Showing posts with label SPONTANEOUS CLEARANCE. Show all posts
Showing posts with label SPONTANEOUS CLEARANCE. Show all posts

Tuesday, February 13, 2018

Understanding Spontaneous Hepatitis C Virus Clearance

MD Magazine

Understanding Spontaneous Hepatitis C Virus Clearance
FEBRUARY 13, 2018
Elizabeth Kukielka, PharmD

Among patients in the acute phase of hepatitis C virus (HCV) infection, a portion will spontaneously clear the infection without treatment, and HCV RNA will completely disappear from the serum. Estimates from various studies project that anywhere from 20% to 30% of patients will spontaneously clear HCV, with the biggest factors being sex, ethnicity, immune status, and genetics.

Sunday, July 31, 2016

Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

NEJM Journal Watch

July 28, 2016
Spontaneous Clearance of HCV Infection in Patients with Chronic Infection

Atif Zaman, MD, MPH reviewing Bulteel N et al. J Hepatol 2016 Aug.

Atif Zaman, MD, MPH
Factors associated with this rare event were younger age, female gender, HBV coinfection, and lower HCV RNA level.

Atif Zaman, MD, MPH
The incidence of spontaneous clearance of hepatic C virus (HCV) infection in the acute phase (infected <6 months) is high (estimated at 20%–40%) but is unknown in the chronic phase.

In a population-based case-control study performed in Scotland, investigators assessed spontaneous clearance incidence and its associated risk factors, using HCV testing data from 1994 to 2013. Case patients were defined as those who spontaneously resolved HCV infection and control patients as those who remained chronically infected. All patients had no prior HCV treatment and had ≥2 sequentially positive HCV RNA tests at least 6 months apart, followed by ≥2 negative tests in cases and no negative tests in controls. Four controls were randomly selected for each case.

Among 10,318 patients identified with positive hepatitis B virus (HBV) RNA samples, 50 had documented late spontaneous clearance, for an incidence of 0.36 per 100 person-years of follow-up. Median duration of infection was 50 months in both cases and controls. Spontaneous clearance was significantly associated with younger age at infection (median age, 29 vs. 33 years), female gender, co-infection with HBV infection, and lower HCV RNA level.

These data demonstrate that spontaneous clearance of HCV infection can occur in patients who are chronically infected, albeit at an extremely low rate. Although the exact mechanism of this late spontaneous clearance is unknown, as seen here, certain host and viral factors appear to play a role. On rare occasion, clinicians may see this occur in practice.

Editor Disclosures at Time of Publication
Disclosures for Atif Zaman, MD, MPH at time of publication Nothing to disclose

Bulteel N et al. Factors associated with spontaneous clearance of chronic hepatitis C virus infection. J Hepatol 2016 Aug; 65:266. (
Gastroenterology Common Reasons for Hospital Readmissions in Patients with Cirrhosis
Atif Zaman, MD, MPH reviewing Tapper EB et al. Clin Gastroenterol Hepatol 2016 Aug.
Top readmission causes were acute complications of cirrhosis, substance abuse, and cancer complications.

Sunday, April 27, 2014

Mother To Child HCV Transmission Among Three Brothers: A Long-Term Follow-Up

Case Report
Volume 5, Number 4, April 2014, pages 227-231 

Transmission of Hepatitis C Virus From a Mother to a Child Carrying IL28B Heterozygote rs8099917 Among Three Brothers: A Long-Term Follow-Up

Takafumi Saitoa, c, Kei Mizunoa, Tomohiro Katsumia, Kyoko Tomitaa, Chikako Satoa, Kazuo Okumotoa, Yuko Nishisea, Hisayoshi Watanabea, Li Shaob, Yoshiyuki Uenoa aDepartment of Gastroenterology, Yamagata University School of Medicine, Yamagata 990-9585, Japan bPublic Health, Yamagata University School of Medicine, Yamagata 990-9585, Japan cCorresponding author: Takafumi Saito, Department of Gastroenterology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan

Manuscript accepted for publication March 4, 2014
Short title: Mother-to-Child HCV Transmission
Abstract  HTML  PDF

Three male children were born every 2 years by spontaneous delivery from a mother infected with hepatitis C virus (HCV) genotype 2b, and all have been followed up after birth. The viral load in the serum of the mother was high before their deliveries, and anti-HCV antibody immunoglobulin G, which is allowed to pass through placenta, was positive in the umbilical blood of all the children. Mother-to-child transmission of HCV was confirmed in the second son, who was positive for both anti-HCV antibody and serum HCV RNA when first examined 108 days after birth, but not in the other siblings. Persistent HCV genotype 2b infection with mild elevation of the serum alanine aminotransferase level has been established in the second son for more than 14 years. The interleukin 28B (IL28B) genotype (rs8099917) of the second son showed the TG heterozygote, which is unfavorable for viral clearance, and this may predict persistent HCV infection. Among the three brothers sharing the same delivery conditions with exposure to the same virus, as well as sharing the same environment after birth, HCV infection has not been consistent, and one of them possessing the TG genotype of the IL28B gene (rs8099917) has had chronic HCV infection. These cases suggest that maternal HCV transmission does not occur so often, even among multiple children who are exposed to the same HCV with a high viral load, and that this variation might be attributable to very minor events that can impact on viral exposure in the perinatal period.

Keywords: Hepatitis; HCV; Perinatal infection; Vertical infection; Interleukin 28B

Mother-to-child transmission of hepatitis C virus (HCV) is a serious health problem, and no effective preventive vaccine has yet been developed. The mechanism and timing of mother-to-child HCV transmission are not understood, nor is the natural history of the infection in mothers and their children. The rate of HCV transmission from HCV-infected mother to child is reported to be approximately 4-10% [1-7], but the associated factors are not fully defined [8].

HCV infection leads to development of chronic hepatitis with a risk of progression to cirrhosis and liver cancer, but some individuals clear the virus spontaneously and the hepatitis resolves in a self-limiting manner in the acute phase of infection [9-11]. Recently, it has been reported that the host genetic single nucleotide polymorphism (SNP) in the region of the interleukin 28B (IL28B) gene encoding interferon-λ-3, rs12979860, is associated with spontaneous HCV clearance in adults [12, 13], and even in infants vertically infected with HCV from their mothers [14]. This SNP is in high linkage disequilibrium with rs8099917, as reported for Japanese subjects [15, 16]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 in the IFNL4 gene encoding interferon-λ-4 protein has been reported to be more strongly associated with HCV clearance, and this variant is in high linkage disequilibrium with the SNPs of IL28B [17]. Thus, these genetic markers are worth investigating further for their possible usefulness in predicting the outcome of maternal HCV infection in children.

The pattern of maternal HCV transmission in multiple children from the same mother is still unclear. There is little evidence to indicate whether mother-to-child transmission of HCV occurs evenly or unevenly in this situation. Such cases would be informative for understanding the risk of perinatal HCV infection. We have experienced three deliveries from the same HCV-monoinfected mother, and prospectively followed up the three children after birth. In all of them, the factors possibly related to maternal HCV transmission, namely, the gender of the children, birth weight, delivery conditions, a high viral titer in the mother before their births, positivity for anti-HCV antibody in their umbilical blood and their environment after birth were uniform.

Here, we report the results of HCV transmission in these three children born from the same mother infected with HCV, with special reference to both the natural course of HCV infection in the children and their genotypes of IL28B (rs8099917) and IFNL4 (ss469415590) associated with the outcome of infection.

Case Report
The mother has been followed up for hepatitis C at our hospital for 18 years. The long-term course of her HCV infection is shown in Fig. 1. The serum alanine aminotransferase (ALT) level was low, at under 30 U/L, during the follow-up period except for two occasions when it exceeded 30 U/L just after delivery of the first and second sons. She had been infected with HCV genotype 2b, and the viral load was always high before she received antiviral therapy. Both hepatitis B surface antigen and anti-immunodeficiency virus antibody were negative in her serum. Six years after the third delivery, she received antiviral therapy with pegylated interferon plus ribavirin for chronic hepatitis C according to the Japanese standard protocol [18], and the therapy was successful in achieving a sustained virologic response.

Figure 1. Clinical course and serum alanine aminotransferase (ALT) levels in the mother with chronic HCV genotype 2b infection. Positivity and negativity for serum HCV RNA are represented as plus (+) and minus (-), respectively. PegIFN/RBV: pegylated interferon plus ribavirin treatment.

The characteristics of the three children are summarized in Table 1 below.

All were boys who were born by normal spontaneous delivery 40 weeks after the start of pregnancy. All were healthy and their birth weight was almost the same, at approximately 3,400 g. Nothing in their history suggested any concern about contamination with HCV during their perinatal periods, namely, wounds, surgery or transfusion of blood products. Anti-HCV antibody in the umbilical blood was tested for at birth, and it was positive in all of them. The first and third sons had no evidence of HCV infection because neither anti-HCV antibody nor HCV RNA in serum was positive after birth. However, the second son was confirmed to be infected with HCV 108 days after the delivery showing positivity for both anti-HCV antibody and HCV RNA in serum by the first postnatal assay. HCV transmission to this child resulted in persistent infection. The long-term follow-up and clinical course of this HCV-infected child are shown in Fig. 2. The serum ALT level had been low, at under 30 U/L, for approximately the first 2 years after birth, but thereafter fluctuated above and below 30 U/L until approximately 14 years of age. The HCV genotype of this child was 2b, which was the same as the mother’s, and the high-level viremia has continued during the follow-up period. Although the factors possibly influencing maternal HCV transmission, namely, gender, birth weight, delivery conditions, the mother’s high viral titer and positivity for anti-HCV antibody in the umbilical blood, were the same among the three siblings, HCV transmission from the mother occurred only in the second child. The genetic polymorphisms of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) associated with spontaneous viral clearance were examined after obtaining written informed consent from their mother. The genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) in the second son, in whom persistent HCV infection had become established, were TG and ΔG/TT, respectively. Those in the other children who were not infected with HCV varied, being TG and ΔG/TT in the first child, and TT and TT/TT in the third child. 

Table 1. Characteristics of Children Born From the HCV-Infected Mother

First child
Second child
Third child
NSD (39 weeks)
NSD (40 weeks)
NSD (40 weeks)
Body weight at birth
3,364 g
3,492 g
3,400 g
HCV RNA in mother’s serum before birth
8.2 Meq/mL*
6.0 log IU/mL**
40.0 Meq/mL*
Anti-HCV antibody in umbilical blood
Positive (CI > 5.0)
Positive (CI > 5.0)
Positive (CI > 5.0)
HCV RNA in umbilical blood
< 0.5 Meq/mL*
Anti-HCV antibody in serum after birth
Positive (CI > 5.0)
HCV RNA in serum after birth
Persistent HCV viremia (period)
Not applicable
15 years
Not applicable
IL28B polymorphism (rs8099917)
IFNL4 polymorphism (ss469415590)

NSD: normal spontaneous delivery; n.t.: not tested; CI: cutoff index. **This assay was done using the preserved sample. HCV RNA was measured by *branched DNA assay, **real time PCR, ***qualitative PCR. 
Figure 2. Long-term follow-up of serum alanine aminotransferase (ALT) levels in the second child with maternal HCV genotype 2b infection. Positivity for serum HCV RNA is represented as plus (+).

In this study, we observed different outcomes of HCV transmission among three brothers who had been exposed to the same HCV strain from the mother during the perinatal period. Interestingly, maternal HCV genotype 2b transmission did not occur evenly in these three siblings, despite the fact that all had the same HCV exposure as well as upbringing environment, and only the second child was infected with HCV genotype 2b. This HCV transmission led to persistent infection in this child, in whom the genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) were TG and ΔG/TT, respectively, which are unfavorable for spontaneous viral clearance after the establishment of infection [13, 19].

It is still unclear how mother-to-child HCV transmission occurs in the perinatal period, and our present findings may help to shed some light on the route of infection. During the perinatal period, there are two possible major routes of HCV transmission from mother to child: placental infection and birth canal infection. Placental infection results from active transport of virus from mother to child, or from micro-transfusion of virus due to placental membrane damage. In all of the three brothers, blood exchange between the fetus and the mother through the placenta had been good, because anti-HCV antibody (immunoglobulin G) had been transferred to all fetuses and was detected in the umbilical blood at birth in all cases. However, only the second child had been infected with HCV. Negativity for HCV RNA in the umbilical blood of this child was different from the viral titer in the serum of his mother, which indicated a very high level of HCV RNA, as shown in Table 1. Thus placental infection by active transport of HCV from mother to fetus appeared to have been negligible. Placental membrane damage possibly induced by a small wound that goes unnoticed at delivery may result in maternal HCV infection. In cases of twin delivery, HCV transmission is more likely to affect the second child because possible partial placental separation upon delivery of the first baby increases the chance of exposing the second child to maternal blood [20]. Otherwise, any small wound in child, such as on the skin or in the mucosa of the oral cavity, or the bulbar conjunctiva, may allow micro-transfusion of HCV from mother to a child, and this may result in maternal HCV transmission in the birth canal. After birth, the present three brothers were brought up in the same environment, and were breast-fed. This kind of background carries little risk of HCV infection [21]. These findings suggest that maternal HCV transmission does not usually occur in the perinatal period, with only rare exceptions due to accidental exposure such as minor placental damage or micro-wounds in the child. The prevalence of maternal HCV infection seems to be relatively low even among children exposed to the same virus, although serologic tests for HCV in children should be carefully conducted during follow-up.

Most adults with HCV infection fail to clear the virus and develop chronic hepatitis, but some are known to show resolution of the infection in a self-limiting manner. The rate of spontaneous viral clearance in the acute phase of infection is reported to be approximately 15-40% of all HCV-infected adults [9-11], and a systematic review of 31 studies has estimated this rate to be 26% [11]. In a recent genome-wide association study, the SNPs in the region of the IL28B gene encoding interferon-λ-3 were shown to be associated with the virologic response of HCV to antiviral therapy [15, 22]. Patients carrying an IL28B homozygote for the major alleles of rs12979860 (CC genotype) [22] or rs8099917 (TT genotype) [15] show a greater propensity for achieving a sustained virologic response to pegylated interferon-α and ribavirin therapy than those carrying an IL28B heterozygote or homozygote for its minor allele. This SNP (rs12979860) also influences the outcome of HCV infection in the context of natural history; the CC genotype of rs12979860, which is in high linkage disequilibrium with the TT genotype of rs8099917, enhances the resolution of HCV infection with spontaneous clearance [12, 13]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 (TT or ΔG) has been reported to be more strongly associated with HCV clearance in individuals of African ancestry than the SNP of IL28B (rs12979860) [17].

The genotype of IL28B is also associated with the outcome of infection in maternal HCV transmission; self-limiting hepatitis or persistent hepatitis has been reported in a child infected with HCV genotype 1 during the perinatal period [14]. The three children in the present report were checked for the SNPs of both the IL28B (rs8099917) and IFNL4 (ss469415590) genes, and the second son in whom HCV genotype 2b infection had been established and led to persistent infection with mild fluctuation of the ALT levels was found to carry the TG (rs8099917) type and ΔG/TT (ss469415590) type in the IL28B and IFNL4 genes, respectively. Thus the SNPs in these two genes predicted the outcome of infection in the second son with chronic HCV genotype 2b infection.

In conclusion, our present findings suggest that the chance of maternal HCV transmission is not so high even in multiple children exposed to the same HCV strain with a high viral load, and that maternal HCV transmission might be attributable to very minor events that can potentially result in viral exposure during the perinatal period. Here, the multiple deliveries did not largely affect the serum levels of ALT and HCV RNA in the mother. The genotype defined by SNPs in the IL28B gene (rs8099917) and the IFNL4 gene (ss469415590) was able to predict the development of persistent infection in the child with established maternal HCV genotype 2b transmission.

Conflict of Interest
The authors have no conflict of interest.

1. Ohto H, Terazawa S, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. 1994;330(11):744-750.
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2. Matsubara T, Sumazaki R, Takita H. Mother-to-infant transmission of hepatitis C virus: a prospective study. Eur J Pediatr. 1995;154(12):973-978.
doi pubmed

3. Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, et al. Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission. Lancet. 1995;345(8945):289-291. doi

4. Resti M, Azzari C, Mannelli F, Moriondo M, Novembre E, de Martino M, Vierucci A. Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Tuscany Study Group on Hepatitis C Virus Infection. BMJ. 1998;317(7156):437-441.
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5. Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, Butler K. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356(9233):904-907. doi

6. Dal Molin G, D'Agaro P, Ansaldi F, Ciana G, Fertz C, Alberico S, Campello C. Mother-to-infant transmission of hepatitis C virus: rate of infection and assessment of viral load and IgM anti-HCV as risk factors. J Med Virol. 2002;67(2):137-142.
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7. Steininger C, Kundi M, Jatzko G, Kiss H, Lischka A, Holzmann H. Increased risk of mother-to-infant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis. 2003;187(3):345-351.
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8. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158(2):109-113.
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9. Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology. 2000;31(4):1014-1018.
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10. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, Schraut WW, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125(1):80-88. doi

11. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13(1):34-41.
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12. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461(7265):798-801.
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13. Hung CH, Chang KC, Lu SN, Wang JH, Chen CH, Lee CM, Hu TH. Spontaneous clearance of hepatitis C virus in an interleukin 28B favorable genotype highly prevalent area. Hepatology. 2013;57(5):2089-2090.
doi pubmed

14. Ruiz-Extremera A, Munoz-Gamez JA, Salmeron-Ruiz MA, de Rueda PM, Quiles-Perez R, Gila-Medina A, Casado J, et al. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children. Hepatology. 2011;53(6):1830-1838.
doi pubmed/

15. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105-1109.
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16. Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010;139(6):1865-1876.
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17. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164-171.
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18. Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res. 2013;43(1):1-34.
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19. Saito T, Ueno Y. Transmission of hepatitis C virus: self-limiting hepatitis or chronic hepatitis? World J Gastroenterol. 2013;19(41):6957-6961.
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20. Boxall E, Baumann K, Price N, Sira J, Brown M, Kelly D. Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies. J Clin Virol. 2007;38(2):91-95.
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21. Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol. 2009;81(5):836-843.
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22. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399-401.
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Monday, August 12, 2013

Hepatitis C - A Look At Disease Progression

After receiving a hepatitis C diagnosis, understanding how the virus damages the liver soon becomes the task at hand.

The natural history of hepatitis C remains controversial. Among HCV-infected individuals progression to advanced liver disease generally requires decades but is influenced by several host factors and has been proven to be highly variable. For instance studies have shown alcohol consumption is associated with HCV progression; active alcohol use increases the relative risk of hepatocellular carcinoma when compared to people who do not drink. Co-infection with HCV and HBV may also lead to a greater risk of hepatocellular carcinoma and more severe liver disease than does HCV infection alone.

Researchers in the 2012 issue of Seminars in Liver Disease found here, named the above mentioned in addition to smoking, age and duration of HCV infection as host factors relevant in determining the progression of hepatitis C;

 (1) the duration of HCV infection; (2) the presence of cofactors for development of liver fibrosis (such as male gender,  ethnicity, older age at infection, heavy alcohol intake,  HIV or chronic hepatitis B virus (HBV) co-infection, diabetes,  obesity, and hepatic steatosis); (3) access to HCV therapy and a favorable treatment response; and (4) competing mortality risk (such as HIV and illicit drug-related overdose).
The generally slowly progressive nature of chronic HCV, with limited advanced liver disease in the initial 10 to 15 years of infection (even in those individuals with cofactors for fibrosis development), means that duration of HCV infection and its surrogate, age, are key determinants of mortality risk.
Thus, a 50-year-old individual with 30 years chronic HCV is likely to have a higher HCV-related mortality risk, even in the absence of liver disease cofactors, than a 30-year-old individual with 5 to 10 years infection and several cofactors. However, the 50-year-old individual with 30 years infection, with heavy alcohol intake, obesity, and regular cannabis smoking (recently shown to be a liver fibrosis cofactor) will be at particularly high risk.

Out Of 100 People Who Contract HCV

Some studies describing hepatitis C progression can be confusing, and may have conflicting results. However, there is a general consensus after acquiring the virus it takes 10 to 15 years before evidence of the disease appears on biopsy, 20 or so years to develop cirrhosis, and around another decade to develop liver cancer. The statistics are overwhelming, Medscape offers a clear perspective in this 2012 article:

Hepatitis C Therapy Update
Lisa C. Casey, William M. Lee
Curr Opin Gastroenterol. 2012;28(3):188-192. 

Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).

A therapy update published in 2013 from the same authors is available @ Medscape.  

*Free registration  required

Unique Study Cohort

Researchers often reference a unique cohort of HCV patients when describing the natural history of hepatitis C. Never has there been a more perfect natural history study, in that - the known dates of infection were clear and precise. This for the most part is difficult to achieve since the time of acute HCV infection is often impossible to establish. The somewhat famous and tragic cohort include 704 Irish women and 917 German women exposed to hepatitis C from contaminated Anti-D immunoglobulin  in 1977–8 from a single source. Researchers have studied the aging population of women at 17, 20, 25 and 35 years after infection. A few of those studies have been added to this summary, with more recent research following each study. Offering an interesting comparison of data. Other highlights include: disease progression- including host factors, achieving SVR in relation to disease outcome, mother to child transmission (from the cohort of women) and the risk for HCV-related liver and non-liver diseases. A few links to learning activities for anyone contemplating treatment with triple therapy and a recent report on the promise of interferon-free therapy.

Spontaneous Clearance

1999 - 2000
Irish women - German women

Early research found the rates of viral clearance in the Irish women were high. Out of the 704 young Irish women infected research from (Kenny-Walsh 1999; Wiese 2000) found only 390 or 55% had detectable HCV RNA. The remaining 45% were HCV-antibody-positive, but had no detectable viremia. Wiese and colleagues observed similar rates of viral clearance among young women in the cohort of 917 German women. Of the 85% (779/917) with antibodies to hepatitis C, only 55% (428/779) had detectable HCV RNA.

Current Research

IL28B, HCV genotypes, sex linked to spontaneous acute HCV clearance 
August 9, 2013

A recent study reported female patients and those with HCV genotype 1 and/or IL28B CC genotype were more likely to experience spontaneous clearance of acute hepatitis C infection. Commentary on the study is available online at Healio.


Irish Women

Pregnancy and pregnancy outcome in hepatitis C type 1b

Full Text Published in QJM (July 2000)
Oxford Journals

The introduction of anti‐D immunoglobulin has proved extremely effective in the management of rhesus haemolytic disease, with deaths attributed to rhesus immunization falling dramatically from 46 per 100 000 births before 1969 to 1.6 per 100 000 in 1990.17 While intravenous immunoglobulin was thought to be a relatively safe product,18 there have been two reported epidemics of hepatitis C as a result of its use. Two distinct cohorts of Irish women became infected following exposure to contaminated anti‐D immunoglobulin in 1977/8 and 1991/3, respectively.1 Intravenous anti‐D immunoglobulin was implicated in the large scale transmission of hepatitis C in the former East Germany in 1978.19 
Production of anti‐D immunoglobulin in Ireland was commenced by the Blood Transfusion Service Board (BTSB) in 1970. Freeze‐dried intravenous anti‐D immunoglobulin was prepared from plasma containing a high concentration of anti‐D antibody procured in Ireland by the Hoppe method.20 The Hoppe method was refined in 1972, with the main objective of increasing the volume of anti‐D produced. The 1972 method replaced the process of ethanol precipitation with an ultrafiltration step, and also involved a quarantine period of 6 months before using plasma for the preparation of anti‐D. Hoppe believed that by pooling and fractionating only those plasmas which had been stored at least 6 months at −40°C provided a further safeguard against transmitting hepatitis. He believed that storing the plasma until the donor had been examined and repeatedly tested would provide further protection. However, modification of the Hoppe method21 in 1972 was not implemented by the Irish BTSB. 
We have studied women who were primipara and received contaminated anti‐D immunoglobulin post delivery in 1977/8. This represents a unique group of patients for whom the source and time of infection are clearly defined. While mindful of the relatively small size of the study group, we have found no evidence of either an increased risk of miscarriage or an adverse effect on subsequent pregnancies. Indeed in the general population, the incidence of spontaneous miscarriage has been estimated at 15–20% of all pregnancies,22 as compared with just 12.4% in the study group. Our study indicates that obstetric intervention and mode of delivery (including normal vaginal delivery, forceps/vacuum delivery and caesarean section) is not significantly influenced by the presence of HCV infection. Our study also shows that HCV infection does not increase the risk of obstetric complications and obstetric interventions. 
The favourable outcome of pregnancy and the low transmission rate of HCV may be explained partially by the endogenous production of interferon (IFN). Evidence of this production is indicated by findings from a number of studies. For example, the human placenta has been demonstrated to be a site of IFN manufacture.23 Interferon activity has also been detected in human amniotic fluid,24,,25 in placental blood26 and in perfused placenta.27 Immunohistochemical studies have demonstrated IFNs in feto‐placental units.28 
Vertical transmission of HCV occurred in one pregnancy in the study group. While we noted two major congenital abnormalities in the affected group, the number of cases is too small to test any hypothesis as to the possible role of HCV infection.  

Continue to full text.......

Current Research 

Mother to child vertical transmission

Chronic HCV infection: epidemiological and clinical relevance
BMC Infectious Diseases 2012, 12(Suppl 2):S2 doi:10.1186/1471-2334-12-S2-S2
Published: 12 November 2012

Mother-to-child vertical transmission of HCV is reported to occur in 3-10% of cases, mostly in the late intrauterine period, at delivery or in the peri-natal period. Many factors have been reported to influence the transmission rate, including maternal high viral load, labour duration, newborn gender, premature membrane rupture and genotype. The role of elective cesarean section to reduce mother-to-child transmission rates is debated and controversial and the guidelines of the European Association for the Study of the Liver (EASL) does not recommend cesarean section to prevent HCV vertical transmission...........

The electronic version of this article is the complete one and can be found online at:

*The risk is 2–3 times greater if the woman is coinfected with HIV.

Irish Women

21/22 years of infection

Published in GUT (February 2001)

An international peer-reviewed journal 

The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection 
The aim of this study was to investigate some of the unresolved issues regarding the natural history of HCV infection in a representative subgroup of women (with chronic infection or spontaneous self limited infection) derived from the Irish cohort. The clinical and histological status of these women was investigated at the time of diagnosis in 1994/95 and after 4–5 years of follow up (21/22 years after inoculation). Other features investigated included: symptomalogy, psychosocial impact of HCV infection, extrahepatic manifestations, and HLA class II associations. 

Discussion Only

Full Text Available Here 

This study investigated the natural course of HCV genotype 1b infection in a representative subgroup of a larger homogenous cohort (n=795) who were infected with HCV via contaminated anti-D immunoglobulin in 1977.5 The 87 women with chronic HCV infection and 68 with spontaneous viral clearance described in this study shared similar ethnic origin, sex, demographic characteristics, duration of disease, mode of acquisition, viral genotype, and lacked other possible causes of liver disease. A benign course of HCV infection, lack of disease progression, and low incidence of extrahepatic manifestations were observed in women with chronic HCV infection after a 22 year period.  
This benign and non-progressive course of chronic HCV infection was reflected clinically in the mildly elevated serum ALT activity at presentation (17 years after inoculation) (mean 50.6 (31) IU/l) and after five years of follow up (mean 51 (37.5) IU/l). Similarly, the mild histological activity observed at presentation was reflected in the mean HAI and fibrosis scores of 4.1 (1.4) and 1.1 (1.3), respectively. Histological deterioration was not observed after a five year follow up period as the mean follow up HAI and fibrosis scores were 4.1 (1.2) and 1.0 (1.0), and 22.7% (10/44) of biopsies even showed a spontaneous reduction in HAI score.19 Cirrhosis or hepatocellular carcinoma was not observed on the first or subsequent liver biopsy. These results confirm the findings of fellow investigators on Irish anti-D patients showing lack of disease progression over similar time spans but conflict with other studies observing significant fibrosis, cirrhosis, and advanced liver disease within 20 years of disease duration.6 19-26 Several variables have been suggested to influence the progression of HCV, including older age at infection and diagnosis, male sex, excess iron, increased alcohol consumption, and coinfection with hepatitis B virus and human immunodeficiency virus.27-33 Mode of transmission is also thought to be important as patients infected via transfusion receive a more infectious inoculum while those who acquire HCV via anti-D immunoglobulin receive a partially attenuated virus.34 The relatively young age (late 20s) of the women in this study at infection, together with the mode of transmission, and absence of excess alcohol consumption, iron on liver biopsy, and coinfection with other viruses probably contributes to the favourable outcome observed in this unique cohort. 
Sixty eight females considered to have spontaneous viral clearance were also investigated in this study. Of these, 32 (47.1%) were still antibody positive 18 years after inoculation. Debate exists as to whether these individuals have truly resolved infection or actually have current infection undetectable in serum but detectable in liver (as viral levels have been demonstrated to be 104-fold higher in the liver than in serum). Furthermore, it has been demonstrated in two separate studies that antibody positive serum PCR patients have similar clinical, histological, and virological profiles as serum PCR positive individuals.35-39 In this study, the mean serum ALT was significantly lower in PCR negative women compared with PCR positive women (p=0.000) (table 3). Similarly, the mean HAI and fibrosis scores of the 27 (40%) PCR negative women who underwent liver biopsy were also significantly lower than those of PCR positive women (p=0.000) (table 3). Furthermore, HCV RNA was not detectable in liver biopsies from serum PCR negative women but was detectable in biopsies from all serum PCR positive women, thus providing evidence that the negative serum PCR status is indeed a true reflection of cleared past infection. Steatosis was however observed at a higher frequency in PCR negative liver biopsies (48%v 10.3% in PCR positive biopsies; p=0.000). In a recent study of a larger group of serum PCR negative individuals, we have demonstrated that 63.6% (21/33) were overweight or obese, as determined by calculation of body mass index, and the histological findings of these women were more suggestive of non-specific reactive changes, steatosis, or non-alcoholic steatohepatitis rather than chronic HCV.40 
The 68 women with viral clearance described in this study represent a subgroup of a much larger group with spontaneous viral clearance. The findings from the total infected cohort from 1977 (n=704) may therefore indicate that more individuals spontaneously clear HCV than previously reported, as 314 (45%) of the original cohort were antibody positive but PCR negative for HCV RNA when tested in 1994.4 5Moreover, an additional 74 recipients of 1977 contaminated anti-D volunteered a history of jaundice shortly post partum and are now known to test both antibody and PCR negative.5 In this (table 1) and in another Irish study, a history of acute icteric hepatitis after inoculation has been demonstrated to be associated with spontaneous viral clearance.41 Why such a large proportion of women spontaneously cleared infection while the remainder went on to develop chronic HCV is unclear as the difference in disease outcome cannot be accounted for by differences in age, sex, source/duration of infection, size of inoculum, or alcohol consumption. These findings may therefore suggest that immune-host factors play an important role in the spontaneous clearance of HCV, and in this study the class II DRB1*01 allele was significantly increased in women with spontaneous viral clearance compared with those with chronic HCV infection. These results confirm the findings of a previous study on a larger cohort of these patients and also the findings of two other studies of separate groups of women from the same homogenous cohort.14 42 43  
A wide spectrum of extrahepatic manifestations has been traditionally ascribed to chronic HCV infection, with varying strengths of association. The best described of these include cryoglobulinaemia, sicca complex, autoimmune thyroiditis, membranoproliferative glomerulonephritis, and porphyria cutanea tarda.44-46 In our experience, cryoglobulinaemia is the most common of these HCV associated autoimmune disorders. Our observed prevalence rate of 12.7% among PCR positive patients and 0% among PCR negative patients further supports the role of the HCV virus in the pathogenesis of cryoglobulinaemia. In keeping with observations made in Britain, type 3 cryoglobulinaemia was the predominant type.47 However, we have previously demonstrated that Irish anti-D/HCV patients without cryoglobulinaemia were as likely to experience significant fatigue as those with cryoglobulinaemia.15 Tranet al reported a high prevalence of thyroid autoantibodies among patients with chronic HCV infection but did not include the known prevalence rate in healthy controls for comparison.48 The well conducted Wickham survey designed 20 years ago and recently updated provided an ideal sex matched population in the community for this purpose.16 17 Our surprising finding of significantly less autoimmune thyroid disease among the PCR positive population compared with that observed in the Wickham survey does not support the earlier investigators' claims. The observed prevalence rate of thyroid autoantibodies among our PCR negative group may mirror the prevalence among healthy women in the community. Indeed, current studies have failed to establish an association between autoimmune thyroid disease and hepatitis C.49 50 It is likely that the only significance of thyroid autoantibodies in patients with HCV lies in their positive predictive value for interferon associated thyroid dysfunction.51 
Glomerulonephritis and HCV dermopathy, including porphyria cutanea tarda and lichen planus, and antibodies to liver-kidney microsome 1 were not detected in this study group.  
Initially the symptom profile of the PCR positive and negative women presented in this study (PCR positive patients were found to have fewer complaints of fatigue and arthralgia than PCR negative patients at presentation) was contrary to what might be expected, but when calendar year was taken into account there were no differences in complaints of fatigue between the two groups. This observation, together with the psychological profile of 66 of these women, suggested that when suddenly diagnosed with chronic HCV the identity of this illness as chronic, infectious, and associated with intravenous drug misuse may have caused great concern to the infected women. The impact of such a diagnosis on psychological well being may have been even further compounded by the high legal profile related to this patient group.5 While accepting the uniqueness of this patient cohort, recent studies in other patient cohorts have also documented problems in quality of life and mental health.52-54  
In conclusion, this study investigated the natural course of HCV infection in a homogenous cohort almost half of whom now have spontaneous viral clearance. A benign course of HCV genotype 1b infection, lack of disease progression, and low incidence of extrahepatic manifestations was observed in women with chronic HCV after a 22 year period. The host HLA class II DRB1*01 allele was found to be associated with spontaneous viral clearance which supports the notion that host factors may play an important role in disease outcome. Finally, although the outcome of HCV infection was favourable, this study also demonstrated that the diagnosis of HCV was a very stressful event for these women who reported high levels of psychological distress and poor quality of life. It is hoped that longer term follow up of this unique cohort may further provide valuable information regarding the natural course of HCV infection.

Continue reading.....

2005 - German cohort of women after 25 years of infection

While reviewing the research the reader can not help but notice in both groups of women the severity of liver disease increases with the duration of infection. A comment from Atif Zaman, MD, MPH, (provided below) published in the 2005 October issue of Journal Watch, noted in the German cohort of women - after 25 years of infection - the rate of progression to cirrhosis increased during the last 5 years of the study.  It's worth noting the women had few coexisting medical conditions and alcohol consumption was minimal. In that, the outcomes in the cohort cannot be generalized to all HCV patients, Zaman concluded in his comment.

Published in the Journal of Hepatology (October 2005) researchers wrote:

One can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection


HCV Natural History: study in women exposed to HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany in 1978-79

Published in Journal Watch Gastroenterology October 25, 2005

Slow Rate of Disease Progression in HCV-Positive Women

Most data on the natural history of hepatitis C virus (HCV) infection are retrospective and suggest that progression to cirrhosis occurs during 20 to 30 years. In this prospective study, researchers reported 25-year outcomes in a cohort of women in East Germany who acquired HCV infection from a single-source outbreak of contaminated anti-D immunoglobulin in 1978 and 1979.  
Researchers reexamined 1980 women from 15 medical centers (70% of the initial cohort). Mean age at infection was 24; 9.7% of women were obese, and 2.6% had diabetes. Only 3% drank more that 40 g of alcohol daily, and 42% did not drink alcohol at all.  
After 25 years, 62% of patients complained of constitutional symptoms, such as headaches, myalgias or arthralgias, and fatigue. Overall, 54% had cleared the virus (48% spontaneously and 6% in response to interferon). Only 9 patients (0.5%) had developed overt cirrhosis, 30 patients (1.5%) had developed advanced fibrosis, and 1 patient had developed hepatocellular carcinoma. Of the 10 patients who had died of HCV-related complications, half had comorbidities (e.g., alcohol abuse). The rate of disease progression increased slightly between the 20-year and the 25-year follow-up evaluations: During these last 5 years, six women developed cirrhosis, and nine developed advanced fibrosis. 
Comment: In this unique cohort of HCV patients with known dates of infection, the overall rate of disease progression during 20 years was low. However, because the women had few comorbidities and minimal alcohol consumption, the outcomes cannot be generalized to all HCV patients. The rate of progression to cirrhosis increased during the last 5 years of the study.

-Atif Zaman, MD, MPH


HCV natural history: The retrospective and prospective in perspective

Journal of Hepatology
Volume 43, Issue 4 , Pages 550-552, October 2005

The key word in this Editorial, Ôiatrogenic,' is derived from the Greek Ôiatros' meaning physician and Ôgenic' meaning Ôproduced by' or Ôrelated to.' In addition, in current usage, an iatrogenic occurrence must be unintended. Thus, the Merriam Webster definition of iatrogenic is, Ôinduced inadvertently by a physician, surgeon, medical treatment or diagnostic procedure'. Two almost identical and temporally related inatrogenic events involving HCV-contaminated lots of Rh immunoglobulin occurred in Ireland and Germany in the late 1970's. Thousands of women were inadvertently infected with HCV and these Ôexperiments in nature' have, through diligent investigation and long-term follow-up, provided enormous insights into the natural history of HCV infection. 
The long-term outcomes of HCV infection have had differing interpretations during the decades since the predecessor virus, non-A, non-B, was first recognized [1]. In the 1970's, non-A, non-B hepatitis (NANBH) was viewed by many as an asymptomatic illness of minor consequence; some considered it merely a non-specific transaminitis. However, as these cases were followed prospectively, it became clear that as many as 20% evolved into cirrhosis [2]. This dramatic outcome stimulated clinical interest in NANBH and in the 1980's increasingly dire reports of severe outcomes emerged. In a now classic study by Tong et al. [3] 46% of post-transfusion hepatitis cases had biopsy evidence of cirrhosis and 11% had hepatocellular carcinoma. However, this and similar severe outcome data in the 1980's, reflected referral bias rather than worsening prognosis. Because of early treatment trials and the emergence of specialized hepatitis centers, the most severe cases of NANBH were being referred and then reported. This is not to impugn the relevance of these observations because Ôa case of cirrhosis is a case of cirrhosis' whether it is found prospectively or retrospectively and confirms that dire outcomes can be part of the natural history of HCV infection. However, such retrospective studies do not provide perspective on the proportion of infected individuals who will manifest these severe outcomes over the lifetime of their infection. In the early 90's, after the monumental cloning of HCV by Houghton and associates [4] and the development of sensitive assays to detect antibody to HCV [5], it became possible to introduce an alternate study design (retrospective-prospective) that allowed testing of unselected samples from decades-old serum repositories and then recall of infected patients and controls to assess outcomes over intervals that that extended from 20 to 45 years. These retrospective-prospective studies, free of selection bias, provided several key insights into the natural history of HCV infection. First, it was observed that the spontaneous recovery rate was higher than previously reported and might approach 25% in adults [6]. Other cohort studies have shown spontaneous recovery rates in children [7] and in some adults [8] to be as high as 45-55%, respectively. The other major finding of retrospective-prospective studies that included liver biopsy data was that the incidence of cirrhosis after approximately 20 years was lower than 15% and sometimes less than 5% and that HCV-related mortality over 20 years only marginally differed from that in uninfected controls [6]. In one, albeit small, study of persons infected as young military recruits, the frequency of cirrhosis after almost 50 years was only 6% [9]. Hence, the outcome of hepatitis C, both in terms of spontaneous recovery and severity, tended to ameliorate as one studied defined cohorts rather than referral cases. 
The ideal study to assess HCV natural history is one in which the onset of infection is precisely defined, the infection emanates from a single identified source, where case ascertainment is high, the study population is large, and where follow-up is prospective, comprehensive and of long-duration. Such an idealized combination of study parameters is very difficult to achieve since acute HCV infection is rarely identified, since large common-source outbreaks are unusual and since long-term prospective studies are difficult to support. The iatrogenic outbreaks of hepatitis C related to contaminated Rh immune globulin, though tragic in their occurrence, provide almost all the elements of the perfect natural history study. This is well exemplified in the 25-year follow-up data of Wiese and co-workers [10]. Basically in 1978-79, 14 batches of HCV (genotype 1b)-contaminated Rh immunoglobulin were administered to 2867 women in East Germany. The investigators were able to trace and then follow 1980 women representing 70% of the exposed cohort. Importantly, there was no selection of participants based on outcome, but solely on whether they could be located and were willing to participate in the study. The major findings in this study are highly relevant to HCV natural history assessment and can be summarized as follows: (1) 7% of those with a documented parenteral exposure did not manifest either biochemical or serologic evidence of HCV infection; it is unclear why this sizeable proportion were protected from this highly infectious inoculum and further genetic, molecular and immunologic study of these patients is warranted; (2) of 1718 untreated subjects, a remarkable 49% (836 patients) spontaneously recovery from their HCV infection as evidenced by normal ALT and the absence of HCV RNA; (3) the spontaneous recovery rate was higher in patients who were jaundiced during their acute hepatitis compared to those who were symptomatic but anicteric and those who were asymptomatic (66% vs., 46% vs. 45%, respectively; P<0.001); (4) of the 868 (51%) who developed chronic hepatitis C, 683 were untreated allowing for assessment of natural history over the 25-year duration of the study. Over this prolonged span, only 9 (1.3%) developed cirrhosis, 1 (0.1%) developed HCC and 30 (4.4%) had significant fibrosis that might evolve to cirrhosis; HCV-related mortality was 0.35%; (5) Although <5% progressed to severe fibrosis between years 15 to 25, the trend to escalating severity with increasing time from disease onset was significant by linear regression analysis. 
As an epidemiologic aside, in the absence of an iatrogenic transmission, it is now quite rare in Germany or other industrialized nations to be exposed to HCV because the blood supply has been protected, because occupational exposures have been minimized and because sexual and perinatal transmissions are rare. New HCV infections in the developed world are now almost exclusively in persons who put themselves at risk through shared needle exposures in the course of intravenous drug abuse. Further prevention is more a sociologic issue than a medical issue. The situation is different in developing nations where traditional risks are still prevalent. 
In sum, from the study of Wiese et al. [10] and a similar study in Ireland [11], one can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection. These relatively benign outcomes are quite encouraging, but this population represents a best-case scenario because of the young age and general good health at the onset of infection, and the rarity of co-morbid factors. Risk might increase slightly in males and would increase significantly in those infected at ages beyond 40, those with immunodeficiency states, those with excessive alcohol intake and perhaps those with high body mass index. Nonetheless, the 25-year outcome in the natural history of HCV infection is one of higher than expected spontaneous recovery and lower than predicted morbidity and mortality. In addition, one can now anticipate that 50% of those with genotype 1 or 4 infection and 80% of those with genotype 2 or 3 infection can be Ôcured' by combination treatment with pegylated interferon and ribavirin. Hence, if one conservatively assumes a 25% spontaneous clearance rate, a mild, non-progressive course in 20% of those chronically infected and a 50% sustained treatment response, one can estimate that in immune-competent persons acutely infected with HCV, the probable lifetime risk of severe liver disease will be less than 30%. This percentage will continue to diminish as therapies improve. While these numbers are encouraging and give reasonable hope to the individual patient who has access to treatment, they do not address the global burden of HCV infection. It is estimated that 170 million persons worldwide are chronically infected with HCV, most of whom reside in developing nations and many of whom may be coinfected with HIV and/or HBV and have very limited access to treatment. Even if only 10% of such individuals advanced to cirrhosis, the global burden of this infection is staggering. Thus HCV, like HIV, is a disease of two worlds, one where new infections are rare and effective treatments are available and one where high population density, inadequate preventive strategies and inaccessible treatments maintain HCV as a common disease with devastating consequences. It is a ÔTale of Two Cities' and we must address them both with equal measure.

Current Research

Chronic HCV infection: epidemiological and clinical relevance
BMC Infectious Diseases 2012, 12(Suppl 2):S2 doi:10.1186/1471-2334-12-S2-S2
Published: 12 November 2012


Natural history and clinical impact

After HCV acute infection an average 50-85% of patients will not clear the virus, with higher rates in HIV-co-infected subjects, and will therefore remain chronically infected with plateau or fluctuating viremia detectable in the blood. The remaining 15-50% will gradually show a decrease and final disappearance of the virus from the blood, usually within 3 months from infection [15,16]. The complex mechanisms regulating virus clearance and persistence are still not completed understood, but probably imply both host and virus factors. The role of ethnicity has not been proved. On the contrary, sexual transmission of HCV and HBV co-infection might favor viral clearance, probably due to limited inoculum and viral interference, respectively [17]. From the virological perspective, the higher the genetic diversity of the infecting virus, the higher the probability that the immune response will not be able to control its replication, resulting in chronic infection, while a narrow quasispecies spectrum is more likely associated to viral clearance [18]. Of note, similar to hepatitis B infection but without genomic integration, it has been recently demonstrated that HCV may replicate in the liver in the absence of detectable viral level in the blood , a condition sometimes referred to as “occult C hepatitis”, with lower potential for progressive disease [19].  
In the setting of persistent hepatitis C viremia, liver fibrosis is the consequence of chronic inflammation leading to the final distortion of hepatic architecture and impairment of liver microcirculation and cell functions. The main consequence of chronic HCV infection is the progression to cirrhosis, often clinically silent apart from non-specific symptoms such as fatigue, upper right quadrant pain or, sometimes, arthralgia and myalgia, until severe complications develop.  
In most cases, abnormal ALT values are the only clinical aspecific findings of the disease, only representing a marker of hepatocellular dysfunction. In particular, a direct correlation between the degree of ALT elevation and stage of the HCV-related disease is often lacking as a significant cytolytic activity is not a surrogate marker of disease severity [20] as well as normal ALT does not always mean an healthy liver. Population-based studies indicate that up to 30%-40% of individuals with chronic HCV have persistently normal ALT values when serially tested. However, significant liver disease, with active inflammation and/or at least significant fibrosis, is biopsy-proven in about 20% of HCV carriers with normal ALT [21].  
Chronic hepatitis C is the most common cause of cirrhosis and the most common indication for liver transplantation in Europe, North and South America, Australia and Japan. The risk of developing cirrhosis ranges from 5% to 25% over periods of 25-30 years [22].  
Environmental and host factors can increase the risk and/or accelerate the natural course of HCV-related disease. Multiple studies have shown that alcohol consumption, in particular a daily intake greater than 40-50 g, is one of the most influential factor driving fibrosis progression in patients with HCV. Age at time of infection also plays a role: the estimated probability of progression is significantly higher in patients that were infected at an older age (> 40 years) [23]. Also, a recent and large analysis of published studies suggests that early acquisition of HCV in childhood is rarely associated to a severe future course of the disease [24]. Other factors that affect the progression of hepatic fibrosis include male gender, the degree of inflammation and fibrosis on the liver biopsy, co-morbidities such as immunosoppression or metabolic condition such as non-alcholic steatohepatitis, obesity and insulin resistance [20].  
In addition, co-infection with HBV or HIV are significant risk factors for liver fibrosis. Approximately 4 to 5 million subjects with chronic hepatitis C are co-infected with HIV. Highest co-infection rates are observed among injection drug users (IDU): in the USA and in Europe, among HIV-infected IDU, HCV prevalence may be as high as 70-90 %. Paradoxically, the longer life-expectancy offered to HIV-infected patients by HAART permits slow-acting HCV-related liver injury to emerge as a significant cause of morbidity and mortality in HIV-HCV co-infected patients. Furthermore, the progression rate to cirrhosis and end-stage liver disease is accelerated in HIV co-infected patients: they have a twofold increased rate of cirrhosis compared to HCV mono-infected individuals [25], particularly when HIV associated immune-depression progresses.  
The mechanisms underlying accelerated liver disease in HIV-HCV co-infected patients are not completely understood, possibly including direct HCV effects on hepatocytes and hepatic stellate cells as well as immunological alterations such as immune activation, apoptosis and impaired HCV specific T-cell response [26]. Furthermore, liver toxicity of anti-retroviral drugs and the burden of metabolic diseases may contribute to a faster progression of liver fibrosis in HIV-HCV co-infected patients.  
Conversely, the role of HCV on the natural history of HIV infection continue to be debated and contrasting evidence exist [27,28].  
HCV replication has been observed in extra-hepatic tissues, such as bone marrow, the central nervous system, endocrine glands, lymph nodes, spleen, monocytes, macrophages and skin cells. HCV is also often associated with profound alterations in the host immune system, resulting in immunological abnormalities and even autoimmune disease such as mixed cryoglobulemia (MC), rheumatoid factor (RF) production, B cell lymphoproliferative disorders that may progress to non–Hodgkin lymphoma, and others. Cryoglobulins are immunoglobulins that precipitate in the cold and are classified into three groups, based on Ig clonality. Type I cryoglobulins are usually associated with lymphoproliferative disorders, including myeloma and Waldenstrom macroglobulinemia, and usually consist of monoclonal IgM or IgG, rarely IgA. Type II cryoglobulins are composed of polyclonal IgG and monoclonal IgM, usually characterizing the condition known as essential MC that is often associated with HCV. Type III MC is also characterized by RF activity, although polyclonal IgG and polyclonal IgM exist. The incidence of HCV infection in MC ranges from 40% to 90%, with geographical variations [29]. The high incidence of disease among Mediterranean people and the association of certain human leukocyte antigen (HLA) supports that genetic factors play a role in the disease. The clinical picture is characterized by the skin manifestations ranging from purpura of lower limbs to chronic torpid skin ulcers, more frequent in the sovramalleolar regions. Skin reactions include Raynaud’s phenomenon, livedo reticularis, urticaria, and edema. Arthralgias more frequently involve the hands and the knees symmetrically. Renal injury may complicate MC in almost 30% of cases and involvement of the nervous system from 17% to 60%. Peripheral sensory-motor neuropathy can represent the first clinical sign of cryoglobulinemia.

The electronic version of this article is the complete one and can be found online at:

Current Research 

JAMA - Deaths from liver disease increased from 1990 to 2010

According to a July 10, 2013 article published in the JAMA Journal of The American Medical Association – “The State of US Health, 1990-2010: Burden of Diseases, Injuries, and Risk Factors” – deaths from liver disease increased from 1990 to 2010. Liver disease also rose as a contributor to premature mortality. The most common causes of both cirrhosis and liver cancer are viral hepatitis, alcoholism, and obesity-related fatty liver disease. However, it is hepatitis C that is the most likely cause of the emergence of liver disease as a growing threat to American lives, according to a recent comment in this AASLD press release.

The report in JAMA is the first comprehensive analysis of disease burden in the United States in more than 15 years. It includes estimates for death and disability from 291 diseases, conditions, and injuries as well as 67 risk factors

Additionally, NATAP reported the rates of liver cancer in the U.S. more than doubled between 1990 and 2010 while deaths resulting from cirrhosis jumped 43 percent, slides and data available @ the National AIDS Treatment Advocacy Project (NATAP).

Current Research 

German cohort 35 years of infection

Mild but significant disease progression at 35 years after infection
Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome

Evaluation of liver disease progression in the German HCV (1b)-contaminated anti-D cohort at 35 years after infection

Manfred Wiese1,*, Janett Fischer2, Micha Löbermann3, Uwe Göbel4, Kurt Grüngreiff5, Wolfgang Güthoff6, Ulrike Kullig7, Franziska Richter1, Ingolf Schiefke8, Hannelore Tenckhoff2, Alexander Zipprich9, Thomas Berg2,†, Tobias Müller2,‡, for the EAST GERMAN HCV STUDY GROUP‡

Accepted manuscript online: 8 AUG 2013 07:53AM EST | DOI: 10.1002/hep.26644

The natural course of HCV infection remains controversial. The German HCV (1b)-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large and homogenous cohort of young women from the date of HCV inoculation.  
Our previous follow-up studies at 20 years and 25 years after infection suggested slow fibrosis progression rates in this unique cohort.  
The aim of our prospective community-based multicenter study was to re-evaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection.  
Patients with self-limited HCV infection (n=189) were compared to those who failed to eliminate the virus spontaneously (n=529), comprising patients who were treatment naive (n=197) or achieved a sustained virological response (SVR, n=149) respectively failed to clear the virus (non-SVR, n=183) after antiviral therapy.  
In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on the HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%, p=6.2x10−6).  
Overall survival was significantly enhanced following SVR compared to treatment naive patients or non-SVR (p=0.027).  
Conclusion: The present study provides further evidence for a mild but significant disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome.

(Hepatology 2013; 00:000-000)

Current Research 

In a study, published online in the August 15th 2012 edition of the Journal of Infectious Diseasesresearchers found increased deaths from both liver-related and non-liver related diseases in patients with active infections who had not cleared their infection

Except from the 2012 press release

The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.  
Chien-Jen Chen, ScD, and researchers from the Genomic Research Center in Taipei, Taiwan, enrolled more than 23,000 adults in Taiwan in their study and followed them from 1991 to 2008. Blood samples were collected at study entry and at follow-up health examinations. Researchers found increased mortality from liver-and non-liver-related diseases—including cancers of the esophagus, prostate, and thyroid, as well as circulatory and renal diseases—among those infected with HCV. Mortality was higher in HCV-infected participants with detectable serum levels of HCV RNA, indicating they had active infections; subjects with previous infections who only had HCV antibodies, but not HCV RNA, in their blood did not have increased mortality on follow-up. The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.

Full text can be found online here, press release here.

Current Research 

SVR reduced all-cause mortality risk in patients with HCV, advanced fibrosis
Van der Meer AJ. JAMA. 2012;308:2584-2593.
December 26, 2012

Patients with chronic hepatitis C and advanced hepatic fibrosis were less likely to die from any cause or from liver-related issues after achieving sustained virologic response to interferon-based therapy in a recent study 
In an international, multicenter study, researchers evaluated 530 patients with chronic HCV and cirrhosis or advanced fibrosis (defined as Ishak scores between 4 and 6), who received interferon-based treatment between 1990 and 2003. Incidence of all-cause or liver-related mortality, liver failure, hepatocellular carcinoma (HCC) and liver transplant was recorded over a median of 8.4 years of follow-up. 
Sustained virologic response (SVR) occurred in 36% of cases, including 125 participants who achieved SVR with initial treatment and 67 who experienced SVR with retreatment after a median of 5.8 years. 
During follow-up, 113 participants died, including 13 who achieved SVR. Investigators noted a significant difference in the 10-year cumulative all-cause mortality rates for the groups (8.9% for patients who achieved SVR vs. 26% for those who did not, P<.001). 
Liver-related death occurred in three SVR cases and 70 non-SVR cases, and liver transplant was not required for patients who achieved SVR. Transplant was necessary for 46 patients without SVR (including 13 who subsequently died). Researchers calculated 10-year cumulative liver transplant or liver-related mortality incidence rates of 27.4% for patients who did not achieve SVR and 1.9% who did. HCC occurred in seven SVR cases and 76 non-SVR cases, for cumulative incidence rates of 5.1% and 21.8%, respectively. Four SVR patients experienced liver failure compared with 111 without SVR, with incidence rates of 2.1% and 29.9%, respectively (P<.001 for all comparisons). 
Multivariate analysis indicated associations between SVR and reduced risk for all-cause (HR=0.26, 0.14-0.49) and liver-related mortality or liver transplant (HR=0.06, 0.02-0.19). Patients who achieved SVR also were less likely to develop HCC (aHR=0.19, 0.08-0.44) or liver failure (aHR=0.07, 0.03-0.20) (95% CI for all). 
“Our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis,” the researchers concluded. “In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure and liver-related mortality or liver transplantation in patients with SVR.”

Disclosure: See the study for a full list of relevant disclosures
Source - Healio

Current Research 

Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy
C. Koh, T. Heller, V. Haynes-Williams, K. Hara, X. Zhao, J. J. Feld, D. E. Kleiner, Y. Rotman, M. G. Ghany, T. J. Liang, J. H. Hoofnagle

Aliment Pharmacol Ther. 2013;37(9):887-894.
May 7 2013


The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment. These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.  
Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some. After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease.  
These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease. 
Similar findings after SVR in chronic HCV have been published in other cohorts. However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C. Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment. 
A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation. However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy. 
Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis. For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions. 
Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment.  
This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment. 
In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.

View Full Text @ Medscape

Current Research

Women With Chronic Hepatitis C Virus Infection

Southern Medical Journal 2013;106(7):422-426.
Mary Jane Burton, MD, James B. Brock, MD, Stephen A. Geraci, MD
July 24, 2013

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited. 
Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure. The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis.  Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies. This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver. Animal models suggest that estrogen suppresses hepatic fibrosis, and a recent in vitro study proposed that estrogen inhibits the production of HCV virions. Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause. In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis; however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.

Complete article and additional information on Women and HCV found here.

Article Source - Medscape

2013 - Treatment Updates

Progress in Treating Hepatitis C Infection

June 6 2013

Video - Hepatitis C: The Pace of  Progress
In recently published studies, sofosbuvir combined with ribavirin alone was shown to be effective for hepatitis C genotype 2 and 3 and possibly genotype 1. This regimen offers a low incidence of side effects, a relatively short duration of treatment, and was effective against all genotypes. These advantages may lower the threshold for HCV treatment for both patients and physicians.

Source - Medscape Medical News from: Digestive Disease Week (DDW) 2013

*Free registration  required

2013 July 12

Video Vignettes -Current Outlook On Hepatitis C Treatment
The Doctor's Channel released a four part video series last month offering key information for anyone considering triple therapy. Sofosbuvir is also included in the series, as is the future of HCV therapy.

2013 "HCV Treatment Pipeline" - By Tracy Swan

Hepatitis C Drug Development Catapults Onward
By Tracy Swan

HCV Treatments in Phase II and Phase III
The Best Combinations
Interferon-Free Regimens in Development for HCV Genotype 1
Interferon-Free Regimens in Development - HCV Genotypes 2, 3, & 4
Cross-company Trials
Next in Line: Simeprevir, Faldaprevir, and Sofosbuvir
Without a PEG to Stand on: The Sofosbuvir Saga Goes on
Biting the (Magic) Bullet
Twinkle, Twinkle, Little (Lone) Star
AbbVie: All Hands on Deck
Bristol-Myers Squibb: All In!
(Genotype) 3 is the new 1
SVR in HCV Genotypes 2 and 3
Cirrhosis: From Frontier to Proving Ground
HIV/HCV Coinfection
Faldaprevir plus PEG-IFN/RBV
Simeprevir plus PEG-IFN and RBV
From Excess to Access
Where Should All the Research Go?
Access the report here.........

Of Interest


July 2012

(Trent HCV Study)
Adam John Lawson
BMedSci, BM, BS, MMedSci (Clin Ed)
Thesis submitted to the University of Nottingham for the degree of Doctor of Medicine


Published in the 2006 issue of the International Journal Of Medical Sciences a paper on the natural history of hepatitis C discussing the virus in both acute and chronic phases, disease progression including host factors, liver fibrosis, cirrhosis, and hepatocellular carcinoma.  

Hopefully, this small summary will leave you with a better understanding of the natural history of  hepatitis C. As once a patient with hepatitis C, understanding disease progression was on the top of my list, followed by starting treatment and finally curing the virus. I achieved all three, may you all safely do the same.

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