Wednesday, March 14, 2018

Side effects associated with different hepatitis C direct-acting antiviral drugs

Aim - To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV), SOF/simeprevir, SOF/daclatasvir (DCV), SOF/DCV/RBV, and paritaprevir/ombitasvir/ritonavir/RBV. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

The adverse effects of interferon-free regimens in 149 816 chronic hepatitis C treated Egyptian patients
D. Attia, K. El Saeed, W. Elakel, T. Elbaz, A. Omar, A. Yosry, M. H. Elsayed, M. El Raziky, M. Anees, W. Doss, Y. El Shazly, H. Wedemeyer and G. Esmat

Version of Record online: 5 MAR 2018 | DOI: 10.1111/apt.14538

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Interferon-free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported.

To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients.

This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported.

Adverse effects developed in 2475 (1.7%) (mean age [54 ± 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development.

Adverse effects associated with DAAs are few, anemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

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To our knowledge, this is the first study with such a large cohort of chronic HCV-infected patients treated with DAAs who reported associated adverse effects and related death. This study revealed that interferon-free regimens are associated with minimal side effects, which are mostly non-serious. The most common side effects were haematological complications, with anaemia being the dominant one, particularly with respect to the SOF/RBV regimen. The serious haematological adverse effects were managed with haematopoietic agents, treatment discontinuation or reduction in RBV dose with prolongation of treatment duration. The SOF/RBV regimen showed the highest rate of side effects, with anaemia being the prominent one. The SOF/SIM regimen was associated with hyperbilirubinemia; however, this was not significant and did not require treatment discontinuation or a change in drug dosage. DCV-containing regimens showed the lowest side effects among all regimens. This study also showed that death was highest in the SOF/RBV regimen and pre-treatment thrombocytopenia and higher Child score were the dominant pre-treatment associated pathologies. In this study, HCC was reported in 33 patients, and this was mostly with the SOF/RBV regimen; however, this was not significant. Serious adverse effects as well as death were prominent with liver cirrhosis under the interferon-free regimens irrespective of the regimen.

The initial approval of DAAs by the Egyptian Council Committee of Viral Hepatitis had dramatically improved the SVR rate in Egyptian chronic HCV-infected patients, from 60% to almost 100% in some studies.[5, 8, 10] Our study showed that SVR24 reached 88% in those who developed side effects. Although the majority of the study cohort were cirrhotic patients (81%), side effects development was minimal (1.7%), in comparison to other studies, the entire cohort of which were cirrhotic patients and reported 24% side effects.[16] Serious side effects that led to reduction in the RBV dose and prolongation of the treatment duration or even treatment discontinuation, were observed in only (1.1%) of cases. Anaemia was the most common serious side effect, and was mostly associated with the SOF/RBV regimen. The rate of serious side effects was lower in comparison to that of the Guard-C study, which reported 5.9% serious side effects, while the incidence of anaemia in our study was higher (29.5% vs 25%).[17] Interestingly, our multivariate analysis confirmed that pre-treatment HB (<12.6 g/dL) and lower platelets (124 × 103/μL) were associated with post-treatment serious side effects development, as previously mentioned.[18] Our large cohort also revealed that the pre-treatment higher Child-Pugh score represented in lower albumin <35 g/dL and higher bilirubin >1.2 μmol/dL were also factors associated with post-treatment serious side effects development. Lower albumin was also described by Maan et al and Foster et al as factors associated with post-treatment serious side effects development.[16, 17]

The second common serious side effect was hyperbilirubinemia, which was not significant and was only prominent in the SOF/RBV regimen. Non-specific side effects such as fatigue, headache and abdominal discomfort were the most commonly reported in all regimens, which is line with all previously published data.[5, 7, 8, 10, 16, 19, 20]

Death was reported in only 0.06% of all treated patients, and was mainly associated with the SOF/RBV regimen. Death was in most of the cases secondary to hepatic decompensation. Three patients died due to diabetic coma and one due to myocardial infarction under the SOF/RBV regimen.

Hepatocellular carcinoma was also reported in 0.02% of all treated patients, and most cases were reported in the SOF/RBV regimen. This incidence is, however, lower when compared to other studies.[21, 22] The incidence of HCC on this regimen can be explained by the associated liver cirrhosis in 89% of patients, which is line with previous published data,[23] and 22% were Child-Pugh B, which may favour disease progression and the presence of regenerative nodules before the start of treatment. It is to be noted, that the presence of cirrhosis was associated with increased death rate and was also the common factor detected in all regimens associated with serious side effects development.

The incidence of serious side effects, death and HCC development was highest in the SOF/RBV regimen. This can be explained by the fact that this regimen was the first approved regimen for DAAs, and all patients treated with this regimen were the most sick (lower platelets and higher Child-Pugh score B). On the other hand, SOF/DCV showed the lowest incidence of side effects in comparison to the other regimens.

This study was conducted on a large cohort of Egyptian patients, more than 90% of which are infected with genotype 4.[7] Egypt is one of the countries with the highest prevalence with HCV infection, and the urgency to treat chronic HCV patients is associated with reduction in prevalence, which already started to appear, with 29% reduction in prevalence in 2015.[4] This study has several limitations; although we are reporting the adverse effects of several regimens, many of these regimens may no longer be used in several countries (eg SOF/RBV combination is no longer recommended in the European and American guidelines). Moreover, SIM is also rarely in use today, not due to efficacy but because of economic reasons. We must highlight that SIM is still used in many regions including Egypt. Another point to highlight is that these data were excluded from the database which were reported by the treating physicians. There may be an underreporting of adverse effects because there was no soft data verification by independent physicians; however, this is also accepted in large cohort studies.

In conclusion, the use of PEG-IFN/RBV combination was limited due to eligibility, tolerability and treatment efficacy (40%-69%).[24, 25] The use of interferon-free regimens increased the SVR rate and improved the tolerability and eligibility of treatment. The use of interferon-free regimens is safe and tolerable, with a higher cure rate in patients with genotype 4 than the previously used regimen. Cirrhotic patients are in particularly urgent need of treatment and those regimens are the most safely used, but this requires close monitoring and the use of haematopoietic agents to avoid anaemia, especially with RBV-containing regimens. Regular sonographic assessment for early detection of HCC is also of great importance in patients with liver cirrhosis. Future worldwide studies are required to address the adverse effects caused by the new regimens used today, such as SOF/velpatasvir, grazopervir/elbasvir and glecaprevir/pibrentasvir.

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