12 research outputs found

    Resistance Patterns Selected by Nevirapine vs. Efavirenz in HIV-Infected Patients Failing First-Line Antiretroviral Treatment: A Bayesian Analysis

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    Background: WHO recommends starting therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs), i.e. nevirapine or efavirenz, with lamivudine or emtricitabine, plus zidovudine or tenofovir. Few studies have compared resistance patterns induced by efavirenz and nevirapine in patients infected with the CRF01_AE Southeast Asian HIV-subtype. We compared patterns of NNRTI-and NRTI-associated mutations in Thai adults failing first-line nevirapine-and efavirenz-based combinations, using Bayesian statistics to optimize use of data. Methods and Findings: In a treatment cohort of HIV-infected adults on NNRTI-based regimens, 119 experienced virologic failure (<500 copies/mL), with resistance mutations detected by consensus sequencing. Mutations were analyzed in relation to demographic, clinical, and laboratory variables at time of genotyping. The Geno2Pheno system was used to evaluate second-line drug options. Eighty-nine subjects were on nevirapine and 30 on efavirenz. The NRTI backbone consisted of lamivudine or emtricitabine plus either zidovudine (37), stavudine (65), or tenofovir (19). The K103N mutation was detected in 83% of patients on efavirenz vs. 28% on nevirapine, whereas Y181C was detected in 56% on nevirapine vs. 20% efavirenz. M184V was more common with nevirapine (87%) than efavirenz (63%). Nevirapine favored TAM-2 resistance pathways whereas efavirenz selected both TAM-2 and TAM-1 pathways. Emergence of TAM-2 mutations increased with the duration of virologic replication (OR 1.25-1.87 per month increment). In zidovudine-containing regimens, the overall risk of resistance across all drugs was lower with nevirapine than with efavirenz, whereas in tenofovir-containing regimen the opposite was true. Conclusions: TAM-2 was the major NRTI resistance pathway for CRF01_ AE, particularly with nevirapine; it appeared late after virological failure. In patients who failed, there appeared to be more second-line drug options when zidovudine was combined with nevirapine or tenofovir with efavirenz than with alternative combinations

    Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand.

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    BACKGROUND: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. METHODS AND FINDINGS: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. CONCLUSIONS: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary

    Number of primary outcomes by arm.

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    a<p>Including nine cases followed by death.</p>b<p>Tuberculosis (8), cryptococcal meningitis (3), <i>P. jirovecii</i> pneumonia (2), systemic <i>P. marneffei</i> (2), disseminated <i>Mycobacterium avium intracellulare</i> (1), sepsis (2).</p>c<p>Tuberculosis (4), cryptococcal meningitis (4), <i>P. jirovecii</i> pneumonia (2), systemic <i>P. marneffei</i> (2), sepsis (3).</p>d<p>Sepsis (3), cerebrovascular accidents (2), heart failure (1), asthma attack (1), <i>P. jirovecii</i> pneumonia (1), hepatic failure (1), unknown cause (2).</p>e<p>Heart failure (3), cancer (2, 1 breast cancer, 1 liver cancer), suicide (2), renal failure (1), hepatic failure (1), pneumonia (1), sepsis (1).</p

    Resistance mutations found at first ARV switch (VL arm).

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    <p>This table shows 18 patients randomized to the VL arm who reached switching criteria of >400 copies/ml. The last samples collected before switch were genotyped. One participant with extensive PI resistance in the pretreatment specimen is omitted from this table.</p>a<p>“Duration of replication before genotype” is defined as time from first detection of VL >400 copies/ml to genotyping. This may be shorter than the duration before ARV drug switching.</p>b<p>These two participants were not included in calculations related to ARV drug switches since, although they met VL criteria for switching during the study, they both switched after the end of the study (April 1, 2010).</p
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