Thursday, May 26, 2011

Hepatitis C Virus Infection During Pregnancy and the Newborn Period

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M. Arshad; S. S. El-Kamary; R. Jhaveri

From Journal of Viral Hepatitis

Hepatitis C Virus Infection During Pregnancy and the Newborn Period
Are They Opportunities for Treatment?

Posted: 05/26/2011; J Viral Hepat. 2011;18(4):229-236. © 2011 Blackwell Publishing

The worldwide prevalence of hepatitis C virus (HCV) infection in pregnant women is estimated to be between 1 and 8% and in children between 0.05% and 5%. While parenteral transmission is still common in children living in developing countries, perinatal transmission is now the leading cause of HCV transmission in developed countries. The absence of an HCV vaccine or approved therapy during pregnancy means that prevention of vertical transmission is still not possible. However, a low vertical transmission rate of 3–5%, a high rate of spontaneous clearance (25–50%) and delayed morbidity have resulted in HCV being overlooked in pregnant women and their infants. Yet a study of the natural history in mothers and children demonstrates that the prognosis of HCV can vary greatly and should be taken seriously. Factors known to increase the risk of perinatal transmission include HIV coinfection and higher maternal viral loads, while elective C-section and withholding breastfeeding have not been demonstrated to reduce vertical transmission. Current guidelines for the diagnosis of persistent perinatal infection require a positive anti-HCV test in infants born to infected mothers after 12 months or two positive HCV RNA tests at least 6 months apart. Current HCV treatment options using pegylated interferon and ribavirin are both unsuitable for use in pregnancy and infancy. However, new agents currently in preclinical phases of development, along with the recently identified association between single-nucleotide polymorphisms within the IL28 gene and treatment response, may serve to create a therapeutic window for these patients.

It is well known that hepatitis C virus (HCV) chronic infection is a major cause of liver disease among adults worldwide[1] and is the leading indication for adult liver transplantation in the United States.[2] There are over 170 million people infected with the virus worldwide, and only half of patients treated with the current standard therapies achieve a sustained viral response.[3] Among the groups less often discussed when considering the burden of HCV infection are pregnant women and their infants. Much remains unknown about the dynamics of chronic HCV infection during and after pregnancy, as well as in the neonatal period. It is clear, however, that chronic HCV infection does have a modified course during these times of tremendous physiological changes. This review will summarize what is known about HCV infection during pregnancy and infancy and offer some perspectives on possible treatment opportunities that may arise during these times as new therapies for HCV become available

Worldwide, the seroprevalance of HCV in pregnant women is thought to be anywhere from 0.15% to 2.4% in the United States and European countries and much higher in countries like Egypt where it is estimated to be as high as 8.6%.[4–8]
The prevalence of HCV infection in children ranges from 0.05% to 0.36% in studies carried out in the United States and Europe[9–11] and is much higher in developing countries where it can range from 1.8% to 5%.[12,13] Insufficient screening of transfused blood and blood products and parenteral exposure continue to be the major causes of HCV transmission in developing countries.[14] In the United States and other developed countries, vertical transmission is the major route of HCV infection. In the United States, an estimated 240 000 children have antibodies to HCV, with seroprevalences of 0.1–0.2%.[11,15,16] A tenfold higher seroprevalence of 2% was reported in incarcerated juveniles, and rates of 10–20% have been reported among children with a variety of other potential exposures such as malignancy, haemodialysis, extracorporeal membrane oxygenation or surgery for congenital heart disease.[17–19] Almost all children who remain viremic after several years have chronic hepatitis,[20] and decompensated HCV-associated cirrhosis in children as young as 4 years has been reported.[21] Given that most perinatal HCV infections are silent with long-term complications that present later in adulthood, it is a considerably underestimated childhood disease with a predicted significant economic and health burden on society. At the current rate of HCV infection in children, it is estimated that in the next decade, 26 million dollars will be spent in screening, 117–206 million dollars in monitoring and 56–104 millions dollars in treatment. The total cost was calculated to be between 199 and 335 million.[22]

Natural History of HCV in Pregnancy
The intensity of HCV infection varies during pregnancy as demonstrated by the varying level of viral loads and HCV-specific T-cell responses that correspond with the progression of pregnancy. Some studies have shown that there is a decrease in serum alanine transferase levels (ALT) in the 2nd and 3rd trimesters of pregnancy,[23,24] along with a corresponding increase in HCV RNA during these trimesters. It is hypothesized that this may be seen because of a relative suppression of immunity as pregnancy proceeds. Oestrogen has shown to suppress intrathymic T-cell differentiation while activating the extrathymic pathways,[25] a phenomenon that has also been noted during pregnancy.[26] The modulation of cytokines as a result of this is important in maintaining tolerance of the paternal antigens in the foetus. This may also increase the proliferation of HCV resulting in higher HCV RNA titres in the 2nd and 3rd trimesters. The seemingly paradoxical decrease in liver enzymes and hepatic inflammation is explained by the decrease in immune-mediated hepatocellular destruction seen in chronic HCV.[23]
Conversely, HCV RNA titres tend to decrease in the postpartum period.[27,28] A study from Japan on 22 pregnant HCV RNA-positive women noted that some women may have spontaneous resolution of viremia following parturition.[28] They also noted significantly greater rates of clearance compared to the nonpregnant control group. In addition, the HCV core protein levels at 3 months postpartum were much lower among patients who cleared their viremia versus those who had persistent HCV elevation. It is thought that the loss of physiological pregnancy-induced immunosuppression after birth leads to a surge in maternal cellular immune activation that results in viral clearance.[27,29] Interestingly, pregnancy is associated with a decrease in Th-1 activity and a corresponding increase in Th-2 activity leading to a greater humoral immunity.[30] One advantage of the weakened Th-1 responses is the reduction in the number of viral quasispecies that usually develop by the rapidly mutating HCV to escape host immunity.[31] The postpartum reversal of this phenomenon with a decrease in Th-2 activity and a surge in Th-1 postpartum, combined with fewer viral quasispecies, may explain the increased ability of some mothers to clear persistent viremia. Some authors have also recommended that this may be an optimal time to initiate antiviral treatment, which can augment the natural defence mechanism.
Recent studies have confirmed that a tremendous surge in HCV-specific T cells in the third trimester and postpartum period is accompanied by a corresponding drop in HCV RNA. Honegger et al. demonstrated that in nine chronically infected women, a 1.4 log drop in HCV RNA titres occurred when the HCV-specific interferon-γ responses increased by more than 100% as measured by ELISpot. Depletion studies confirmed that this surge consisted of both CD4+ and CD8+ T cells, indicating a broad and potent response.[32]
Risks of obstetrical complications in HCV-infected pregnant women are varied. A study on 506 patients in the United States showed that the infants born to such mothers were more likely to be low in birth weight, small for gestational age, be admitted to the intensive care nursery or require assisted ventilation of some sort.[33] However, a smaller study carried out on mothers who were infected by contaminated anti-D immunoglobulin in Ireland did not show any adverse outcomes in the study group versus the control group.[34]
In a five-year study on 208 women, Locatelli et al. [35] showed that the risk of cholestasis increased in pregnant women who are also HCV antibody positive, and this tends to occur earlier in the gestation compared to HCV-negative mothers. This has also been noted in other studies.[36] While gestational cholestasis is a common complication of pregnancy, it has been suggested that HCV alters the epithelial cells in a way that predisposes women to cholestasis.[35] Berkley et al. [37] noted that neonates born to HCV antibody-positive mothers were more likely to have neonatal abstinence syndrome when adjusted for the dose of methadone used. The authors speculate that this may be because of poor metabolism of methadone in an HCV-infected liver; hence, a considerably higher dose is transferred transplacentally compared to women who are not infected.

The Pathogenesis of HCV Vertical Transmission
Studies on the pathogenesis of HCV have been numerous, diverse and, in many cases, yielded conflicting results. Studies to examine the timing of transmission indicate that many infants who are infected with HCV have PCR tests that are positive at or soon after delivery, suggesting in utero transmission.[38] Testing of amniotic fluid for HCV did not demonstrate evidence of detectable virus, which suggests that transmission may occur directly through the placenta.[39] This is supported by numerous studies that have demonstrated no significant differences with mode of delivery.[40,41] Case reports of divergent outcomes in monochorionic, diamniotic twins suggest that this placental infection is likely a sporadic event.[42] Studies of the hypervariable regions of HCV from infants demonstrated limited diversity, which indicates that transmission is likely restricted to a few virions.[43–46] Maternal factors that have been cited as playing a significant role in HCV vertical transmission are certain HLA types, as well as the presence of HCV RNA in maternal peripheral blood mononuclear cells.[47,48] The presence of maternal neutralizing antibodies was studied and found to have no role in promoting or protecting against HCV vertical transmission.[49]
One can make some general conclusions from the results of these disparate studies. In cases where vertical transmission occurs, it is likely that HCV is transmitted in utero at an early or middle stage of pregnancy. The event likely consists of a few virions with limited or no diversity crossing the placenta through direct infection in an inefficient manner given the low rate of transmission. This may be influenced by maternal genetic or immune factors.

Modifiers of and Risk Factors for HCV Vertical Transmission
Perinatal transmission is thought to be the leading cause of mother to baby transmission.[50] Both intrauterine and intrapartum transmission are possible. It is estimated that up to one-third of the infected children acquire the infection in utero, as evidenced by the positive PCR testing within the first 3 days of life, and up to one-half as late intrauterine or intrapartum and are PCR positive after 3 days of life.[38] Other studies have shown that HCV RNA reaches detectable levels several weeks after birth in infants born to infected mothers, raising the likelihood that HCV can also be transmitted perinatally and postnatally.[46,51,52]
Several factors have been studied as potential modifiers of the frequency of HCV vertical transmission. Multiple obstetric, immunological and virologic factors may influence perinatal transmission of HCV. These include maternal HCV RNA levels (at viral titres beyond 105 to 106 copies/mL), HIV coinfection, HCV genotype, neutralizing antibodies, cytokine modulation, amniocentesis, foetal blood monitoring, prolonged membrane rupture and type of delivery.[53,54]

HIV Coinfection
Maternal HCV and HIV coinfection has consistently been shown to be associated with higher transmission rates. Studies have shown that vertical transmission is 3- to 4-fold higher compared to maternal HCV alone [40,55–57]. Polis et al. in a meta-analysis of 10 articles showed that HIV and HCV coinfection increase the odds of vertical transmission by 90%. The incidence of HCV vertical transmission is approximately 3–5% in HCV RNA-positive-monoinfected mothers, but can be as high as 19% in HIV-coinfected mothers. Even when controlling for HIV, presence of HCV viremia increases the odds of vertical transmission by 2.82-fold.[55] Studies have shown a 0% transmission, when maternal HCV RNA is negative.[40,58]

Prolonged Rupture of Membranes
Rupture of membranes for more than 6 h has been significantly associated with viral transmission.[40,59] However, there is lack of any statistically significant data on the impact of obstetrical procedures on intrapartum HCV exposure. There is some suggestion that use of scalp electrodes may lead to HCV exposure.[40] Another study demonstrated a potential increase in HCV infection in infants following amniocentesis.[60] Benefits of doing elective C-section in mothers with HCV viremia are controversial. Gibb et al. [51] in a study on 441 mother–infant pairs in United Kingdom and Ireland reported a transmission rate of 7.7% among infants delivered vaginally, 5.9% among those delivered via an emergent C-section and 0% among those delivered by elective C-section (i.e. prior to membrane rupture). Paccagnini et al. [61] in a study on 70 high-risk mother–infant pairs (HIV positive and/or a history of drug use) showed a 32% rate of vertical transmission in infants born vaginally compared to 6% in those who were born by C-section. There were only two infants who were HIV positive, and both were born by caesarean section. However, most studies have not found any association between route of delivery and a decrease in transmission rates.[56,62,63] The European Paediatric Hepatitis C Virus Network showed in a study carried out on 1758 mother–infant pairs that there was no significant difference (P = 0.16) in vertical transmission between elective C-section, vaginal delivery or emergent C-section.[64]

Severity of Maternal HCV Disease
The effects of maternal HCV disease activity on vertical transmission are not completely understood. Two recent studies showed that mothers with HCV infection of the peripheral blood monocytes have a higher rate of transmission to their infants.[48,65] This is similar to what is noticed in the vertical transmission of other viruses, e.g. HIV. It has also been noted that persistently high ALT levels in the year preceding pregnancy or during pregnancy are associated with higher rates of vertical transmission.[66] This is likely related to the higher viral loads that may cause the more extensive hepatic damage and subsequent elevated ALT. Elevated ALT is also associated with certain HCV genotypes that are more likely to be transmitted like 1a or 1b.[67]
A small study carried out on 12 HCV seropositive mothers and their infants and a control group of 16 healthy mothers and their infants showed an increase in the natural killer (NK) cells in the placenta of HCV-positive mothers compared to the control group.[68] It also showed that these cells had greater cytotoxicity in the HCV-positive mothers. This may be an explanation for the relatively low rates of vertical transmission; though, the increased cytotoxicity of the NK cells may also lead to a higher risk of preterm delivery in HCV-positive mothers.

Breastmilk/Breastfeeding Transmission
HCV RNA has been detected in breast milk and colostrum.[69,70] However, there are only isolated studies that show some indication of HCV infection of the infant secondary to breastfeeding in mothers with a high viral load.[69] Most studies indicate that even though theoretical transmission may be possible, the viral count in breast milk is extremely low and likely becomes inactivated in the digestive tract of the infant [51,54,70–72]. Infants in several of the aforementioned studies had a single positive HCV RNA, which could be explained by vertical transmission and not necessarily breastfeeding itself. The European Paediatric Hepatitis C Virus Network noted no difference in infection rates in breast- vs formula-fed infants in a study carried out on 1758 infants.[64] The risk of transmission is higher if the mother has cracked or bleeding nipples. Mothers who are coinfected with HIV and HCV are recommended to follow the current guidelines for the prevention of HIV transmission

HCV Infection in Children: Short- and Long-term
As noted earlier, the most common cause of chronic hepatitis in children is HCV infection. With the improvements in HCV detection in transfused blood products and the prevention of other modes of parenteral transmission, the most common method of transmission in children is maternal–infant perinatal transmission. Conservative estimates suggest that 10 000–60 000 infants can be infected with HCV per year worldwide because of vertical transmission.[54] Current CDC guidelines recommend testing for anti-HCV in infants born to infected mothers after 12 months.[73] Passively acquired antibodies from the mother fall below detectable levels at this time. If earlier testing is required, CDC recommends RT-PCR for HCV RNA 1–2 months after birth.
The European Pediatric HCV network prospectively studied 357 HCV-exposed infants and found that the sensitivity of PCR for HCV RNA was 22% at birth and increased dramatically to 70–85% after 1 month of age.[74] This study also showed that the PPV of the PCR test was 33% at birth and increased to 78% at 9 months of age, while NPV ranged from 96% to 99%. While these results could be attributed to very low and undetectable viral loads in the first month of life, they could also be explained by the widely variable incubation period of HCV that can range from 2 weeks to 6 months. These results suggest that negative testing at birth using PCR is not an adequate predictor of the infant's HCV infection status at a later date. Conversely, a negative PCR test after 12 months of age should be confirmed with the 'gold' standard of anti-HCV to detect children who were previously infected and successfully cleared their viremia.
Spontaneous clearance of HCV can occur in up to 25–30% of children.[75,76] Rates of clearance are not different among those who are infected via vertical transmission or parenteral transmission. However, a younger age at follow-up and normal ALT levels favour HCV clearance.[76] Another prospective study with seven infants was carried out in Italy and showed constant viremia in all of the subjects at least in the first few years of life.[77] They all had initial elevation of ALT, with some subsequently recovering from it. Liver biopsies showed varying degrees of chronic persistent hepatitis. Most other studies reviewed showed similar low rates of HCV RNA clearance and a high rate of chronicity in the paediatric population.[78–80] Although most patients continued to have only mild elevations of their liver enzymes, liver biopsies showed evidence of mild to moderate hepatitis. Data from the adult population suggest that approximately 10–20% of patients with HCV can go on to develop cirrhosis and hepatocellular carcinoma.[81] Currently, there are no long-term studies to show the rates of cirrhosis or hepatocellular carcinoma in adults who acquired HCV through vertical transmission.

What Potential Treatment Opportunities Exist?
The current standard of care in HCV therapy is the combination of pegylated interferon and ribavirin. These medications have several drawbacks that are magnified during pregnancy and in the neonatal period. Pegylated interferon would be problematic given its psychiatric side effects in these women given the high background rate of postpartum depression. Addition of an agent that could promote these symptoms would not be tolerated. Similarly, ribavirin is a known teratogen and could not be used during pregnancy. Likewise, in the neonatal period, given the low rates of vertical transmission, relatively high rate of spontaneous resolution and lack of symptoms, one ought to be highly selective in who would be treated. Given the concern for growth suppression seen with pegylated-interferon treatment in older children, using it in any infant during a period of intense growth could have devastating effects. Thus, any consideration of treatment during this period could only occur once new anti-HCV agents are approved and have a demonstrated long-term safety profile.

A first strategy would be to select who would most benefit from therapy. The recent association of single-nucleotide polymorphisms within the IL28B gene being significantly associated with treatment response is highly provocative.[82] Obviously, these data are based on interferon being the primary agent used in treatment, which has already been discussed as problematic. However, perhaps IL28B profiling could be used in a broader campaign to treat those young women infected with HCV who intend to become pregnant, thus resolving their infection prior to conception. This could be carried out immediately now that IL28B testing is commercially available.
Another strategy would be to follow the model used for the interruption of HIV vertical transmission. Initial strategies centred around use of an antiviral agent, in this case zidovudine, for the last 6 weeks of pregnancy, as an infusion intrapartum and then for the first 6 weeks of the infants life. This strategy when it was first applied reduced the transmission rate of HIV from 25% to 8%.[83] Over the years, other agents have been added so that antiviral use has reduced transmission to <2% in developed nations. Obviously, HCV vertical transmission does not have the immediate consequences that HIV does, so the need to be so aggressive in prevention is not there. However, if it was possible to use short-term treatment with a combination of an HCV protease and polymerase inhibitor to coincide with the natural drop in HCV RNA in the pregnant woman postpartum, combined with treatment in those infants that demonstrated viremia soon after birth, this could be a viable strategy. Obviously, the costs associated with this kind of regimen would have to be considered.
To most effectively design treatment strategies, more research on HCV infection during pregnancy and infancy needs to be conducted. Further understanding of the influence of pregnancy on the immune response to HCV within the liver as well as how HCV infects the foetal liver as it matures is needed. This knowledge would allow better selection of treatment candidates as well as agents used for therapy.

HCV infection during pregnancy and the post-partum period appears to be a highly unique period in the interaction between virus and host. These periods of intense physiological change appear to force some adaptation of the virus that may offer a therapeutic window when more suitable agents come into use. Further studies of how and when the virus is transmitted from mother to child will only enhance the ability for prevention and treatment in the future.

Update June 20 2011

Pregnancy After Liver Transplant Raises Risk of Graft Loss

PHILADELPHIA – Women who become pregnant after receiving a transplanted liver face an elevated risk of graft rejection, especially during or immediately following the pregnancy, based on a review of 161 U.S. cases.

"The data suggest poorer outcomes for both mothers and their newborns in female liver recipients with risk factors for graft loss within 5 years post pregnancy," Dr. Carlo B. Ramirez said at the American Transplant Congress. "The findings highlight the high-risk nature of this group, warranting closer follow-up of both mother and child," said Dr. Ramirez, a transplant surgeon at Thomas Jefferson University, Philadelphia.
Of the 161 women who became pregnant following a liver transplant and were enrolled in the National Transplantation Pregnancy Registry (in place since 1991), 16 (10%) lost their graft within 5 years following their first posttransplant pregnancy. The pregnancy and the 3 months following pregnancy posed a particular risk, with half of the women who eventually lost their graft experiencing rejection during that time. In a multivariate model that took into account baseline risk factors, women with a liver transplant faced a 14-fold increased risk for graft loss during the pregnancy, Dr. Ramirez said.

"A lot of patients who have a stable equilibrium with their graft may destabilize under stress. It is possible that there is low-grade, clinically insignificant rejection in some of these patients prior to pregnancy" that then becomes exacerbated by the stress of pregnancy, commented Dr. Jean C. Emond, professor of surgery and director of transplantation at Columbia University in New York. Dr. Emond suggested that a liver biopsy prior to pregnancy might be warranted to assess the stability of the transplant.

Other risk factors for graft loss included younger age of the mother and low gestational age at the time of delivery. In the multivariate analysis, the risk for graft loss fell by a statistically significant 26% for each additional year of age for the mother. Graft loss fell by a statistically significant 5% for each additional week of gestational age when delivery occurred.

Among the 16 women who lost their graft during pregnancy or the following 5 years, their average age when they conceived was 22 years old, compared with an average age of 28 years old among the 145 women who did not lose their graft. Average gestational age at delivery was 33 weeks among the women who lost their graft, and 37 weeks among the women who did not lose their graft.

The average age of the women at the time they received their liver transplant was 18 years among those who later lost their grafts, and 23 years among those who retained their grafts. However, the average time between transplantation and conception was an identical 4.3 years in both groups.

The only other risk factor for graft loss that approached statistical significance in the multivariate model was viral hepatitis as the etiologic agent for the liver failure that led to the transplants. Viral hepatitis was the cause of liver failure for six (38%) of the women who lost their grafts following pregnancy, and for 23 (16%) of the women who did not lose their grafts. In the multivariate model, viral hepatitis as the cause of liver failure was linked with a nearly fourfold increased risk for women losing their graft during or after pregnancy, but this relationship failed to meet the standard criterion for statistical significance, Dr. Ramirez said.
The congress was sponsored by the American Society of Transplant Surgeons. Dr. Ramirez said he had no disclosures. The National Transplantation Pregnancy Registry has been supported by grants from Novartis, Astellas, Genentech, Pfizer, Teva, and Sandoz.


Pittsburgh medical center demotes surgeon after transplant

PITTSBURGH | Thu May 26, 2011 8:25pm EDT
PITTSBURGH (Reuters) - A Pennsylvania medical center demoted a surgeon and suspended a nurse who were involved in the transplant of a kidney from a donor who had hepatitis C, a spokeswoman said on Thursday.

The medical center voluntarily suspended its live-donor kidney transplant program earlier this month after discovering the infected kidney and notified the United Network for Organ Sharing, a national transplant agency. The agency plans to conduct a review. UPMC said the program suspension will allow the medical center "to thoroughly evaluate our protocols and donor screening processes," adding that it expects "a resumption of cases in the very near term."
"We have taken appropriate disciplinary action against the individuals involved in the kidney transplant," Yates said. "This disciplinary action included the suspension of a nurse and the demotion of a surgeon."
She declined to provide further details about the disciplinary action or the people involved.
(Reporting by Daniel Lovering. Editing by Peter Bohan)
The University of Pittsburgh Medical Center has also suspended its live-donor liver program as a precaution, though no problems were found with that program, UPMC spokeswoman Jennifer Yates said in a statement.

Telaprevir/Boceprevir: New therapy for hepatitis C sparks debate of who to treat first

Arrival of direct antiviral agent therapy for hepatitis C sparks debate of who to treat first

Scarcity of resources calls for equitable distribution system for novel treatment

For many patients with the hepatitis C virus (HCV), direct antiviral agents (DAA) offer a potential cure for the disease. The Food and Drug Administration (FDA) has recently approved two new DAAs, telaprevir and boceprevir, and with that clinicians must now decide who should be the first to receive this treatment. Discussion of this timely topic is now available in the June issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

The World Health Organization (WHO) estimates up to 170,000 million individuals worldwide are infected with chronic HCV. In the U.S., HCV is the leading cause of liver-related mortality and most common cause for liver transplantation. Medical evidence has shown that for the past ten years response rates to pegylated interferon and ribavirin treatment have been stagnant, with less than half of patients achieving a sustained virologic response. Now with the introduction of new DAA therapy, it is expected to significantly improve virus clearance rates, particularly in patients with genotype 1, compared to the current standard of care.
"The availability of DAA therapy will forever change the landscape of HCV," explains Andrew Aronsohn, M.D., from the University of Chicago Medical center and co-author of the current paper. "We will now be able to cure patients of HCV disease who we were unable to cure in the past." However, as the authors note, the medical breakthrough with DAAs is coupled with resource scarcity and an equitable distribution based upon medical need is essential.

DAA therapy and its promise to improve efficacy has been well publicized for a number of years, prompting clinicians and patients to defer standard care in cases where there was a low risk of HCV progressing to severe liver disease. The authors point out that in one large study of 4084 patients evaluated for HCV therapy with interferon and ribavirin, of those that declined therapy more than half did so in anticipation of more effective therapy.

The advent of DAAs will likely create a surge in requests to initiate treatment given the number of patients who deferred treatment, along with those patients who failed to respond to standard HCV regiments. The authors performed a time analysis study at their institution to understand the time needed to treat patients with DAA therapy. They found that on average, a health care provider could initiate therapy on three patients each week, and at least 500 requests for evaluation of HCV therapy are anticipated during the first few weeks of DAA availability. "Current staffing will be unable to meet the demands of all HCV patients requesting treatment," concluded co-author, Donald Jensen, M.D. "We propose a plan to educate patients and triage therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact
Full citation: Article: "Distributive Justice and the Arrival of Direct Acting Antivirals. Who Should be First in Line?" Andrew Aronsohn and Donald Jensen. Hepatology; Published Online: April 21, 2011 (DOI: 10.1002/hep.24374); Print Issue Date: June 2011.
About the Journal
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NICE’s next round of drug appraisals is set to include two new hepatitis C drugs

NICE’s next round of drug appraisals is set to include two new hepatitis C drugs - Merck Sharpe and Dohme’s Victrelis and Johnson & Johnson’s telaprevir.

Neither of the drugs is yet licensed in Europe but if they are they may meet a pressing unmet medical need for more effective hepatitis C treatments and NICE is already lining up to assess them.
Victrelis is set to be the first on the market, having just been recommended for European approval, while J&J’s telaprevir could be licensed in Europe by the end of the year.
If approved the drugs will be among six treatments Ministers have referred to NICE to appraise.
NICE said it will assess Victrelis for use in previously untreated genotype 1 chronic hepatitis C patients – the licensed indication it is seeking in Europe.
It will also look to appraise Victrelis for previously treated patients who have used the NICE approved treatments ribavirin and Roche’s Pegasys (peginterferon alfa).
Telaprevir, recently approved in the US as Incivek, would also be appraised for previously untreated genotype 1 chronic hepatitis C and previously treated with peginterferon alfa and ribavirin.

Management of hepatitis C virus genotype 4: Recommendations of An International Expert Panel

Received 4 October 2010; received in revised form 17 November 2010; accepted 23 November 2010. published online 09 December 2010.
Volume 54, Issue 6, Pages 1250-1262 (June 2011)
Management of hepatitis C virus genotype 4: Recommendations of An International Expert Panel
HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.


Hepatitis C virus (HCV), a member of the Flavivirida family of RNA viruses, is characterized by a high spontaneous mutation rate with an estimated frequency of 1.4–1.9×10−3 mutations per nucleotide per year [1], [2]. As a result, HCV exists as a heterogeneous group of viruses sharing approximately 70% homology. On the basis of nucleotide sequence homology, HCV has been classified into no fewer than six major genotypes and a series of subtypes [3]. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy [4]. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries [5], [6]. HCV-4 is considered a major cause of chronic liver disease and cirrhosis, which leads to liver failure and is the root cause of hepatocellular carcinoma. Because of these complications, extended cirrhosis during chronic infection is a primary cause of liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections.

Approximately 34 million people are chronically infected with HCV-4. The Iinfection is common in the Middle East and Africa, where it accounts for more than 80% of all hepatitis C cases [5], [6], [7], [8]. The risk factors for HCV-4 transmission are determined by the geographical distribution of this genotype.
Egypt has the highest prevalence of HCV worldwide (15%) and the highest prevalence of HCV-4, which is responsible for 90% of infections, with a predominance of subtype 4a (55%) [5], [6], [7], [8], [9]. Epidemiological and molecular evolutionary analysis on Egyptian genotype 4a isolates suggest the origin of the HCV-4 epidemic arises from the antischistosomal campaign, which was administered parenterally, and only stopped in the mid-1960s [10], [11]. However, other risk factors, mostly related to prevailing social and cultural conditions, are responsible for maintaining the high rates of HCV-4 transmission even after the treatment campaign was stopped. Currently, the major route of transmission appears to be health-related procedures with inadequately sterilized instruments. Procedures performed by non-medical professionals and traditional healers have been identified as important risk factors for HCV transmission in Egypt [12], [13], [14]. Intrafamilial and sexual transmissions also play a role in the high prevalence of HCV-4 in this country [15], [16].

The prevalence of HCV in Saudi Arabia is 1–3%, [17] with a predominance of genotype 4 (62%). Unlike the predominance of subtype 4a in Egypt, subtypes 4c/4d are the most prevalent subtypes among Saudis, followed by subtypes 4h, 4e, and 4a, suggesting that the origin and transmission of HCV-4 is different from that in Egypt [17]. Similarly, studies from other parts of the Middle East also suggest a high prevalence of HCV-4. For example, 36–46% of HCV-infected Lebanese patients have HCV-4 [18], 59% of Syrian patients [19] and 27% of HCV-infected Jordanian patients on dialysis have HCV-4 [20].
HCV-4 is also endemic throughout Central and West African countries such as the Congo, Liberia, and Uganda (where it accounts for 100% of HCV infections), as well as Gabon, Tanzania, and Cameroon (97%, 50%, and 36% of HCV infections, respectively) [21], [22], [23], [24], [25]. Scarification, circumcision practices, and sexual transmission may contribute to the persistence and propagation of HCV transmission in these countries [21], [25].

Recently, HCV-4 has become increasingly prevalent in some southern European countries on the Mediterranean Sea, particularly Italy, France, Greece, and Spain, where prevalence rates of 10–24% have been reported in some areas [26], [27], [28], [29], [30], [31]. HCV-4 infection is frequent among intravenous drug users (IVDUs) (European and non-European), HCV/HIV-coinfected patients, and immigrants from North and sub-Saharan Africa [26], [27], [28], [29], [30], [31]. HCV-4 was probably introduced into Europe through immigration and the movement of IVDUs across European borders [31].
HCV-4 infections are uncommon in the United States, Canada, South America, and Asia. The prevalence of HCV-4 in the United States is about 1% [32]. Most HCV-4 cases reported from the United States were clustered among IVDUs or immigrants from countries where subtype HCV-4 is known to be most prevalent or among individuals who acquired the infection in these countries [32], [33]. There are no reliable data on the prevalence of HCV-4 either in Australia or in South East Asia. However, HCV-4 appears to be rare in these regions.

Natural History
There are few data on the natural history of HCV-4. It is likely that the course of genotype 4 infection is similar to that of other genotypes [25], [34].

HCV-4 represents more than 30% of the annually reported acute hepatitis cases in Egypt [35]. Very few studies address the outcome of acute HCV-4 infection. Indeed, prospective studies have shown 20–50% rates of spontaneous resolution in acute HCV-4 infections [36], [37], [38]; whereas those rates are reduced in patients with a coinfection with HIV or Schistosoma mansoni, as frequently occurs in Egyptians [34], [37]. The presence of schistosomiasis is a negative predictor of outcome, being associated with accelerated progression of hepatic fibrosis among HCV-4 patients. In fact, the fibrosis progression rate of 0.1±0.06 fibrosis units/year observed in HCV-4 patients (similar to that of patients infected with other genotypes) increased up to 0.6±0.13 in patients with associated schistosomiasis [39], [40], [41], [42], [43]. An Egyptian origin was independently associated with severe fibrosis in two French studies, however the higher fibrosis scores in these studies might be attributed to concomitant schistosomiasis in these Egyptian patients rather than ethnicity or HCV subtype [39], [40]. Insulin resistance was also found to be correlated independently with severity of fibrosis [40]. The known association between hepatocellular carcinoma (HCC) and HCV needs to be weighed against other potential risk factors for HCC like schistosomiasis and exposure to aflatoxins or pesticides [44], [45], [46], [47].

Utility of liver biopsy and noninvasive fibrosis tests 
The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression [48]. The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis [49], [50] and excess of hepatocellular iron [51]. The pathological findings in chronic HCV-4 are in general similar to other types of viral hepatitis C. However, certain features may be prominent in this genotype, one of which is the presence of moderate to severe steatosis [50], [52], [53] with no associated sinusoidal fibrosis [53]. Host and viral factors contribute to the development of steatosis in hepatitis C, but their relative importance varies with genotype [54], [55], [56]. Hepatic steatosis in patients infected with HCV-4 is mainly associated with metabolic factors and follows the same pattern as those infected with genotype 1 [50], [54]. Steatosis, in particular moderate-to-severe steatosis was detected in similar proportions of patients with genotype 1 and 4 [50], [52], [54]. Several studies have shown that steatosis in chronic HCV-4 is macrovesicular [50], [52], [53] and is seen without any prominent zonal preference [53]. More detailed studies are needed to determine if there is a characteristic histological pattern that might distinguish chronic HCV-4. Efforts are ongoing to seek alternative means focusing on noninvasive blood marker panels. In a recent study, the combination of hyaluronic acid, YKL-40, platelet count and serum aminotransferases provided information about the amount of hepatic inflammation and steatosis in Egyptian patients and achieved this cost-effectively [57].

Hepatocellular carcinoma 

HCC is a major cause of cancer death worldwide [58], with evidence that its incidence has sharply increased in many countries as a consequence of the accumulation of patients with chronic liver disease caused by viral hepatitis or alcohol abuse [58], [59]. The incidence of HCC in Egypt is also increasing [60], [61], [62] and is now the second most frequent cause of cancer and cancer mortality among men [63]. Hospital based studies have reported an increase in the relative frequency of all liver-related cancers in Egypt (>95% as HCC), from ∼4.0% in 1993 to 7.3% in 2003 [60], [61], [62].
Data from the National Cancer Registry of Egypt, the National Cancer Institute and the Middle East Cancer Consortium recently reported that the incidence rate among males was 7times greater than the next highest rate (among Israeli Jews) and more than 3times that reported in the United States Surveillance Epidemiology and End Results summary [63], [64].
A possible association has been suggested between HCV-4 and HCC based on the similarity of distribution of HCC and HCV-4 in Egypt [63], [64], [65], [66], [67], [68]. A recent meta-analysis showed that more than 84% of Egyptian patients with HCC are positive for HCV-4 [68].
A significant association seems to exist not only with the most prevalent subtype 4a, but also with subtype 4o [44] even though this association has not been confirmed by others [69]. Other factors related to HCC development may play a role, such as coinfection with schistosomiasis which is known to increase risk of HCC [4], [66], exposure to pesticides [47], and dietary aflatoxins [70].

Evolution of treatment 
Combination therapy with pegylated interferon alpha and ribavirin represents the current standard of care in chronic HCV-4. Interferon (IFN) based therapies were introduced in chronic hepatitis C in the 1980s and have improved dramatically over the subsequent years. With conventional IFN-α monotherapy the SVR rates were very poor, similar to those achieved in HCV genotype 1 infection, ranging between 5% and 25% [71], [72]. However, with the addition of ribavirin to conventional IFN-α, SVR rates increased to 25–42% [73], [74], about intermediate between those achieved in HCV-1 and HCV-2 or HCV-3. With the introduction of pegylated IFN compounds in combination with ribavirin, the efficacy of treatment in HCV-4 further improved significantly. In various studies from European and Middle Eastern countries, SVR rates ranging from 43% to 70% were reported [39], [40], [53], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91] (Table 1). These results are indeed higher than those (42–46%) achieved in genotype 1 patients but still lower than those (76–82%) reported in chronic hepatitis C genotype 2 and 3.

Table 1.
Summary of studies of PEG-IFN-α in patients with chronic HCV-4.



Studies looking at predictive factors on HCV-4 patients are relatively scarce. Negative predictive factors at baseline include high viral load, presence of cirrhosis and steatosis, insulin resistance, IL-28B polymorphism TT, and HIV coinfection [75], [86], [73], [91], [92], [93]; these factors are associated with a lower SVR. A rather unexpected finding of the therapeutic trials in HCV-4 has been that under the same treatment regimen, patients from Egypt and the Middle East experienced higher SVR rates than patients from Europe or Africa. In a French retrospective study, conducted in 242 HCV-4 patients from various geographical areas (40% Egyptians, 35% Europeans, and 24% Africans) the respective SVR rates were 54.9%, 40.3%, and 32.4%. Egyptian origin and the absence of severe fibrosis were found to be independently associated with SVR [39]. It remains unclear whether the difference in SVR is related to ethnicity, HCV-G4 subtype, the mode of transmission or IL-28B genotype [93].

Similar results have recently been reported in a prospective study of HCV-4 patients from Europe, France, and Africa with respective SVR rates of 63%, 51%, and 39% and an overall SVR percentage of 54%. Despite the presence of severe fibrosis in a large proportion of the Egyptian patients, Egyptian origin was again independently associated with SVR (p=0.001); OR: 5.87 (95% CI: 2.75–12.55) (p=0.001). SVR was also independently associated with insulin resistance measured by the homeostasis model assessment index (HOMA-IR)<2 (p=0.001) and by non-severe fibrosis (p=0.001) [40]. Moreover, in another trial from Egypt, HOMA-IR was found to be a predictor not only of SVR but also of rapid virologic response (RVR) (p=0.002 and 0.0041; respectively) [77]. The use of insulin-sensitizing agents such as pioglitazone in conjunction with HCV-4 treatment increases both SVR and RVR rates [78]. HCV kinetics under therapy has been found to be extremely useful to predict SVR [53], [88]. Other factors during treatment are patients’ compliance and no dosage reductions or dose fulfilled with 80/80/80 [94].

IL28B polymorphism 
A genome wide association study in patients infected with HCV-1 revealed a single nucleotide polymorphism (SNP)-rs12979860 in the IL-28B region on chromosome 19 (19q13.13), associated with a more than twofold increased rate of SVR [95]. In a multivariate analysis of HCV-4 patients, baseline viral load, fibrosis and the IL28 (rs8099917 T/T allele) (OR: 0.124, 95% CI: 0.030–0.505) were significantly associated with SVR [95]. The strongest predictor for the final outcome was RVR (OR: 26.00; 95% CI: 7.148–94.545, p<0.0001). If RVR was included into the multivariate model, only the RVR and the fibrosis score remained significant. Thus, determination of IL28B polymorphism may not be useful to select patients with HCV-4 for abbreviated treatment schedules. However these data need further confirmation.

Duration of treatment 
The duration of treatment is based on HCV genotype in current guidelines [96], [97]. Forty-eight-week regimens are recommended for patients infected with HCV-1 and 4. This recommendation is based on the results of large randomized, international, phase III trials of peginterferon alfa-2 combined with ribavirin [98], [99], [100]. Unfortunately these studies included very few patients with HCV-4.
Measurement of the virological response at 4 and 12weeks of therapy is a simple and reliable tool that allows the treatment regimen to be tailored to the individual. Patients who become HCV-RNA negative (<50IU/ml by qualitative PCR assay) or have a 2log10 drop in serum HCV RNA level by quantitative PCR assay after 12weeks of therapy are defined as having an early virological response (EVR). Failure to achieve an EVR can predict which patients are unlikely to have a successful outcome with combination therapy. Those who are HCV-RNA negative after 4weeks of treatment are defined as having a RVR. In contrast to EVR, RVR predicts which patients are most likely to have a successful outcome with combination therapy.
The probability of SVR increases with the speed of viral load decline. For example, a higher proportion of patients with HCV-1 who become HCV-RNA negative after 4weeks of treatment will achieve an SVR than those who become HCV-RNA negative after 12weeks of treatment [101]. SVR rates were much lower in patients who did not clear HCV RNA during the first 12weeks of treatment. A completely negative test for HCV RNA at week 12 (complete EVR) is a better predictor of an SVR after 48weeks of combination therapy than a partial EVR (2log10 drop in serum HCV RNA at week 12). Those who achieved an RVR had an SVR rate of 91%, those who achieved a complete EVR had an SVR rate of 75%, and among the 22% of patients with a partial EVR and virus negative by week 24 only 27% achieved an SVR [101].

Response-guided therapy 
There are only two randomized controlled trials in patients with HCV-4 reporting viral response at week 4 (Table 2). Patients with HCV-4 who achieve an RVR are potential candidates for abbreviated 24-week treatment regimens; provided that no other predictors of poor response (Fig. 1). [53], [84]. Response rates are similar to those treated for 48weeks [87]. The prospect of shorter treatment for these patients is appealing because the overall tolerability is likely to be better and the costs lower with an abbreviated treatment regimen; conversely, slow responders who do not achieve HCV RNA negativity by week 4 or 12 are potential candidates for prolonging treatment up to 72-weeks. Only one randomized study examined prolonged 72-week regimens in HCV4 patients [102] but the number of patients was too small to draw any conclusions.

Table 2.
Outcome by virological response at weeks 4 and 12 in genotype four patients treated for 48weeks with peginterferon alfa-2 plus ribavirin.

Click Here To Enlarge Table

Fig. 1 presents a proposed algorithm for treating patients with chronic HCV-4 based on the kinetics of viral response (response-guided therapy). In conclusion, measurement of RVR and complete/partial EVR is a simple and reliable tool that allows clinicians to estimate the likelihood of an SVR and to individualize the duration of treatment. Unfortunately, in contrast to patients with HCV-1 the concept of response-guided therapy has not been validated in patents with HCV-4. In the current absence of any firm data on HCV-4 patients, we suggest that similar response-guided approaches used in HCV-1 patients may be considered. Thus those with an RVR are highly likely to achieve SVR and are candidates for abbreviated, 24-week regimens. Patients with a complete EVR at week 12 have a high probability of achieving an SVR with a 48-week regimen. Patients with a partial (slow) EVR (no RVR and detectable HCV RNA but >2log10 drop at week 12 and virus negative at week 24) may be considered for treatment prolongation to 72weeks, if they can tolerate this.

Click Here To Enlarge

Fig. 1. A proposed algorithm for treating patients with chronic HCV-4 based on the kinetics of viral response (response-guided therapy). RVR, rapid viral response.

Treatment in special populations 
Treatment of compensated cirrhosis is a relevant issue since sustained HCV clearance is associated with a better survival, reduced HCC occurrence and absence of decompensation [103]. However, severity of liver fibrosis and HCV genotype are the two major determinants of SVR. The published data on the efficacy of Peg-IFN and ribavirin in cirrhotic patients infected by HCV-4 are limited (Table 3) [39], [53], [79], [84], [86], [73], [104], [105], [106], [107]. Overall the cumulative response rate is about 30% of treated patients, but this figure includes also incomplete cirrhosis, or F3, that probably overestimates the real treatment efficacy in cirrhotic patients.

Table 3.
Summary of studies on combined therapy in HCV-4 patients with incomplete (F3) or complete (F4) cirrhosis.

HIV coinfection
It has been reported that the prevalence of HCV-4 among HIV-infected individuals is at least 15% of all anti-HCV positive subjects [108]. Data derived from two trials showed that among 75 HIV-infected patients with HCV-4 treated with Peg-IFN alfa-2a plus ribavirin, only 21 (28.0%) achieved SVR [92]. The major factor of low rate of response was related to premature treatment discontinuation due to severe adverse effects.

The prevalence of HCV infection in patients with end stage renal disease is highly variable ranging from 3% to 80% between different countries and centers [109]. HCV-4 infected subjects have a shorter graft survival after kidney transplantation due to increased risk of severe infection and liver disease deterioration. As a consequence, the current recommendation is to give antiviral therapy before transplantation with the aim to eradicate the infection. However the use of Peg-IFN and ribavirin in dialysis patients is hampered by fairly frequent side-effects [110]. Two recent meta-analyses have shown that the overall SVR after Peg-IFN with or without ribavirin was 40%, including 33% for genotype 1 [111]. No data on efficacy of combined therapy in patients infected by genotype 4 are available so far

Combination therapy with Peg-IFN-alpha and ribavirin treatment is effective in children with chronic hepatitis C [112], [113] with SVR rates across different genotypes comparable to adults. One study reported the results of Peg-IFN plus ribavirin treatment in 12 adolescents infected by genotype 4 [76]. Nine patients (75%) achieved SVR suggesting that combination therapy is effective in this clinical context.

Acute hepatitis C 
Scant data are available about the optimal treatment regimen in acute HCV-4 and demonstrated a high SVR with IFN-based therapies compared with no treatment [37], [114], [115]. The available clinical trails showed that acute hepatitis patients infected with HCV-4 have higher rates of SVR compared with HCV-1 infections. In one study [116], an SVR was achieved in 60% and 88% of genotype 1 patients and in 93% and 100% of HCV-4 patients after 12 and 24weeks of treatment, respectively [37].

Thalassamia major 
Few data are available on the treatment of HCV-4 in patients with thalassamia. Current literature is lacking sufficient evidence about the use of PEG-IFN as monotherapy or in combination with ribavirin in thalassamic patients. Inati et al. evaluated in a randomized study [117] the safety and efficacy of PEG-IFN-α with or without ribavirin therapy in 20 patients with thalassamia and HCV-4. An SVR was achieved in (30% and 62.5%; p=0.19) in the monotherapy and combination groups, respectively. They reported an increase in the transfusion requirements by 34% in the combination group (p=0.08). In another study, Kamal et al. [118] reported that the overall SVR rates were (46% and 64%) with PEG-IFN alfa-2b vs. PEG-IFN alfa-2b plus ribavirin combination therapy, respectively. However, the reported adverse events were more frequent with combination therapy than with PEG-IFN alfa-2b alone.

Liver transplantation 
End-stage liver disease secondary to HCV infection is the major indication for orthotopic liver transplantation (OLT) worldwide [119]. The percentage of HCV-4 patients among recipients of OLT varies depending on the geographic location from around 29% in Saudi Arabia [120] to more than 90% in Egypt, [121] while it represents a relatively uncommon indication in the western world [122], [123].
The natural history of HCV-4 re-infection after liver transplantation is inadequately described in the literature. Re-infection of the graft with HCV is universal after liver transplantation regardless of the genotype, leading to an accelerated course of liver injury in many cases [124]. Most studies conducted worldwide have investigated disease recurrence in HCV genotypes 1, 2, and 3 [119]. However, there are few reports on post-OLT recurrence of HCV-4.
Four studies have been reported from liver transplant centers in Europe and Australia. Gane et al. reported on 14 patients with recurrent HCV-4 post-OLT and found that about 50% of these patients have progressive liver disease [125]. They also found that patients infected with genotypes 1b and 4 had the worst outcomes, while genotype 2 and 3 patients had less severe disease recurrence. Similarly, an analysis of 182 patients transplanted for HCV in Australia and New Zealand (16 of whom had HCV-4) found that among the many factors studied in univariate and multivariate analyses, genotype 4 was associated with an increased risk for re-transplantation and death [123]. By contrast, a study from another Australian center, including patients with HCV-4, showed that genotype 1b, but not 4, was associated with higher recurrence rates after transplantation [126]. In a more detailed study from the UK, 32 of 128 patients who underwent OLT for hepatitis C were infected with HCV-4 [122]. A statistically significant greater fibrosis progression rate was observed in HCV-4 patients compared to non-genotype-4, although their rates of survival were similar. The authors attributed the difference between these two groups to the significantly older donor age in the HCV-4 group and the ethnic background of these patients (predominantly Egyptian). On the other hand, studies from the Middle East show a more favorable outcome of HCV-4 patients. In a study from Saudi Arabia on biopsy proven recurrence HCV post-OLT there were no significant differences between genotype 1 and 4 patients in terms of epidemiological, clinical, and histological factors as well as outcome (patients and graft survival) [127]. Among many epidemiologic, laboratory, virologic factors included in that analysis, the only factor predictive of an advanced histological score was the HCV RNA level at the time of biopsy.
In Egyptian studies of living-related liver transplantation of HCV-4 patients a similar good outcome was observed. HCV clinical recurrence was observed in 31% of patients and was mostly mild, as 91% of patients had fibrosis scores less than F2 [128]. After 36months of follow-up, 91% of patients were alive with good graft function. Similar to the study from Saudi Arabia, recurrent HCV was associated with pre-transplant and post-transplant viral load and to the presence of antibodies to hepatitis B core antigen.
Published studies on the response rates and outcome of antiviral therapy in patients with HCV-4 post-OLT are lacking. In an abstract from Saudi Arabia, 25 patients infected with HCV-4 were treated with PEG-IFN alfa-2a at a dose of 180μg/week plus ribavirin 800mg/day, (dose was adjusted as tolerated range 400–1200mg) [129]. Fourteen patients (56%) achieved sustained virological response (SVR). The results of this study suggest that the post-transplant treatment outcome in HCV-4 is probably better then genotype 1 and less favorable than genotypes 2 and 3. This response pattern among the different genotypes parallels the response pattern in the immunocompetent population.
More studies are warranted to further understand HCV4 and OLT and to establish effective strategies for limiting the progression of liver disease post-OLT in HCV-4 patients.

Novel treatments 
In spite of the improvement of chronic hepatitis C treatment over the last two decades, treatment with PEG-IFN and ribavirin is still associated with frequent and sometimes severe side effects and many patients cannot be treated because of contraindications [130]. A major step forward in the therapy of HCV infection is expected by the approval of new direct inhibitors of HCV replication. Several compounds, mainly inhibitors of the HCV NS3/4A protease and NS5B polymerase, are currently in phase II and III trials and the first HCV protease inhibitors will hopefully be licensed in 2011–2012. [131], [132]. The large majority of the new antiviral drugs are currently developed only for HCV-1 infection. The most advanced compounds in clinical development are two protease inhibitors: telaprevir (VX950) and boceprevir (SCH503034). Telaprevir has shown an improvement of SVR rates in treatment naive HCV-1 patients to almost 70% and up to 40% in previously unresponsive patients [133], [134]. In a proof of concept study, telaprevir has also shown activity against HCV-4 during 15days monotherapy or combination with Peg-IFN and RBV compared to Peg-IFN, RBV and placebo [134]. Boceprevir is effective in HCV-1 patients [135], however, preclinical data suggests, that boceprevir might not be effective in HCV-4 with the currently used dosages [136], and data on boceprevir in HCV-4 patients haves not been published. R7128 is another nucleoside analog polymerase inhibitor that has demonstrated potent antiviral activity. In a recent interim analysis at week 12; the combination of R7128 (1500mg twice daily) plus Peg-IFN α-2a and ribavirin in treatment-naive patients with HCV-1 and 4; R7 128 has show high rates of early viral response with promising safety profiles and low rates of resistance or breakthrough [137].

Further data haves been published for two other compounds with different mode of actions, nitazoxanide (NTZ) and Debio 025. NTZ, a synthetic antiprotozoal agent, is licensed in the United States for the treatment of infections with Cryptosporidium parvum and Giardia lamblia. Antiviral properties of this compound were discovered when patients with acquired immune deficiency syndrome (AIDS) coinfected with hepatitis B and C were treated for cryptosporidiosis. As a potential mechanism of action, NTZ activates the protein kinase activated by double-stranded RNA (PKR), a key kinase that regulates the cell’s innate antiviral response [138]. These observations could explain the clinical antiviral effect of NTZ. In this context, two clinical studies are of interest. A pilot trial explored NTZ monotherapy in Egyptian hepatitis C patients infected with HCV-4. HCV-RNA became undetectable in seven out of 23 patients who all had a rather low viral load before treatment (400,000IU/ml). Interestingly, four patients achieved SVR after 24weeks of NTZ treatment [139]. A recent study by Rossignol et al. explored the combination of NTZ and standard PEG-IFN/RBV combination therapy in Egyptian HCV-4 infected patients [93].

The trial was conducted in two Egyptian centers and included 96 treatment-naïve patients – all were infected with HCV-4. Patients were randomized in one of three arms, a control arm with Peg-IFN alfa-2a and ribavirin for 48weeks (n=40), and two arms with a 12week lead-in monotherapy with NTZ followed by a 36week course of NTZ in combination with pegylated interferon with (n=28) or without ribavirin (n=28). SVR rates in the control arm were only 50%, which is relatively low as compared to most other previous HCV-4 trials [140]. Importantly, 79% of the patients receiving triple therapy with NTZ and PEG-IFN/RBV achieved a SVR that reached statistical significance although patients in the triple therapy arm were treated for only 36weeks with PEG-IFN. Of note, patients receiving NTZ and PEG-IFN without RBV also showed a surprisingly high SVR of 61%. Although these data are promising, several issues need to be considered, for example the rather small overall number of patients with only five of the 96 patients having advanced fibrosis or cirrhosis (Ishak S F4-6) [141]. In addition, there were some differences in patient characteristics between the study arms as the body mass index (BMI) was significantly lower in patients who received PEG-IFN, RBV, and NTZ as compared to the control group. This also could have contributed to the better response in the triple therapy arm although the BMI was not an independent factor associated with SVR. Nevertheless, it is quite obvious that further studies are needed to investigate NTZ in genotype 4 patients. The antiviral efficacy of NTZ was confirmed during the 12week lead-in phase when NTZ was administered alone. NTZ induced a modest but significant HCV-RNA decline of −0.27log10, which is in line with the previous monotherapy study [93]. However, only two out of 53 patients treated with NTZ monotherapy had a decline of more than 1log10 and just one patient achieved a complete response (HCV-RNA negative) after 12weeks, which is in contrast to a previous trial where six out of 23 patients (26%) were HCV-RNA-negative after 12weeks [141]. Thus, it is very unlikely that NTZ monotherapy will play any role in future treatment of chronic hepatitis C.

The cyclophilin inhibitior Debio 025 inhibits HCV replication by inhibiting endogenous cyclophilin and interaction with the NS5B polymerase, but without immunosuppressive activity. For treatment-naïve HCV-1 monoinfected patients a reduction of HCV-RNA of up to 4.75log10 after 29days of combination therapy with Debio 025, PEG-IFN alfa-2a, and ribavirin was shown [142]. Two HCV-4 patients were treated underin this study, one of them ose in a Debio 025 monotherapy arm. With a dose of 1000mg per day the mean viral load reduction after 29days was 2.2±2.4log10 for the 12 patients in that arm (11 patients with genotype 1, one with HCV-4). Importantly, the one genotype-4 patient also had a viral load decline of >2log10 [142]. Finally, silibinin, for which the mechanism of action is not yet entirely resolved, administered intravenously (20mg/kg/day) for 7days, led to a mean decline of the HCV-RNA concentration by 3log10IU/ml. So far, mainly genotype 1 and single patients with genotype 2, 3, and 4 infections have been investigated and no data on differences of antiviral activities for the different HCV genotypes are available [143]. Recently, Beinhardt et al. reported a case that the use of silibinin IV are associated with prevention of graft re-infection in a patient infected with mixed genotype 1a/4. [144].
The available data on NTZ is are promising, but has need to be confirmed in larger studies. Other new compounds have been shown to suppress viral load in HCV-4 patients in proof-of-concept studies. Further larger trials on the combination of new compounds with PEG-IFN and RBV are needed to explore the beneficial effect in terms of SVR improvement in patients with HCV-4.

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In recent years the study of HCV kinetics under therapy has been found to be extremely useful to guide the appropriate duration of therapy, motivate the patient and improve the cost/effectiveness of treatment. By the application of the RVR, as well as of the complete (cEVR) and partial early responses (pEVR), the duration of therapy can be individualized between 24 and 48weeks. In this context it has become clear that in HCV genotype 4 – similar to genotype 1, 2, and 3 – a response guided duration of combination therapy is becoming the current standard of care.
The ongoing spread of HCV-4 to European and other countries is expected to facilitate further therapeutic studies including promising drugs like NTZ and direct acting antiviral agents specifically targeted to the proteins of HCV genotype 4.