Julio A. Gutierrez

Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single‐center treatment protocol of patients with HCV genotype 1 infection who received a 12‐week combination regimen of sofosbuvir and simeprevir. Sixty‐one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9‐8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%‐97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%‐100%), whereas SVR12 was 89% (95% CI, 74%‐95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3‐F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%‐86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12‐week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse. Liver Transpl 21:823‐830, 2015.

Short Communication: Inadequate Vitamin D Exacerbates Parathyroid Hormone Elevations in Tenofovir Users

Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.

Influenza Vaccination in Orthotopic Liver Transplant Recipients: Absence of Post Administration ALT Elevation

Influenza vaccination has reduced life‐threatening complications from influenza virus infection in adult liver transplant recipients. We evaluated changes in aminotransferase level and immunogenicity of influenza vaccination in liver transplant recipients. Fifty‐one liver transplant recipients were administered a standard dose of the 2002–2003 inactivated trivalent influenza vaccine. ALT values were measured at baseline, 1 week and 4–6 weeks postvaccination. Antibody responses to each component of the vaccine were measured at baseline and after 4–6 weeks by a hemagglutination inhibition (HAI) assay. Response was defined as an HAI titer ≥ 1: 40 and/or a 4‐fold increase in antibody titers from baseline. An ALT elevation was defined as a rise of ≥ 50% from baseline. There was no difference in the median rise in ALT value between seroconverters and nonseroconverters. A significant number of recipients developed potentially protective antibody titers (p‐value < 0.0001). At less than 4 months post transplantation, 1/7 (14%), at 4–12 months, 6/9 (67%), and after 12 months, 30/35 (86%) subjects responded to the H1 strain. Of 51 recipients, one HCV (−) recipients vaccinated within 3 months of transplantation developed acute cellular rejection. Influenza virus vaccination is not associated with allograft rejection or ALT flares in liver transplant recipients.

Mutation Master: profiles of substitutions in hepatitis C virus RNA of the core, alternate reading frame, and NS2 coding regions.

The RNA genome of the hepatitis C virus (HCV) undergoes rapid evolutionary change. Efforts to control this virus would benefit from the advent of facile methods to identify characteristic features of HCV RNA and proteins, and to condense the vast amount of mutational data into a readily interpretable form. Many HCV sequences are available in GenBank. To facilitate analysis, consensus sequences were constructed to eliminate the overrepresentation of certain genotypes, such as genotype 1, and a novel package of sequence analysis tools was developed. Mutation Master generates profiles of point mutations in a population of sequences and produces a set of visual displays and tables indicating the number, frequency, and character of substitutions. It can be used to analyze hundreds of sequences at a time. When applied to 255 HCV core protein sequences, Mutation Master identified variable domains and a series of mutations meriting further investigation. It flagged position 4, for example, where 90% or more of all sequences in genotypes 1, 2, 4, and 5, have N4, whereas those in genotypes 3, 6, 7, 8, 9, and 10 have L4. This pattern is noteworthy: L (hydrophobic) to N (polar) substitutions are generally rare, and genotypes 1, 2, 4, and 5 do not form a recognized super family of sequences. Thus, the L4N substitution probably arose independently several times. Moreover, not one member of genotypes 1, 2, 4, or 5 has L4 and not one member of genotypes 3, 6, 7, 8, 9, or 10 has N4. This nonoverlapping pattern suggests that coordinated changes at position 4 and a second site are required to yield a viable virus. The package generated a table of genotype-specific substitutions whose future analysis may help to identify interacting amino acids. Three substitutions were present in 100% of genotype 2 members and absent from all others: A68D, R74K, and R114H. Finally, this study revealed thatARFP, a novel protein encoded in an overlapping reading frame, is as conserved as conventional HCV proteins, a result supporting a role for ARFP in the viral life cycle. Whereas most conventional programs for phylogenetic analysis of sequences provide information about overall relatedness of genes or genomes, this program highlights and profiles point mutations. This is important because determinants of pathogenicity and drug susceptibility are likely to result from changes at only one or two key nucleotides or amino acid sites, and would not be detected by the type of pairwise comparisons that have usually been performed on HCV to date. This study is the first application of Mutation Master, which is now available upon request (http://tandem.biomath.mssm.edu/mutationmaster.html).

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

This study tested the hypothesis that hepatitis C virus (HCV) RNA and core antigen levels rise more rapidly after liver transplantation (LT) in recipients of grafts from living donors (LD) versus deceased donors (DD). Eleven consecutive LD and 15 DD recipients were followed prospectively. Before LT, median HCV RNA levels were similar: 5.42 (LDLT) and 5.07 (DDLT) log10 IU/mL (P = NS). During the first 7 hours after LT a trend toward a greater HCV RNA decrease in LDLT patients was seen, although they received fewer blood replacement products during surgery. HCV RNA levels rose more rapidly in LDLT patients between days 1 and 3 (P = .0059) and were higher in this group on days 2, 3, 4, and 5. Core antigen levels were significantly higher in LDLT patients on days 3 and 5, although they were similar before LT (P = NS). Alanine aminotransferase (ALT) values were higher among LDLT patients from 8 to 14 days and from 4 to 24 months. Two‐year graft and patient survival were 73% for LDLT patients and 80% for DDLT patients (P = NS). In conclusion, viral load rose more rapidly in LD recipients and reached higher levels shortly after surgery. Greater ALT elevations were evident in the LDLT group, but survival rates were similar. The trend toward a greater initial viral load decrease in patients with LD grafts and the significantly sharper increase suggest that the liver plays a predominant role in both HCV clearance and replication. (HEPATOLOGY 2005;42:1420–1428.)

Classical and emerging roles of vitamin D in hepatitis C virus infection.

According to the Institute of Medicine, the risk of clinically significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL. By this standard, most cirrhotic hepatitis C virus- (HCV-) positive patients and many noncirrhotic patients are vitamin D-deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin Ds beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. Information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients is provided.

Evaluation of fatigue in U.S. patients with primary biliary cirrhosis

OBJECTIVES:Fatigue, which may have a significant impact on quality of life, is the most common reported symptom in primary biliary cirrhosis (PBC). Multiple instruments to quantify fatigue and quality of life in liver disease have been validated, but have not been broadly applied to U.S. PBC patients. This study examines the extent of fatigue and its effect on quality of life in U.S. PBC patients.METHODS:Seventy patients with PBC were administered two validated questionnaires about quality of life (the Mayo version of the NIDDK-QA) and fatigue (the Fisk Fatigue Impact Score) and a proposed physical measure of fatigue in PBC (the grip strength test) on the day of routine physician visit. Nonparametric methods were employed.RESULTS:The fatigue and quality of life domain scores (physical functioning, liver symptoms, health satisfaction, Karnofsky index) discriminated between patients with and without self-reported fatigue (p < 0.05), as opposed to the grip strength results. Fatigue and quality of life domains correlated strongly with each other (r between 0.33 and 0.74, p ≤ 0.006) and not with the grip strength results. Neither quality of life nor fatigue scores correlated with age.CONCLUSIONS:The correlation between fatigue and quality of life scores suggests fatigue has an impact on quality of life in U.S. primary biliary cirrhosis patients. However, our fatigue scores suggest U.S. PBC patients have less fatigue than non-U.S. PBC patients. The grip strength is an insensitive measure of fatigue in U.S. PBC patients.

Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in direct‐acting antiviral–experienced patients with genotype 1 hepatitis C virus

The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1–infected patients who fail direct‐acting antiviral (DAA)‐based regimens remains unknown. In this phase 2, open‐label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA‐based regimen were randomized to receive treatment with a fixed‐dose combination tablet of sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86‐100) receiving sofosbuvir‐velpatasvir‐voxilaprevir alone and 24 of 25 (96%; 95% CI, 80‐100) receiving the same treatment with RBV. None of the patients discontinued sofosbuvir‐velpatasvir‐voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with sofosbuvir‐velpatasvir‐voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir‐velpatasvir‐voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. Conclusion: A fixed‐dose combination of sofosbuvir‐velpatasvir‐voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803‐1809).

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Aim:  This long‐term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).

Ledipasvir/sofosbuvir-based treatment of patients with chronic genotype-1 HCV infection and cirrhosis: results from two Phase II studies.

BACKGROUND Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis. METHODS In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRILOGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety. RESULTS In both studies, most patients were male (each 65%) and white (92-96%), infected with HCV genotype-1a (62-70%) and had IL28B non-CC genotypes (82-87%). In total, 37-39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRILOGY-1 (82-91%) and TRILOGY-2 (88-95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent. CONCLUSIONS All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.