Global elimination of hepatitis C virus infection: Progresses and the remaining challenges.

Today, with the introduction of interferon-free direct-acting antivirals and outstanding progresses in the prevention, diagnosis and treatment of hepatitis C virus (HCV) infection, the elimination of HCV infection seems more achievable. A further challenge is continued transmission of HCV infection in high-risk population specially injecting drug users (IDUs) as the major reservoir of HCV infection. Considering the fact that most of these infections remain undiagnosed, unidentified HCV-infected IDUs are potential sources for the rapid spread of HCV in the community. The continuous increase in the number of IDUs along with the rising prevalence of HCV infection among young IDUs is harbinger of a forthcoming public health dilemma, presenting a serious challenge to control transmission of HCV infection. Even the changes in HCV genotype distribution attributed to injecting drug use confirm this issue. These circumstances create a strong demand for timely diagnosis and proper treatment of HCV-infected patients through risk-based screening to mitigate the risk of HCV transmission in the IDUs community and, consequently, in the society. Meanwhile, raising general awareness of HCV infection, diagnosis and treatment through public education should be the core activity of any harm reduction intervention, as the root cause of failure in control of HCV infection has been lack of awareness among young drug takers. In addition, effective prevention, comprehensive screening programs with a specific focus on high-risk population, accessibility to the new anti-HCV treatment regimens and public education should be considered as the top priorities of any health policy decision to eliminate HCV infection.

Core tip: Despite the outstanding progresses in the management of hepatitis C virus (HCV) infection, the elimination of HCV would be difficult due to the emergence of injection drug use as the main source of HCV transmission. Asymptomatic nature of HCV infection, restricted accessibility to diagnostic approaches and appropriate antiviral treatments in the injecting drug users (IDUs) community are the root cause of failure in control of HCV infection among IDUs. These circumstances create a strong demand for timely diagnosis and proper treatment of HCV-infected patients as well as raising general awareness of HCV infection through public education to mitigate the risk of HCV transmission.

INTRODUCTION

With a global prevalence rate of 2.8%, equating to over 185 million infections, and more than 350000 deaths annually, hepatitis C virus (HCV) infection is undoubtedly considered a major public health problem[1]. Globally, an estimated 3 million to 4 million new cases of HCV infection emerge every year[1]. Furthermore, the HCV-related mortality is increasing and HCV infection is projected to be the most important leading cause of viral hepatitis-related mortality in the near future[1,2]. Apparently, the management of HCV infection faces several challenges. These challenges merit further attention if elimination of HCV infection is aimed to be achieved.

HCV

HCV is a member of the family Flaviviridae and the genus Hepacivirus. The HCV genome is a positive-stranded RNA, which encodes a core protein (C), two envelope glycoproteins (E1 and E2), and several non-structural proteins (NS1, NS2, NS3, NS4A, NS4B, NS5A and NS5B)[3,4]. This enveloped positive-stranded RNA virus is usually acquired through exposure to infected blood. This might happen through transfusion of blood and blood products, surgery, organ transplantation, intravenous drug use, tattooing, hemodialysis, unsafe injection practices, mother to fetus, and sexual intercourse[5-8]. However, sexual transmission of HCV is less common and most often observed among men who have sex with men and HIV-infected patients[9,10].

HCV is the causative agents of hepatitis C infection. This infection is characterized by an acute or chronic course in the host. The complications are preliminary asymptomatic, mild or severe, which spontaneously clear or slowly progress to chronic liver disease, cirrhosis and finally hepatocellular carcinoma (HCC) within about 20 years[11,12]. The clinical symptoms of acute HCV infection might include fever, fatigue, malaise, and gastrointestinal symptoms such as anorexia, nausea, vomiting, right upper quadrant pain, dark urine, grey-colored stool, and yellow skin and sclera of the eyes, the well-characterized symptoms of jaundice. These symptoms might appear from 3 to 12 wk after being infected. The clinical symptoms of chronic HCV infection might take decades to develop, and they are usually indicative of an advanced liver disease[13-15].

The long-term chronic HCV infection is capable of causing some extra hepatic manifestations with serious consequences, such as glomerulonephritis, diabetes mellitus, thyroid disorders, porphyria cutaneous tarda, mixed cryoglobulinemia, lichen planus, and B cell lymphoproliferative disorders[16-21]. These extrahepatic complications might outshine the hepatic manifestations of HCV infection, and the presence of HCV infection might be overlooked, paving the way for the silent development of advanced liver disease. Therefore, the possible role of HCV in the development of extrahepatic manifestations merits further attention.

Due to genomic heterogeneity, there are 7 major genotypes and over 67 subtypes of HCV[1,22,23]. HCV genotype distribution varies by the route of transmission and geographical location[24,25]. In addition, pathogenicity, response to antiviral therapy and the duration of treatment can be influenced by different HCV genotypes[5,24,26]. The genotypes 1, 2 and 3 show a widespread distribution in almost all parts of the world. HCV genotype 4 has been traditionally restricted to a few countries in the Middle East and Africa and is more prevalent in Saudi Arabia, Bahrain, Jordan, Egypt and Ethiopia[1,27,28]. HCV genotype 5, 6 and 7 have been reported in South Africa, South East Asia and Central Africa, respectively[11,29,30] (Figure 1).

Figure 1

Geographical distribution of hepatitis C virus genotypes. Hepatitis C virus (HCV) genotypes 1, 2 and 3 show a widespread distribution in almost all parts of the world. HCV genotype 4 has been restricted to a few countries in the Middle East and Africa. HCV genotype 5, 6 and 7 have been reported in South Africa, South East Asia and Central Africa, respectively[1,11,30,35,36].

Genotype 1 is more prevalent among patients with history of blood and blood products transfusion, surgery, and dental procedure[24,25,27]. Infection with HCV genotype 2 is mainly associated with nosocomial transmission and prior dental treatment[1,22]. Genotype 3 is frequently found in the intravenous drug user communities and in those with history of tattooing and piercing[24,31,32]. Genotype 4 is mainly transmitted through high-risk sexual practices, especially among homosexual males, and intravenous drug use[1,22].

Infection with HCV genotype 3 is associated with a more rapid progression of fibrosis, a higher degree of steatosis, and a higher incidence of cirrhosis and hepatocellular carcinoma[1,22,31,33]. Spontaneous clearance is more often observed in infection with HCV genotype 1, while if patients remain HCV RNA positive, the disease progresses in a more aggressive manner than the other genotypes[11]. Genotypes 1 and 4 are associated with lower response rates and higher treatment duration in response to interferon (IFN) and ribavirin (RBV) combination therapy as compared to genotypes 2 and 3[6,24,34].

PROGRESSES IN THE MANAGEMENT OF HCV INFECTION

In addition to IFN-based therapies, the direct-acting antivirals (DAAs) have been developed, which specifically inhibit the function of viral proteins that are essential for viral replication[4,37,38]. These DAAs include NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleoside NS5B polymerase inhibitors, and non-nucleoside NS5B polymerase inhibitors (Table 1)[39-43]. These novel antiviral drugs, despite having considerable advantages over conventional IFN-based therapy, suffer from the resistance-associated mutations, which occur naturally during the replication of the virus and select under the pressure of DAAs. The emergence of HCV resistance-associated variants (RAVs) decreases the susceptibility to DAAs and finally results in treatment failure[38,44-46]. Assessment of resistance substitutions at pretreatment baseline in patients candidate for DAA therapy seems to be the best option to optimize first-line therapeutic strategies, to avoid the fitness of resistant variants as the predominant viral population and to prevent DAA failure due to baseline resistant variants. In addition, failing DAA-based therapy should be discontinued as soon as possible to avoid an increase in the frequency of RAVs, to preserve HCV re-treatment options. Finally, development of next-generation DAAs with higher resistance barrier is strongly recommended[45,47].

Table 1

Profile of direct-acting antiviral agents[4,37,40,42,44,48-78]

Direct-acting antiviral agent	Generic name (abbreviation)	Code name	Trade name	Active against HCV genotype (based on clinical trial outcomes)	Combination therapy
NS3/4A protease inhibitors (-previr)	Telaprevir (TVR)	VX-950	Incivek/Incivo	1	TVR + IFN ± RBV
	Boceprevir (BOC)	SCH-503034 EBP-520	Victrelis	1	BOC + IFN ± RBV
	Faldaprevir (FDV)	BI-201335	-	1	FDV + Peg-IFN + RBV
	Simeprevir (SIM)	TMC-435	Olysio	1 and 4	SIM + SOF ± RBV
	Vaniprevir (VNV)	MK-7009	Vanihep	1	VNV + IFN ± RBV
	Asunaprevir (ASV)	BMS-650032	Sunvepra	1 and 4	ASV + DCV
	Paritaprevir (PTV)	ABT-450	Veruprevir	1 and 4	PTV+R+OBV+DAV ± RBV
	Voxilaprevir (VOX)	GS-9857	-	Pan-genotypic antiviral activity	VOX + SOF + VPR
	Sovaprevir	ACH-1625	-	1	Sovaprevir + ODV + RBV
	Grazoprevir (GZP)	MK-5172	-	1a, 1b, 4 and 6	Zepatier (GZP + EBV)
	Danoprevir (DNV)	RG-7227	-	1 and 4	DNV + PEG-IFN + RBV
		ITMN-191			DNV + R + PEG-IFN + RBV
		ASC08
	Deldeprevir (DDV)	ACH-2684 ACH-0142684	-	1	DDV + ODV
	Neceprevir
	Narlaprevir (NVR)	SCH-900518	Arlansa	1	NVR + R + PEG-IFN ± RBV
	Vedroprevir (VDV)	GS-9451	-	1	VDV + LDV + SOF
					VDV + LDV + TGV + RBV
	Glecaprevir (GLE)	ABT-493	-	Pan-genotypic antiviral activity	GLE + PIB ± RBV
	-	GS-9256	-	1	GS-9256 + PEG-IFN + RBV
					GS-9256 + TGV + Peg-IFN ± RBV
NS5A replication complex inhibitors (-Asvir)	Daclatasvir (DCV)	BMS-790052	Daklinza	1, 2 and 3	Sovodak (DCV + SOF) ± RBV
					DCV + VX-135
	Ledipasvir (LDV)	GS-5885	-	1, 3, 4, 5 and 6	Harvoni (LDV + SOF) ± RBV
					LDV + SOF ± (VDV or Radalbuvir)
	Ombitasvir (OBV)	ABT-267	-	1 and 4	Viekira Pak (OBV + PTV + R + DSV) ± RBV
					Technivie (OBV + PTV + R)
	Elbasvir (EBV)	MK-8742	-	1a, 1b, 4 and 6	Zepatier (EBV + GZP) ± RBV
	Velpatasvir (VPR)	GS-5816	-	Pan-genotypic antiviral activity	Epclusa (VPR + SOF) ± RBV
	Odalasvir (ODV)	ACH-3102	-	1	ODV + Sovaprevir + RBV
	Ravidasvir (RVD)	PPI-668	-	4	RVD + SOF ± RBV
		ASC16
	-	PPI-461	-	1	-
	-	JNJ-56914845	-	1	GSK2336805 + PEG-IFN + RBV
		GSK2336805			GSK2336805 + VX-135 + SIM
	Samatasvir	IDX-18719 IDX-719	-	1, 2, 3 and 4	Samatasvir + SIM + RBV
		MK-1894
	-	BMS-824393	-	1	BMS-824393 + PEG-IFN + RBV
	Pibrentasvir (PIB)	ABT-530	-	Pan-genotypic antiviral activity	PIB + GLE ± RBV
	Ruzasvir (RZR)	MK-8408	-	Pan-genotypic antiviral activity	RZR + UPR + GZP
Nucleoside NS5B polymerase inhibitors	Sofosbuvir (SOF)	PSI-7977;	Sovaldi; Soforal	Pan-genotypic antiviral activity	SOF + IFN ± RBV
(-Buvir)		GS-7977			Sovodak (DCV + SOF) ± RBV
	Mericitabine (MCB)	RG-7128	-	1 and 4	MCB + PEG-IFN + RBV
		RO5024048			MCB + DNV
					MCB + R + DNV ± RBV
	-	VX-135	-	1	VX-135 + GSK2336805 + SIM
		ALS-2200			VX-135 + TVR + RBV
					VX-135 + DCV
					VX-135 + RBV
					VX-135 + SIM
	Valopicitabine	NM283	-	1	Valopicitabine + Peg-IFN
Non-nucleoside NS5B polymerase inhibitors (-Buvir)	Beclabuvir (BCV)	BMS-791325	-	1	BCV+ ASV+ DCV
	Dasabuvir (DAV)	ABT-333	Exviera	1	DAV + OBV+ PTV + R ± RBV
	Lomibuvir	VX-222	-	1	VX-222 + TVR + RBV
		VCH-222			VX-222 + Filibuvir
	Filibuvir	PF-00868554,	-	1	Filibuvir + Peg-IFN + RBV
		PF-868554			Filibuvir + VX-222
	Setrobuvir (STV)	ANA-598	-	1	STV + IFN + RBV
		RO-5466731			STV + R + DNV + RBV ± MCB
		RG-7790
	Nesbuvir (NBV)	HCV-796	-	1	NBV +Peg-IFN + RBV
		VB-19796
	Tegobuvir (TGV)	GS-9190	-	1	TGV + GS-9256 +Peg-IFN ± RBV
					TGV + LDV + VDV + RBV
	Deleobuvir (DBV)	BI-207127	-	1	DBV + PEG-IFN + RBV
					DBV + FDV
					DBV + FDV + RBV
	Uprifosbuvir (UPR)	MK-3682	-	Pan-genotypic antiviral activity	UPR + RZR
					UPR + RZR + GZP
	Radalbuvir	GS-9669	-	1	Radalbuvir + LDV + SOF
	AL-335	ALS-335	-	1	AL-335 + ODV + SIM

IFN: Interferon; RBV: Ribavirin; R: Ritonavir; PEG-IFN: Pegylated interferon.

Telaprevir and boceprevir are not recommended by WHO due to the frequent adverse effects and low cure rates[79].

Prior to the treatment, the infected individuals need to be identified. HCV infection is described by the presence of anti-HCV antibodies and HCV-RNA in plasma or serum with either elevated or normal levels of liver enzymes[29]. Anti-HCV antibodies are detected by using serological screening tests, including enzyme linked immunosorbent assay and recombinant immunoblot assay. Detection of anti-HCV antibodies indicates current or past HCV infection. An additional test called HCV RNA test or reverse transcriptase polymerase chain reaction assay (RT-PCR) is needed to determine if a person is currently infected with HCV[17,80-82].

However, those infected individuals with undetectable levels of HCV-RNA in serum or plasma might remain undiagnosed. In this condition, HCV-RNA can be detected in peripheral blood mononuclear cells (PBMCs) specimens, liver biopsies, and ultracentrifugated serum samples[81,83]. Serological screening tests might be negative or positive in these patients. This kind of infection is defined as occult HCV infection, which is a serious threat to blood safety[84,85]. Since, despite having undetectable level of HCV RNA, blood and blood products are potentially infectious[84,86]. In fact, the presence of blood donors with occult HCV infection can increase the risk of HCV transmission through blood transfusion and therefore is a potential source of HCV transmission in the society[87].

Despite having appropriate antiviral treatments and diagnostic approaches, diagnosis rate and access to treatment is considerably low especially in resource-limited settings. Perhaps the most promising strategy to control HCV infection is the development of a prophylactic vaccine[88,89]. Several vaccine candidates against HCV have been developed so far, including recombinant protein vaccine, peptide-based vaccine, virus-like particles, bacterial-vectored vaccine, viral-vectored vaccine, and DNA vaccine (Table 2)[29,88,90-96]. The currently developed vaccines against HCV, despite inducing strong humoral and cellular immune responses in preclinical animal models or clinical trials in humans, have not been approved for use in human beings[89,90,97]. The reason is high genomic diversity of HCV and viral escape from immune responses[88,90,93,98,99]. Targeting the conserved regions within HCV proteins might help to overcome this genetic variability[100].

Table 2

Vaccine candidates against hepatitis C virus in preclinical and clinical trials

Type of vaccine	Vaccine structure/adjuvant	Stage of development	Outcome	Application	Developer	Year	Current status	Ref.
Recombinant protein vaccine	Recombinant E1 or E2/MF59	7 chimpanzees	Induce strong humoral immune response; complete protection in 5 chimpanzees	Prophylactic vaccine	Chiron/ Novartis	1994	Completed	[101]
	Recombinant E1 or E2/Alum	4 Chimpanzees	Induce antigen-specific T-helper cytokines in either E1 or	Therapeutic vaccine	BPRC	2011	Published	[102]
	Recombinant E1/Alum	Phase I 20 healthy volunteers	E2-vaccinated animals; clear HCV infection in only E1-vaccinated animals (neutralizing antibodies) Induce strong cellular and humoral anti-E1 responses	Therapeutic vaccine	Fujirebio Europe	2004	Published	[103]
	Recombinant E1 and E2/MF59	Phase I 60 healthy volunteers	Induce humoral and cellular immune responses	Prophylactic vaccine	Novartis	2010	Completed	[104]
	Recombinant E1/Alum	Phase I/II 20 healthy volunteers and 35 patients with chronic HCV infection/122 HCV-infected patients	Induce HCV specific humoral and cellular immune responses (Th1 type); no change in HCV viral load	Therapeutic vaccine	Innogenetics/ GenImmune	2003/2008	Published	[103,105,106]
	HCV core protein/ISCOMATRIX	Phase I/IIa 30 healthy volunteers	Induce strong humoral immune responses in all except one patients; induce CD8+ T cell responses in 2 of 8 patients receiving the highest dose	Prophylactic vaccine	CSL Ltd	2009	Published	[107]
	GI5005: Inactivated recombinant Saccharomyces cerevisiae expressing NS3-core fusion protein/ GI-5005 plus SOC	Phase I/II 66 patients with chronic HCV infection/	Improve SVR	Therapeutic vaccine	GlobeImmune	2009/2010	Completed	[108,109]
Peptide-based vaccine	Peptide from core protein (C35-C44)/ISA51	Phase I 26 patients with chronic HCV infection	Induce peptide-specific cellular and humoral immune responses in 15 of 25 patients; decline HCV viral load in 2 of 25 patients	Therapeutic vaccine	Karume University	2009	Published	[110]
	Four peptides from E1, E2, NS3 and NS5A/Freund’s adjuvant	Phase I 12 nonresponder patients with chronic HCV infection	Induce peptide-specific cellular and humoral immune responses; decline HCV viral load in 3 patients	Therapeutic vaccine	Karume University	2007	Published	[111]
	Autologous dendritic cell delivered six CD8+ T cell epitope peptides from core, NS3 and NS4B	Phase I 6 nonresponder patients with chronic HCV infection	Induce transient T-cell response	Therapeutic vaccine	Burnet Institute + others	2010	Completed	[112]
	IC41: Five peptides from core, NS3, and NS4/Poly-L-arginine	Phase I/II 128 volunteers/60 non-responders with chronic HCV infection	Induce HCV-specific T-cell responses	Therapeutic vaccine	Intercell AG	2006/2008	Published	[113,114]
	IC41/Poly-L-arginine + imiquimod	Phase I 54 healthy volunteers	Induce significant T cell responses; low immunogenicity of topical imiquimod	Therapeutic vaccine	Intercell AG	2010	Published	[115]
	IC41 + imiquimod	Phase II 50 HCV-infected patients	Decline viral load; induce T cell responses	Therapeutic vaccine	Intercell AG	2012	Completed	[116]
Virus-like particles	Recombinant HCV-like particles (HCV-LPs) containing core, E1, and E2/AS01B	4 chimpanzees	Induce HCV-specific cellular immune responses; viral clearance	Prophylactic vaccine	NIH	2007	Published	[117]
	Recombinant baculovirus containing core, E1 and E2	Mice	Induce high titers of anti-E2 antibodies and strong HCV-specific cellular immune responses (CD8+ T and Th1 cells)	Prophylactic vaccine	NIH	2001	Published	[118]
Bacterial-vectored vaccine	Attenuated Salmonella typhimurium containing NS3 gene	Mice	Induce long-lasting T-cell responses	Therapeutic vaccine	NIH	2001	Published	[119]
Viral-vectored vaccine	Recombinant adenoviral vectors and plasmid DNA expressing NS3-NS5B	5 chimpanzees	Induce memory HCV-specific T cells; control of viremia	Prophylactic vaccine	NIH/Okairos	2012	Completed	[120]
	Multiple adenoviral vectors (Ad5, Ad6, Ad24, ChAd32 and ChAd33) expressing NS3-NS5B proteins	Mice and rhesus macaque	Induce strong cellular immune responses; long-term maintenance of memory cells	Prophylactic vaccine	Okairos	2006	Published	[121]
	Recombinant vaccinia viruses (rVV) expressing core, E1, E2, P7, NS2 and NS3	4 chimpanzees	Induce cellular immune responses; reduce viral load; resolve HCV infection	Prophylactic vaccine	NYC Blood Center	2008	Published	[122]
	Recombinant adenoviral vectors (Ad6 and ChAd3) expressing NS3-NS5B proteins	Phase I 40 healthy volunteers	Induce sustained HCV-specific T cell responses	Prophylactic vaccine	Okairos	2012	Completed	[123]
	Adenovirus vector (Ad6 and ChAd3) expressing NS3-NS5B proteins	Phase I 36 healthy volunteers	Highly immunogenic; induce HCV specific T cell responses	Prophylactic vaccine	Okairos and Oxford University	2009	Published	[124]
	TG4040: MVA vector expressing NS3, NS4 and NS5B proteins	Phase I 15 patients with chronic HCV infection	Decline HCV viral load in 7 of 15 patients associated with T-cell response	Therapeutic vaccine	Transgene	2009	Withdrawn	[125]
	MVA and ChAd3 vectors expressing NS3, NS4, NS5A and NS5B proteins	Phase I/II Healthy at risk population (68/472 IDU)	July 28, 2018: Final data collection date	Prophylactic vaccine	NIAID	2017	Ongoing	[126]
	TG4040 + SOC	Phase II 153 patients with chronic HCV infection	Induce HCV- and MVA-specific T-cell responses; develop anti-MVA antibodies; increase rate of early virologic response	Therapeutic vaccine	-	2014	Published	[127]
DNA vaccine	Recombinant DNA plasmid encoding E2	2 chimpanzees	Induce humoral and cellular immune responses; resolve the infection; prevent progression to chronicity	Prophylactic vaccine	NIAID/NIH	2000	Published	[128]
	Recombinant DNA plasmid and adenovirus vector expressing core, E1, E2 and NS3-5	8 chimpanzees	Induce HCV-specific T-cell and long-lasting E2-specific antibody responses; reduce viral load	Prophylactic vaccine	NIH	2005	Published	[129]
	Recombinant DNA plasmids and MVA vector expressing core, E1, E2 and NS3	6 chimpanzees	Induce HCV-specific immune responses; reduce viral load; early control of acute HCV infection; fail to impact on chronicity	Prophylactic vaccine	Transgene	2007	Published	[130]
	CIGB-230: Plasmid expressing core/E1/E2 plus recombinant core protein	Phase I 15 non-responder patients with chronic HCV infection	Induce humoral and cellular immune responses; no viral clearance	Therapeutic vaccine	University of Montreal + others	2009	Published	[131]
	ChronVac-C: Plasmid expressing NS3 and NS4A delivered by in vivo electroporation	Phase I/IIa 12 HCV-infected patients	Decline HCV viral load in 4 of 6 patients receiving the highest dose with corresponding HCV-specific T-cell response in 3 patients	Therapeutic vaccine	Tripep AB	2009	Recruiting	[132]

HCV: Hepatitis C virus; SOC: Standard-of-care (PEGylated-IFNalpha and ribavirin); Imiquimod: An activator of the toll-like receptor (TLR) 7; Ad: Human Adenovirus; ChAd: Chimpanzee Adenovirus; MVA: Modified vaccinia Ankara virus; IDU: Injecting drug user.

In the absence of an approved prophylactic vaccine for hepatitis C, reducing exposure to HCV through prevention seems to be the best option. This can be achieved through routine screening of donated blood for HCV markers, providing safe medical procedures, promoting risk-reduction counseling and services for at risk population, increasing public awareness and offering regular HCV testing to high-risk populations with the goal of breaking the cycle of HCV transmission in the society[7,9,82,133]. Despite the so-called improvements in the management of HCV infection, still a long way is ahead to achieve a world free of HCV infection. Here, the remaining challenges to eliminating HCV infection will be discussed.

REMAINING CHALLENGES TO ELIMINATING HCV INFECTION

For many years, IFN-based therapy, despite having frequent side effects, poor tolerability, suboptimal efficacy and prolonged treatment course, was recommended as the standard treatment for HCV infection[134,135]. Introduction of IFN-free DAAs has solved most of these problems in the treatment course of HCV infection. Switch the HCV treatment regimens from IFN-based therapy to DAA therapy is a desirable approach, yet encounter practical barriers such as high price and the restricted accessibility of DAAs[135-138]. Most of the time, the cost of antivirals rather than their effectiveness is the main driver in the treatment decisions. The use of these DAAs is far beyond the financial means of the most-in-need patients especially those who are IFN-intolerant or non-responder. While, equity in health demands that all patients with every socioeconomic status have equitable access to these treatment regimens. Currently, reducing treatment costs and providing DAAs with a relatively high health insurance coverage seem to be best options to improve access to DAA therapy[139].

Accessibility to DAAs, though, by itself is a superb health achievement, still alone might not be sufficient to mitigate the burden of HCV infection. A further challenge is continued transmission of HCV infection in high-risk population specially injecting drug users (IDUs) as the major reservoir of HCV infection[133,137,139]. Considering the fact that most of these infections remain undiagnosed, unidentified HCV-infected IDUs are potential sources for the spread of HCV infection in the society[133,139-141]. While, silent introduction of HCV infection into the community is a serious threat to the national effort to eliminate HCV infection, a threat that will increase with time. Therefore, timely diagnosis of HCV-infected patients through risk-based screening is of the greatest importance[126,133,137]. Screening of blood donations for hepatitis C initiated in the early 1990s has remarkably reduced the risk of HCV transmission through blood transfusion since then. Blood transfusion before the early 1990s was a major contributor to the HCV transmission, but today this risk has become minute[142]. However, it is far, far more difficult to screen IDUs, those who most need risk assessment. Despite the remarkable advantages, the cultural objections hinder screening progress, resulting in low diagnosis rate and, consequently, persistent silent spread of infection. On the other hand, the stigma of injecting drug use makes recognition of all HCV-infected IDUs impossible or logistically difficult at best[133]. In addition, establishment of HCV screening system with a specific focus on IDUs imposes high financial burden on the health system. Given the treatment expenses and dependence of these expenses on the stage of liver disease, screening of all at-risk populations seems much more affordable in a long run. Overall, in addition to interrupting unrecognized transmission of HCV, a part of costs expended in the treatment sector will also be saved with the prompt diagnosis and timely treatment of infected but asymptomatic patients[133,143]. While this process would demand allocation of adequate budgets and resources to integrate routine screening of high-risk population into national health programs.

As another solution, the coverage of needle and syringe exchange program should be expanded to increase the daily access to fresh needles and syringes among IDUs[144]. However, this program has not been very successful to control HCV transmission thus far, as the prevalence of HCV infection among IDUs is on the rise[139]. In fact, the overall focus on syringe sharing as the main vehicle for HCV spread has taken focus away from the other risk behaviors of IDUs such as the shared use of drug ampoules or the other injecting paraphernalia, engagement in high-risk sexual practices and the other drug-related harms[145]. These circumstances create a strong demand for precise surveillance of IDUs to obtain a reliable insight into risk behaviors of IDUs community, and subsequently harm reduction interventions should be tailored to the common risk behaviors among IDUs to mitigate the risk of HCV transmission. In addition, raising general awareness of HCV infection, diagnosis and treatment through public education should be the core activity of any harm reduction intervention, as the root cause of failure in control of HCV infection has been lack of awareness among young drug takers[133,141,146]. The growing number of IDUs and the relatively young age distribution of HCV-infected IDUs have evoke huge attention and provided a good opportunity to drive down the increasing trend of HCV-related mortality in near future through timely interventions and appropriate treatment[139,147].

The changes in HCV genotype distribution attributed to injecting drug use is another challenge in eliminating HCV infection. The changes in genotype distribution are so slight as to be unnoticeable but can have a deep impact on the epidemiology of HCV infection in a long run. These changes merit further attention if we want to properly manage the future burden of HCV infection. Globally, the most prevalent genotype is 1 (46%), followed by 3 (22%), 2 (13%) and 4 (13%)[35,137]. Over the last decade, however, a gradual decrease in the prevalence of genotype 1 and an increase in genotype 3 have been reported due to some changes in the route of transmission, risk factors, source of infection, human migration flow, and age distribution[148,149].

Blood transfusion before 1990 was the most important contributor to the spread of HCV, which has been reflected in the predominance of genotype 1 among older individuals[149,150]. In fact, screening for hepatitis C made blood transfusion remarkably safe since 1990s, paving the way for a gradual increase in the prevalence of genotype 3, which is mostly transmitted by IDU[148-150]. In recent years, IDU has become the main source of HCV transmission[35,137,144,145]. Globally, the estimated number of HCV-infected IDUs is up to 10.0 million (6.0-15.2 million), most of whom are young[35,139,144,147,151]. Meanwhile, the most common risk behavior of IDUs, syringe sharing, is more frequent among young drug injectors than in experienced and long-term injectors[152], amplifying the transmission of HCV among young IDUs population and favoring the continuous increase of HCV genotype 3. In addition to the change in the route of HCV transmission, the ongoing civil strife in the Middle East and the active migration flow from India, Afghanistan and Pakistan, where subtype 3a is endemic, have fuelled the increasing prevalence of genotype 3[148]. On the other hand, death of elderly HCV carriers is slowly driving down the prevalence of HCV genotype 1.

These changes in genotype distribution have profound effects on the prevalence of HCV infection, response to antiviral therapy, cost and duration of treatment, and future burden of HCV infection. Given the higher rates of sustained virological response (SVR) to IFN-based therapy, the first-line therapy in low- and middle-income countries, in patients with HCV genotype 3 as compared to genotype 1[149], an increase in the prevalence of genotype 3 beneficially affects the treatment course both in terms of duration and in terms of cost and brings high benefits on an individual level. However, this increase would impose a greater risk on a population level. In reality the rising prevalence of HCV infection along with the continuous increase in the number of IDUs outweigh this benefit. The disastrous interacting epidemics of HCV infection and IDU are harbinger of a forthcoming public health dilemma, presenting a serious challenge to control transmission of HCV infection. On the other hand, high prevalence of HCV infection among young IDUs is a cause for concern, paving the way for rapid spread of HCV in the community. The old story of hepatitis C has gotten a new scenario. The emergence of IDU as the main risk factor for transmission of HCV is a surrogate in this new scenario. If this scenario is to continue, the emergence of an uncontrollable epidemic of hepatitis C will be expected in the near future.

CONCLUSION

The global community has always been concerned about the future burden of HCV infection. Although action on this concern has started many years ago with great hopes to eliminate HCV infection, the success remains elusive and will become even more elusive if the current HCV management paradigm is to be continued. We believe that it is now time to reconsider the wisdom of the current management strategies, admit failure, and act with all the strength. If we want to succeed in eliminating HCV infection, a more integrated international effort will be required, involving health policy makers, healthcare practitioners, public health organizations, antiviral drug manufacturers, health insurance companies, and all major stakeholders. In addition, effective prevention, comprehensive screening programs with a specific focus on high-risk population, accessibility to the new anti-HCV treatment regimens and public education should be considered as the top priorities of any health policy decision to eliminate HCV infection. While waiting for a solution, prevalence of HCV infection continues to increase. If we do not want to encounter another uncontrollable public health dilemma, the time to act is now, tomorrow will be very late.