P. Clevenbergh

Impact of Various Antiretroviral Drugs and Their Plasma Concentrations on Plasma Lipids in Heavily Pretreated HIV-Infected Patients

Abstract Objective: To evaluate the frequency and the magnitude of lipid abnormalities (LA) in respect to the nature of the antiretroviral drug and its plasma concentrations. Patients/Method: Trough concentrations (Ctrough) of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed at Weeks 4, 8, 24, 28, and 32. Fasting triglycerides (TG) and total cholesterol (CH) were sampled at Weeks 0, 12, 20, and 32. We analyzed the probability of occurrence of grade 3-4 CH (> 7.8 mmol/L) and TG (> 8.4 mmol/L) during a 24-week period according to the drug taken using a Kaplan-Meier analysis and log rank test. Relation between Week 8 PI or NNRTI Ctrough and Week 12 lipid levels was assessed using the Kendall correlation measure. Results: The PharmAdapt study included 252 patients (mean age 41 years, 83% males); the patients received a PI (73%), an NNRTI (50%), and/or a ritonavir (RTV) booster-containing (46%) regimen. Compared to any other regimen, use of lopinavir (LPV)/RTV or efavirenz (EFV) was associated with a higher risk of grade 3-4 CH. Use of LPV/RTV and RTV booster was associated with a higher risk of grade 3-4 TG. Use of any PI-containing regimen was associated with a higher risk for grade 3-4 CH and TG compared to non PI-based regimens. Kendall correlation coefficients for PI or NNRTI Ctrough and blood lipid levels were close to zero for all drugs and CH or TG, showing the absence of relation between drug concentrations and lipid levels. Conclusion: Severity of lipid abnormalities is related to the nature of the antiretroviral drug. There is no short-term relation between PI or NNRTI trough concentrations and blood lipid levels in heavily pretreated patients.

Early CD4+ T Cell Recovery in Human Immunodeficiency Virus-Infected Patients Receiving Effective Therapy Is Related to a Down-Regulation of Apoptosis and Not to Proliferation

This prospective study investigated the contributions of apoptosis and proliferation of CD4(+) T cells obtained by the introduction of a new antiretroviral treatment for human immunodeficiency virus infection. Virus load; T cell counts; apoptosis of T cell subsets, including naive cells; and proliferation were determined from treatment initiation to the third month in a cohort of patients. An increase in CD4(+) T cell count > or = 100 cells/microL over baseline was considered to be a satisfactory immune reconstitution. Sixty-nine patients completed the protocol, 22 of whom met our definition of a satisfactory immune reconstitution, showing a significantly more pronounced reduction in spontaneous CD4(+) T cell apoptosis at month 1 as well as month 3, compared with the other patients. In contrast, neither Fas-induced apoptosis down-regulation nor Fas-induced increased proliferation capacity was associated with a satisfactory immune reconstitution. Down-regulation of CD4(+) T cell apoptosis by antiretroviral treatment is the main mechanism associated with early CD4(+) T cell increase.

Improved Interpretation of Genotypic Changes in the HIV-1 Reverse Transcriptase Coding Region That Determine the Virological Response to Didanosine

BACKGROUND Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed. METHODS Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set. RESULTS A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) copies/mL (95% confidence interval, +0.11 to +0.57; P=.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation. CONCLUSION The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.

HIV resistance to antiretroviral drugs: mechanisms, genotypic and phenotypic resistance testing in clinical practice.

Abstract HIV resistance to antiretroviral agents is a major contributory cause of treatment failure. The dynamics of HIV replication, together with patient-, physician-, and drug-related factors, lead to emergence of HIV resistant strains in most of the patients. Phenotypic assays look for an increase in the antiretroviral drug (ARV) concentration that inhibits 50% of the growth of the tested HIV strain (IC50), comparatively with a reference strain cultivated in parallel. Genotypic tests detect resistance mutations in the reverse transcriptase and protease genes by comparing the gene sequences of a resistant virus to those of a wildtype strain that has previously been described. The efficacy of each ARV class and each individual ARV is threatened by specific mutations and resistance mechanisms. In retrospective studies of genotypic or phenotypic resistance testing, baseline resistance tests results were correlated with virological outcomes. There is some evidence from prospective studies that resistance testing may have some benefits when used to choose salvage regimens. However, problems in the areas of test interpretation, patient compliance, availability of active drugs, and technical test performance limit the usefulness of resistance testing in clinical practice. This article reviews the mechanisms underlying HIV resistance, the principles of phenotypic and genotypic tests, and the use of these tests in clinical practice.

Variable Virological Outcomes According to the Center Providing Antiretroviral Therapy Within the PharmAdapt Clinical Trial

Abstract Purpose: Differences in virological response between HIV-infected patients at different study centers were analyzed as a substudy of PharmAdapt, a multicenter prospective randomized study to evaluate the utility of therapeutic drug monitoring after a genotypic-based treatment adaptation. Results: After 12 weeks, the percentage of patients participating in PharmAdapt with HIV RNA < 200 copies/mL ranged from 17% to 69% between centers providing antiretroviral care. In a multivariate analysis, independent factors predictive of viral load <200 HIV RNA copies/mL at Week 12 included: lower baseline viral load, lower nonnucleoside reverse transcriptase inhibitor resistance, lower protease inhibitor resistance, and the center providing antiretroviral therapy. To evaluate the final factor, study sites were divided into two groups based on Week 12 HIV RNA values above or below the median. Conclusion: Using this definition, observed differences between centers included the use of stavudine, abacavir-, and/or efavirenz-based regimens and use of online expert advice.