Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial

Aboud, Michael; Kaplan, Richard; Lombaard, Johannes; Zhang, Fujie; Hidalgo, José A.; Mamedova, Elmira; Losso, Marcelo; Chetchotisakd, Ploenchan; Brites, Carlos; Sievers, Jörg; Brown, Dannae; Hopking, Judy; Underwood, Mark; Nascimento, Maria Cláudia; Punekar, Yogesh Suresh; Gartland, Martin; Smith, Kimberly Y.

doi:10.1016/s1473-3099(19)30036-2

Cited by 142 publications

(142 citation statements)

References 19 publications

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“…Based upon healthy volunteer studies measuring raltegravir and dolutegravir concentrations, co‐administered with 300 mg once daily (od) rifabutin, no dose changes are recommended . Data from the DAWNING study support use of dolutegravir as a second‐line option where it is used in combination with at least one fully active nucleoside reverse transcriptase inhibitor . Therefore, the co‐administration of rifabutin with dose unadjusted raltegravir or dolutegravir in first line cART and the co‐administration of rifabutin with dolutegravir in second line cART, would be easier to implement in a programmatic setting and potentially cost saving.…”

Section: Pharmacokinetic Data and Dosing Considerations With Antiretrmentioning

confidence: 99%

Global access of rifabutin for the treatment of tuberculosis – why should we prioritize this?

et al. 2019

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Introduction Rifabutin, a rifamycin of equivalent potency to rifampicin, has several advantages in its pharmacokinetic and toxicity profile, particularly in HIV co‐infected patients on combined antiretroviral therapy (cART). In this commentary, we evaluate evidence supporting increased global use of rifabutin and highlight key recommendations for action. Discussion Although extrapolation of data from HIV uninfected patients would suggest non‐inferiority, there has been no randomized controlled study comparing rifabutin versus rifampicin in the outcomes of relapse‐free cure, in drug susceptible tuberculosis (TB), in HIV co‐infected patients on currently utilized cART regimens or in paediatric populations. An important advantage of rifabutin is that compared to the dose adjustments required with rifampicin, it can be co‐administered with the integrase strand transfer inhibitors raltegravir or dolutegravir without the need for dose adjustments. This strategy would be easier to implement in a programmatic setting and would save costs. We have assessed cost incentives to utilize rifabutin and have estimated generic costs for a range of rifabutin dosage scenarios. Where facilities are present for drug re‐challenge and monitoring for drug toxicity and cross‐reactivity, rifabutin offers a switch alternative for adverse drug reactions (ADR)s attributed to rifampicin. This would negate the need to prolong treatment in the absence of a rifamycin as part of short‐course multidrug therapy. There is evidence of incomplete cross‐resistance to rifampicin and rifabutin. Rifabutin may be useful in rifampicin‐resistant TB, in an estimated 20% of cases, based on phenotypic or genotypic rifabutin susceptibility testing. Conclusions Rifabutin should be available globally as a first‐line rifamycin in HIV co‐infected individuals and as a switch option in cases of rifampicin associated ADRs. Further studies are needed to ascertain the utility of rifabutin in rifampicin‐resistant rifabutin‐susceptible TB.

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Section: Pharmacokinetic Data and Dosing Considerations With Antiretrmentioning

confidence: 99%

Global access of rifabutin for the treatment of tuberculosis – why should we prioritize this?

et al. 2019

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“…Notably the proportion of people suppressed at 48-weeks on DTG arm was lower than in most prior clinical trials, albeit of rst-line therapy. 21 As such, additional studies are needed to better elucidate the impact of pre-treatment NNRTI drug resistance on virologic outcomes with both EFV-based and DTG-based used rst-line regimens in the region.…”

Section: Introductionmentioning

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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“…was not certified by peer review) (which The copyright holder for this preprint this version posted December 19, 2019. . https://doi.org/10.1101/19007963 doi: medRxiv preprint Changes to cART recommendations are developing, based on the success of dual therapy with dolutegravir (DTG) regimens, both in the context of prior viraemic suppression [35] and for salvage after failure of first-line treatment [36,37]. DTG/3TC is a common combination, but other regimens do not contain any HBV active agents, (e.g.…”

Section: Changes To Cart Regimens With Influence On Hbv Therapymentioning

confidence: 99%

“…DTG/3TC is a common combination, but other regimens do not contain any HBV active agents, (e.g. DTG combined with rilpivirine (RPV) [38], emtricitabine (FTC) [39], or ritonavir-boosted lopinavir (LPVr) [37]). These regimens have not yet been robustly evaluated in African populations, and are deemed inappropriate in the context of HBV coinfection [40], although there are data demonstrating the efficacy of TDF/FTC in mediating HBV suppression [41].…”

Section: Changes To Cart Regimens With Influence On Hbv Therapymentioning

confidence: 99%

Treatment advantage in HBV/HIV coinfection compared to HBV monoinfection in a South African cohort

Maponga

McNaughton

Schalkwyk

et al. 2019

Preprint

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Objective: Prompted by international targets for elimination of hepatitis B virus (HBV) infection, we performed a cross-sectional observational study of adults with chronic HBV (CHB) infection in South Africa, characterising individuals with HBV monoinfection vs. those coinfected with HBV/HIV, to evaluate the impact of therapy and to guide improvements in clinical care as guidelines for antiviral therapy change over time. Design: We prospectively recruited 115 adults with CHB, over a period of one year at a university hospital in Cape Town, South Africa. HIV coinfection was present in 39 (34%) subjects. We recorded cross-sectional demographic, clinical and laboratory data. Results: Adults with HBV monoinfection were comparable to those with HBV/HIV coinfection in terms of age, sex and body mass. HBeAg-positive status was more common among those with HIV coinfection (p=0.01). However, compared to HBV/HIV coinfection, HBV monoinfected patients were less likely to have had assessment with elastography (p<0.0001) and less likely to be on antiviral treatment (p<0.0001). The HBV monoinfected group was more likely to have detectable HBV viraemia (p=0.04), and features suggesting underlying liver disease including moderate/severe thrombocytopaenia (p=0.007), elevated bilirubin (p=0.004), and APRI score >2 (p=0.02). Three cases of hepatocellular carcinoma were documented, all in patients with HBV monoinfection. Conclusion: In this setting, individuals with HBV monoinfection are disadvantaged in terms of clinical assessment and appropriate antiviral therapy compared to those with HIV coinfection, associated with relatively worse liver health. Enhanced advocacy, education, resources and infrastructure are required to optimise interventions for CHB.

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Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial

Cited by 142 publications

References 19 publications

Global access of rifabutin for the treatment of tuberculosis – why should we prioritize this?

Global access of rifabutin for the treatment of tuberculosis – why should we prioritize this?

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

Treatment advantage in HBV/HIV coinfection compared to HBV monoinfection in a South African cohort

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