Objective To quantify HIV‐RNA in plasma, in lymphoid tissue and proviral DNA in peripheral blood mononuclear cells and to relate these to immunological markers among patients with plasma viral load counts of ≤ 200 HIV‐RNA copies/mL. Methods A prospective study of one hundred and three patients was undertaken with an inclusion criteria of plasma viral load of ≤ 200 copies/mL. The patients had advanced HIV infection; 25% had developed AIDS. Patients were seen every 6 months for a period of 2 years. Results The median plasma viral load was < 20 copies/mL with no increase during follow‐up. Thirty‐one per cent had plasma viral load of ≤ 20 copies/mL at all visits, 44% had ≥ 1 measurement with 21–200 and 25% had ≥ 1 sample with plasma HIV‐RNA > 200 copies/mL. Lymphoid tissue viral load was low at enrolment and declined further during follow‐up. Baseline HIV‐DNA and immunoglobulin (IgA) differed significantly between the plasma viral load rebound groups (P < 0.05). Conclusion In this cohort, selected solely on the basis of having a plasma viral load of ≤ 200 copies/mL, we found stable or declining viral loads in the measured compartments during 2 years of follow‐up. Baseline HIV‐DNA and IgA levels were higher among patients with less complete virological suppression relative to patients with persistently undetectable plasma HIV‐RNA. Hence, a high cellular level of HIV‐DNA and high plasma IgA may predict subsequent development of low‐grade viraemia.
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...
To determine resistance mutations emerging in HIV-1-infected patients experiencing their ®rst protease inhibitor (PI)-failure on nel®navir-containing highly active antiretroviral therapy (HAART), and to assess virological response to rescue regimens. MethodsPlasma HIV-1 RNA from 24 patients failing nel®navir-containing HAART was sequenced. Failure was de®ned as two consecutive measurements of viral load > 400 HIV-1 RNA copies/mL. Patients with previous failure on other PIs were excluded. Data on response to second-line treatment was extracted from patient ®les. ResultsAt failure primary protease mutations were found in 14 patients (58%). Ten patients had D30N (38%), ®ve patients had L90M (19%), two patients had V82A/F (8%) and two patients had M46I/L (8%). Two patients had both D30N and L90M. Pronounced increases of secondary protease mutations were seen at codon 88 (D: 33%), codon 36 (D: 30%) and codon 71 (D: 17%). Of eight patients with N88D, seven also harboured D30N (P < 0.01). Polymorphisms at codon 63 were detected at baseline in all patients who developed primary resistance mutations at failure (P < 0.01). On rescue regimens, 78% achieved viral loads below limit of detection (BLD). The presence of primary protease mutations was not associated with a higher risk of failure on second-line treatment. ConclusionIn patients failing nel®navir-containing HAART, D30N was detected frequently and L90M occasionally. A pronounced accumulation of the secondary protease mutations N88D, M36I, and A71V/T was found, and D30N was strongly associated with N88D. A high proportion of patients became undetectable on second-line treatment and the presence of primary resistance mutations did not negatively affect the outcome of rescue regimens.
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