Open access peer-reviewed chapter
Abstract
Thalassemic patients, especially in limited resources settings, are prone to multi-transfusion acquired Hepatitis C virus (HCV). After the discovery of direct acting antivirals (DAAs), many programs were designed to achieve HCV eradication both on the macro-elimination and micro-elimination axes. Thalassemic patients are good candidates to be addressed by a unique HCV micro-elimination model since they face some challenges during their treatment journey. Some of these challenges are the young age at infection, frequent blood transfusion, polypharmacy, drug–drug interactions, pharmacokinetic considerations and the risk of reinfection. The available data of success rates of HCV cure in thalassemic patients alert that the success rate in thalassemic patients might be lower than that reported in general population. These factors make HCV micro-elimination model, a hurdle towards the 2030 world health organisation (WHO) HCV eradication plan.
Keywords
- Thalassemia
- Hepatitis C
- Direct acting antivirals
- challenges
- micro-elimination
1. Introduction
Haematologic diseases include any disease affecting the blood or blood forming organs such as bone marrow. Haematologic diseases include haemoglobinopathies, malignancies, different types of anaemia and other less common diseases. Thalassemia is one of the most common haemoglobinopathies [1].
Hepatitis C virus (HCV) is a liver disease that can cause both acute and chronic infections. Chronic HCV infection can lead to liver cirrhosis or hepatocellular carcinoma (HCC). If liver cirrhosis became decompensated, no cure is available except liver transplantation [2].
Thalassemia patients have high prevalence of HCV and are more susceptible to its complications. Some challenges face the health care givers while developing their therapeutic plans for thalassemia patients [3].
2. Thalassemia
Thalassemia is a congenital disease where haemoglobin is malformed resulting in premature haemolysis. Thalassemia is classified into alfa thalassemia and beta thalassemia according to the affected globin chain. Thalassemia is also denoted a grade according to its severity into trait, carrier, intermedia, or major where major is the most severe case [1].
Thalassemia patients suffer from premature haemolysis, leading to increased Red blood cells (RBCs) turnover, ineffective erythropoiesis, and varying degrees of anaemia [4]. Thalassemia can be cured by bone marrow transplantation. If bone marrow transplantation is not feasible, thalassemia can be managed by regular blood transfusion along with other supportive therapies such as iron chelation [1].
2.1 Thalassemia and HCV
Thalassemia patients are at risk of multi-transfusion HCV infection specially in limited resources settings. Due to the relatively young age at infection, some thalassemia patients miss early diagnosis and treatment.
2.1.1 HCV discovery and genotypes
HCV is positive-stranded ribonucleic acid (RNA) enveloped virus which was first discovered in 1989. HCV genome is highly variable. Therefore, HCV has been classified into six genotypes (GTs) numbered from one to six. Different GTs show different response to treatment. Hence, treatment is genotype (GT) based. HCV GTs has numerous sub-genotypes which are also different with regard to response to treatment [2, 5].
The geographic distribution of HCV GTs show that GT-1 is the most prevalent GT worldwide followed by genotype 3. They account for about 46.2% and 30.1% of all HCV infections, respectively. On one hand, some countries have diverse HCV genotypic distribution such as China. On the other hand, in some countries, such as Egypt, more than 90% of HCV infections are caused by single genotype which is GT-4 [2, 6, 7].
2.1.2 HCV prevalence
Globally, between 130 and 150 million people had chronic HCV infection and 700,000 people died due to HCV related complications in 2013 [2, 8]. HCV global paediatric burden was estimated to be 3.5 million children or adolescents [9, 10]. Some countries such as Egypt suffers from an endemic HCV prevalence. HCV prevalence in Egypt was estimated to be the highest worldwide in 2015 where viraemic prevalence was estimated to be 6.3% in adults 1.1% in children aged 10–19 years [7, 11].
2.1.3 Mode of transmission of HCV among thalassemia patients
HCV infection is blood borne. The main source of HCV infection in thalassemia patients is unscreened blood transfusions. This does not preclude that unsafe injection practices, health-care-associated transmission and renal dialysis are among the other causes of HCV transmission in thalassemia patients. According to a previous World Health Organisation (WHO) report on blood safety, some countries do not properly screen blood transfusions for blood borne viruses on routine basis. Hence, the WHO developed its guidance on phlebotomy [2, 12, 13]. Prior to the implementation of the WHO guidance, multi-transfusion associated HCV acquisition was a common mode of transmission among multi-transfusers such as thalassemia patients specially of major type. HCV prevalence by HCV antibody test widely vary from 4–85% according to different reports [14].
Less common routes of HCV transmission among thalassemia patients are mother-to-child, also known as vertical transmission, sexual transmission, and intranasal drug use [2].
2.1.4 Thalassemia consequences that interfere with HCV treatment
Because of premature haemolysis and ineffective erythropoiesis, that thalassemia patients suffer, the core of their supportive care is regular blood transfusion. The major consequences of multi-transfusion are iron overload, oxidative stress, splenomegaly, liver fibrosis and blood borne infections.
Thalassemia induced haemolysis results in chronic anaemia. Severe anaemia is compensated by hyperdynamics. Hyperdynamic results in an initial increase in the cardiac index and blood flow to vital organs such as liver and kidney. However, over long term, thalassemia patients develop heart failure and renal impairment [15, 16, 17, 18, 19].
Iron overload can negatively impact the patients’ cardiovascular and endocrine systems leading to heart failure, osteoporosis and other diseases [20]. Excessive haemolysis leads to splenomegaly which in turn leads to increased transfusion requirements and difficult control of iron overload. Therefore, many beta-thalassemia patients who suffer severe anaemia are splenectomised [21].
Among the complications of thalassemia are blood borne infections especially in low to intermediate income countries that do not implement rigorous blood products screening systems [2]. Multi-transfusion related HCV is one of the blood borne infections thalassemia patients suffer. According to the WHO Regional Office for the Eastern Mediterranean (WHO-EMRO), 11–69% of Beta-thalassemia major patients suffer from chronic HCV in the aforementioned region [22].
2.1.5 HCV prognosis in thalassemia
The early phase of HCV prognosis in thalassemia patients does not differ secondary to their disease nature. HCV infection manifest in thalassemia patients as acute or chronic hepatitis. 15–45% of cases show spontaneous clearance of untreated acute HCV infection within six months of infection similar to patients without thalassemia. The remaining 55–85% develop chronic HCV which is usually asymptomatic. If left untreated, chronic HCV infection causes liver cirrhosis and consequently liver failure. Liver cirrhosis is associated with high risk of hepatocellular carcinoma (HCC). This normal course of chronic HCV prognosis is aggravated by thalassemia since the pathophysiology of thalassemia include iron overload and consequently, increased oxidative stress that result in necro-inflammatory responses aggravating the course of HCV induced liver fibrosis and eventually cirrhosis. Thalassemia could induce liver fibrosis even on absence of HCV infection due to the iron deposits and iron overload induced oxidative stress. Liver fibrosis progress in thalassemia patients even in absence of HCV infection [2, 23].
2.1.6 HCV treatment
2.1.6.1 HVC treatment development
For decades, there was no available treatment for HCV until the discovery of the role interferon-alpha in HCV immune response. Interferon-alpha-2b/ribavirin for 48 weeks were the standard treatment for more other decades where Interferon was injected three times a week and ribavirin was orally administered daily.
Pegylated interferon-alfa-2b/ribavirin regimen was the next step in the development of interferon-based regimens for the treatment of HCV, where pegylation allowed once weekly injection of interferon. Pegylated interferon/ribavirin regimen was poorly tolerated, and its cure rates were between 40% and 65% depending mainly on the HCV GT and cirrhosis status. HCV cure is measured by sustained virologic response twelve weeks post treatment (SVR12). Pegylated interferon/ribavirin regimen was sometimes associated with life-threatening adverse reactions [2, 8].
The introduction of direct acting antivirals (DAAs) comprised a revolutionary step in HCV treatment. DAAs directly inhibited the replication cycle of HCV through targeting three important regions within the HCV genome. These three regions are the non-structural (NS) NS3/4A protease, NS5A and NS5B RNA-dependent polymerase. DAAs achieved higher success rate than interferon-based regimens. DAAs based therapy has a success rate of about 90% after 12 weeks therapy. Other advantages of DAAs based regimen are the shorter treatment duration which range from 8 to 24 weeks, oral administration leading to better compliance and more favourable safety profile. DAAs based regimens are combination therapies. Individual DAAs based regimens vary in their therapeutic efficacy, genotypic efficacy, and safety profile [2, 8].
The first-generation DAAs were protease inhibitors. They were co-administered with interferon and ribavirin according to the WHO guidelines in 2014. However, they were only effective against GT-1 infection. In addition, they had frequent and sometime severe side-effects. Therefore, the WHO no longer recommends first generation DAAs.
Second-generation DAAs have higher SVR12 rates and better safety than the first generation. The strongest advantage of the second generation DAAs is that they can be used in combinations obviating the need for interferon and ribavirin. Interferon-free combinations of two or three second generation DAAs have demonstrated excellent efficacy in general, although cure rates among certain patient subgroups were lower [2, 8].
The WHO currently recommends that, all HCV infected patients to be treated with DAAs based therapy, except those having GT-5 or 6 infection and cirrhotic GT-3 patients in whom interferon-based therapy can still be used as an alternative regimen. DAAs are tremendously developing with the aim of improved efficacy and safety profiles [2].
Some DAAs combination showed approximately 100% cure rate in adults such as sofosbuvir (SOF)/simeprevir (SMV) combination with or without ribavirin for 24 weeks, SOF/daclatasvir (DAC) combination with or without ribavirin for 24 weeks and ombitasvir/paritaprevir/ritonavir combination with either dasabuvir or ribavirin for 12 weeks [2, 8].
In children, until recently, the only food and drug administration (FDA) approved regimens were interferon based [24]. The treatment success rates and adverse effects of interferon-based therapy among children were similar to those of adults [25].
Till January 2017, six DAAs combined into four regimens with ribavirin were in clinical trials for paediatric patients. These regimens are SOF/ribavirin, SOF/ledipasvir (LDV) and paritaprevir/ombitasvir/ritonavir ± ribavirin/dasabuvir. The duration of therapy ranged from 12 to 24 weeks [24]. SOF/LDV for 12 weeks proved to be 98% effective in adolescents with genotype-1 infection with favourable safety profile [26]. Consequently, in April 2017, the FDA approved SOF/LDV and SOF/ribavirin for HCV treatment in paediatric patients aged 12–17 years [27]. SOF/LDV had 98–100% SVR12 rate in adolescents [28, 29, 30, 31, 32, 33]. SOF/LDV SVR12 rate sometimes differs in special sub-populations where its SVR12 rate in adolescent beta-thalassemia major patients was previously reported to be 89% (95% confidence interval (CI) 74–100%) [34]. Later in 2017, a clinical trial of glecaprevir (GLC)/pibrentasvir (PBR) for 8–16 weeks in adolescents were launched. Glecaprevir/pibrentasvir was approved for use in adolescents in April 2019 [35]. After about one year, SOF/velpatasvir (VLP) was approved in March 2020 [36].
Until the current date, only four DAAS based regimens were approved in paediatric patients namely, SOF/ribavirin, SOF/LDV, GLC/PBR and SOF/VLP [27, 35, 36]. In April 2017, SOF/ribavirin and SOF/LDV were approved in adolescents weighing at least 35 Kg. Afterwards, the FDA approved the pan-genotypic GLC/PBR in adolescents weighing at least 45 Kg and approved SOF/LDV use in children starting from the age of 3 years. The last milestone in the DAAs development process in paediatric patients was the approval of the pan genotypic SOF/VLP in children starting from the age of six years [27, 35, 36, 37].
2.1.6.2 HCV treatment in thalassemia
Before April 2017, the only available HCV treatment for paediatric patients was interferon-alfa 2b/ ribavirin-based regimen. Ribavirin based regimens were of limited applicability in thalassemia patients due to ribavirin haematologic side effects which include haemolysis. Interferon monotherapy had about 30% success rate in terms of sustained virologic response 12 weeks post-treatment (SVR12). Ribavirin use in thalassemia patients lead to higher SVR12 at the expense of increased blood requirements during the treatment period [22].
Before the approval of direct acting antivirals (DAAs) based regimens in April 2017, thalassemia paediatric patients were supported by different hepatoprotective agents to counteract HCV induced liver fibrosis and cirrhosis until the initiation of therapy. Hepatoprotectives were also recommended as an adjunct to DAAs based therapy to stop the progression of liver fibrosis after SVR12 achievement. Hepatoprotective agents include some plant derived compounds such as silymarin, silibinin, and Curcumin, antioxidants, such as N-acetyl cysteine, L-carnitine, and vitamin E and some drugs such as metformin hydrochloride [23, 38, 39].
After adulthood, many DAAs based regimens are available nowadays. HCV treatment in selected based on evidence based medicine [2]. Selection of DAAs based regimen is mainly dependent on the HCG genotype, patient’s cirrhosis previous treatment trials. Many regimens achieved SVR12 rated exceeding 90% with acceptable safety level. SVR12 in thalassemia patients after DAAs based regimens were reported to be 80–100%. These regimens include SOF/LDV, SOF/DAC, SOF, SOF/simeprevir (SIM), elbasvir/grazoprevir and ombitasvir/pibrentasvir/glecaprevir [34, 40, 41, 42, 43, 44, 45, 46]. The interest in investigating the reasons behind treatment failure among thalassemia patients is growing.
The WHO set a goal and targeted to eliminate HCV by 2030 [10]. To eliminate HCV infection, treatment should be offered and optimised not only in the general population, but also in special sub-populations. Thalassemia patients have an increased risk of multi-transfusion acquired HCV, particularly in resource limited settings, and an increased risk of its hepatic complications. In addition, their congenital disease nature may influence the pharmacokinetics of some drugs [3, 20, 22, 47].
2.1.6.3 Pharmacokinetic considerations in thalassemia
Thalassemia’s effect on the pharmacokinetics of drugs might be attributed to haemolysis, hyperdynamics, altered plasma protein binding, splenectomy, blood transfusion or drug–drug interactions [1, 20].
Some anti-HCV prodrugs are activated in the RBCs such as SOF [48]. Consequently, SOF activation might be altered in thalassemia patients.
Thalassemia induced hyperdynamics was found to increase the cardiac index by 60% in beta-thalassemia major patients. Since the hepatic blood flow comprises about 25% of the cardiac output, it was expected to rise consequently [18, 19, 49]. Since the hepatic metabolism of high extraction ratio drugs is flow dependent [50]. Therefore, hyperdynamics-enhanced hepatic blood flow might affect the clearance of high hepatic extraction ratio anti-HCV drugs such as SOF and LDV.
During the hyperdynamic phase, thalassemia patients were also found to go through initial renal hyperfiltration. Renal hyperfiltration might enhance the clearance of renally eliminated drugs such as SOF metabolite GS-331007 [51, 52]. Eventually, thalassemia patients suffer from renal impairment secondary to chronic anaemia, iron overload and iron chelators induced nephrotoxicity [17].
Thalassemia induced iron overload might alter the plasma protein binding of highly plasma protein bound anti-HCV drugs such as LDV, telaprevir, asunaprevir, DAC, ombitasvir, elbasvir, VLP, and dasabuvir that are at least 99% plasma protein bound [53, 54]. Blood transfusion might also alter the steady state of regularly administered drugs.
Moreover, splenectomy was proved to affect the pharmacokinetics of some iron chelating drugs [55]. The effect of splenectomy on anti-HCV drugs needs further research. It has been found that splenectomy does not affect the pharmacokinetics of SOF/LDV [56] but its effect on other anti-HCV drugs needs further investigation.
In conclusion, thalassemia may affect the pharmacokinetics of some anti-HCV drugs such as SOF, SOF metabolite GS-331007 and LDV [56] and some aspects still need further studies such as plasma protein binding alteration, blood transfusion effect on the drugs levels, splenectomy effect and drug–drug interactions.
3. Conclusions
Many challenges still awaiting thalassemia HCV micro-elimination model. More research is still required to rationalise treatment failure.
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