Effect of simplification from protease inhibitors to boosted atazanavir‐based regimens in real‐life conditions

Background

Atazanavir (ATV) boosted with ritonavir (ATV/r) is a potent, well‐tolerated, once‐daily protease inhibitor (PI). Few data are available on this agent as a treatment simplification option for patients taking other PIs.

Objective

The aim of the study was to determine the effectiveness and safety of ATV‐containing regimens in patients who have simplified their antiretroviral treatment.

Methods

SIMPATAZ was a multicentre, prospective, noninterventional study in patients who had undetectable HIV RNA on their current PI‐containing therapy and who were switched to an ATV/r‐based regimen. Patients underwent a routine physical examination, and data were collected on HIV RNA levels, CD4 cell counts, liver function, lipid parameters, adverse reactions, adherence to treatment and patient satisfaction.

Results

A total of 183 patients were enrolled in the study and included in the analysis (80% were male, 29% had AIDS, and 52% were coinfected with HIV and hepatitis B virus or hepatitis C virus). The median baseline CD4 count was 514 cells/μL. Median exposure to previous HIV therapy was 8 years, and 32% of patients had a history of PI failures. Lopinavir boosted with ritonavir was the most frequent PI replaced (62%) and tenofovir+lamivudine /emtricitabine the backbone most used during the study (29%). The study drug was discontinued early by 25 patients (14%), two of whom discontinued as a result of adverse events (Hodgkin lymphoma and vomiting). Two patients died (lung cancer and myocardial infarction). At month 12, 93% of the study population had an undetectable HIV RNA viral load. Hyperbilirubinaemia >3 mg/dL and increased alanine aminotransferase levels>200 IU/L were observed in 38.5% and 4.4% of patients, respectively. Median changes from baseline to month 12 in total cholesterol, triglycerides and low‐density lipoprotein cholesterol were ?13 mg/dL (?7%; P<0.0001), ?19 mg/dL (?13%; P<0.0001) and ?7 mg/dL (?6%; P=0.021), respectively.

Conclusions

In a real‐world setting, switching from other PIs to ATV/r is a well‐tolerated and safe option for improving the lipid profile and for retaining virological response in controlled pretreated patients.

     

Serum lipid profile in highly active antiretroviral therapy‐naïve HIV‐infected patients in Cameroon: a case–control study

Background

HIV status has commonly been found to affect the serum lipid profile.

Objectives

The aim of this study was to determine the effect of HIV infection on lipid metabolism; such information may be used to improve the management of HIV‐infected patients.

Methods

Samples were collected from December 2005 to May 2006 at Yaounde University Teaching Hospital, Yaounde, Cameroon. Lipid parameters were obtained using colorimetric enzyme assays, while low‐density lipoprotein cholesterol (LDLC) values were calculated using the formula of Friedewald et al. (1972) and atherogenicity index by total cholesterol (TC)/high‐density lipoprotein cholesterol (HDLC) and LDLC/HDLC ratios.

Results

HIV infection was most prevalent in subjects aged 31 to 49 years. Most of the HIV‐positive patients belonged to Centers for Disease Control and Prevention categories B (43.0%) and C (30.23%). Compared with control subjects, patients with CD4 counts<50 cells/μL had significantly lower TC (P<0.0001) and LDLC (P<0.0001) but significantly higher triglyceride (TG) values (P<0.001) and a higher atherogenicity index for TC/HDLC (P<0.01) and HDLC/LDLC (P=0.02); patients with CD4 counts of 50–199 cells/μL had significantly lower TC (P<0.001) and significantly higher TG values (P<0.001); patients with CD4 counts of 200–350 cells/μL had significantly higher TG (P=0.003) and a higher atherogenicity index for TC/HDLC (P<0.0002) and HDLC/LDLC (P=0.04); and those with CD4 counts >350 cells/μL had a higher atherogenicity index for TC/HDLC (P<0.0001) and HDLC/LDLC (P<0.001). HDLC was significantly lower in HIV‐positive patients irrespective of the CD4 cell count. Lipid parameters were also influenced by the presence of opportunistic infections (OIs).

Conclusion

HIV infection is associated with dyslipidaemia, and becomes increasingly debilitating as immunodeficiency progresses. HDLC was found to be lower than in controls in the early stages of HIV infection, while TG and the atherogenicity index increased and TC and LDLC decreased in the advanced stages of immunodeficiency.

     

Management of treatment‐naïve chronic hepatitis C genotype 1 patients: a cost‐effectiveness analysis of treatment options

New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost‐effectiveness analysis of boceprevir (BOC)‐ and telaprevir (TVR)‐based triple therapy according to different patients’ selection strategies. A semi‐Markov model of CHC natural history and progression towards end‐stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1–F4 fibrosis, (ii) only F2–F4 and (iii) only F3–F4. For each strategy, TVR interleukin‐28B‐guided (IL28B‐guided) and BOC rapid virologic response‐guided (RVR‐guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5‐year time horizon, and adopting the Italian National Health System perspective. The incremental cost‐effectiveness ratio (ICER) for F1–F4 strategy relative to F3–F4 was €5132 per quality‐adjusted life years gained, across TVR IL‐28B‐guided therapy, and €7042 in the BOC RVR‐guided therapy. Conversely, in the 5‐year scenario, the ICER for F1–F4 strategy relative to F3–F4 was €1 818 679 (TVR IL28B‐guided) and €1 866 437 (BOC RVR‐guided) per end‐stage liver disease or death (ESLD‐D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost‐effective strategy to optimize resource utilization.     

Safety and efficacy of faldaprevir in combination with pegylated interferon α‐2b and ribavirin in Japanese patients with genotype‐1 chronic hepatitis C virus infection

Aim

We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α‐2b and ribavirin (PegIFNα‐2b/RBV) in Japanese patients with HCV genotype‐1 infection.

Methods

Treatment‐naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response‐guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα‐2b/RBV for 24 or 48 weeks (RGT). Response‐guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment‐experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα‐2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα‐2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post‐treatment (SVR12) was a secondary end‐point.

Results

All except one patient experienced drug‐related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment‐naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively.

Conclusions

In treatment‐naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα‐2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV, with at least comparable efficacy. In treatment‐experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV. Clinicaltrials.gov NCT01579474.

     

The HIV protease inhibitor lopinavir/ritonavir (Kaletra) alters the growth,differentiation and proliferation of primary gingival epithelium

Objective

This study was designed to evaluate the effects of the HIV protease inhibitor lopinavir/ritonavir on gingival epithelium growth, integrity and differentiation.

Methods

Organotypic (raft) cultures of gingival keratinocytes were established and treated with a range of lopinavir/ritonavir concentrations. To examine the effect of lopinavir/ritonavir on gingival epithelium growth and stratification, haematoxylin and eosin staining was performed. To investigate the effect of this drug on tissue integrity, transmission electron microscopy (TEM) was performed on untreated and drug‐treated tissues. Further, immunohistochemical analysis of raft cultures was performed to assess the effect of lopinavir/ritonavir on the expression of key differentiation and proliferation markers including cytokeratins, proliferating cell nuclear antigen (PCNA) and cyclin A.

Results

Lopinavir/ritonavir treatments drastically inhibited the growth of gingival epithelium when the drug was present throughout the growth period of the tissue. When the drug was added on day 8 of tissue growth, lopinavir/ritonavir treatments compromised tissue integrity over time and altered the proliferation and differentiation of gingival keratinocytes. Expression of cytokeratins 5, 14, 10 and 6, PCNA and cyclin A was induced, and their expression patterns were also altered over time in treated rafts.

Conclusions

The findings of our studies suggest that lopinavir/ritonavir treatments compromised tissue integrity over time and deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. Our study provides a model of potential utility in studying the effects of antiretroviral drugs in vitro.