Resistance profiles and adherence at primary virological failure in three different highly active antiretroviral therapy regimens: analysis of failure rates in a randomized study

Abstract

ObjectivesTo investigate the interplay between resistance and adherence in the virological failure of three fundamentally different highly active antiretroviral therapy (HAART) regimens. MethodsWe retrospectively identified 56 verified primary virological failures (viral load 4400 HIV-1 RNA copies/mL) among 293 patients randomized to two nucleoside reverse transcriptase inhibitors (NRTIs) 1 ritonavir 1 saquinavir (RS-arm) (n 5 115), two NRTIs 1 nevirapine 1 nelfinavir (NN-arm) (n 5 118), or abacavir 1 stavudine 1 didanosine (ASD-arm) (n 5 60) followed up for a median of 90 weeks. Data on adherence were collected from patient files, and genotyping was performed on plasma samples collected at time of failure. ResultsTreatment interruption or poor adherence was mainly caused by side effects and accounted for 74% of failures, and was associated with absence of resistance mutations. In the 30 failing patients not switched from randomized treatment, we found resistance in two of 12 patients in the RS-arm (M184 V only), four of six patients in the NN-arm [all four had non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations], and seven of 12 patients in the ASD-arm (NRTI mutations only). Two adherent patients on randomized treatment failed in the RS-arm, none in the NN-arm, and six in the ASD-arm. ConclusionsPrimary virological failure was caused mainly by treatment interruption. No primary protease inhibitor (PI) mutations were found in patients failing on boosted saquinavir, whereas resistance to NNRTIs and NRTIs was prevalent in several patients failing on regimens based on these medications.Keywords: highly active antiretroviral therapy, HIV, patient adherence, treatment failure, viral drug resistance IntroductionFailure of highly active antiretroviral treatment (HAART) regimens is still an obstacle to persistent suppression of viral replication in HIV-infected patients. Studies of different antiretroviral regimens have achieved highly variable failure rates (5 to 68% of patients above the limit of detection), which presumably reflects varying efficacy of the regimens, different failure definitions and dissimilarities in treatment settings [1][2][3][4] HAART [5,6]. However, the extent of adherence-explained failures within randomized clinical trials is still poorly defined. The interplay between resistance and adherence has mainly been analysed in cohorts receiving unboosted protease inhibitor (PI)-based HAART or in clinical trials of less potent maintenance therapy [7,8]. The aim of the present study was to delineate the degree to which virological failure compromises future treatment options.In a randomized clinical trial of HIV-infected patients naïve to HAART, we have previously reported failure rates ranging from 34 to 59% [9,10], and a unique resistance pattern observed in the triple nucleoside reverse transcriptase inhibitor (NRTI) arm [11]. Because the study arms consisted of a boosted protease inhibitor (PI) regimen, a triple NRTI regimen and a triple-class combination, this randomized trial prov...

Long-Term Efficacy of First Line Antiretroviral Therapy in Indian HIV-1 Infected Patients: A Longitudinal Cohort Study

“…Previous studies have shown that sub-optimal adherence, treatment interruptions and improper dosing can lead to drug resistance [10], [23], [24]. A recent meta-analysis on studies from resource limited settings showed that early identification of virological failure limits the emergence of drug resistance [25].…”

Burden of Nonnucleoside Reverse Transcriptase Inhibitor Resistance in HIV-1-Infected Patients: A Systematic Review and Meta-Analysis

“…Of the 17 randomized controlled trials (RCTs) reporting resistance at time of treatment failure, nine were not included into the quantitative analyses due to not reporting the total number of patients failing treatment, 151,152 trial not conducted in treatment-naive patients, 153,154 both, 140,[155][156][157] or not reporting the time point of assessment. 56 The remaining eight studies [158][159][160][161][162][163][164][165] included 613 treatment-naive patients failing treatment by weeks 48, 96, or 144 of the trials.…”

‘Simply forgot’ is the most frequently stated reason for missed doses of HAART irrespective of degree of adherence

“…These studies were from such diverse settings as Europe [3,4], the USA [5,6], Costa Rica [7] and Hong Kong [8]. Other studies have found that patients who stop their medication completely most often cite 'side effects' as the reason [9,10]. It is therefore reasonable to hypothezize that patients who miss a larger proportion of their doses do so for reasons that are different from those of patients who miss only a few doses.…”