Drug resistance and optimizing dolutegravir regimens for adolescents and young adults failing antiretroviral therapy

Kouamou, Vinie; Manasa, Justen; Katzenstein, David; McGregor, A M; Ndhlovu, Chiratidzo E.; Makadzange, Tariro

doi:10.1097/qad.0000000000002284

Cited by 20 publications

(19 citation statements)

References 45 publications

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“…In a cross-sectional study conducted between June 2018 and September 2019, we evaluated the sensitivity and specificity of the PANDAA assay in detecting major DRMs (Ն20%) compared to standard GRT by Sanger sequencing and in detecting low-level (Ͻ20%) major DRMs compared to next-generation sequencing (NGS). We used plasma samples collected during a randomized clinical trial at the Parirenyatwa Hospital HIV ART treatment clinic (OI clinic) in Harare, Zimbabwe, as previously described (5).…”

Section: Methodsmentioning

confidence: 99%

Diagnostic Accuracy of Pan-Degenerate Amplification and Adaptation Assay for HIV-1 Drug Resistance Mutation Analysis in Low- and Middle-Income Countries

et al. 2020

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Background: HIV drug resistance (HIVDR) is a barrier to sustained virologic suppression in low and middle-income countries (LMICs). Point mutation assays targeting priority drug resistance mutations (DRMs) are being evaluated to improve access to HIVDR testing. Methods: In a cross-sectional study (June 2018 - September 2019), we evaluated the diagnostic accuracy of a simple and rapid HIVDR assay (the PANDAA assay targeting K65R, K103NS, M184VI, Y181C and G190A mutations) compared to Sanger sequencing and Next Generation sequencing (NGS). Plasma samples from adolescents and young adults (aged 10-24 years) failing antiretroviral therapy (Viral load >1000 cps/mL x 2) were analyzed. Sensitivity and specificity of the PANDAA assay were determined by a proprietary application designed by Aldatu Biosciences. Agreement between genotyping methods was evaluated using the Cohen's kappa coefficient. Results: 150 samples previously characterized by Sanger sequencing were evaluated using PANDAA. For all DRMs detected, PANDAA showed a sensitivity and specificity of 98% and 94% respectively. For NRTI DRMs, sensitivity (95%CI) and specificity (95%CI) were 98% (92%-100%) and 100% (94%-100%) respectively. For NNRTI DRMs, sensitivity and specificity were 100% (97%-100%) and 76% (61%-87%) respectively. PANDAA showed a strong agreement with Sanger sequencing for K65R, K103NS, M184VI and G190A (Kappa >0.85) and a substantial agreement for Y181C mutation (Kappa = 0.720). Of the 21 false positive samples genotyped by PANDAA, only 6 (29%) were detected as low abundance variants by NGS. Conclusion: With the high sensitivity and specificity to detect major DRMs, PANDAA could represent a simple and rapid alternative HIVDR assay in LMICs.

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Section: Methodsmentioning

confidence: 99%

Diagnostic Accuracy of Pan-Degenerate Amplification and Adaptation Assay for HIV-1 Drug Resistance Mutation Analysis in Low- and Middle-Income Countries

et al. 2020

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“…Here, children and adolescents were changed from nucleotide reverse transcriptase inhibitor fixed dose combinations of tenofovir disoproxil fumarate and lamivudine to abacavir and lamivudine in second-line. The response to a new nucleotide reverse transcriptase inhibitor in the presence of the drug resistance mutations M184V and K65R is predicted to be sub-optimal [ 23 ]. Nevertheless, the response to lopinavir/ritonavir or atazanavir/ritonavir and 2 nucleotide reverse transcriptase inhibitors is consistent with studies of adults in Africa where nucleotide reverse transcriptase inhibitor resistance has been found to have little impact on second-line protease inhibitor-based regimens [ 50 – 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies in LMICs have shown that virologic failure of first-line ART is associated with reverse transcriptase inhibitor resistance [21][22][23]46]. Switching from a first-line non-nucleoside reverse transcriptase inhibitor-based regimen to a second-line protease inhibitor-based regimen calls for continued administration of lamivudine and substitution of a new nucleotide reverse transcriptase inhibitor in the new regimen [10].…”

Section: Plos Onementioning

confidence: 99%

“…After virologic failure of a first-line regimen, pediatric co-formulations of generic lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) as a heat stable tablets were combined with a nucleotide reverse transcriptase inhibitor backbone of abacavir (ABC) and lamivudine [18,19]. Protease inhibitors and a new nucleotide reverse transcriptase inhibitor were recommended with switching because of the extensive drug resistance to first-line therapy [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Viral load care of HIV-1 infected children and adolescents: A longitudinal study in rural Zimbabwe

et al. 2021

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Introduction Maintaining virologic suppression of children and adolescents on ART in rural communities in sub-Saharan Africa is challenging. We explored switching drug regimens to protease inhibitor (PI) based treatment and reducing nevirapine and zidovudine use in a differentiated community service delivery model in rural Zimbabwe. Methods From 2016 through 2018, we followed 306 children and adolescents on ART in Hurungwe, Zimbabwe at Chidamoyo Christian Hospital, which provides compact ART regimens at 8 dispersed rural community outreach sites. Viral load testing was performed (2016) by Roche and at follow-up (2018) by a point of care viral load assay. Virologic failure was defined as viral load ≥1,000 copies/ml. A logistic regression model which included demographics, treatment regimens and caregiver’s characteristics was used to assess risks for virologic failure and loss to follow-up (LTFU). Results At baseline in 2016, 296 of 306 children and adolescents (97%) were on first-line ART, and only 10 were receiving a PI-based regimen. The median age was 12 years (IQR 8–15) and 55% were female. Two hundred and nine (68%) had viral load suppression (<1,000 copies/ml) and 97(32%) were unsuppressed (viral load ≥1000). At follow-up in 2018, 42/306 (14%) were either transferred 23 (7%) or LTFU 17 (6%) and 2 had died. In 2018, of the 264 retained in care, 107/264 (41%), had been switched to second-line, ritonavir-boosted PI with abacavir as a new nucleotide analog reverse transcriptase inhibitor (NRTI). Overall viral load suppression increased from 68% in 2016 to 81% in 2018 (P<0.001). Conclusion Viral load testing, and switching to second-line, ritonavir-boosted PI with abacavir significantly increased virologic suppression among HIV-infected children and adolescents in rural Zimbabwe.

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“…Published data emanating from SA estimate that ~25% of the ~145 000 people receiving SLART experience treatment failure within 1 year as a result of treatment nonadherence, subtherapeutic ART, delayed switching, and accumulation of PI-resistant mutations. [2,5,6] Although these data are from the predolutegravir (DTG) era, the growing pool of patients urgently needing TLART requires innovative systems to ensure that patients receiving TLART are alive, engaged in care, and virologically suppressed for the duration of their treatment.…”

Section: Editorialmentioning

confidence: 99%

A third-line antiretroviral therapy register to track patient clinical and virological outcomes

Naidoo

Ramruthan

Reddy³

et al. 2022

S Afr Med J

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Drug resistance and optimizing dolutegravir regimens for adolescents and young adults failing antiretroviral therapy

Cited by 20 publications

References 45 publications

Diagnostic Accuracy of Pan-Degenerate Amplification and Adaptation Assay for HIV-1 Drug Resistance Mutation Analysis in Low- and Middle-Income Countries

Diagnostic Accuracy of Pan-Degenerate Amplification and Adaptation Assay for HIV-1 Drug Resistance Mutation Analysis in Low- and Middle-Income Countries

Viral load care of HIV-1 infected children and adolescents: A longitudinal study in rural Zimbabwe

A third-line antiretroviral therapy register to track patient clinical and virological outcomes

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