OLA-Simple: A software-guided HIV-1 drug resistance test for low-resource laboratories

Panpradist, Nuttada; Beck, Ingrid; Vrana, Justin D.; Higa, Nikki; McIntyre, David J.; Ruth, Parker S.; So, Isaac; Kline, Enos; Kanthula, Ruth; Wong-On-Wing, Annie; Lim, Jonathan; Ko, Daisy; Milne, Ross; Rossouw, Theresa M.; Feucht, Ute Dagmar; Chung, Michael H.; Jourdain, Gonzague; Ngo‐Giang‐Huong, Nicole; Laomanit, Laddawan; Soria, Jaime; Lai, James J.; Klavins, Eric; Frenkel, Lisa M.; Lutz, Barry

doi:10.1016/j.ebiom.2019.11.002

Cited by 26 publications

(57 citation statements)

References 37 publications

(47 reference statements)

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“…Without such data, treatment programs should be advised to maintain virologic monitoring programs, adherence monitoring and support programs for those with failure, and regimen change guidance for individuals with intolerance or persistent virologic failure, even when documented drug resistance is absent. More novel strategies, such as real-time adherence and resistance monitoring, and long-acting injectable formulations of ART for those with adherence challenges should also be explored as these options become more widely available [37][38][39] . NAMSAL is the only other randomized controlled trial that has compared DTG vs EFV-based first-line ART in sub-Saharan Africa.…”

Section: Discussionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

et al. 2020

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Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.

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Section: Discussionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

et al. 2020

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“…Future work should explore the e cacy and feasibility of innovative means of mitigating the effect of drug resistance on treatment outcomes, such as targeted point-of-care resistance testing to identify individuals at greater risk of VF, or longer acting regimens to reduce imperfect adherence in those most susceptible to it. [38][39][40] NAMSAL is the only other randomized controlled trial which has compared DTG versus EFV-based rst-line ART in sub Saharan Africa. That study, conducted in Cameroon, compared low-dose 400 mg EFV to DTG as third agent at 48 weeks.…”

Section: Discussionmentioning

confidence: 99%

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Siedner¹,

Moorhouse²,

Simmons³

et al. 2020

Preprint

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Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

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“…In addition, OLA identified all participants with DRM by Sanger sequencing at virologic failure, including several participants with drug resistance not detected by Sanger sequencing. An economical and easy to use point of care OLA kit that assesses NNRTI mutations K103N, Y181C, G190A and NRTI mutations M184V and K65R [31] could be used in resource-limited settings to test patients prior to starting EFV-based ART, at virologic failure to guide the choice of 2nd-line ART, or before switching to dolutegravir-based ART.…”

Section: Discussionmentioning

confidence: 99%

Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya

Beck¹,

Levine²,

McGrath

et al. 2020

eClinicalMedicine

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Background: Pre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2À9%) or higher (10%) frequencies during efavirenz-vs. nevirapine-ART. Methods: We conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA 400 copies/mL at month-12 of ART, was compared by PDR genotypes. Findings: PDR was detected in 59/1231 (4¢8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69¢2% (27/39) vs. wild-type 10¢4% (70/674); p = 0¢0001], whether detected as minority [66¢7% (4/6)] or higher [69¢7% (23/33)] frequencies in an individual's HIV quasispecies (p = 0¢002 and p < 0¢0001, respectively), or mutations at single [50¢0% (12/24)] or multiple [100¢0% (15/15)] codons (p < 0¢0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25¢0% (5/20) vs. wild-type 5¢0% (25/498); p = 0¢005], but only if detected at multiple drugresistant codons [50¢0% (3/6); p = 0¢003] or high frequencies PDR [33¢3% (5/15); p = 0¢001]. Interpretation: The risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz-compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings.

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OLA-Simple: A software-guided HIV-1 drug resistance test for low-resource laboratories

Cited by 26 publications

References 37 publications

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya

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