Treatment of Chronic HCV Infection in Patients With Thalassemia

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Abbreviations

DAA

direct‐acting antiviral

DBV

dasabuvir

DCV

daclatasvir

EBR

elbasvir

GZR

grazoprevir

HCV

hepatitis C virus

LDV

ledipasvir

OBV

ombitasvir

r

ritonavir

PTV

paritaprevir

RBV

ribavirin

SMV

simeprevir

SOF

sofosbuvir

SVR

sustained virological response

VEL

velpatasvir

Thalassemia is an inherited blood disorder characterized by decreased or absent globin‐chain production. With nearly 60,000 individuals affected every year, thalassemia is one of the most common genetic diseases in the world.1 The lifelong need for blood transfusions in thalassemia makes these patients vulnerable to transfusion‐transmitted viral infections, notably hepatitis C virus (HCV). Infection with HCV results in chronic infection in a vast proportion of individuals, and the prevalence rate of chronic hepatitis C in patients with thalassemia major in the EMRO (WHO Regional Office for the Eastern Mediterranean) region ranges from 11% to 69% depending on the age of the patient and the local seroprevalence of HCV (Fig. 1).2, 3 Although the natural history of chronic HCV infection in patients with thalassemia is unclear, the morbidity and mortality of those patients is thought to be increased. Liver disease is more severe in patients with thalassemia and may be accelerated by hepatic siderosis. Hepatic iron overload, in transfusion‐dependent thalassemia, negatively affects the outcome of liver disease, leading to more severe hepatic inflammation and fibrosis, and is associated with a diminished response to interferon‐based regimens.2, 4, 5, 6

Figure 1.

Geographical distribution of pooled or individual epidemiology of HCV infection among patients with thalassemia in EMRO. Adapted and updated with permission from Iranian Red Crescent Medical Journal.23 Copyright 2010, Koswar.

Treatment of HCV in patients with thalassemia is aimed at viral eradication, resolution of liver inflammation and control or reversal of fibrosis, reduction of the risk for hepatocellular carcinoma, and improvement of health‐related quality of life and survival. However, the major impediment to the treatment of HCV infection in patients with transfusion‐dependent thalassemia has been the risk for ribavirin (RBV)‐associated hemolysis, as well as the effect of iron overload on virological response rates and the potential for drug‐drug interactions with various iron chelators. Initial studies using interferon monotherapy had shown a sustained viral response rate of ~30%,7, 8, 9 whereas limited case series confirmed that the addition of RBV with peginterferon in selected patients with thalassemia can lead to sustained virological response (SVR) rates similar to other low‐risk populations but at the cost of 30% to 50% increase in transfusion requirements during treatment.10, 11, 12, 13 Despite these data, most treatment‐naive patients with thalassemia, as well as relapsers/null responders to interferon monotherapy, were not considered candidates for the combination of peginterferon and RBV, the standard of care at the time.

The introduction of highly effective and safe direct‐acting antivirals (DAAs) has largely addressed the needs of special populations including those with chronic kidney disease, decompensated cirrhosis, HIV coinfection, people who inject drugs, and organ transplantation recipients, and has transformed the treatment landscape for many patients with HCV who were previously ineligible or had unsuccessful peginterferon‐based therapy results, including those with thalassemia. Recent studies have addressed different DAAs regimens in this patient population. Mangia et al.14 reported an SVR rate of 98% with sofosbuvir/ledipasvir (SOF/LDV). The study reported in a significant number of patients (76%) negative side effects that were mild, including headache (34%), fatigue (41%), and nausea (43%). Other SOF‐based combinations have shown similar SVRs ranging from 90% to 100%. In 2017, Sinakos et al.15 published a trial with five different DAA combinations out of which four included SOF (SOF/RBV, SOF/simeprevir [SMV], SOF/daclatasvir [DCV], and SOF/LDV). The study included 100 patients with thalassemia major and reported an SVR rate of 90%. No serious adverse events were reported, including no drug‐drug interactions between the DAAs and the iron chelation medications used (deferoxamine, deferiprone, and deferasirox). In a similar study, Origa et al.16 reported an SVR rate of 93.5% in 114 patients with thalassemia major and 13 patients with thalassemia intermedia with the same five regimens used. Both studies included an SOF/RBV arm (approved at the time for genotype 2) and as expected, transfusion demand increased in patients receiving this regimen. In a recent randomized control trial including an immediate and a delayed treatment arm, Hézode et al.17 reported on DAA regimens in patients with different blood disorders including 41 patients with beta‐thalassemia. The trial included patients with HCV genotypes 1a, 1b, 1‐other, 4, and 6 who received elbasvir/grazoprevir (EBR/GZR), resulting in an SVR rate of 97.6% (40 out of 41) in patients with thalassemia. No significant difference was reported between the deferred and immediate treatment group in terms of adverse events, with only one patient with beta‐thalassemia reporting a serious event (erosive gastritis and hypophosphatemia). Other minor negative side effects included headache and nausea. Nagral et al.18 explored the efficacy and safety of DAAs in adolescents with thalassemia major. Regimens included SOF/LDV and SOF/DCV with two patients in the latter group also receiving RBV. SVR at 3 months was reported in 16 out of the 18 subjects (89%), and no major adverse events were reported. Recently, Sharara et al.19 reported 100% SVR with the pangenotypic single‐tablet combination of SOF/velpatasvir (VEL), and no adverse events in seven patients with genotype 4 HCV infection. Table 1 summarizes the literature on various DAA regimens in the thalassemia population.14, 15, 16, 17, 18, 19, 20, 21

Table 1.

Summary of Studies Treating HCV Using DAAs in Patients With Thalassemia

Reference	No. of Patients	Genotype	DAA Regimen	SVR	Comments
Mehta et al.20	10	3	SOF+DCV	100%	No serious adverse events
Mangia et al.14	100	1	SOF+LDV	98%	No serious adverse events
		4
Hézode et al.17	41	1a	EBR+GZR	97.60%	No difference between deferred and immediate treatment group in terms of adverse events
		1b
		1‐other
		4
		6
Sinakos et al.15	100	1a	SOF+RBV	90%	Pooled from eight liver units
		1b	SOF+SMV	(80%‐100%)	Regimen based on availability and physician discretion
		2	SOF+DCV		No serious adverse events
		3	LDV+SOF
		4	OBV/PTV/r+DBV
Zamani et al.21	61	1a	SOF+DCV	98.40%	No serious adverse events
		1b
		2a
		2b
		3a
Origa et al.16	114 (thalassemia major)	1a	SOF+SMV	93.50%	No serious adverse events
	13 (thalassemia intermedia)	1b	SOF+DCV
		2	SOF+LDV
		3	OBV/PTV+DBV
		4	SOF+RBV
		5
Nagral et al.18	18	1	SOF+LDV	89%	Adolescents (mean age, 15.1 years)
		3	SOF+DCV±RBV		No major adverse events reported
Sharara et al.19	7	4	SOF+VEL	100%	No adverse advents

In conclusion, patients with thalassemia and chronic HCV infection are no longer considered a special population with an unmet need given the availability of safe and highly effective DAA therapy. Continued screening and access to treatment constitute the present challenge. The position paper by the Thalassemia International Federation on viral hepatitis C (endorsed by the European Association for the Study of the Liver) highlights the need for continued screening for HCV infection in patients with thalassemia and the importance of facilitating wide access to safe, effective, and affordable therapy for all eligible patients.22