On the impact of hepatitis C virus and heterologous immunity on alloimmune responses following liver transplantation.

Virus-induced heterologous immunity is considered a barrier to transplantation tolerance. Yet, hepatitis C (HCV)-infected liver transplant (LT) patients occasionally achieve operational tolerance. We investigated the mechanisms through which HCV infection modulates donor-specific T cell responses following LT and the influence of HCV eradication. We generated T cell lines from HCV-infected LT and non-LT patients before and after HCV eradication and quantified alloreactive responses using cell lines expressing single-HLA class-I antigens in the presence/absence of PD-1/CTLA-4 blockade. HCV-specific CD8+ T cells cross-reacted with allogeneic class-I HLA molecules. HCV-positive LT recipients exhibited a higher proportion of CD8+ T cells coexpressing inhibitory receptors (PD-1/CTLA4) than HCV-negative LT, and their expression correlated with CXCL10 plasma levels. This resulted in decreased antidonor and third-party proliferative responses, which were significantly reversed by HCV eradication. PD-1/CTLA-4 blockade increased the proportion of HCV-specific CD8+ T cells reacting against donor only before viral clearance. In conclusion, HCV infection results in the generation of HCV-specific CD8+ T cells capable of reacting against allogeneic HLA molecules. Following LT, this results in a PD-1/CTLA4-dependent decrease in alloimmune responses. Our findings challenge the notion that heterologous immunity is necessarily detrimental in LT and provide an explanation for the association between HCV eradication and immune-mediated allograft damage.

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C.

BACKGROUND & AIMS: HCV subtypes which are unusual in Europe are more prevalent in the African region, but little is known of their response to direct-acting antivirals (DAAs). These include non-1a/1b/ non-subtypeable genotype 1 (G1) or non-4a/4d (G4). In this report we aimed to describe the genotype distribution and treatment outcome in a south London cohort of African patients. METHODS: We identified all patients born in Africa who attended our clinic from 2010-2018. Information on HCV genotype, treatment regimen and outcome were obtained. Non-subtypeable samples were analysed using Glasgow NimbleGen next-generation sequencing (NGS). Phylogenetic analysis was carried out by generating an uncorrected nucleotide p-distance tree from the complete coding regions of our sequences. RESULTS: Of 91 African patients, 47 (52%) were infected with an unusual subtype. Fourteen novel, as yet undesignated subtypes (G1*), were identified by NGS. Three individuals were infected with the same subtype, now designated as subtype 1p. Baseline sequences were available for 22 patients; 18/22 (82%) had baseline NS5A resistance-associated substitutions (RASs). Sustained virological response (SVR) was achieved in 56/63 (89%) overall, yet only in 21/28 (75%) of those with unusual G1 subtypes, with failure in 3/16 G1*, 1/2 G1p and 3/3 in G1l. Six treatment failures occurred with sofosbuvir/ledipasvir compared to 1 failure on a PI-based regimen. The SVR rate for all other genotypes and subtypes was 35/35 (100%). CONCLUSIONS: Most individuals in an unselected cohort of African patients were infected with an unusual genotype, including novel subtype 1p. The SVR rate of those with unusual G1 subtypes was 75%, raising concern about expansion of DAAs across Africa. Depending on the regimen used, higher failure rates in African cohorts could jeopardise HCV elimination. LAY SUMMARY: Direct-acting antiviral medications are able to cure hepatitis C in the majority of patients. The most common genotype of hepatitis C in Europe and the United States is genotype 1a or 1b and most clinical trials focused on these genotypes. We report that in a group of African patients, most of them had unusual (non-1a/1b) genotype 1 subtypes, and that the cure rate in these unusual genotypes was lower than in genotypes 1a and 1b.

Cirrhosis and liver transplantation in patients co-infected with HIV and hepatitis B or C: an observational cohort study.

This study assessed the likelihood of referral for liver transplantation assessment in a prospective cohort of patients co-infected with HIV and hepatitis B or C with complications of cirrhosis. There were 141 co-infected patients from 11 UK centres with at least one complication of cirrhosis recorded (either decompensation or hepatocellular carcinoma) out of 772 identified with cirrhosis and/or HCC. Only 23 of these 141 (16.3%) were referred for liver transplantation assessment, even though referral is recommended for co-infected patients after the first decompensation episode.

Clinical factors that predict noncirrhotic portal hypertension in HIV-infected patients: a proposed diagnostic algorithm.

Noncirrhotic portal hypertension (NCPH) is a rare but important clinical entity in human immunodeficiency virus (HIV) populations. The purpose of this study was to describe the clinical factors associated with the condition in an effort to formulate a diagnostic algorithm for easy and early diagnosis. We performed a multicenter, retrospective case-control study of 34 patients with NCPH and 68 control HIV patients. The study found that thrombocytopenia, splenomegaly, didanosine use, elevated aminotransferases, and an elevated alkaline phosphatase level were all significantly more prevalent in the NCPH cohort. Using these easily available clinical parameters, we developed an algorithm for early diagnosis of NCPH in HIV.

Switching Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide Fumarate (TAF) in Hepatitis B/HIV Co-Infection: A Feasibility Study.

PURPOSE: Tenofovir alafenamide (TAF) delivers the active metabolite more efficiently to target cells compared with tenofovir disoproxil fumarate (TDF). Recent studies suggest that TAF is efficacious in treatment naïve individuals who are co-infected with HBV/HIV and may have superior effects on HBV e antigen (HBeAg) seroconversion in this setting. The primary objective of this study was to explore the feasibility of switching from TDF to TAF in HBV/HIV co-infection. METHODS: In this single-arm, multicenter, open-label study, we recruited patients (n = 20) who were on stable TDF-based antiviral therapy for at least 12 months. All participants had undetectable HIV RNA and HBV DNA levels at the time of screening and were converted to a TAF-based treatment regimen (TAF + emtricitabine + third agent) for 48 weeks. FINDINGS: Twenty-seven individuals were invited to take part in the screening process; 3 met the exclusion criteria and a further 4 withdrew consent prior to enrolment. The remaining participants were predominantly male (70%), non-cirrhotic (95%) and of Afro-Caribbean ethnicity (60%). All were co-infected with HIV-1 and established on long-term antiretroviral treatment prior to enrolment (median 6.5 years). No adverse events related to the study drug were observed, and most patients (89.5%) maintained undetectable HIV RNA and HBV DNA throughout the follow-up period. IMPLICATIONS: Switching from TDF to TAF in HBV/HIV co-infection was safe, well tolerated and maintained virological suppression in most patients. Additional studies are needed to confirm these findings in larger cohorts and explore other endpoints.

Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom.

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central [adjusted odds ratio (aOR) 2.40 (95% confidence interval (CI) 1.23--4.67) and West [2.10 (1.29-3.41)] African ancestry was associated with HBV and Central [6.98 (2.00-24.43)] African ancestry with HCV.

Dolutegravir-induced liver injury leading to sub-acute liver failure requiring transplantation: a case report and review of literature.

A patient with human immunodeficiency virus-1 infection presented with sub-acute liver failure, temporally related to commencement of an antiretroviral therapy regimen containing dolutegravir (Triumeq). The patient was not a carrier of HLA-B5701, and abacavir hypersensitivity was unlikely. We believe this is the first report of severe dolutegravir-related hepatotoxicity resulting in sub-acute liver failure and transplantation and highlights a potential need for closer monitoring after drug initiation.

Efficacy and Tolerability of Direct-Acting Antivirals for Hepatitis C in Older Adults.

OBJECTIVES: To evaluate the efficacy and tolerability of direct-acting antiviral (DAA) therapy in individuals aged 65 and older. DESIGN: Retrospective review between June 2014 and January 2017. SETTING: Viral hepatitis outpatient clinic. PARTICIPANTS: Individuals aged 65 and older treated with DAA therapy for hepatitis C virus (HCV) during the study period (N=113) divided into 2 cohorts: aged 65 to 74 (n=88) and aged 75 and older (n=25). MEASUREMENTS: Drug-drug interactions (DDIs), adverse events (AEs), and rates of sustained virologic response with DAA therapy were assessed. RESULTS: Sustained virologic response rate was 97.7% in individuals aged 65 to 74 and 95.8% in those aged 75 and older. Individuals aged 75 and older were more likely to be taking more than 2 medications per day for chronic conditions (84% vs 62%, p=.02) and more likely to have clinically significant DDIs necessitating cessation or adjustment of medications before commencement of DAA therapy (80% vs 36%, p=.001). Moreover, individuals aged 75 and older were more likely to experience an AE during therapy (50% vs 26%, p=.03) and were more susceptible to developing anemia secondary to ribavirin (60% vs 20%, p=.02). CONCLUSION: DAA therapy is highly efficacious for the treatment of HCV in older adults, but those aged 75 and older are more likely to have clinically significant pretreatment DDIs and experience AEs, including ribavirin-induced anemia, during therapy.

Immunological Predictors of Nonresponse to Directly Acting Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis.

BACKGROUND: Sustained virological response rates (SVRs) to directly acting antiviral (DAA) therapy for hepatitis C virus (HCV) are lower in decompensated cirrhosis. Markers of innate immunity predict nonresponse to interferon-based HCV treatment; however, whether they are associated with the response to DAAs in patients with decompensation is not known. METHODS: Information on demographics, adherence, viral kinetics, and resistance were gathered prospectively from a cohort with decompensated cirrhosis treated with 12 weeks of DAAs. C-X-C motif chemokine-10 (CXCL-10) level and T-cell and natural killer (NK) cell phenotype were analyzed pretreatment and at 4 and 12 weeks of treatment. RESULTS: Of 32 patients, 24 of 32 (75%) achieved SVR (responders). Eight of 32 (25%) experienced relapse after the end of treatment (nonresponders). There were no differences in demographics or adherence between groups. Nonresponders had higher CXCL-10; 320 pg/mL (179461) vs 109 pg/mL (88170) in responders (P < .001) and differential CXCL-10 dynamics. Nonresponders had lower NK cell frequency, higher expression of activation receptor NKp30, and lower frequency of the NK subset CD56-CD16+. CONCLUSIONS: Nonresponders to DAAs displayed a different NK phenotype and CXCL-10 profile to responders. Nonresponders did not have poorer adherence or baseline virological resistance, and this shows that immunological parameters are associated with treatment response to interferon-free treatment for HCV in individuals with decompensated cirrhosis.

Directly acting antivirals for hepatitis C virus arrive in HIV/hepatitis C virus co-infected patients: from 'mind the gap' to 'where's the gap?'.

In patients living with HIV infection with hepatitis C (HCV) is common. HIV/HCV co-infection results in more rapid liver fibrosis progression than HCV alone and end-stage liver disease is a major cause of morbidity and mortality in co-infected patients. Historically, treatment outcomes with interferon based therapy in this group have been poor but with the advent of directly acting antiviral (DAA) drugs for HCV, rates of cure have improved dramatically. This article reviews recent evidence on the treatment of HCV in co-infected patients including the efficacy of new regimens and information on drug-drug interactions between DAAs and antiretroviral therapy. We also discuss the relationship between the pathogenesis of HIV and HCV infections, the treatment of acute hepatitis C and the current debate regarding the cost-effectiveness and affordability of DAAs.

Tenofovir-based combination therapy for HIV/HBV co-infection: factors associated with a partial HBV virological response in patients with undetectable HIV viraemia.

OBJECTIVE: The aim of this study was to identify and describe patients with detectable hepatitis B virus (HBV) DNA in the presence of undetectable HIV RNA after 48 weeks of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) treatment. DESIGN: Case-control study. Cases or delayed responders were defined as detectable HBV DNA (>20 IU/ml) with undetectable HIV RNA (<40 c/ml) after 48 weeks TDF/3(F)TC combination therapy. Controls or virological responders were defined as both undetectable HIV and HBV after 48 weeks TDF/3(F)TC therapy. RESULTS: Twenty-three cases were identified and matched to 24 controls. 87% cases and 46% controls were eAg-positive (P=0.005). Nine of 23 (39%) cases and seven of 24 (29%) controls had 3TC monotherapy prior to TDF. Similar proportions had 3TC/FTC resistance pre-TDF (30% cases, 24% controls). The cases had significantly higher baseline HBV DNA pre-3TC (median 1.2×10(8) vs. 3.1×10(6) IU/ml; P=0.009) and pre-TDF (1.1×10(8) vs. 2.6×10(4) IU/ml; P=0.012). Sixteen of 23 cases eventually achieved undetectable HBV DNA after 42.2 (27.2, 54.9) months. Six of 23 still have detectable HBV DNA after 46.2 (28.2, 65.6) months. Only one delayed responder patient developed a new 3(F)TC mutation and they received intensification with entecavir and achieved undetectable HBV DNA. No patient developed TDF resistance. CONCLUSION: We report the largest series of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This outcome was associated with positive eAg and higher baseline HBV DNA. Our data suggest that clinicians should not intensify therapy with entecavir unless there is evidence of new 3TC/FTC mutations as the majority of patients go on to suppress HBV. TDF resistance was not seen.

Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase.

OBJECTIVE(S): To identify factors (including exposure to specific antiretroviral drugs) associated with severe vitamin D deficiency (VDD) in HIV-infected individuals and to explore the effects of severe VDD and antiretroviral drug exposure on serum alkaline phosphatase (ALP) as surrogate marker of bone turnover. DESIGN: Cross-sectional survey of vitamin D status among HIV-infected patients attending for routine clinical care at a large London HIV clinic. METHODS: Severe VDD was defined as 25(OH)D levels of less than 10 microg/l (<25 nmol/l). Multivariate logistic regression analysis was used to identify factors associated with severe VDD and upper quartile ALP levels. RESULTS: Vitamin D levels were measured in 1077 patients and found to be suboptimal in 91%. One-third of patients had severe VDD. Black ethnicity, sampling in winter, nadir CD4 cell count less than 200 cells/microl, and exposure to combination antiretroviral therapy were associated with severe VDD. In analyses restricted to patients on combination antiretroviral therapy, current efavirenz use was significantly associated with severe VDD [adjusted odds ratio 2.0 (95% confidence interval 1.5-2.7)]. Current tenofovir [adjusted odds ratio 3.5 (95% confidence interval 2.3-5.2)] and efavirenz use [adjusted odds ratio 1.6 (95% confidence interval 1.02-2.4)], but not severe VDD [odds ratio 1.1 (0.8-1.5)], were associated with increased bone turnover (upper quartile ALP). CONCLUSION: Efavirenz was associated with severe VDD, a condition associated with multiple adverse health outcomes, and efavirenz and tenofovir with increased ALP. The clinical significance of these findings requires further investigation, given the widespread use of efavirenz and tenofovir in first-line combination antiretroviral therapy.