Resistance at Virological Failure Using Boosted Protease Inhibitors Versus Nonnucleoside Reverse Transcriptase Inhibitors As First-Line Antiretroviral Therapy—Implications for Sustained Efficacy of ART in Resource-Limited Settings

Hill, Andrew; McBride, Angela; Sawyer, W. A.; Clumeck, Nathan; Rk, Gupta

doi:10.1093/infdis/jit112

Cited by 29 publications

(24 citation statements)

References 26 publications

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“…Despite this tendency to wait to switch on PIs, which hypothetically would result in more resistance mutations, we still saw less resistance accumulate in PI-higher compared to NNRTI-higher. These data are consistent with clinical trials and observational studies in adults, reporting fewer NRTI mutations on PIs than NNRTIs [8, 9], as well as additional reports on accumulation of NRTI resistance on NNRTIs [10–12]. …”

Section: Discussionsupporting

confidence: 88%

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Harrison

Melvin

Fiscus

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold. Methods PENPACT-1 had a 2x2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART, and switch at a 1000c/ml versus 30000c/ml threshold. Switch-criteria were: not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or CDC-C event. Resistance tests were performed on samples ≥1000c/ml before switch, re-suppression and at 4-year/trial-end. Results Sixty-seven children started PI-based ART and were randomized to switch at 1000c/ml (PI-1000), 64 PIs and 30000c/ml (PI-30000), 67 NNRTIs and 1000c/ml (NNRTI-1000), and 65 NNRTI and 30000c/ml (NNRTI-30000). Ninety-four (36%) children reached the 1000c/ml switch-criteria during 5 years follow-up. In 30000c/ml threshold arms, median time from 1000c/ml to 30000c/ml switch-criteria was 58 (PI) versus 80 (NNRTI) weeks (P=0.81). In NNRTI-30000 more NRTI resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000c/ml (23% NNRTI-1000, 27% NNRTI-30000). Sixty-two children started abacavir+lamivudine, 166 lamivudine+zidovudine or stavudine, and 35 other NRTIs. The abacavir+lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30000, 64% NNRTI-1000 and 100% NNRTI-30000 were <400c/ml 24 weeks later. Conclusion Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet re-suppressed on second-line. An abacavir+lamivudine NRTI combination seemed protective against development of NRTI resistance.

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Section: Discussionsupporting

confidence: 88%

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Harrison

Melvin

Fiscus

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…23–25 Additionally, HIV with resistance mutations to protease inhibitors generally replicates poorly, 26 the decline in CD4 cell count is less rapid in the presence of virological failure with a boosted protease inhibitor-based regimen than it is with an NNRTI-based regimen, 27–29 and risk of death could be higher in patients whose treatment is failing because of NNRTI resistance compared with protease inhibitor resistance. 26 Although findings of clinical trials comparing outcomes between first-line NNRTIs and boosted protease inhibitors show small differences in viral load, 30,31 these studies typically include people who are more likely to adhere to ART, and our modelling suggests that among less adherent people, the long-term outcomes of boosted protease inhibitor-based regimens will be superior. To date, scant data are available for the rate at which mutations to protease inhibitors emerge in people maintained on a boosted protease inhibitor-based regimen in the face of virological failure without options to switch.…”

Section: Discussionmentioning

confidence: 95%

Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis

et al. 2014

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Summary Background With continued roll-out of antiretroviral therapy (ART) in resource-limited settings, evidence is emerging of increasing levels of transmitted drug-resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial levels of transmitted drug resistance. Methods We created a model of HIV transmission, progression, and the effects of ART, which accounted for resistance generation, transmission, and disappearance of resistance from majority virus in the absence of drug pressure. We simulated 5000 ART programmatic scenarios with different prevalence levels of detectable resistance in people starting ART in 2017 (t0) who had not previously been exposed to antiretroviral drugs. We used the model to predict cost-effectiveness of various potential changes in policy triggered by different prevalence levels of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) measured in the population starting ART. Findings Individual-level resistance testing before ART initiation was not generally a cost-effective option, irrespective of the cost-effectiveness threshold. At a cost-effectiveness threshold of US$500 per quality-adjusted life-year (QALY), no change in policy was cost effective (ie, no change in policy would involve paying less than $500 per QALY gained), irrespective of the prevalence of pretreatment NNRTI resistance, because of the increased cost of the policy alternatives. At thresholds of $1000 or higher, and with the prevalence of pretreatment NNRTI resistance greater than 10%, a policy to measure viral load 6 months after ART initiation became cost effective. The policy option to change the standard first-line treatment to a boosted protease inhibitor regimen became cost effective at a prevalence of NNRTI resistance higher than 15%, for cost-effectiveness thresholds greater than $2000. Interpretation Cost-effectiveness of potential policies to adopt in response to different levels of pretreatment HIV drug resistance depends on competing budgetary claims, reflected in the cost-effectiveness threshold. Results from our model will help inform WHO recommendations on monitoring of HIV drug resistance in people starting ART. Funding WHO (with funds provided by the Bill & Melinda Gates Foundation), CHAIN (European Commission).

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“…Theoretically, modern boosted PIs are good candidates for use as monotherapy as this class is known to have a high genetic barrier to resistance following viral failure, requiring several mutations before phenotypic drug susceptibility is significantly reduced. 1,2 In an era when patients will initiate treatment earlier and can expect to be taking therapy for decades, other potential advantages of PI monotherapy include the avoidance of toxicity and preservation of long-term treatment options. 3,4 …”

Section: Introductionmentioning

confidence: 99%

Virological efficacy of PI monotherapy for HIV-1 in clinical practice

Bouzidi

Collier

Nastouli

et al. 2016

J. Antimicrob. Chemother.

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BackgroundClinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied.MethodsAn observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation.ResultsNinety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes.ConclusionsThere was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation.

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Resistance at Virological Failure Using Boosted Protease Inhibitors Versus Nonnucleoside Reverse Transcriptase Inhibitors As First-Line Antiretroviral Therapy—Implications for Sustained Efficacy of ART in Resource-Limited Settings

Cited by 29 publications

References 26 publications

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds

Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis

Virological efficacy of PI monotherapy for HIV-1 in clinical practice

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