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HEPATITIS C TOWARDS A CURE!!!
SEVERE FATIGUE & ARTHRALGIAS IN A YOUNG MALE.
This is a case report of a 28 year old male from Baramulla Kashmir with chronic hepatitis C infection who received antiviral therapy and completed it successfully and was cured of this infection. CASE REPORT: A 28 year old male, a government office worker, complained of fatigue and aches and pains for 2 years. The fatigue had become progressive and it was difficult for him to do his office work and keep up to his daily routine. He starting taking multiple offs from his office to take rest and had been threatened to lose his job. In addition to fatigue, he had aches and pains involving joints of arms, legs and back. There was no joint swelling, morning stiffness or limitation of movements. There was no fever, weight loss, cough, abdominal pain, diarrhea, and headaches. He had consulted many physicians and was told to have rheumatism and prescribed analgesics and antidepressives. There was no relief of symptoms and he in addition had developed features of anxiety and depression. Clinical examination showed an anxious man with vitals: pulse 72 per minute, blood pressure systolic 110 mmHg, diastolic 90 mm Hg, weight 60 kg, BM1 23 and SpO2 95%. General physical and systemic examinations were unremarkable. CBC revealed hemoglobin 14.8 g/dl (normal 13 to 18 g per dl), WBC 4900 per cumm (normal 4,000 to 10,000 per cumm), platelet count 125000 per cumm (normal 130000 to 440000 per cumm). ESR was 30 mm first hour westergren (normal less than 10 mm first hour). Liver function tests showed serum bilirubin 3.2 mg per dl (normal 0.4 to 1.2 mg per dl), SGOT 73 U per L (normal 0 to 38 U per L), SGPT 144 U per L (normal 5 to 41 U per L), ALP 358 IU per L (normal 100 to 240 IU per L), and albumen 4.2 g per dl (normal 3.2 to 5.0 g per dl). AFP was 2.1 ng per ml (normal less than 15 ng per ml). Rheumatoid factor and anti-CCP (cyclic citrullinated peptide, a marker for rheumatoid arthritis) were negative. Serum cryoglobulins were negative. Kidney function tests were normal. Thyroid profile was within normal limits. An abdominal ultrasound including Doppler studies of hepatic veins and portal venous

system was normal. Serology for hepatitis markers were as follows: HBsAg nonreactive, anti-HBc IgM nonreactive, anti-HCV reactive, anti-HEV IgM nonreactive, anti-HAV IgM nonreactive. Serology for HIV-1 & HIV-2 was nonreactive. HCV viral load was more than 700000 copies per ml and HCV genotype was 3a. Upper gastrointestinal endoscopy was normal. There was no evidence of esophageal varices or congestive gastropathy. He was assessed for any high risk for hepatitis C infection. He was married with one child and maintained single partner heterosexual practice. He refused social or habitual alcohol intake. He was never transfused in the past, did not undergo any major surgical procedure nor was a drug abuser. He remembered to have dental work up done 10 years back. He had a psychiatric evaluation and was detected to have depression and was started on antidepressant drug therapy. He was considered for HCV antiviral combination therapy and counseled for the same. He was advised an adequate contraception during and 6 months after drug therapy. Liver biopsy was not ordered or done (not indicated for HCV genotype 3a). Drug therapy included pegylated interferon (Pegasys 180 microgram subcutaneously per week,) and ribavirin tablets 800 mg per day for 6 months. (Note- Two pegylated interferons are commercially available. Pegasys is a peginterferon alfa 2a 40 kDa from Roche and Pegintron is a peginterferon alfa 2b 12 KDa from Schering-Plough. Both Peginterferons are equally effective for chronic hepatitis C infection). First dose of Pegasys was given under nurses supervision and remaining doses were allowed to be self administered. Prior to each Pegasys dose, he was given paracetamol 1.0 g orally and allowed repeat dose at 4 hours and on demand. A CBC with reticulocyte count and LDH were ordered at one week, 2 weeks, 4 weeks and thereafter every 4 weeks. Liver function tests were ordered at one month, 3 months, 6 months (end of therapy biochemical response) and 6 month after therapy (sustained biochemical response). HCV RNA Quantitative viral load was ordered at 6 months of therapy (end of therapy virologic response) and 6 months after completing therapy (sustained virologic response). HCV RNA quantitative at 4 weeks therapy (early virologic response) was not ordered (not indicated for genotype 3). Thyroid function tests and TPO (thyroid peroxidase) antibodies were ordered at 3 month and 6 moths of therapy and 6 months after completing therapy (for evaluating autoimmune thyroiditis, a known complication of interferon therapy).

Prior to next dose of Pegasys, the patient was questioned by the nurse and his laboratory tests were evaluated and drug adjustment dose done as per defined criteria. On therapy he reported mild aches and pains and flu like illness which responded to analgesics. At 6 weeks of therapy he dropped his hemoglobin to 9 g per dl which needed adjustment of ribavirin dose as per defined guidelines. Platelet counts stayed above 50,000 per cumm for first 3 months and dropped to 40,000 per cumm on his 12th due dose. This needed a temporary adjustment of Pegasys dose for 3 weeks. Absolute neutrophil counts were above 750/cumm and needed no adjustment for drug dosage or additional therapy. During treatment he continued his anti-depressant medication. During the treatment and thereafter his fatigue and aches and pains improved. He felt more cheerful and confident. Liver function tests normalized by 3 months of therapy and stayed so thereafter. HCV RNA viral load was below detectable level (less than 600 copies per ml) at end of therapy and 6 months after, thus he had achieved end of treatment and sustained virologic response. His thyroid function tests were normal during and after treatment. TPO antibodies levels were 250 IU per ml (normal less than 150 IU per ml). He was counseled at 6 months after completing treatment and told of the cure of his hepatitis C infection. At one year of follow up he is well attending his work without any symptoms and with normal serum biochemistry. (Source: Case records of Dr. Khuroos Medical Clinic).

REVIEW: Hepatitis C virus (HCV) is a significant cause of liver disease throughout

the world. The main reason for this is the extraordinary propensity of this infection to follow a chronic course and cause chronic hepatitis, cirrhosis, end stage liver disease and hepatocellular carcinoma. It has been estimated that at least 170 million people are infected with HCV and of these 4 million live in USA. HCV infection is slowly progressive and clinical manifestations may not be apparent for decades after infection. The prevalence of HCV varies geographically and ranges from 1 percent in Europe to 5.6 percent in Africa. Certain countries like Egypt have extremely high prevalence of up to 20 percent. In USA HCV prevalence is 1.8 percent. In India the prevalence is around 3 percent and same is the case in Kashmir, India. HCV has 6 major genotypes (genotype 1 to 6) and over 50 subtypes (named as a, b, c, etc). There is marked global variation in prevalence of various genotypes. Genotype 1b occurs frequently (over 75 percent) in

USA and Western Europe. Remaining patients in such countries are infected with genotype 1a, 2a, 2b and 3a). Genotype 4 is common in Middle East and surrounding regions. Genotype 3a is common in India, followed by 1b. In Kashmir most of the patients are infected with genotype 3a. High risk groups for HCV infections include intravenous drug users, hemophiliac patients, patients on chronic hemodialysis, health care workers and children borne to mothers who are infected with HCV. Blood transfusions have been a risk factor prior to screening of the blood for HCV, but now this is a rare cause of newly acquired infections in developed countries. However, we have seen that blood transfusion continues to be a risk factor for HCV infection in our community. Majority of acute HCV infections are relatively mild with self-limiting systemic manifestations and may go undiagnosed. Once infected, HCV patients resolve their acute infection in around 25 percent and over two thirds become chronic life time HCV carriers. The clinical course of chronic HCV infection is variable and most of patients have no symptoms. The disease may cause fatigue and arthalgias and also present with a group of extrahepatic manifestations including cryoglobinemia (essential mixed type), glomerulonephritis, B-cell lymphomas, porphyria cutanea tarda, thyroiditis, lichen planus, sialadenitis and Mooren corneal ulcers. More often than not, chronic HCV infection may present first time with cirrhosis and end stage liver disease and because of this HCV is one of the commonest indications for liver transplant in adults throughout the world. Hepatocellular carcinoma (HCC) develops in chronic HCV once cirrhosis is established and HCV is the commonest cause of HCC in countries like Japan and second to HBV in Africa. Diagnosis of HCV depends heavily upon detection of antibodies to HCV (anti-HCV) by an enzyme linked immunoassay (ELISA). The test has high sensitivity and specificity (more than 95 percent). Anti-HCV positive test in patients with chronic hepatitis and cirrhosis is nearly diagnostic of HCV infection. Anti-HCV may be nonreactive in immunosuppressed patients such as those on renal dialysis, on chemotherapy and those coinfected with HIV. In such patients a nucleic acid test for HCV (HCV RNA) should be used if HCV infection is under consideration. False positive test may occur in persons with normal liver tests and no known liver disease or identified risk factors and demands further supplemental testing for HCV infection. Earlier RIBA (Recombinant immunoblast assay) has been utilized to increase specificity of anti-HCV

reactive test in this group of patients. But now with easy availability of nucleic acid testing, HCV RNA PCR is ideal to confirm or refute HCV infection in such patients. HCV therapy has been revolutionized in the past decade and as of today a combination of pegylated interferon and ribavirin is the standard treatment. The response to such therapy is evaluated by early virologic response (EVR), end of treatment response (ETR) and sustained virologic response (SVR). SVR defines cure of infection as relapse after SVR is less than 2 percent. Only a select group of patients with HCV infection fit in to criteria for antiviral therapy. Contraindications to therapy include pregnancy, pregnancy in a partner, contemplating a pregnancy, unwillingness to adequate contraception or breast feeding (Ribavirin is a strong teratogenic agent), poorly controlled psychiatric disease (interferon can cause depression or induce suicidal reactions in those with uncontrolled depression) and symptomatic coronary artery disease (ribavirin can cause hemolysis and lead to sudden drop in hemoglobin and cause sudden deaths in patients with symptomatic coronary artery disease). Patient with established cirrhosis and portal hypertension and liver failure are relative contraindication to treatment, as liver disease and portal hypertension may worsen in these patients. Patients who have had renal transplant also cannot be treated by antiviral therapy as there is a distinct possibility of transplant rejection on such therapy. For therapy platelet counts should be above 80000 per cumm and absolute neutrophil count above 750 per cumm. Once drug therapy is contemplated, HCV RNA viral load and HCV genotype are key to define the success to treatment. HCV genotype 1 and 4 achieve at best a SVR of 50 percent with therapy given for one year. Such patients need a bigger dose of ribavirin (1000 mg in patients with weight less than 75 kg and 1200 mg in patients with weight 75 kg or above). EVR is worthwhile to evaluate in such patients as it can predict chances of SVR (Cure). Most hepatologists would advice their patients to have a liver biopsy prior to starting therapy in patients with genotype 1 and 4. Genotype 2 and 3 achieve a much higher cure with antiviral therapy (over 80 percent) and such patients need only 6 months drug therapy and a low dose of ribavirin (800 mg per day). There is no need to assess EVR in such patients and a liver biopsy is not mandatory to start treatment. HCV RNA viral load is another criterion to define success of therapy. A viral load of less than 2 million viral copies per ml achieves a much higher cure than those with higher viral load. Peginterferons and ribavirin have

significant side effects that require close monitoring and frequent interventions to maintain patient safety and drug efficacy. Thus only health care providers with considerable experience with use of such therapy should treat these patients. All patients experience flu like symptoms early in therapy. Depression and neuropsychiatric manifestations are reported in 20 to 30 percent patients. Reversible neutropenia is often detected on interferons and ribavirin universally causes hemolytic anemia with a drop of hemoglobin of over 2.5 g per dl. Sometimes sudden drop in hemoglobin may occur needing blood transfusions. Autoimmune thyroiditis is often seen during interferon therapy and causes rise in TPO antibodies. A small percentage develops hypothyroid state necessitating thyroid replacement treatment. Despite these side effects, most patients complete drug therapy successfully.

Source:

Review

prepared

by

Mehnaaz

Sultan

Khuroo

MD,

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