Treatment adherence and support for people who inject drugs taking direct‐acting antiviral therapy for hepatitis C infection

A community‐based public health facility in Sydney, Australia, the Kirketon Road Centre (KRC), provides health care to people who inject drugs (PWID), homeless and other marginalized people. Since March 2016, KRC has provided treatment for chronic hepatitis C virus (HCV) with direct‐acting antivirals (DAAs). We aimed to evaluate treatment adherence amongst clients taking DAAs in a highly marginalized population. All clients who commenced DAA therapy prior to March 2018 at KRC were included in this observational cohort with a subset of clients attending daily or weekly for enhanced adherence support and dosing. Demographic, behavioural, clinical measures and medication dosing were recorded, and adherence was calculated as the proportion of doses taken during the expected treatment duration. Factors associated with adherence were examined using logistic regression. A total of 242 individuals commenced DAA therapy, of whom 79 (32%) received enhanced adherence support. Enhanced support was associated with homelessness, daily injecting, Aboriginality, mental health co‐morbidity and poly‐drug use (all P < .001). Overall adherence was 86%, and 92% of patients missed one or more doses (median 10, IQR 4‐24). At least 90% adherence during planned duration was seen in 38%, but increased to 66% by continuing therapy beyond planned duration. Intention‐to‐treat SVR12 was 68% and 66% in the enhanced adherence support sub‐population, with 29% lost to follow‐up by SVR12 testing. There were only 2 (0.8%) documented virological failures. Per‐protocol SVR12 was 99% and 96% in the enhanced adherence support sub‐population. In conclusion, adherence support may benefit those with multiple markers of marginalization. Extension of therapy beyond planned duration is a pragmatic strategy to enhance completion. Strategies to improve follow‐up, particularly post‐treatment are required.     

Effectiveness and cost‐effectiveness of interventions targeting harm reduction and chronic hepatitis C cascade of care in people who inject drugs: The case of France

Direct‐acting antivirals (DAAs) represent an opportunity to improve hepatitis C virus (HCV) care cascade. This combined with improved harm reduction interventions may lead to HCV elimination especially in people who inject drugs (PWID). We assessed the effectiveness/cost‐effectiveness of improvements in harm reduction and chronic hepatitis C (CHC) care cascade in PWID in France. We used a dynamic model of HCV transmission and CHC natural history and evaluated the following: improved needle/syringe programmes‐opioid substitution therapies, faster diagnosis/linkage to care, earlier treatment initiation, alone and in combination among active PWID (mean age = 36). Outcomes were as follows: life expectancy in discounted quality‐adjusted life years (QALYs); direct lifetime discounted costs; incremental cost‐effectiveness ratio (ICER); number of infections/reinfections. Under the current practice, life expectancy was 15.846 QALYs, for a mean lifetime cost of €20 762. Treatment initiation at F0 fibrosis stage alone was less effective and more costly than faster diagnosis/linkage to care combined with treatment initiation at F0, which increased life expectancy to 16.694 QALYs, decreased new infections by 37%, with a ICER = €5300/QALY. Combining these interventions with harm reduction improvements was the most effective scenario (life expectancy = 16.701 QALYs, 41% decrease in new infections) but was not cost‐effective (ICER = €105 600/QALY); it became cost‐effective with higher initial HCV incidence rates and lower harm reduction coverage than in our base‐case scenario. This study illustrated the high effectiveness, and cost‐effectiveness, of a faster diagnosis/linkage to care together with treatment from F0 with DAAs. This “Test and treat” strategy should play a central role both in improving the life expectancies of HCV‐infected patients, and in reducing HCV transmission.     

Directly observed therapy of chronic hepatitis C with ledipasvir/sofosbuvir in people who inject drugs at risk of nonadherence to direct‐acting antivirals

An important subgroup of people who inject drugs (PWID) receiving opioid agonist therapy (OAT) cannot be treated in the setting of a hepatology centre and would not regularly ingest their medication when handed to them for self‐administration. Our hypothesis was that chronic hepatitis C in these patients could be ideally managed if modern, interferon‐free regimens were administered together with OAT under direct observation of a physician or nurse at a low‐threshold facility. In this open‐label, noninterventional, proof‐of‐concept study (ClinicalTrials.gov number, NCT02638233), 40 PWID at risk of nonadherence to direct‐acting antivirals (DAA) and previously untreated chronic hepatitis C virus genotype 1 infection without cirrhosis were treated with ledipasvir/sofosbuvir for 8 weeks. Patients received antiviral treatment together with OAT under direct observation of a physician or nurse at a low‐threshold facility. By following the concept of directly observed therapy, excellent adherence to antiviral therapy was achieved as follows: only 0.16% (95% CI: 0.03‐0.47) of scheduled dates for ingestion of the antiviral therapy in combination with OAT were missed by the 40 patients. The rate of sustained virological response 12 weeks after end of therapy was 100% (95% CI: 91.2‐100.0). Between week 12 and week 24 of follow‐up reinfections were recorded in 2 of 40 patients (5%). Directly observed therapy of chronic hepatitis C is highly effective in PWID at risk of nonadherence to DAA. By this new concept, a group of difficult‐to‐treat patients can be cured, who could not have been treated in settings of studies published so far.     

Successful treatment of hepatitis C virus infection with direct‐acting antivirals during hematopoietic cell transplant

Current guidelines recommend that hepatitis C virus (HCV) infection be treated completely prior to hematopoietic cell transplantation or delayed until immune reconstitution after transplantation to avoid drug‐drug interactions and treatment interruption. However, these recommendations were informed by outcomes using treatment with ribavirin and pegylated interferon. We report the first case of successful treatment of HCV using direct‐acting antivirals during hematopoietic cell transplantation. This case study suggests that treatment of HCV concurrent with hematopoietic cell transplantation for malignancy may be the best option for some patients in whom it is unsafe to delay treatment for either disease.     

Association between rapid utilisation of direct hepatitis C antivirals and decline in the prevalence of viremia among people who inject drugs in Australia

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Hepatitis C virus eradication with direct‐acting antiviral improves insulin resistance

Sustained virological response (SVR) after interferon‐based therapy is associated with improvement of insulin resistance (IR) in HCV‐infected patients. Few data are available in the direct‐acting antivirals (DAAs) era, especially in cirrhotic patients. We prospectively evaluated the long‐term effect of DAAs on IR. Patients treated with DAAs between May 2015 and December 2016 in 3 tertiary care centres were recruited. Patients with diabetes were excluded. Biochemical and virological data were collected at baseline, 12/24/48 weeks (W) after the end of therapy (EOT). Presence of IR was defined by a ‘homeostasis model assessment index for IR’ [HOMA‐IR])> 2.5. Liver fibroscan was performed at baseline, at 24/48W after EOT. Hundred and thirty‐eight patients were enrolled (mean age 58 years, M/F 85/53, GT1 61%, 68.8% cirrhotic). Sixty‐eight patients (94/138) had IR. Patients with IR had significantly higher stiffness than patients without it (23 ± 12 vs 15 ± 8; P < .0001). SVR12 was achieved in 135 (98%) patients, and 124 (90%) patients reached the 48W post‐EOT. At this time point, the percentage of patients with IR significantly decreased to 49% (P = 0,01). HOMA‐IR was significantly lower than baseline (1.8 vs 3; P < .001), and this was related to a significant reduction of insulin level (11.7 ± 6.3 vs 16.4 ± 8.3). High BMI was associated with a significantly lower probability of achieving a non‐IR status at 24W (P = .05) and 48W (P = .03).In conclusion, SVR following DAAs led to a significant reduction of IR, even in patients with cirrhosis. Nevertheless, IR can persist after the achievement of SVR, especially in patients with high BMI.     

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.