Oscar Gallego

Drug resistance in patients experiencing early virological failure under a triple combination including indinavir.

ObjectiveTo assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir. Patients and methodsPlasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes. ResultsThe mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359 460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients. ConclusionThe overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.

Predictors of Virological Response to Atazanavir in Protease Inhibitor-Experienced Patients

Abstract Background: Atazanavir (ATV) is the latest approved HIV protease inhibitor (PI). Even though it is very convenient (only two capsules once a day), concerns have risen about its potency. Method: The clinical performance of ATV 400 mg once a day was examined in all PI-experienced patients who were included in the ATV expanded access program conducted in a single institution. The predictive value of baseline drug resistance HIV genotypes, ATV plasma trough levels, and the genotypic inhibitory quotient (GIQ) on the virological response at week 24 was assessed. Results: Data from 92 patients were analyzed. ATV was prescribed as part of a rescue intervention (45%), a simplification strategy (11%), or an attempt to ameliorate hyperlipidemias (23%) or other toxicities (16%). Tenofovir (TDF) was concomitantly used with ATV in 78% of patients. None received ritonavir boosting. In patients with detectable viremia at baseline (65%), the median HIV RNA drop was 0.7 logs. The median ATV Cmin was 0.12 μg/mL (IQR, 0.05-0.22 μg/mL), which is clearly above the IC90 (90% inhibitory concentration) for ATV in wild-type viruses. The virological response did not correlate significantly with ATV Cmin. The median number of protease resistance mutations was lower in patients showing virological response than in nonresponders (1 vs. 5; p = .07). A higher HIV RNA drop was associated with a higher GIQ (p = .02; β = –5.4; 95% CI, –10 to –1). Only 4 patients (4%) discontinued treatment due to ATV-related toxicities (hyperbilirubinemia in 1). Bilirubin levels were associated with ATV plasma concentrations (p = .05; β = 3.2; 95% CI, –0.1 to 6.5). The rate of hypertriglyceridemia and hypercholesterolemia declined significantly with respect to baseline. Conclusion: ATV is relatively safe and provides significant virological response in PI-experienced patients, mainly among those with a low number of protease resistance mutations. The GIQ predicts accurately the virological response in patients receiving ATV. Hyperbilirubinemia is associated with higher ATV plasma levels.

Prediction of virological response to lopinavir/ritonavir using the genotypic inhibitory quotient.

The predictive value of virological response to lopinavir (LPV)/ritonavir (r) was assessed in 126 HIV-infected patients who failed antiretroviral therapy and had begun a rescue intervention based on LPV/r. At 3 months, subjects with < or =6 protease (PRO) resistance mutations showed a higher rate of virological response (HIV-RNA drop > 1 log or to <50 copies/ml) than patients with >6 PRO resistance mutations (77% versus 48%; p = 0.01). On the other hand, virological responders had greater mean LPV plasma trough levels than nonresponders (6.4 versus 3.9 microg/ml; p = 0.02). A positive correlation was found between LPV trough concentration and viral load reductions at 3 months under LPV/r (r = 0.23; p = 0.017). Overall, virological response was seen in 80.8% of patients with LPV trough levels >4.8 microg/ml while in only 52.5% of patients with lower LPV trough concentrations (p = 0.002). In the multivariate analysis, both < or =6 PRO resistance mutations and LPV trough levels >4.8 microg/ml were independent predictors of virological response to salvage therapy with LPV/r. A genotypic inhibitory quotient (GIQ) was estimated for each patient based on the ratio between LPV trough levels and the number of PRO resistance mutations. A positive strong correlation was found between GIQ and viral load reductions (r = 0.42; p = 0.002). Virological response was seen in 78% of patients with a GIQ >0.7 but only in 41.6% of those with lower GIQ (p = 0.004). When LPV trough levels >4.8 microg/ml, PRO resistance mutations < or =6, and GIQ >0.7 were all included in a stepwise multivariate analysis, GIQ remained as the main independent predictor of response to LPV/r.

Changes in the rate of genotypic resistance to antiretroviral drugs in Spain.

Genotypic resistance to antiretroviral drugs was examined in 684 individuals attending 18 outpatient clinics distributed across Spain in June 2000. Compared with similar surveys conducted before 1998, the prevalence of resistance to nucleosides has declined significantly among naive chronic HIV carriers. In contrast, resistance among pre-treated patients has increased; resistance to all three drug families having been recognized in nearly a quarter of patients.

Changes in the human immunodeficiency virus p7-p1-p6 gag gene in drug-naive and pretreated patients.

ABSTRACT Resistance to antiretroviral agents often results from mutations within the human immunodeficiency virus (HIV) pol gene. Moreover, insertions within the p6 gag-pol region have recently been found to be involved with resistance to nucleoside analogs. Overall, we found that 21% of 156 specimens collected from HIV-infected individuals (17.6% from 74 drug-naive patients and 24.4% from 82 pretreated patients) harbored these insertions. Insertions around the KQE (Lys-Gln-Glu) motif were found in 12.2% of the pretreated patients but in none of the drug-naive subjects (P = 0.002). In contrast, insertions around the PTAP (Prol-Thre-Ala-Prol) motif were seen at similar rates (∼15%) among drug-naive and pretreated patients, which supports the idea that they may be natural polymorphisms.

Rate of Virological Treatment Failure and Frequencies of Drug Resistance Genotypes among Human Immunodeficiency Virus-Positive Subjects on Antiretroviral Therapy in Spain

ABSTRACT The knowledge of which drug-resistant human immunodeficiency virus (HIV) genotypes are the most prevalent in a community may be helpful for designing the best salvage regimens. A total of 540 individuals on antiretroviral therapy attending 18 different outclinics in Spain were examined in a cross-sectional study conducted during June 2000. The overall rate of virologic failure (>50 HIV RNA copies/ml) was 54%. Among the subjects showing treatment failure, 79% harbored resistant HIV genotypes, 77% showed resistance to nucleoside analogues, 53% showed resistance to protease inhibitors, and 42% showed resistance to nonnucleoside reverse transcriptase inhibitors. Overall, 78.5% of individuals harbored HIV strains which showed resistance to two or more drug classes. Moreover, nucleotide substitutions causing broad cross-resistance among compounds within each drug family were quite common. These findings suggest that drug resistance mutations are very prevalent among subjects who have experienced several treatment failures. Therefore, facilitating the arrival of compounds belonging to new drug classes should be considered a priority.

Prevalence of G333D/E in naive and pretreated HIV-infected patients.

A substitution at codon 333 (G -->D/E) within the reverse transcriptase (RT) gene causes resistance to both zidovudine (AZT) and lamivudine (3TC) in a background of mutations associated with loss of sensitivity to both drugs. In the absence of G333D/E, M184V restores the sensitivity to AZT in viruses harboring AZT-resistant genotypes. In this study, we examined the prevalence of the G333D/E mutation in plasma samples from 401 HIV-infected individuals from a routine clinical practice. Genotypic results could be obtained in 277 (81%) specimens belonging to pretreated subjects and in all 65 samples from treatment-naive individuals. The overall prevalence of the G333D/E mutation was 13.2%, without significant differences when comparing naive (10.8%) and treatment-experienced patients (13.7%). The codon 333 mutation was associated with AZT/3TC-resistant genotypes in 76.3% of pretreated individuals but in none of the treatment-naive individuals. In conclusion, the G333D/E mutation must be considered a natural polymorphism, which appears in 11% of treatment-naive HIV-infected individuals. In AZT-experienced patients, it might be advisable to exclude its presence before adding 3TC in combination in the hope of obtaining a restoration of AZT sensitivity if M184V develops.

Higher efavirenz concentrations determine the response to viruses carrying non-nucleoside reverse transcriptase resistance mutations

We examined the influence of both efavirenz plasma concentrations and non-nucleoside reverse transcriptase (NNRTI) resistance mutations on the antiviral activity of efavirenz in patients experiencing early virological failure under nevirapine-containing regimens. Up to 41% of patients reach less than 50 copies/ml at 48 weeks. No association was found between the presence of NNRTI resistance mutations and virological outcome. Nevertheless, patients responding virologically and carrying NNRTI-resistant viruses had higher efavirenz levels than those who did not respond.

Indinavir plasma concentrations and resistance mutations in patients experiencing early virological failure.

Virological failure under protease inhibitor (PI)-based antiretroviral regimens is often not explained by the selection of resistance mutations. The role of low indinavir (IDV) plasma levels in treatment failure was assessed in 46 subjects experiencing early virological failure to a first-line IDV-containing triple combination. Overall, 69% of patients showed subtherapeutic IDV plasma levels (it was not detected at all in 75% of them). Subjects with detectable but suboptimal IDV levels developed more IDV resistance mutations. Thus, drug monitoring may be useful to assess treatment adherence and risk of drug resistance in early virological failures. This information may be crucial for choosing the most appropriate rescue intervention.

Long-Term Outcome of HIV-Infected Patients with Multinucleoside-Resistant Genotypes

Abstract Background: Multiple resistance to nucleoside analogs mediated by the Q151M complex and/or codon 67-69 inserts/deletions represents a growing problem among HIV-infected persons, most of whom have been exposed to sequential therapies for long periods of time. Patients and Method: All plasma samples collected from HIV-infected patients failing antiretroviral therapy and referred for HIV genotyping to our institution during the last 3 years were examined. Genetic analysis of the reverse transcriptase (RT) and protease (PR) genes was performed using an automatic sequencer. Results: Multinucleoside-resistance (MNR) genotypes were recognized in 22 (2.9%) of 761 participants. Twelve of them carried the Q151M complex and 9 harbored different codon 67-69 inserts. One participant carried a deletion at codon 67 of the RT gene. All patients with MNR viruses had been exposed to nucleoside analogs for a median of 54 months (range, 19-96). The mean plasma HIV RNA at the time MNR was first identified was 4.62 log and the mean CD4 count was 227 cells/μL. All patients with MNR viruses except two began salvage therapies based on protease inhibitors (PIs). Overall, 54.5% (12/22) of participants showed a significant virologic response (defined as >1 log reduction in plasma HIV RNA). Seven of them reached <50 copies/mL and remained with undetectable viremia for a median of 17 months (range, 8-50). No differences were found when patients with Q151M and codon 67-69 rearrangements were compared. The only predictor of response was the inclusion of ritonavir-boosted PI in the salvage regimen. In all patients with virologic failure, MNR genotypes have persisted over time. Conclusion: The prevalence of viruses with MNR genotypes is currently low (~3%) among HIV-infected patients failing antiretroviral therapy. The expected poor prognosis of patients harboring MNR viruses may often be overcome using rescue interventions based on potent ritonavir-boosted PI combinations.