviral therapy (cART) using dried blood spot-based genotyping. Overall, 81% (73/90) of successfully genotyped participants harbored resistance mutations, including 69% (62/90) who harbored resistance to both Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Strikingly, 42% of resistant participants harbored resistance to all four NRTIs recommended for second-line use in this setting, meaning that there are effectively no remaining cART options for these children. Longer cART duration and prior regimen changes were significantly associated with detection of drug resistance mutations. Replicate genotyping increased the breadth of drug resistance detected in 34% of cases, and thus is recommended for consideration when typing from blood spots. Implementation of timely drug resistance testing and access to newer antiretrovirals and drug classes are urgently needed to guide clinical decision-making and improve outcomes for HIV-infected children on first-line cART in Ethiopia.

Rates and Correlates of Short Term Virologic Response among Treatment-Naïve HIV-Infected Children Initiating Antiretroviral Therapy in Ethiopia: A Multi-Center Prospective Cohort Study

“…In Ethiopia, high rates of virological suppression have been reported among HIV infected adults [15][16][17][18] and children [16], which are similar to figures reported for the rest of sub Saharan Africa [19]. However, increasing trends of acquired HIV drug resistance and treatment failure have also been reported in Ethiopia, at least in adults [20,21]. Moreover, a study among HIV-infected Ethiopian adults showed that presence of baseline drug resistance mutations was associated with lower rates of virologic suppression at months six and 12 months of cART [22].…”

“…Total nucleic acids were extracted using the NucliSENS easyMAG System according to manufacturer's instructions (BioMerieux, Marcy-l'Étoile, France). HIV Protease and a portion of Reverse Transcriptase (RT) spanning a minimum of codons 1-234 were amplified via an initial Reverse Transcriptase step (Expand Reverse Transcriptase; Roche, Basel, Switzerland) followed by nested PCR (Expand Hifi System; Roche) or alternatively by RT-PCR (using the SuperScript III One-Step RT-PCR System with Platinum Taq High Fidelity DNA Polymerase; Invitrogen, MA, USA) followed by nested PCR (using the Expand HiFi System; Roche) [21]. Amplification was attempted using up to four oligonucleotide primer sets designed to amplify various HIV-1 group M subtypes: if amplification failed using the primary set, amplification was attempted using the backup sets.…”

High predictive efficacy of integrase strand transfer inhibitors in perinatally HIV-1-infected African children in therapeutic failure of first- and second-line antiretroviral drug regimens recommended by the WHO

“…Currently, INSTIs are still not available for the treatment of HIV-infected children in sub-Saharan Africa, while the effectiveness of the current first- and second-line WHO-recommended paediatric regimens appears to be rapidly waning 15 , 16 , 18 . Data on the efficacy of INSTIs in African children are scarce.…”

“…As a consequence, the increasing number of DRMs to the main ARV drugs prescribed in sub-Saharan Africa has considerably reduced the effectiveness of current paediatric regimens 1 , 4 , 16 . Thus, the paediatric therapeutic regimens currently recommended by the WHO may become no longer suitable in African settings, leading to a decrease in convenient therapeutic options in many sub-Saharan African countries 15 , 16 , 18 …”

A viral genome wide association study and genotypic resistance testing in patients failing first line antiretroviral therapy in the first large countrywide Ethiopian HIV cohort

“…Only a few studies with relatively small number of patients from limited geographical regions in Ethiopia have reported ART failure rates, including acquired HIV drug resistance (HIVDR) [9–12]. Although ART has been rapidly scaled up throughout the country, to the best of our knowledge, there is no data at the national level.…”