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 ~  Materials and Me...
 ~ Results
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  Table of Contents  
Year : 2018  |  Volume : 36  |  Issue : 2  |  Page : 224-229

The effectiveness of sofosbuvir and daclatasvir in the treatment of hepatitis C in thalassaemia major patients and their effect on haematological factors

1 Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Pediatric Hematology Oncology, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Thalassemia Clinic, Tehran, Iran
3 Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran; Gastroenterology and Hepatology Disease Research Center, Qom University of Medical Sciences, Qom, Iran

Date of Web Publication7-Aug-2018

Correspondence Address:
Prof. Jamshid Vafaeimanesh
Gastroenterology and Hepatology Disease Research Center, Qom University of Medical Science, Qom
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_18_90

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 ~ Abstract 

Context: Patients with thalassaemia are at risk of infections such as hepatitis C virus (HCV) due to their repeated blood transfusions; meanwhile, the treatment of thalassaemia patients who had developed HCV infection is a controversial issue. Aims: Although the effectiveness of direct-acting antivirals on HCV infection has been confirmed, their side-effects as well as effects on haematological factors due to the resultant need for blood transfusion remain to be further understood. Materials and Methods: In this study, 61 patients with major beta thalassaemia and HCV infection, and who had a history of interferon treatment failure were examined. The patients underwent a 24-week treatment with sofosbuvir (SOF) and daclatasvir (DAC). Sustained virological response 12 was used to assess response to treatment. At the end of the study, the need for blood transfusion and serum ferritin was evaluated. Results: About 98.4% of the patients responded to the treatment, and only one patient with genotype 1b did not respond positively. No significant complications necessitating treatment cessation were observed, and all the patients tolerated the treatment well. The level of liver enzymes showed a significant reduction 12 weeks after the treatment. The need for blood transfusions in patients before treatment was averagely 1.595 ± 0.65 bag per month, in which 1.593 ± 0.64 bags were received after treatment (P = 0.9). This regimen did not affect the amount of anaemia in patients and did not differentiate the need for blood transfusions. The rate of haemoglobin before treatment was 9.5 ± 1.42 g/dl, which reached 9.6 ± 1.6 g/dl after treatment (P = 0.54). Ferritin levels decreased significantly (from 1948.08 ± 1539.54 to 1315.73 ± 1207.67 ng/ml) (P = 0.001) in the patients after the treatment. Conclusion: Combination of SOF and DAC is an effective and tolerable treatment regimen without affect on the amount of anaemia in patients and did not differentiate the need for blood transfusions.

Keywords: Anaemia, daclatasvir, hepatitis C virus, sofosbuvir, thalassaemia major

How to cite this article:
Zamani F, Ajdarkosh H, Safarnezhad-Tameshkel F, Azarkeivan A, Keyvani H, Naserifar F, Vafaeimanesh J. The effectiveness of sofosbuvir and daclatasvir in the treatment of hepatitis C in thalassaemia major patients and their effect on haematological factors. Indian J Med Microbiol 2018;36:224-9

How to cite this URL:
Zamani F, Ajdarkosh H, Safarnezhad-Tameshkel F, Azarkeivan A, Keyvani H, Naserifar F, Vafaeimanesh J. The effectiveness of sofosbuvir and daclatasvir in the treatment of hepatitis C in thalassaemia major patients and their effect on haematological factors. Indian J Med Microbiol [serial online] 2018 [cited 2020 Sep 28];36:224-9. Available from:

 ~ Introduction Top

Thalassaemia is among the most common monogenic abnormalities in the world with an estimated 270 million carriers worldwide, including 80 million β-thalassaemia carriers, and about 60,000 children are born with it every year.[1],[2] In the Eastern Mediterranean region, Iran has one of the highest prevalence rates of β-thalassaemia and is located exactly in the middle of the region known as the thalassaemia belt.[3] Given the high prevalence of in-family marriages, 2–3 million β-thalassaemia carriers and 25,000 patients are estimated to being Iran. Like in many other countries in the region, a large number of thalassaemia patients in Iran have the β type.[4]

The survival of thalassaemia patients is mainly dependent on regular blood transfusions, which may end up causing the patients other complications such as iron overload and transfusion-transmitted infections, leading to the exacerbation of the disease and an increased risk of mortality.[5] Patients with β-thalassaemia major who get regular blood transfusions are at risk of post transfusion hepatitis (PTH). The most commonly known of these infections are Hepatitis B, C and E.[6],[7] hepatitis C virus (HCV) is a common variety of PTH that can cause severe liver inflammation and long-term problems such as liver cell cirrhosis and carcinoma.[8],[9]

In a study conducted in Egypt, 37.11% of the children with thalassaemia major suffered from hepatitis C infection, and age was indicated as a risk factor for these infections.[10] In a study conducted in Iran, of the 1113 thalassaemia patients examined, 152 had positive anti-HCV results and the overall prevalence of hepatitis C infection in these patients was reported to be 13.6%.[3] In another study on thalassaemia, 19.3% of the patients tested positive for HCV Ab.[11] Due to this significant prevalence and the important complications of chronic hepatitis C (CHC) infection, the proper treatment of this infection is essential for reduction of its complications. In patients with thalassaemia, the treatment of CHC (HCV) is difficult due to their likelihood of developing haemolytic anaemia as a treatment sideeffect. One study reported an increase of almost 30% in the need for blood transfusion due to anaemia in thalassaemia patients.[12],[13] The first generation of direct-acting antivirals (DAAs) emerged in 2011, and following the introduction of a new wave of DAAs in 2013, which were extraordinarily effective, the use of these medications gained significance.[14] Following the production of new oral DAAs, the treatment of hepatitis C became reliant on the use of these medications. Despite their desirable effects in the treatment of hepatitis C, the efficacy of these medications in specific groups and their side-effects are not yet fully identified. Given the substantial side-effects of ribavirin (RBV) in thalassaemia patients, RBV-free hepatitis C treatment regimens should be emphasised. Very few clinical trials have been conducted on the efficacy and side-effects of DAA in the treatment of HCV infection in thalassaemia patients. The current study aimed to evaluate the therapeutic effect of sofosbuvir (SOF) + daclatasvir (DAC) and its effect on haematological factors in HCV infection in patients with major thalassaemia and have experienced intraneural facilitation (IFN) treatment failure, at least once. The aim of this study was to evaluate the effects of CHC treatment in thalassemic patients, on blood factors and the need for blood transfusion in these individuals. The second objective is to measure serum ferritin levels.

 ~ Materials and Methods Top

Patient selection

A total of 70 patients with beta-thalassaemia major and chronic HCV infection were analysed from July 2016 to December 2017 [Figure 1]. The study inclusion criteria consisted of a previous history of interferon treatment failure with or without RBV in HCV-infected thalassaemia patients. The exclusion criteria were: Concomitant infection with hepatitis B virus or HIV; hepatocellular carcinoma; bone marrow disease or history of liver transplantation; creatinine clearance <30 mL/min/1.73 m 2; severe heart or chronic liver diseases; drug abuse; and receiving amiodarone therapy.
Figure 1: Flow diagram of this study patient

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The present prospective open-label controlled trial was conducted at a tertiary referral health centre to which patients were referred from different parts of the country. The patients were treated with daily doses of SOF (Sobiovir ®) 400 mg/day plus DAC (Daklibiox ®) 60 mg/day ([Bakhtar Bioshimi Co [BBpharmaco], Iran]). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the Institution's Human Research Committee. The project was designed and implemented by academic scholars, approved by the Ethics Committee of Iran University of Medical Sciences (code No. IR. IUMS. REC1396.30196; 2016) and registered at the Iranian Registry of Clinical Trials ( IRCT2017052426097N2). At baseline, all the participants underwent a polymerase chain reaction to have their virus genotype, and viral load assessed and underwent a FibroScan to check for cirrhosis.[9],[13] Cirrhosis was defined based on the FibroScan results, that is, values >14.6 KPa were taken to indicate cirrhosis.[14] Thalassaemia major was confirmed in all the patients based on their haemoglobin electrophoresis or early DNA testing. In addition, all the patients who regularly received Deferoxamine therapy also received a regular blood transfusion. Adherence to the treatment was assessed through telephone counselling and questionnaires. The patients were visited every month during the treatment by a specialist. In this study, the treatment was done for 24 weeks.

Assessment of efficacy

Efficacy and safety assessment

Blood samples were obtained for the assessment of biochemical and haematological parameters and treatment safety at baseline and 4, 8 and 12 weeks after the start of the treatment and 12 weeks after the end of the treatment. The treatment ended with the non-detectability of HCV RNA 12 weeks after the end of the treatment sustained virological response (SVR 12), which was identified using a molecular technique with a lower limit of detection (≤25 IU/ml). The patients that reported serious or intolerable side-effects or a major laboratory dysfunction were excluded from the study. The patients were visited in person every month by a hepatologist and asked about the treatment of side-effects and tolerance, and their answers were recorded in a questionnaire. Their kidney and liver functions were controlled by taking blood samples and comparing them at baseline, 4, 8 and 12 weeks after the start of the treatment and 12 weeks after the end of the treatment. The treatment procedure in the current study was 24 weeks for all the patients. A haematological assessment was used to monitor the effects of anti-hepatitis C treatment on blood cells, possible anaemia and the need for blood transfusion. The hepatologist's phone number was given to the patients to report potential side-effects. Sampling was performed before the patients' scheduled blood transfusion to assess the exact effect of the treatment on the need for blood transfusion.

The quantitative measurement of the virus was performed using Cobas TaqMan technique (Roche Molecular Systems, Branchburg, NJ) with the lowest limit of detection (25 copy/ml) of HCV RNA.[9]


Data were presented as frequency (percentage); the statistical t-test was used to compare the mean variables, and the results were presented as mean ± standard deviation data were analysed in SPSS software, version 24.0 (SPSS Inc, Chicago, IL, USA) and P < 0.05 was set as the level of statistical significance.

 ~ Results Top

In the present study, 61 patients (53.5% of whom were male) with the age range of 18–40 years and mean of 30.19 ± 5.8 years, were evaluated. The mean height of the patients was 162.37 ± 8.83 cm, and their mean body weight was 56.05 ± 9.9 kg. A total of 88% had experienced Interferons (IFNs) treatment failure once, 8% had experienced it twice and 4% three times; 32% were non-responsive, 60% had experienced a relapse, and 8% had unsuccessful treatment (virological breakthrough). In the virological assessments, 54.1% (n = 33) had genotype 1a, 29.5% (n = 18) genotype 3a, 6.6% (n = 4) genotype 1b, 4.8% (n = 3) genotype 2a, 3.2% (n = 2) genotype 2b and 1.6% (n = 1) genotypes 1a and 3a. The fibroscan results showed that 34.4% (n = 21) had developed cirrhosis while 65.6% (n = 40) were non-cirrhotic cases. SVR-12 was used to evaluate the treatment response rate, and only one patient with genotype 1b was non-responsive, and his fibroscan result was 24 KPa (diagnosed with cirrhosis). The treatment response rate was therefore 98.4% in the present study. The level of liver enzymes showed a significant reduction in all the study participants 4 weeks after the treatment; for example, the post-treatment AST dropped from 63.71 ± 43.69 to 42.21 ± 69.38 IU/dL (P = <0.05) and alanine aminotransferase (ALT) reduced from 78.11 ± 59.83 to 26.83 ± 22.912 IU/dL (P = <0.05). This improvement in the liver enzymes was maintained until 12 weeks after the treatment. The test results are presented in [Table 1].
Table 1: Liver enzymes in the study patients before and after the treatment

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No significant side-effects that necessitated the cessation of treatment were reported. No death was reported during the treatment and the 3-month follow-up. One subject reported an increase in appetite, two patients developed diarrhoea, six complained of headaches and five felt fatigue over the course of the treatment, but none of the reported complications necessitated the cessation of treatment and all the patients tolerated the treatment well. The rate of haemoglobin was 9.5 ± 1.42 g/dl before the treatment and reached 9.6 ± 1.6 g/dl after (P = 0.54). The patients' test results before and after the treatment are presented in [Table 2]. The need for blood transfusion in the patients was 1.595 ± 0.65 bags per month on an average before the treatment, but they received 1.593 ± 0.64 bags per month after the treatment (P = 0.9). This regimen did not affect the level of anaemia in the patients and did not make any change in the need for blood transfusion. Ferritin levels decreased significantly (from 1948.08 ± 1539.54 to 1315.73 ± 1207.67 ng/ml) (P = 0.001) in the patients after the treatment.
Table 2: Tests results of the study patients before and after the treatment

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 ~ Discussion Top

The first generation of DAAs, including boceprevir (BOC) and telaprevir (TVR), was introduced in 2011 and added to the previous regimen of pegylated interferon/RBV Peg IFN/RBV.[15] This new triple treatment strategy increased the SVR, but still relied on IFN and presented severe side-effects. Triple treatment with BOC or TVR rapidly declined with the new wave of more effective DAAs introduced in 2013, and the production of new medications caused changes in the standards of HCV treatment. In December 2013, the Food and Drug Administration (FDA) approved a combination of SOF and Peg IFN/RBV for the treatment of genotype-1 HCV infection.[16] The combination of SOF and RBV or Peg IFN was also approved for the treatment of HCV genotypes 2, 3 and 4, and with a limited efficacy for genotype-3 HCV.[17] In October 2014, the FDA approved the use of ledipasvir (LDV) in combination with SOF for the treatment of HCV genotype 1, which had an efficacy of more than 95%.[18] In December 2014, the FDA also approved another IFN-free medication regimen, which was a combination of three DAAs, including ombitasvir/paritaprevir-r/dasabuvir, for the treatment of HCV genotype 1, with efficacy of more than 95%.[19]

Finally, in January 2016, the FDA approved the combination treatment of Grazoprevir/Elbasvir/GZR-EBR with a 95% SVR. A clinical trial showed that SOF-based regimens could provide an effective and safe treatment for HCV patients with or without cirrhosis.[20] Previous studies have proposed that DAC plus SOF is a safe and effective option for the treatment of all HCV genotypes.[14],[17] Despite the acceptable number of studies on the treatment of hepatitis C, there is still little information on the treatment of this disease in special groups, and the treatment of thalassaemia patients infected with HCV remains a controversial subject. Double treatment with Peg IFN/RBV, the use of the Protease inhibitors BOC and TVR, and triple treatment based on Peg IFN/RBV appears to reduce RBV bleeding in many thalassaemia patients.[21] Moreover, removing RBV and using low-dose RBV in the treatment of thalassaemia might reduce SVR.[19] Given the significant side-effects of RBV in thalassaemia patients, it is important to emphasise on the RBV-free hepatitis C treatment regimens, and since there are very few clinical trials on the effect of DAAs in the treatment of HCV infection in thalassaemia patients, the present study aimed to assess the therapeutic effects of SOF and DAC on the treatment of hepatitis C in patients with thalassaemia major with at least one previous interferon treatment failure.

Patients with congenital anaemia such as thalassaemia, are at risk of HCV infection, which is the most important cause of liver-related death. The treatment of thalassaemia patients infected with HCV is still a controversial issue. Double treatment with Peg IFN/RBV, the use of Protease inhibitors (BOC and TVR) and triple treatment based on Peg IFN/RBV has led to RBV anaemia in many thalassaemia patients.[15] According to some reports, up to 50% of these patients experience a degree of anaemia after these treatments and have an increased need for blood transfusion.[22] There is therefore a restriction on the combined use of interferon and RBV in patients with thalassaemia due to the haemolysis associated with RBV. Moreover, removing RBV from treatment regimens and using low-dose RBV in the treatment of thalassaemia might help in the reduction of SVR.[21] With the emergence of oral DAAs, the treatment of HCV has dramatically transformed.

Currently, there are very few studies on the use of DAA in the treatment of hepatitis C in thalassaemia patients. In a study conducted by Mangia et al.,[23] 100 thalassaemia patients were treated with SOF and LDV (SOF/LDV); before then, these patients were treated with interferon-based regimens and showed poor outcomes. A total of 16% of the patients with genotypes 1–4 suffered from cirrhosis. These patients were compared with 96 patients with genotypes 1–4 who had received Peg IFN/RBV. The researchers observed that the patients that received SOF/LDV had higher SVR when compared with the ones that received Peg IFN/RBV (98 vs. 47.9%).[23] In addition, the patients treated with SOF/LDV responded to the treatment better and showed fewer adverse side-effects such as fatigue, headache, nausea, vomiting and reduced haemoglobin or increased ferritin. In the SOF/LDV group, the haemoglobin level was 10.44 ± 1.26 g/dl at baseline as compared to the 10.63 ± 1.27 g/dl level by the end of the treatment (P = 0.059); meanwhile, in the Peg IFN/RBV group, the mean haemoglobin level reduced at the end of the treatment. The haemoglobin level decreased significantly from 9.71 ± 0.73 at baseline to 8.81 ± 1.08 g/dl at the end of the treatment (P = 0.001).

In a multicentre study conducted on thalassaemia major patients with HCV infection and who were receiving Elbasvir/Grazoprevir as their treatment,[16] the response rate was 97.6% (40 out of 41), and no change was observed in the patients' haemoglobin level. Hesamizadeh et al.[12] administered SOF in some patients with thalassaemia and HCV at the Middle East Liver Disease Centre and reported acceptable SVRs. Nevertheless, these researchers recommended further clinical tests using DAAs for evaluation of the proposed approach.

Based on new clinical guidelines, two medication combinations are helpful for all cases of hepatitis C infection, namely, SOF-DAC and SOF-Velpatasvir.[14],[17],[20] The review of the literature showed no clinical trials on the effects of DAAs on the treatment of HCV in thalassaemia patients. New clinical studies on DAA are required to assess this treatment approach. Some articles have reported positive effects of SOF-DAC combination on the treatment of hepatitis C in people with no thalassaemia. For example, in a study conducted in Australia by Leroy et al.[24] On 50 patients with genotype-3 hepatitis C and advanced liver disease using a randomised clinical trial, the SVR-12 was 87.5% in those that received the treatment for 12 weeks and 92.3% in those that were treated for 16 weeks. In another clinical trial in the United States, 60 patients with HCV and advanced liver cirrhosis and 53 cases of recurrence after liver transplantation were assessed, and SVR-12 was reported as 83.3% in the advanced cirrhosis group and 94.3% in the post-transplant-rejection group.[25]

In the present study, the SOF/DAC combination was selected for the treatment of the participants based on the results of studies conducted on patients with thalassaemia and hepatitis C infection. An acceptable SVR-12 was reported in 98.4% of the participants, and proper treatment responses were reported for the different genotypes and the cirrhotic and non-cirrhotic patients. The patients also showed good tolerance of the treatment, and unlike the injectable interferon treatment regimen, no change was observed in need for blood products or the level of anaemia in the patients. This finding, of course, contradicts the study of Nagral et al.[26] which suggests that treatment based on SOF increases the need for blood transfusions. This finding has not been proven in other studies, and like the present study, these drugs did not have any effect on the level of haemoglobin.[16],[27] The response to treatment in the present study was the same as that in the studies of.[16],[27] The SOF plus DAC regimen, therefore, seems to be effective in treating patients with thalassemia. Like in the two previously-cited studies, the patients' anaemia was not exacerbated after treatment in the present study.

This regimen had a favourable effect on the ferritin level, which is a key parameter in patients with thalassemia. In some studies, ferritin and transferrin levels were found to be higher in thalassaemia patients, and these parameters were associated with liver fibrosis.[16],[28] In the present study, a significant reduction was observed in ferritin levels from 1948.08 ± 1539.54 to 1207.67 ± 1315.73 ng/ml (P = 0.001). This finding is supported by a similar study.[26] The reduction in ferritin has beneficial effects on liver toxicity in thalassaemia patients.

Several studies have reported that elevated serum iron markers (ferritin, iron and transferrin saturation) and iron accumulation within the liver occur frequently in patients with CHC infection and may worsen the liver injury.[28],[29] Increased levels of ferritin and serum iron levels and the decreased levels of TIBC were correlated with progressive hepatic parenchymal disease. A possible explanation for these elevations is that a necroinflammatory hepatic status can release iron and ferritin from damaged hepatocytes, a process also sustained by the concomitant high serum levels of ALT.[30] On the other hand, it is known that ferritin is an acute phase reactant protein. In the study of Barut et al.,[31] it was shown that combined antiviral therapy induced a marked increase in serum ferritin that falls below baseline values after the sustained viral response, suggesting that the cause of hyper-ferritinemia in many patients is HCV infection itself rather than iron overload. This observation leads to the assumption that increased levels of serum ferritin in non-treated CHC are most often a result of actions by HCV itself or of chronic inflammation which stimulated an immune response, and ferritin levels will decrease after adequate treatment.

Comparison of the treatment response rate in the present and cited studies showed that patients with thalassaemia major responded well to treatment with DAA. These drugs do not require blood transfusions in patients with thalassaemia and also have beneficial effects on serum ferritin levels. Therefore, DAAs can be the choice therapy for thalassaemia patients with HCV infection.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

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Barut S, Günal O, Erkorkmaz U. Serum ferritin levels in chronic hepatitis C patients during antiviral therapy and prediction of treatment response. Scand J Infect Dis 2012;44:761-5.  Back to cited text no. 31


  [Figure 1]

  [Table 1], [Table 2]


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2004 - Indian Journal of Medical Microbiology
Published by Wolters Kluwer - Medknow

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