Efficacy and safety of nucleoside-sparing regimen based on raltegravir and ritonavir-boosted darunavir in HIV-1-infected treatment-experienced patients.

AIM: To assess the efficacy and tolerability of dual therapy containing raltegravir (RAL) and ritonavir boosted darunavir (DRV/r) in HIV-1-infected treatment-experienced patients. METHOD: Retrospective analysis of 81 HIV-1-infected treatment-experienced patients (56 male and 25 female, 5 Polish centers) who switched to RAL/DRV/r. RESULTS: The main reasons for the introduction of dual therapy were renal dysfunction (16/81 patients-19.8%) and virologic failure on previous regimens (15/81 patients-18.5%). At 48 weeks the treatment was continued in 58/81 (71.6% of patients). In three patients the therapy was discontinued because of virologic failure. However, no mutations to DRV or integrase inhibitors (InI) were detected. At 48 weeks of treatment CD4+ lymphocyte count increased statistically significantly (median 121 cells/µL) P < 0.005. The main reasons for the discontinuation of therapy were treatment simplification (11/23-47.8% patients), adverse events (7/23 patients 30.4%), virologic failure (3/23 patients 13.0%). All patients who switched to RAL/DRV/r therapy because of prior renal impairment were maintained on the treatment for 48 weeks. In this group, before the introduction of dual therapy eGFR (estimated glomerular filtration rate) <60 mL/min/1.72 m2 was reported in nine patients and after 48 weeks in four patients (56.3% vs 25%) (P > 0.05). We found a statistically significant decrease in the prevalence of proteinuria or eGFR <60 mL/min/1.72 m2 (93.8% vs 37.5%; P = 0.004 before and after the introduction of dual therapy, respectively). CONCLUSIONS: Dual therapy was effective and safe for the vast majority of antiretroviral-experienced subjects. Such therapy can be recommended especially for patients with renal impairment or NRTIs intolerance.

Simplification of Antiretroviral Treatment from Darunavir/Ritonavir Monotherapy to Darunavir/Cobicistat Monotherapy: Effectiveness and Safety in Routine Clinical Practice.

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops.

HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein - an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV-1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29-35) and the 80s loop (residues 79-84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1' subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation.

Yeast cells as a tool for analysis of HIV-1 protease susceptibility to protease inhibitors, a comparative study.

HIV develops drug resistance at a high rate under drug selection pressure. Resistance tests are recommended to help physicians optimize antiretroviral drug therapies. For this purpose, genotypic and phenotypic tests have been developed. In order to propose a new phenotypic test that will be less laborious, expensive, and time consuming than the standard ones, a new procedure to measure HIV-1 protease susceptibility to protease inhibitor (PIs) in Saccharomyces cerevisiae yeast cells was developed. This procedure is based on HIV-1 protease expression in yeast. While the viral protein induces yeast cell death, its inhibition by PIs in the culture medium allows the cell to grow in a dose-dependent manner. In a comparative study of standard genotypic analysis vs. yeast cell-based phenotypic tests, performed on HIV-1 protease coding DNA in 17 different plasma samples from infected individuals, a clear match was found between the results obtained using the two technologies. This suggests that the yeast-based procedure is at least as accurate as standard genotypic test in defining susceptibility to protease inhibitors. This encouraging result should be the basis for large-scale validation of the new phenotypic resistance test.

Optimizing treatment in HIV/HCV coinfection.

Sustained virological response (SVR) to anti-hepatitis C virus (HCV) treatment is an outcome that can improve life expectancy in persons with human immunodeficiency virus (HIV) infection. Results of anti-HCV treatment are poor, and less than 50% of treated patients show SVR to peginterferon plus ribavirin combination therapy; in infections from HCV genotype 1 this proportion is less than 40%. Pilot studies have demonstrated that Boceprevir or Telaprevir in combination with peginterferon plus ribavirin are able to increase the SVR rate from 45% to 74% with Telaprevir, and from 26% to 61% with Boceprevir in persons never treated for hepatitis C. Interim data seem to indicate a high rate of HCV RNA undetectability on treatment also in patients without sustained response to peginterferon plus ribavirin. Both Telaprevir and Boceprevir have drug-drug interactions with antiretrovirals, and options for concurrent antiretroviral therapy are restricted. There are also several new anti-HCV drugs under study with the potential for more tolerable effective future regimens. The indication for treatment in a patient with HCV/HIV coinfection should take into account the priority of treatment, the probability of sustained response, the potential toxicities, the concurrent antiretroviral therapy options, the patient's motivation, and the sustainability of current and future therapies.