Disappearance of perihepatic lymph node enlargement after hepatitis C viral eradication with direct‐acting antivirals

Perihepatic lymph node enlargement (PLNE) which has been shown to be negatively associated with hepatocellular carcinoma (HCC) occurrence is frequently observed in chronic liver disease; however, changes in the state of perihepatic lymph nodes after eradication of hepatitis C virus (HCV) have not been investigated yet. We aimed to evaluate this issue. We enrolled 472 patients with chronic HCV infection who achieved viral eradication with direct‐acting antivirals (DAA). We investigated whether the status of perihepatic lymph nodes changed before and after HCV eradication (primary endpoint). We also evaluated the association between PLNE and clinical findings such as liver fibrosis or hepatocellular injury before HCV eradication (secondary endpoint). Perihepatic lymph node enlargement was detected in 164 of 472 (34.7%) patients before DAA treatment. Surprisingly, disappearance of PLNE was observed in 23.8% (39 patients) of all PLNE‐positive patients after eradication of HCV. Disappearance of PLNE was not associated with baseline clinical parameters or changing rates of clinical findings before and after DAA treatment. At baseline, presence of PLNE was significantly associated with a lower serum HCV‐RNA level (P = .03), a higher serum AST level (P = .004) and a higher ALT level (P < .001) after adjustment for sex and age. In conclusion, PLNEs became undetectable after DAA treatment in 23.8% of PLNE‐positive patients. Further study with a longer follow‐up period is needed to clarify the clinical importance of this phenomenon especially in relationship with the risk of HCC development.     

Persistent augmentation of central arterial stiffness following viral clearance by direct‐acting antivirals in chronic hepatitis C

Chronic hepatitis C virus (HCV) infection is associated with risk of cardiovascular diseases. Although direct‐acting antivirals (DAA) result in rapid eradication of HCV, their long‐term impact on arterial stiffness remains unclear. This study aimed to evaluate changes in parameters of central arterial stiffness from pretreatment, through sustained virological response, to one year after viral clearance. Patients with chronic HCV receiving DAA treatment were enrolled prospectively. Medical history and comorbidities of all patients were collected. Lipid profiles, liver stiffness by transient elastography and central blood pressures using pulse wave analysis of the brachial artery by cuff sphygmomanometry were measured before treatment, at viral clearance and at one year following viral clearance. Augmentation index (AIx), a parameter of aortic stiffness, was calculated as the ratio of augmentation pressure to central pulse pressure. After DAA treatment, all included patients with chronic HCV (n = 102) had achieved viral clearance. Cholesterol, low‐density lipoprotein (LDL) and triglyceride/high‐density lipoprotein (TG/HDL) increased significantly at viral clearance and persisted at one year (all P < .001). AIx was also elevated significantly at viral clearance and persisted one year later (P < .001). Changes in AIx remained significant only in patients with increased values from baseline in either LDL (P < .01) or TG/HDL (P < .001). Central arterial stiffness and lipid profiles in patients with chronic HCV worsen immediately after viral eradication by DAA treatment and persist at one year. Worsening of lipid profiles after DAA treatment contributes to central arterial stiffness in this patient population and persists long term.     

Outcome of cutaneous psoriasis in hepatitis C virus‐infected patients treated with Direct‐Acting Antiviral therapy

Apart from chronic liver disease, hepatitis C virus (HCV) may be responsible for several extra‐hepatic manifestations. Its involvement in psoriasis development is still controversial. The aim of this study was to evaluate the possible effect of anti‐HCV direct‐acting antiviral (DAA) treatment on cutaneous psoriasis. Thirty‐seven consecutive HCV patients with cutaneous psoriasis underwent efficacious DAA treatment, and all of them were efficiently cured as shown by HCV RNA negativity 24 weeks after stopping therapy (PT24W). An expert dermatologist evaluated the skin lesions at baseline, end of treatment (EOT) and PT24W using the psoriasis area severity index (PASI) scoring system. The impact on quality of life was measured with the Dermatologic Quality of Life Index (DLQI). Six patients had a stable disease throughout the study period, whereas 31/37 patients (83.8%) showed a significant improvement of the skin lesions at EOT (P < .0001). However, 24 of these 31 patients (77.4%) had a dramatic worsening of the psoriatic lesions at PT24W compared with EOT (P < .001), with lesion severity comparable to baseline. The outcome of psoriasis during and after treatment was independent of baseline PASI score, age, sex, HCV genotype, liver disease stage and of the presence of arterial hypertension, diabetes and autoimmune diseases. In conclusion, DAA‐based HCV cure has only a transient effect on skin lesions of patients with concomitant cutaneous psoriasis.     

Hepatitis C cure improved patient‐reported outcomes in patients with and without liver fibrosis in a prospective study at a large urban medical center

Patient‐reported outcomes (PROs) are important measures of quality of life. Direct‐acting antiviral (DAA) drugs for hepatitis C virus (HCV) improved PROs in clinical trials. We prospectively evaluated the impact of DAA‐based HCV cure on PROs and liver‐related outcomes in real‐world patients at a large urban medical center. The short form (SF)‐36 and three additional validated instruments were used. F3‐4 fibrosis was defined as > 9.6 kPa by transient elastography (TE); S2‐3 steatosis was defined as > 270 dB/m by TE‐controlled attenuation parameter (CAP). Data were analysed by paired and unpaired t tests. Patients (n = 16) who did not achieve a sustained virologic response at 12 weeks (SVR12) were excluded. The study achieved its primary endpoint and showed a significant 30% improvement in the SF‐36 vitality score, measured baseline to SVR12: 63 versus 82, P < .001 (n = 111). Scores in 24 of 25 PRO domains improved at SVR12 (P < .05). Nearly all gains exceeded 5%, indicating their clinical significance. Transaminase values and liver stiffness improved (decreased) significantly, baseline to SVR12 (P < .005), but steatosis was unchanged (P = .58). Patients with baseline F0‐2 fibrosis and those with F3‐F4 fibrosis both improved in 22 domains. Patients with baseline S0‐S1 steatosis improved in more domains (23) than patients with S2‐S3 steatosis (19). At baseline, patients with F3‐F4 fibrosis and patients with S2‐3 steatosis had worse scores in certain PRO domains than patients with F0‐2 fibrosis or S0‐S1 steatosis, but this difference resolved by SVR12. HCV cure led to meaningful gains in PROs, and these findings may encourage patients to seek treatment.     

Similar recovery of liver function after response to all‐oral HCV therapy in patients with cirrhosis with and without HIV coinfection

Among patients with cirrhosis, recovery of liver function after SVR to all‐oral direct‐acting antivirals (DAA) in HIV/HCV coinfection could be different to that in HCV monoinfection. Because of this, we compared the changes in several markers of liver function between HCV‐monoinfected and HIV/HCV‐coinfected patients with cirrhosis who achieved SVR12 to DAA combinations. In this retrospective cohort study, cirrhotics included in the HEPAVIR‐DAA and GEHEP‐MONO cohorts were selected if they had SVR12 to all‐oral DAAs. Patients treated with atazanavir were excluded. Liver function improvement was defined as Child‐Pugh‐Turcotte (CPT) decrease ≥1 and/or MELD decrease ≥2 between baseline and SVR12. Liver function worsening was defined as a CPT increase ≥1 and/or MELD increase ≥2 and/or decompensations between baseline and SVR12. We included 490 patients, 270 (55%) of them with HIV coinfection. Liver function improved in 50 (56%) HCV‐infected individuals and in 82 (57%) HIV/HCV‐coinfected patients (P = 0.835). Liver function worsened in 33 (15%) HCV‐monoinfected patients and in 33 (13%) HIV/HCV‐coinfected patients (P = 0.370). Factors independently related with liver function improvement were male gender [adjusted OR (AOR) 2.1 (95% confidence interval, 95% CI: 1.03‐4.2), P = 0.040], bilirubin < 1.2 mg/dL (AOR 1.8 [95% CI: 1.004‐3.3], P = 0.49), and INR < 1.3 (AOR 2.4 [95% CI: 1.2‐5.0], P = 0.019) at baseline. After multivariate analysis, albumin < 3.5 g/dL was associated with liver function worsening (AOR 6.1 [95% CI: 3‐12.5], P < 0.001). Liver function worsening and improvement rates after responding to DAA are similar among HCV‐monoinfected and HIV/HCV‐coinfected cirrhotics. Gender, INR, bilirubin, and albumin levels were associated with liver function changes after response to DAAs.     

The impact of SVR from direct‐acting antiviral‐ and interferon‐based treatments for HCV on hepatocellular carcinoma risk

We evaluated the effect of sustained virologic response (SVR) from direct‐acting antiviral (DAA)‐ and interferon‐based treatments on hepatocellular carcinoma (HCC) risk in a large population‐based cohort in Canada. We used data from the BC Hepatitis Testers Cohort, which includes ~1.3 million individuals tested for HCV since 1990, linked with healthcare administrative and registry datasets. Patients were followed from the end of HCV treatment to HCC, death or 31 December 2016. We assessed HCC risk among those who did and did not achieve SVR by treatment type using proportional hazard models. Of 12 776 eligible individuals, 3905 received DAAs while 8871 received interferon‐based treatments, followed for a median of 1.0 [range: 0.6‐2.7] and 7.9 [range: 4.4‐17.1] years, respectively. A total of 3613 and 6575 achieved SVR with DAAs‐ and interferon‐based treatments, respectively. Among DAAs‐treated patients, HCC incidence rate was 6.9 (95%CI: 4.7‐10.1)/1000 person yr (PY) in SVR group (HCC cases: 26) and 38.2 (95%CI: 20.6‐71.0) in the no‐SVR group (HCC cases: 10, P < .001). Among interferon‐treated individuals, HCC incidence rate was 1.8 (95%CI: 1.5‐2.2) in the SVR (HCC cases: 99) and 13.9 (95%CI: 12.3‐15.8) in the no‐SVR group (HCC cases: 239, P < .001). Compared with no‐SVR from interferon, SVR from DAA‐ and interferon‐based treatments resulted in significant reduction in HCC risk (adjusted subdistribution hazard ratio (adjSHR) DAA = 0.30, 95%CI: 0.19‐0.48 and adjSHR interferon = 0.2, 95%CI: 0.16‐0.26). Among those with SVR, treatment with DAAs compared to interferon was not associated with HCC risk (adjSHR = 0.93, 95%CI: 0.51‐1.71). In conclusion, similar to interferon era, DAA‐related SVR is associated with 70% reduction in HCC risk.     

Time‐dependent improvement of liver inflammation,fibrosis and metabolic liver function after successful direct‐acting antiviral therapy of chronic hepatitis C

Sofosbuvir‐based direct‐acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy‐one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir‐based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8 mg/L, P < .0001), whereas the change in sMR was more subtle (0.37 vs 0.30 mg/L, P < .0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3 kPa, P < .0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P < .0001), suggestive of fibrosis regression. The GEC improved at follow‐up (all: 1.74 vs 1.98 mmol/min), mainly at 12 weeks post‐treatment, both in patients with cirrhosis (n = 56) and those with advanced liver fibrosis (n = 15) (P < .001). The CRT improved at one‐year follow‐up (1.86 vs 2.09, P = .04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.     

Liver transplant listing for hepatitis C‐associated cirrhosis and hepatocellular carcinoma has fallen in the United Kingdom since the introduction of direct‐acting antiviral therapy

Following the introduction of direct‐acting antivirals (DAA), there have been reports of declining incidence of hepatitis C (HCV)‐related liver disease as a liver transplantation indication. In this study, we assessed the impact of DAA on liver transplant indications in the UK and waiting list outcomes for patients with HCV. We assessed UK adult elective liver transplant registrants between 2006 and 2017. The aetiology of liver disease at registration was reclassified using an accepted hierarchical system and changes were assessed over time and compared before and after the introduction of DAA. Registration UKELD scores and 1‐year waiting list outcomes were also compared. The proportion of waiting list patients registered with HCV‐related cirrhosis reduced after the introduction of DAA from 10.5% in 2013 to 4.7% in 2016 (P < 0.001). Alcohol‐related liver disease (ARLD) was the leading indication for liver transplantation followed by liver cancer (26.1% and 18.4% in 2016, respectively). The proportion of registrations with Hepatocellular carcinoma (HCC) associated with HCV reduced from 46.4% in 2013 to 33.7% in 2016 (P = 0.002). For patients with HCV‐related cirrhosis at one year the outcomes of death, transplantation, delisting due to improvement or deterioration and awaiting a graft at 1 year were similar. For patients with HCV‐related HCC, the proportion dying at 1 year reduced significantly from 2.9% to 0.0% (P = 0.04). These data demonstrate an association between DAA and reduced listing rates for HCV‐related cirrhosis and HCC, but no significant changes in waiting list outcomes other than reduced mortality in the HCC group.     

Hepatitis C diagnosis and treatment,impact on engagement and behaviour of people who inject drugs,a service evaluation,the hooked C project

There is emerging evidence that Hepatitis C (HCV) treatment engagement is associated with change in drug behaviours and reduced drug‐related death rates among people who inject drugs (PWID). The project aims to investigate whether HCV diagnosis and treatment engagement reduces all‐cause mortality and drug‐related death, and whether any effect is dependent on treatment regimen and intensity of engagement with staff. Case‐control studies comparing: PWID with active HCV infection (PCR positive) to PWID HCV infected but spontaneously resolved (PCR negative); PCR‐positive patients who engaged with treatment services to nonengagers; and patients who received interferon vs direct‐acting antiviral (DAA) based treatment. No differences in risk of all‐cause mortality or drug‐related death between PCR‐negative controls and PCR‐positive cases were detected. The odds of all‐cause mortality was 12.2 times higher in nonengaging persons compared to treatment engaging cases (aOR 12.15, 95% CI 7.03‐20.99, P < .001). The odds of a drug‐related death were 5.5 times higher in nonengaging persons compared with treatment engaging cases (aOR 5.52, 95% CI 2.67‐ 11.44, P < .001). No differences in risk of all‐cause mortality or drug‐related death between interferon‐treated cases and DAA‐treated controls were detected. HCV treatment engagement is significantly protective against all‐cause mortality and drug‐related death. This engagement effect is independent of treatment regimen, with the introduction of DAA therapies not increasing risk of drug‐related death, suggesting intensity of HCV therapy provider interaction is not an important factor.     

Quality of life in adolescents with hepatitis C treated with sofosbuvir and ribavirin

Chronic HCV infection has been associated with impairment of HRQL in both adults and paediatric patients. Our aim was to assess the HRQL of HCV‐positive children treated with SOF + RBV. The data for this post hoc analysis were collected in a phase 2 open‐label multinational study that evaluated safety and efficacy of SOF (400 mg/day) plus RBV (weight‐based up to 1400 mg/day) for 12 or 24 weeks in adolescents with chronic HCV (GS‐US‐334‐1112). Patients and their parents/guardians completed the PedsQL‐4.0‐SF‐15 questionnaire at baseline, at the end of treatment and in post‐treatment follow‐up. We included 50 adolescents with HCV genotype 2 and 3 without cirrhosis (14.8 ± 1.9 years; male: 58%; treatment‐naïve: 82%; vertically transmitted HCV: 70%). After treatment, 100% of patients with HCV genotype 2 and 95% with genotype 3 achieved SVR‐12. During treatment with SOF + RBV, there were no significant decrements in any of patients’ self‐reported or parent‐proxy‐reported PRO scores regardless of treatment duration (all P > .05). After treatment cessation, we recorded a statistically significant improvement in patients’ self‐reported Social Functioning score by post‐treatment week 12: on average, +4.8 points on a 0‐100 scale (P = .02). By post‐treatment week 24, parent‐proxy‐reported School Functioning score increased by, on average, +13.0 points (P = .0065). In multivariate analysis, history of abdominal pain and psychiatric disorders were predictive of impaired HRQL in adolescents with HCV (P < .05). Adolescents with HCV do not seem to experience any HRQL decrement during treatment with SOF + RBV and experience some improvement of their HRQL scores after achieving SVR.     

Chronic hepatitis C treatment in HIV co‐infection in Portugal: Results from a cohort OF 2133 patients presented by GEPCOI (Portuguese Coinfection Study Group)

Direct‐acting antiviral drugs (DAAs) have recently changed the paradigm of hepatitis C therapy, significantly improving treatment response rates, patient life expectancy and quality of life. In Portugal, sofosbuvir (SOF) and SOF/ledipasvir (SOF/LDV) were fully reimbursed by the National Health System since early 2015 and generalized use of interferon‐free DAA based regimens became current practice. During 2016, the remaining DAAs were sequentially added and covered by the same health access policy. The Portuguese Study Group of Hepatitis and HIV Co‐infection (GEPCOI) collected data from 15 clinical centres in Portugal, pertaining to the HCV treatment experience with DAA regimens. A cohort of 2133 patients was analysed, representing one of the largest DAA treated HCV/HIV co‐infected individuals. The global sustained virologic response (SVR) achieved was 95% in this real‐life cohort setting. Linear regression analysis showed significant differences in treatment response rates when using SOF plus ribavirin (RBV) combination in genotype 2 or 3 infected individuals (P < .002) and in those with liver cirrhosis (P < .002). These findings corroborate that early treatment is mandatory in HIV/HCV co‐infected patients, as response rates may be negatively influenced by higher fibrosis stages and suboptimal DAA regimens. The current national Portuguese health policy should continue to promote wider treatment access and individualized therapy strategies, aiming at the elimination of HCV infection in this high‐risk co‐infected population.     

Longitudinal evolution of vertically HIV/HCV–co‐infected vs HCV–mono‐infected children

HIV co‐infection has been suggested to play a deleterious role on the pathogenesis of liver fibrosis among vertically HCV‐infected children. The aim of this study was to describe the longitudinal evolution of vertically acquired HIV/HCV co‐infection in youths, in comparison with HCV infection alone. This was a retrospective, multicentre study including vertically HIV/HCV–co‐infected patients and age‐ and sex‐matched vertically HCV–mono‐infected patients. Progression to advanced liver fibrosis, defined as F3 or more by elastography or METAVIR biopsy staging, and response to treatment were compared by means of univariate and multivariate regression analyses and Cox regression models. Sixty‐seven co‐infected patients were compared with 67 matched HCV–mono‐infected patients. No progression to advanced liver disease was observed during the first decade. At a median age of 20.0 [19.0, 22.0] years, 26.7% co‐infected vs 20% mono‐infected had progressed to advanced fibrosis (P = .617). Peg‐IFN/RBV for HCV treatment was given to 37.9% vs 86.6% (P‐value < .001). At treatment initiation, co‐infected patients were older (16.9 ± 4.1 vs 11.7 ± 4.5 years, P < .001), and 47.1% vs 7.1% showed advanced fibrosis (P < .003), with no differences in hard‐to‐treat genotype distribution. Sustained viral response was comparable between groups (43.5% vs 44.0%, P = .122). In vertically HIV/HCV–co‐infected patients, the progression to liver fibrosis was rare during childhood. At the end of adolescence, over 25% of patients displayed advanced liver disease. Response to Peg‐IFN/RBV was poor and comparable in both groups, supporting the need for fast access to early treatment with direct‐acting antivirals against HCV for vertically co‐infected patients.     

Improved liver transplant waitlist mortality and lower risk of disease progression among chronic hepatitis C patients awaiting liver transplantation after the introduction of direct‐acting antiviral therapies in the United States

Direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV‐related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on US liver transplant (LT) waitlist outcomes. We retrospectively evaluated US adults (age ≥18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6‐month period after approval (Era 1: 1/1/2002‐5/31/2014 vs Era 2: 6/1/2014‐12/31/2016) using the United Network for Organ Sharing registry. Overall, LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002 to 2016, 158 045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R²: 0.99, P < 0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non‐HCV patients, those listed in Era 2 had lower likelihood of LT (HR: 0.91, P < 0.001), more pronounced in the HCV cohort (HR: 0.83, P < 0.001) compared to the non‐HCV cohort (HR: 0.93, P < 0.001). Compared to non‐HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR: 1.08, P < 0.001) but not in Era 2 (HR: 1.02, P = 0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post‐DAA era, HCV patients on the LT waitlist had improved waitlist mortality.     

Hepatitis C treatment from “response‐guided” to “resource‐guided” therapy in the transition era from interferon‐containing to interferon‐free regimens

Peginterferon/ribavirin has been the standard‐of‐care for chronic hepatitis C virus (HCV) infections: 48 weeks for genotype 1 or 4 (HCV‐1/4) and 24 weeks for HCV‐2/3. Response‐guided therapy recommended shorter 24‐ and 16‐week regimens for HCV‐1 with lower baseline viral loads (< 400 000–800 000 IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV‐2/3 with RVR, respectively; and extending to 72 and 48 weeks for HCV‐1 slower responders and HCV‐2 non‐RVR patients, respectively, to improve the efficacy. The progress of directly acting antivirals (DAA), moving from interferon‐containing regimens in 2011 to interferon‐free regimens in 2013, has greatly improved the treatment success. Interferon‐containing regimens include boceprevir or telaprevir or simeprevir or daclatasvir plus peginterferon/ribavirin, 24–48 weeks, for HCV‐1 or 4. However, adding these DAA has no benefit for HCV‐1 with lower baseline viral loads/RVR. Instead, 12‐week sofosbuvir plus peginterferon/ribavirin attained sustained virological response rates of > 90% for HCV‐1/3–6. Interferon‐free regimens include two main categories: NS5B nucleotide inhibitor (sofosbuvir)‐based regimens and NS3/4A inhibitor/NS5A inhibitor‐based regimens (daclatasvir/asunaprevir, paritaprevir/r/ombitasvir/dasabuvir and grazoprevir/elbasvir). About 8–24 weeks interferon‐free regimens could achieve sustained virological response rates of 82–99% for corresponding HCV genotypes. Although the newly DAA interferon‐free regimens have high efficacy and safety, the huge budget impact increases the treatment barriers. The current recommendation should, therefore, base on the availability, indication, and cost‐effectiveness in the transition era of DAA. Based on the concept of “resource‐guided therapy,” peginterferon/ribavirin might be applied for easy‐to‐treat interferon‐eligible patients in resource‐constrained areas. Prioritizing patients for interferon‐free regimens according to “time‐degenerative factors” (age and fibrosis) is justified before the regimens becoming available and affordable.     

Dynamics of liver stiffness by transient elastography in patients with chronic hepatitis C virus infection receiving direct‐acting antiviral therapy—Results from the German Hepatitis C‐Registry

The impact of direct‐acting antiviral (DAA) therapies on fibrosis regression remains uncertain. In the current study, we prospectively evaluated dynamics of liver stiffness by transient elastography (TE) in patients with chronic HCV infection receiving DAA‐based treatment. Patients (260) were enrolled in the German Hepatitis C‐Registry (DHC‐R), a national multicentre real‐world cohort. Liver stiffness (LS) was assessed at baseline, end of treatment (EOT) and 24 weeks after EOT (FU24) by TE. Biochemical, virological and clinical data were obtained in parallel. In patients with SVR, there was a significant improvement of LS between baseline (median [range], 8.6 [1.7‐73.5] kPa) and FU24 (7.9 [1.7‐75 kPa]; P < .0001) as well as between EOT (8.4 [1.7‐73.5 kPa]) and FU24 [P < .0001]. Stratified by fibrosis stage, patients classified into F4 had higher magnitude of LS reduction between BL (median [range], 25.1 [13.5‐73.5] kPa) and FU24 (21.5 [3.1‐75] kPa; P = .002) compared to those with F2‐F3 (8.9 [7.1‐12.4] kPa and 8.8 [4.2‐29.1]; P = .060) or F0‐F1 (5.3 [1.7‐7] kPa and 5.2 [1.7‐7.7]; P = .064). In cirrhotic patients, low platelets were significantly associated with lack of liver stiffness improvement, both at EOT (P = .018) and at FU24 (P = .012). LS significantly correlated with ALT (r = .371), AST (r = .552), platelets (r = ?.499), GGT (r = .250), bilirubin (r = .230), APRI score (r = .512), FIB‐4 score (r = .517) and FORNS index (r = .562); P < .0001. Liver elastography improved significantly in our real‐world cohort after DAA‐based therapy. As LS correlates similarly with transaminase levels and serum fibrosis markers, it might reflect both reduction of necroinflammation and fibrosis regression.     

Early emergence of opportunistic infections after starting direct‐acting antiviral drugs in HIV/HCV‐coinfected patients

Varicella‐zoster virus and hepatitis B virus reactivations have been reported after starting interferon‐free direct‐acting antiviral agent (DAA) combinations. HIV/HCV‐coinfected patients could be a high‐risk group for the reactivation of latent infections. Because of these, we report the occurrence of severe infections after starting DAA regimens in HIV/HCV‐coinfected patients. Individuals included in the HEPAVIR‐DAA (NCT02057003) cohort were selected if they had received all‐oral DAA combinations. A retrospective review of clinical events registered between the start of DAAs and 12 months after SVR12 was carried out. Overall, 38 (4.5%) of 848 patients presented infections. The incidence (95% confidence interval) of infections was 4.6 (3.3‐6.3) cases per 100 person‐years. The median (Q1‐Q3) time to the infection since baseline was 23 (7.3‐33) weeks. Five (13%) of the patients with infections died; four of them had cirrhosis. The frequency of previous AIDS was 21 (54%) for patients with infections and 324 (40%) for those without infections (P = 0.084). The median (Q1‐Q3) nadir CD4 cell count of individuals with and without infections was 75 (53‐178) and 144 (67‐255) cells/μL, respectively (P = 0.047). Immunodepression‐associated infections were observed in 9 (1.1%) patients. All of them had suppressed HIV replication with antiretroviral therapy. In conclusion, severe infections are relatively common among HIV/HCV‐coinfected patients receiving all‐oral DAA combinations. Some unusual reactivations of latent infections in patients with suppressed HIV replication seem to be temporally linked with DAA use.     

Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct‐acting antiviral therapy

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon‐free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co‐infected patients and 765 patients with resolved HBV infection during and after treatment with direct‐acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti‐HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)‐positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti‐HBs titres at baseline with those at post‐DAA therapy in 123 patients without HBsAg. There was no significant difference in anti‐HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg‐negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV‐reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.     

Evolution of renal function under direct‐acting antivirals treatment for chronic hepatitis C: A real‐world experience

Renal toxicity of direct‐acting antivirals (DAAs) in chronic hepatitis C (CHC) patients has not been well‐characterized. The aim of this study was to assess renal safety of DAAs in an Asian CHC patient cohort. Data from CHC patients (n = 1536) treated with DAAs were used in this retrospective study. Serial estimated glomerular filtration rate (eGFR) at pretreatment (1‐year prior to treatment), baseline, end of treatment (EOT), and 12 weeks after treatment (SVR₁₂) was evaluated. While a significant decrease in eGFR from baseline to EOT (84.8 → 81.8 mL/min/1.73 m², P < .001) was observed; subsequently, a slight rise at SVR₁₂ (84.3 mL/min/1.73 m²) was also evident. Changes in eGFR after DAA treatment were similar to those seen in PrOD, DCV/ASV and GZP/EBV regimens, except in the SOF‐based regimen wherein eGFR remained unchanged from EOT to SVR₁₂, especially in liver transplant recipients. Multivariate analysis revealed that age >65 years (OR = 1.862, P = .011), baseline eGFR ≥ 60 mL/min/1.73 m² (OR = 2.684, P = .023), and liver transplant (OR = 3.894, P = .001) were independent risk factors for deteriorating renal function. In conclusion, DAA treatment led to a significant decline in eGFR at EOT but was followed by a slight rise at 12 weeks after treatment. A similar trend was observed with PrOD, DCV/ASV and GZP/EBV, but not in SOF‐based regimens. As age >65 years, baseline eGFR ≥ 60 mL/min/1.73 m² and liver transplantation are significant risk factors for deterioration in renal function, we strongly advice close monitoring of renal function in these populations.     

TLL1 variants do not predict hepatocellular carcinoma development in HCV cirrhotic patients treated with direct‐acting antivirals

Tolloid‐like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to interferon or direct‐acting antiviral (DAA)‐based regimens. We investigated whether this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014 and December 2016 in a single centre were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM > 11.9 kPa). TLL1 rs17047200 was analysed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28‐87) years, 58% males, 47% HCV‐1b, LSM 19.1 (12.0‐75.0) kPa and Fibrosis‐4 (FIB‐4) score 4.9 (0.3‐46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%) and AT/TT in 123 (27%) (MAF = 0.14, HWE P > 0.05). Patients’ clinical features were similar across TLL1 genotypes. After 33 (3‐47) months from DAA start, 31 patients developed HCC, with a 3‐year estimated cumulative probability being 7.5% (95% CI: 5%‐10%). The cumulative incidence of HCC was 9% in TLL1 AA vs 7% in AT/TT patients (P = 0.55). Male sex (HR: 3.78, 95% CI: 1.4‐10.1, P = 0.008), diabetes (HR: 3.5, 95% CI: 1.68‐7.27, P = 0.001) and FIB‐4 (HR: 1.09, 95% CI: 1.03‐1.14, P = 0.001) were baseline‐independent predictors of HCC. The incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.     

Pan‐genotypic treatment regimens for hepatitis C virus: Advantages and disadvantages in high‐ and low‐income regions

During the last 5 years, the availability of direct‐acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV). Compared with interferon/ribavirin—the previous standard of care—DAA combination regimens offer improved sustained virological response (SVR) rates, shorter treatment durations of 8‐24 weeks, convenient once‐daily single‐tablet formulations and more favourable tolerability profiles. HCV treatment is complex, and the choice of therapy must consider a complex range of factors, including baseline viral load, fibrosis stage, the HCV genotype and subgenotype, and the presence of resistance‐associated substitutions at baseline. Globally, HCV genotype 1 predominates, and there are extensive data and various treatment options available for this genotype. Genotypes 2–6 are prevalent and may even predominate in different geographical regions, reflecting diverse factors including human migration patterns and unsafe use of injection drugs and blood products. Such factors are themselves influenced by socio‐economic factors, and poor regions often have the greatest unmet need for effective HCV therapies. The latest pan‐genotypic DAA combination regimens provide the potential to eradicate HCV around the globe, regardless of genotype, hence minimizing the need for virological testing services, which often are unavailable in poorer regions. Economics inevitably remain a barrier to access, and extensive cooperation will be required between clinical organisations and pharmaceutical manufacturers to agree appropriate pricing policies, especially in poorer economic regions. This review considers key data and treatment guidelines for DAA therapies, including pan‐genotypic combination regimens, in the context of regional differences in HCV genotype and socio‐economic factors.