Boceprevir, peginterferon and ribavirin for acute hepatitis C in HIV infected patients.

BACKGROUND & AIMS: Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy. METHODS: We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint. RESULTS: One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers. CONCLUSION: With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495.

Effect of abacavir on sustained virologic response to HCV treatment in HIV/HCV co-infected patients, Cohere in Eurocoord.

BACKGROUND: Contradicting results on the effect of abacavir (ABC) on hepatitis C virus (HCV) treatment responses in HIV/HCV co-infected patients have been reported. We evaluated the influence of ABC on the response to pegylated interferon (pegIFN) and ribavirin (RBV)-containing HCV treatment in HIV/HCV co-infected patients in a large European cohort collaboration, including data from different European countries. METHODS: HIV/HCV co-infected patients were included if they were aged ≥16 years, received pegIFN alfa-2a or 2b and RBV combination treatment and were enrolled in the COHERE cohort collaboration. Logistic regression was used to evaluate the impact of abacavir on achieving a sustained virologic response (SVR) to HCV treatment. RESULTS: In total 1309 HIV/HCV co-infected patients who had received HCV therapy were included, of whom 490 (37 %) had achieved an SVR. No statistically significant difference was seen for patients using ABC-containing regimens compared to patients using an emtricitabine + tenofovir (FTC + TDF)-containing backbone, which was the most frequently used backbone. In the multivariate analyses, patients using a protease inhibitor (PI)-boosted regimen were less likely to achieve an SVR compared to patients using a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen (OR: 0.61, 95 % CI: 0.41-0.91). The backbone combinations zidovudine&lamivudine (AZT + 3TC) and stavudine&lamivudine (d4t + 3TC) were associated with lower SRV rates (0.45 (0.24-0.82) and 0.46 (0.22-0.96), respectively). CONCLUSION: The results of this large European cohort study validate that SVR rates are generally not affected by ABC. Use of d4T or AZT as part of the HIV treatment regimen was associated with a lower likelihood of achieving an SVR.

Preventive versus "on-demand" nutritional support during antiviral treatment for hepatitis C: a randomized controlled trial.

BACKGROUND & AIMS: Although antiviral treatment for hepatitis C (HCV) is highly effective, side effects often occur, including weight loss, digestive symptoms, and impaired quality of life. We aimed at exploring the beneficial effects of preventive nutritional support. METHODS: In a randomized controlled trial, 53 HCV patients were allocated to "on demand" support (n=26: nutritional intervention if weight loss >5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack). Nutritional state (including validated Jamar Hand Grip Strength), digestive symptoms (visual analog score), and quality of life (SF-36 survey) were evaluated at baseline, and after 24 and 48 weeks of peginterferon α-2b and ribavirin treatment. RESULTS: The primary end point (weight loss at 24 weeks) was reached in 22 patients in both groups. Weight decreased markedly in the "on demand" group (decrease at 24 weeks: 5.4 kg or 6.9%, p<0.001), but not in the preventive group (decrease 0.3 kg or 0.3%, p=n.s.). Jamar Hand Grip Strength deteriorated in the "on demand" group (from 40.3 ± 15.5 kg to 32.0 ± 13.1 kg, p<0.001) but not in the preventive group (from 40.7 ± 10.4 kg to 39.7 ± 8.9 kg, p=n.s.). Intake of energy, proteins, and fat decreased markedly in the "on demand" group but increased in the preventive group. Although digestive symptoms and quality of life deteriorated, impairment was significantly less in the preventive group. CONCLUSIONS: Preventive nutritional advice plus supplementation prevents weight loss and catabolic state during HCV antiviral therapy, with improved digestive symptoms and quality of life.

Effects of preventive versus "on-demand" nutritional support on paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for hepatitis C.

BACKGROUND AND OBJECTIVE: Deterioration of nutritional status during PEG-interferon containing therapy for chronic hepatitis C can be ameliorated by preventive nutritional support. We aimed to explore whether such support also affects paid labour productivity, physical exercise and performance status. METHODS: In this prospective randomized controlled trial (J Hepatol 2012;57:1069-75), 53 patients with chronic hepatitis C had been allocated to "on demand" support (n=26: nutritional intervention if weight loss>5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack) during PEG-interferon-containing therapy. Paid labour productivity, physical exercise and performance status were evaluated at baseline, after 24 and (if applicable) after 48 weeks of treatment. RESULTS: At baseline, 46% of patients performed paid labour and 62% performed some kind of physical exercise. Furthermore, most patients were able to carry out normal activity with only minor symptoms of disease (mean Karnofsky performance score: 94). Decreases of paid labour productivity (-21% vs. -70%, P=0.003), physical exercise activity (-43% vs. -87%, P=0.005) and Karnofsky performance scores (-12% vs. -24%, P<0.001) were less in the preventive than in "on demand" group after 24 weeks of treatment. Effects of preventive nutritional support were even more pronounced after 48 weeks. CONCLUSIONS: Preventive nutritional support markedly ameliorates decreases of paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for chronic hepatitis C.

Association between IL28B polymorphisms and first-phase viral load decrease in chronic hepatitis C virus-infected patients treated with peginterferon alfa-2b/ribavirin.

Host polymorphisms in the IL28B region have recently been associated with outcome of treatment for hepatitis C virus (HCV) infection. This study clearly shows an association between first-phase viral load decrease and the IL28B rs12979860 polymorphism in chronic HCV-infected patients. Furthermore, a higher treatment efficiency factor (ɛ) was found in those HCV-infected patients with a CC genotype compared with those with a CT and TT genotype. This study highlights the importance of host response mechanisms in relation to favourable clearance of HCV.

Pegylated interferon-α monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C.

BACKGROUND: Despite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-α [PEG-IFN-α] monotherapy or in combination with ribavirin) is still under debate. METHODS: A total of 23 HIV-infected patients were prospectively diagnosed with acute HCV and treated with PEG-IFN-α2a monotherapy (180 µg/week) for 24 or 48 weeks. Add-on ribavirin was allowed from week 4 of therapy onwards. There were three patients who were not included for different reasons. Blood samples were routinely drawn for viral load measurement and IL28B polymorphism analysis. RESULTS: Spontaneous viral clearance occurred in 1 (4%) patient. Nineteen patients (13 genotype 1 and 6 genotype 4) received treatment with PEG-IFN-α monotherapy (3 with add-on ribavirin) resulting in a rapid virological response (HCV RNA<50 IU/ml at week 4) in 7 (37%) patients. A sustained virological response (SVR) was reached in 7 (37%) patients, whereas 9 (47%) patients were null-responders to treatment (that is, <2 log10 drop in HCV RNA at week 12 of therapy). The unfavourable G allele of the IL28B polymorphism rs8099917 was detected in 66% of the non-responders. In case of re-emergence of HCV viraemia after treatment discontinuation, sequence analysis of quasispecies confirmed an HCV relapse in 3 patients while 2 patients were re-infected by their previously non-responding partner. CONCLUSIONS: PEG-IFN-α monotherapy resulted in a low SVR rate and a high percentage of null-response, whereas non-SVR was associated with a polymorphism in the IL28B gene (rs8099917).

T-cell responses at baseline and during therapy with peginterferon-alpha and ribavirin are not associated with outcome in chronic hepatitis C infected patients.

BACKGROUND: Since the association between hepatitis C virus (HCV)-specific T-cell responses both pre-treatment and during interferon-alpha based therapy and viral clearance is unresolved, a combined analysis of distinctive T-cell characteristics (proliferation and interferon-gamma production) is important to clarify this issue. METHODS: Peripheral blood mononuclear cells (PBMC) collected in 22 chronic HCV infected patients at pre-treatment and at week 4 during pegIFN-alpha/ribavirin therapy, were stimulated with overlapping peptide pools in a [3H]-thymidine assay, an interferon-gamma-ELISA, and a sensitive 12-day T-cell expansion assay. RESULTS: Compared to the [3H]-thymidine proliferation and interferon-gamma secretion assays, the 12-day T-cell expansion assay was more sensitive in detecting T-cell responses. No significant association was demonstrated between pre-treatment HCV-specific CD4+ or CD8+ T-cell responses and either a sustained virological response (SVR) or a rapid virological response (RVR). However, a skewing of individual responses towards the non-structural antigens was observed. During pegIFN-alpha/ribavirin therapy, HCV-specific CD4+ and CD8+ T-cells declined similarly in both SVR/RVR and non-SVR/non-RVR patients. CONCLUSION: No correlation was found between the magnitude of pre-treatment HCV-specific T-cell responses and the outcome of pegIFN-alpha/ribavirin therapy in terms of SVR and RVR. Moreover, the magnitude of HCV-specific T-cell responses declined in all patients early during treatment.

Ruffini endings are absent from the periodontal ligament of trkB knockout mice.

To clarify the role of neurotrophin receptors in the development of Ruffini endings, periodontal ligaments and trigeminal ganglia of trkA, trkB, and trkC knockout mice were immunostained for protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), parvalbumin (PV), and calretinin (CR). Innervation patterns of PGP 9.5- and CGRP-immunoreactive fibers were examined in the periodontal ligament of the knockout mice. PGP 9.5-positive fibers in the incisal periodontal ligaments of trkA and trkC knockout mice form Ruffini endings distinguished by dendritic ramifications and branches. However, Ruffini endings were not present in the periodontal ligament of trkB knockout mice. Only free nerve endings were observed in tissue of trkB knockout mice. Compared with trkA and trkC knockouts, the proportion of CR-positive neurons in mandibular and maxillary regions of the trigeminal ganglion of trkB knockout mice is decreased. These findings indicate that the development of periodontal Ruffini endings is regulated by trkB-dependent and CR-coexpressing neurons.