The impact of viral hepatitis‐related hepatocellular carcinoma to post‐transplant outcomes

Hepatocellular carcinoma (HCC) is the most common complication of HCV infection leading to liver transplantation. We evaluated the impact of aetiology of liver disease on patient and graft survival following liver transplantation for HCC. From the Scientific Registry of Transplant Recipients (2002–2011), all adults who underwent liver transplantation for HCC were retrospectively included. Aetiology of liver disease was grouped into HCV, HBV, HCV–HBV co‐infection and nonviral liver disease. Of 8,733 liver transplant recipients with HCC, 5507 had HCV, 631 had HBV, 163 were co‐infected, and 2432 had nonviral causes of liver disease. In follow‐up (48 ± 32 months), 8.2% had graft failure and 29.5% died. The mean rates of graft failure were 9.5%, 4.7%, 6.1% and 6.4% in HCV, HBV, HCV–HBV co‐infection and nonviral liver disease, respectively (P < 0.0001). Post‐transplant mortality rate in patients with HBV was 20.2%, HCV 31.0%, HCV–HBV 28.5% and nonviral 28.5% (P < 0.0001). This difference was significant starting one year post‐transplant and became even more prominent later in follow‐up. Five‐year post‐transplant survival was 64.7% in HCV, 77.7% in HBV, 71.0% in HCV–HBV and 69.1% in nonviral HCC (P < 0.0001). A diagnosis of HCV in patients with HCC was also independently associated with an increased risk of both graft failure (adjusted hazard ratio = 1.84 (1.46–2.33), P < 0.0001) and mortality (1.35 (1.21–1.50), P < 0.0001) in multivariate analysis. Patients with HCV‐related HCC are at higher risk of adverse post‐transplant outcomes. These patients should be considered for preemptive interferon‐free antiviral therapy prior to or immediately following liver transplantation.     

Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 1: hepatitis B virus)

Abstract: This two-part article discusses serologic testing of prospective donors for viral hepatitis B and C as part of the comprehensive donor evaluation and reviews of the current policies and practices aimed at preventing donor-to-recipient transmission of hepatitis B and C viruses (HBV, HBC). This second part of the review discusses HCV. Organs procured from HCV-infected donors can transmit the virus to their recipients. Because a number of studies have associated infections with HCV with increased morbidity and mortality among renal transplant recipients, it is important to prevent HCV transmission with renal transplantation. The majority of organ procurement organizations (OPOs) perform routine screening of organ donors for antibodies to HCV (anti-HCV). The prevalence of HCV infection among cadaver organ donors, ascertained based on a positive anti-HCV test by ELISA2, varies worldwide between 1.08% and 11.8%. The use of kidneys from donors negative for anti-HCV by ELISA2 carries negligible or no risk of transmitting HCV infection. The use of organs from anti-HCV-positive donors has been restricted to life-saving transplants (heart, liver or lung) by the majority of OPOs worldwide. However, discarding kidneys from all anti-HCV positive donors would lead to unnecessary waste of organs because not all anti-HCV positive donors are infectious. Recently, the policy of unconditional restriction on the use of kidneys from anti-HCV positive donors has been challenged, and transplantation of organs from anti-HCV-positive donors into anti-HCV-positive recipients has been found to be safe. An even better alternative might be a policy of transplanting kidneys from anti-HCV-positive donors only in HCV RNA-positive recipients. However, until more data become available, these two strategies remain experimental treatments.     

Outcome of hepatitis B and C virus‐associated hepatocellular carcinoma occurring after renal transplantation

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case‐control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co‐infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha‐fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.     

Use of a hepatitis C virus (HCV) RNA‐positive donor in a treated HCV RNA‐negative liver transplant recipient

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA‐positive donor organs are typically not given to patients who have cleared HCV. A 64‐year‐old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24‐week treatment course, the patient underwent deceased‐donor LT and received an organ from an anti‐HCV‐positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV‐infected transplant patients.     

Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009‐2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non‐hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver‐kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor‐derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post‐transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti‐viral prophylaxis.     

Effect of hepatitis B virus on steatosis in hepatitis C virus co‐infected subjects: A multi‐centre study and systematic review

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi‐centre cohort of HBV‐HCV subjects, and by performing a systematic review and meta‐analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV‐HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV‐HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV‐HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV‐HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV‐HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV‐HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53‐1.6) although there was significant heterogeneity (I² 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV‐HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV‐induced steatogenesis by HBV in certain subgroups of patients.     

Direct‐acting antivirals and hepatitis B virus (HBV) reactivation in co‐infected HBV/HCV kidney‐transplant recipients

Direct‐acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg‐positive and HBsAg‐negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA‐associated sustained virological response in 3 kidney‐transplant recipients initially HBsAg‐negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti‐HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation.     

Liver‐specific deceased donor risk indices

In order to assess the quality of the donor liver, procuring surgeons should accurately evaluate not only general donor risk indices, such as donor age, causes of brain death and cold ischemic time, but also consider the specific donor risk indices. In this review, we focus on liver‐specific deceased donor risk indices, including liver steatosis, anti‐hepatitis B core (HBc) positive or hepatitis C virus (HCV) positive donors, hypernatremia and anatomical variations. Liver steatosis is strongly associated with poor graft function after liver transplantation. Liver with more than 40–50% macrosteatosis should not be used. However, at present the quantity of fatty livers lack accepted standards. The computerized image analysis programs should be used to automate the determination of fat content in liver biopsy specimens. Liver grafts from anti‐HBc positive donors can be safely used, preferentially in hepatitis B surface antigen (HBsAg) positive or anti‐HBc/anti‐HBs positive recipients. HCV positive allografts free from fibrosis or severe inflammation are a safe option for HCV positive recipients. The procurement team should consider liver biopsy to evaluate these HCV positive allografts. Donor serum sodium over 150 mm may predict a higher rate of graft primary non‐functions. Recently, however, some investigators reported the sodium level likely has little clinical impact on post‐transplant liver function. The incidence of hepatic artery variations has been reported to be approximately 30%. To avoid injuries, it is very important to know and identify these variations with precision at the time of organ procurement.     

Utilization of increased risk for transmission of infectious disease donor organs in solid organ transplantation: Retrospective analysis of disease transmission and safety

The inadequate supply of transplantable organs necessitates new approaches to organ availability. Serologies and nucleic acid testing (NAT) for hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are used in microbiologic screening of potential organ donors. Organs from donors considered at “high risk” (Centers for Disease Control and Prevention, CDC 1994) or “increased risk” (U.S. Public Health Service, PHS 2013) for transmission of viral infection to recipients may provide an expanded source of organs for transplantation. We review a single‐center experience with 257 adult organ recipients of organs from donors meeting either CDC 1994 or PHS 2013 risk criteria between 2011 and 2016. Tracking these transplants required modification of the Transplant Center electronic database to identify all recipients of increased‐risk donor (IRD) organs, documentation of informed consent, and microbiologic testing data. No transmissions of HIV, HBV, or HCV were identified by NAT or clinically. Nine patients developed positive serologic assays for one of the tested viruses; all recipients were retested and remain negative by NAT. Notably, post‐transplant HBV core serologies reverted to negative on re‐testing; these positive serologies are likely false positives caused by receipt of blood products. Use of IRD organs can be performed safely with appropriate informed consent and rigorous pre‐ and post‐transplant microbiological testing.     

Hepatitis C genotype change after transplantation utilizing hepatitis C positive donor organs

A shortage in organs for transplantation has led to the increased use of hepatitis C (HCV) infected donor organs for solid organ transplant recipients infected with HCV. However, the donor HCV genotype is not routinely checked or known prior to transplant. Here, we report 4 cases of genotype conversion after transplantation in patients receiving HCV infected donor organs. This change in genotype may potentially impact HCV progression as well as treatment choice for these patients.     

Reactivation of hepatitis B virus during interferon‐free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co‐infection

Direct‐acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti‐HBe hepatitis during interferon (IFN)‐free DAA therapy in HBV/HCV co‐infected patients with inactive HBV. A 69‐year‐old male patient was diagnosed with chronic hepatitis due to HBV/HCV co‐infection with serum levels of alanine aminotransferase (ALT) of 94 U/L, HCV RNA of 4.2 log IU/mL and HBV DNA of 2.5 log copies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core‐related antigen (3.1 log U/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237 U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0 log copies/mL at that time. The treatment was stopped due to suspicion of drug‐induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti‐HCV DAA therapy and the commencement of anti‐HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co‐infection.     

Unexpected hepatitis B virus transmission after liver transplant from nucleic acid testing- and serology-negative liver donors who are hepatitis C viremic

The opioid epidemic has led to increased availability of organs for liver transplantation. The success of direct-acting antiviral therapy for hepatitis C (HCV) has led to the acceptance of HCV viremic donor organs. Nucleic acid testing (NAT) has led to increased detection of HCV and hepatitis B (HBV) in potential donors. A total of 36 patients underwent liver transplantation from donation after brain death donors who were HCV NAT-positive, and three of them were diagnosed with HBV several months after. All three recipients received livers from HCV viremic donors who were negative for HBV by serology and NAT. Soon after liver transplantation, HCV was treated, and all achieved sustained virologic response. They became HBV DNA-positive shortly thereafter. To date, there have been no reported cases of unexpected HBV transmission since universal donor NAT was implemented in 2013. We postulate that the inhibitory effect of HCV viremia on HBV may have prolonged the “NAT window period” in these donors beyond the 20–22 days quoted for solitary HBV infection. These cases highlight the need for more intensive and prolonged screening for HBV in recipients of livers from HCV viremic donors.     

Successful heart‐kidney transplantation from a Hepatitis C viremic donor to negative recipient: One year of follow‐up

Every year the number of patients waiting for a heart transplant increases faster than the number of available donor organs. Some potential donor organs are from donors with active communicable diseases, including hepatitis C virus (HCV), potentially making donation prohibitive. The advent of direct‐acting antiviral agents for HCV has drastically changed the treatment of HCV. Recently, these agents have been used to treat HCV in organ donor recipients who acquired the disease from the donor organ. We report a case of heart‐kidney transplantation from an HCV viremic donor to HCV negative recipient with successful treatment and sustained virologic response.     

Safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B and/or C virus coinfection

Objective

The aim was to examine the long‐term safety and efficacy of raltegravir in patients with HIV‐1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double‐blind, randomized, controlled Phase III studies.

Methods

In STARTMRK, treatment‐naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK‐1 and ‐2, highly treatment‐experienced patients with multi‐drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK.

Results

Hepatitis coinfection was present in 6% (34 of 563) of treatment‐naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment‐experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug‐related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2–4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV‐1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK).

Conclusion

Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV‐infected patients with HBV/HCV coinfection.     

Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course

Bone marrow transplant recipients are at risk for acquiring hepatitis C infection from the donated marrow. Twelve patients who were hepatitis C virus (HCV) RNA-negative pretransplant received marrow from anti-HCV seropositive donors. HCV RNA was present in the sera of seven of these donors. After transplant, serial serum specimens were obtained from all marrow recipients for determination of HCV RNA and aminotransferase levels. All seven recipients of marrow from HCV RNA-positive donors were HCV RNA-positive after marrow infusion; none cleared virus from the serum. All five recipients of marrow from anti-HCV seropositive, HCV RNA-negative donors remained free of HCV RNA in serum up to day 100. Abnormal serum aminotransferases were common in both HCV RNA- negative and HCV RNA-positive marrow recipients. One HCV-infected recipient developed marked elevation in aminotransferases after immunosuppressive drugs were stopped. We conclude that the presence of HCV RNA in the serum of marrow donors is an accurate predictor of HCV infection in marrow recipients. The acute infection was subclinical in all patients. The long-term risk of chronic hepatitis C virus infection in these patients remains to be determined.     

Vibration‐controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection

Noninvasive detection of cirrhosis via vibration‐controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006‐2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV‐112; HCV‐132; HDV‐75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB‐4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut‐off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.     

Prevention of hepatitis B virus infection from hepatitis B core antibody-positive donor graft using hepatitis B immune globulin and lamivudine in living donor liver transplantation.

BACKGROUND: Hepatic grafts from hepatitis B surface antigen-negative and anti-core antibody (HBcAb)-positive donors have been shown to transmit hepatitis B virus (HBV) infection. Recently, it has been reported that combined hepatitis B immune globulin (HBIG) and lamivudine therapy is effective in the prevention of hepatitis B recurrence after living donor liver transplantation (LDLT). In this report, we assessed the efficacy of combined HBIG and lamivudine therapy in preventing HBV transmission by graft with HBcAb-positive donors. METHODS: We studied 22 patients who had undergone LDLT with allografts from HBcAb-positive living donors at Gunma University Hospital and Kyushu University Hospital. Long-term combined HBIG and lamivudine therapy were administrated to all recipients. Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody. Liver biopsies from grafts were tested for HBV DNA. RESULTS: All recipients were HBcAb negative before LDLT. All of the donor livers were HBV DNA positive at the time of LDLT. All of the recipients had HBsAb titers greater than 300 mIU/ml 4 weeks after LDLT, and remained 100 mIU/ml thereafter. None of the recipients have become infected with HBV with a follow-up of 25-86 months. CONCLUSIONS: Perioperative combined HBIG and lamivudine therapy can prevent HBV infection in recipients who receive liver grafts from HBcAb-positive donors.     

Risk of diabetes in viral hepatitis B or C patients compared to that in noninfected individuals in Korea, 2002‐2013: A population‐based cohort study

While the association between hepatitis C virus (HCV) infection and diabetes has been established, the relationship between hepatitis B virus (HBV) infection and diabetes remains unclear. Therefore, we compared the association between diabetes development in HBV, HCV and co‐infected (HBV/HCV) patients to that in noninfected participants using population‐based cohort data. We used the National Health Insurance Service‐National Sample Cohort, which consists of 514 791 randomly selected persons among those who underwent health check‐ups from 2002 to 2003 aged 40‐79 years. Adults found to have HBV or HCV infection from 2002 to 2003, without a prior history of diabetes, were selected as subjects. Competing risk regression models were used to estimate cumulative incidence and hazards ratios (HRs) of diabetes development. The cumulative incidences, incidence densities and HRs of diabetes were highest in the co‐infected group, followed by those in the HCV‐, HBV‐ and noninfected groups. The 12‐year cumulative incidences were as follows: 42.0% in HBV/HCV‐, 32.9% in HCV‐, 23.9% in HBV‐ and 18.3% in the noninfected groups. The incidence density per 1000 person‐years was 55.0, 51.5, 38.2 and 28.2 for the HBV/HCV‐, HCV‐, HBV‐ and noninfected groups, respectively. The adjusted HRs for diabetes were 1.90, 1.68 and 1.41 for the HBV/HCV‐, HCV‐ and HBV‐infected groups, respectively. Our findings suggest that both HCV and HBV infections are associated with the development of diabetes; therefore, prevention of, screening for, and treatment of both may reduce the risk of diabetes in these patients.     

Trends in hepatitis C‐related mortality in Switzerland

In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the United States, HCV‐related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995‐31 December 2014) in HCV‐specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV‐related mortality to HIV‐related and hepatitis B (HBV)‐related mortality. To determine potential under‐reporting in HCV‐related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV‐related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person‐years. Since 2000, HCV‐related mortality has been higher than HIV‐related mortality and was about fivefold higher in 2014. HBV‐related mortality remained low at ~0.5/100 000 person‐years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV‐related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV‐related mortality remained constant, possibly because quality of care was high, or because of under‐reporting or because mortality has not yet increased. However, HCV‐related mortality is now much higher than HIV‐ and HBV‐related mortality, and under‐reporting was common.