VOLUME

Hepatitis C virus is one of the most important causes of cirrhosis and hepatocellular carcinoma in Thailand and worldwide. In 1999, WHO estimated global prevalence of hepatitis C virus infection at 3% affecting 170 million people worldwide.1 In Thailand, the prevalence of hepatitis C infection ranges between 0.94-2.15%.2,3 Most patients are asymptomatic after acute hepatitis C infection. In acute infection, only 20% will develop jaundice and spontaneous resolution occurs in 15-25%.4 In patients who become jaundiced, children and young women may clear the infection in up to 45% of cases. Clearance of infection is also influenced by genetic factors and the immune status of the host. HIV coinfection is associated with increased persistence of hepatitis C infection.5 Chronic hepatitis C infection is defined as persistence of the virus in the blood for more than 6 months after the onset of infection. Spontaneous resolution of chronic hepatitis C infection is quite rare. Most of the patients with chronic hepatitis C infection will be asymptomatic but with fluctuations in ALT levels. It is estimated that 20-30% of chronic hepatitis C infection patients will develop cirrhosis after 20 years of infection.4 The higher risk of fibrosis progression is associated with obesity, alcohol consumption and co-infection with hepatitis B or HIV infection. The development of cirrhosis increases the risk for decompensation, which include ascites, variceal hemorrhage and hepatic encephalopathy. The rate of developing hepatic decompensation after cirrhosis was found to be 2-5% per year.6 The risk of hepatocellular carcinoma (HCC) was 1-4% per year in hepatitis C cirrhosis.

Although complications related with cirrhosis and deaths remain  important causes of morbidity and mortality from chronic hepatitis C, there are extrahepatic manifestations of chronic hepatitis C which have also been identified. The established (well known) association with chronic hepatitis C are mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma.7 Almost 90% of MC patients have active hepatitis C infection and circulating cryoglobulins are found in 40-60% of patient with hepatitis C.   However only 5-10% of patients who have circulating cryoglobulins have any clinical consequence. 8 From the retrospective study in Japan, patients with chronic hepatitis C who never received any treatment developed lymphoma in 2.6% compared with none of those whom had been cured from chronic hepatitis C in fifteen years.9  Other significant extrahepatic manifestations of chronic hepatitis C are porphyria cutanea tarda (PCT), lichen planus and monoclonal gammopathies. The other possible associations are Sicca syndrome, corneal ulceration, thyroid disease, nephropathies, neuropathy, diabetes mellitus and insulin resistance.7

Almost one third of chronic hepatitis C patients with type 2 cryoglobulinemia have renal involvement.¹⁰ Laboratory studies in these patients showed hypocomplementemia and circulating cryoglobulins. The renal disease in chronic hepatitis C infection usually present with glomerular diseases. They can manifest as cryglobulinemic nephropathy, membranoproliferative glomerulonephritis (MPGN), and membranous  nephropathy.The most  common   disease is MPGN. The MPGN is mostly associated with type 2 cryoglobulinemia. The renal involvement in chronic hepatitis C could also present with proteinuria, microscopic hematuria, hypertension, acute nephritis and nephrotic syndrome.¹⁰ Patients with hepatitis C infection should be tested at least once a year for kidney function, including measurement of urinary protein and estimate glomerular filtration rate.¹¹ If there is evidence of renal abnormalities,patients should be tested for cryoglobulins, complement levels and rheumatoid factor. A kidney biopsy should be considered in patients with significant proteinuria or impaired renal function.

Hepatitis C virus has high mutation rates that result in genetic variation. There are six major genotypes of hepatitis C virus with numerous subtypes. Genotype determination helps to determine the treatment regimen, duration and predict the outcome of treatment. However, genotype does not influence the severity of liver disease such as fibrosis or progression to cirrhosis. There are different genotypes predilections in each part of the world. Genotype 1 is most common in the United States (60-75%) and in the world (42.6%).¹² In Thailand, genotype 3 is the most common (50-60%) followed by genotype 1 and 6.¹³ The treatment goals for viral hepatitis B and C infection have some minor differences. The goals for both viral hepatitis would be to prevent patients from cirrhosis and its complication including hepatocellular carcinoma. For chronic hepatitis B infection, the aim is to suppress the number of virus but this occurs with a low probability of getting cured. However, we are able to eradicate chronic  hepatitis C virus and cure the patients from the disease with our current treatment. The success of the treatment is the sustained virologic response (SVR) which is defined by the absence of the virus detected by polymerase chain reaction twenty-four weeks after finishing the treatment. Long-term  follow  up of patients who achieved SVR almost all demonstrate virological negativity (99%)₁₄ and are thus consider cured. The current standard treatment for chronic hepatitis C in Thailand is peginterferon and ribavirin. The treatment consists of weekly subcutaneous dose of pegylated interferon and twice-daily ribavirin. The treatment duration and outcome depends on the patient’s genotype. The treatment durations are either 24 or 48 weeks. In Genotype 1, the treatment duration is 48 weeks which results in an overall SVR of 40-56%.^15,16 For genotype 2 and 3, the duration of treatment is only 24 weeks. The SVR rate for genotype 2 and 3 is 60-84%.¹⁵ Genotype 4, 5 and 6 also need 48 weeks of treatment, with the SVR of 55-64% for all three genotypes. The positive predictors of response to treatment are non-genotype 1, low initial viral load, higher ALT, absence of advanced fibrosis and younger age. The other important predictor of outcome is the rapidity of viral clearance (rapid viral response or RVR) during therapy. The definition of RVR is HCV RNA undetectable after 4 weeks of treatment. Patients who achieve RVR  in  all genotypes have higher chance of achieving SVR, up to 88-100%.¹⁷ However only 16% of genotype 1 and 60-71% of genotype 2 or 3 achieve RVR when treated with pegylated interferon and ribavirin.¹⁷

Treatment with pegylated interferon and ribavirin are contraindicated in decompensated cirrhosis due to high rates of morbidity and mortality. There are many side effects from the treatment, which varies from mild flu-like symptoms to severe life threatening events that could lead to termination of treatment. There are some common side effects such as fatigue, myalgia, flu-like symptoms, anorexia, diarrhea, depression or irritability. In addition, laboratory abnormalities can occur and include anemia, neutropenia or thrombocyto penia. These side effects from treatment are the most important causes of premature discontinuation of therapy. In recent years, new, safe and effective interferon-free treatments for hepatitis C using direct-acting antiviral agents (DAA) have become standard regimen for many countries. The HCV genome encodes a polyprotein of 3000 amino acid, which is cleaved by host and viral protease.18 The polyprotein is used to produce the virus particle, supported particle, envelope glycoprotein and viral  RNA  replication.19  The  identification of the non-structural proteins of HCV virus (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) serves as targets for therapy. DAAs target the critical enzymes in the replication of hepatitis C virus. However, there are some issues with the development of drug resistant virus in part due to the error-prone nature of HCV RNA replication. This article will only mention some of the new DAAs that are currently available or are soon to become available in Thailand.