Hepatitis C


Article Author:
Hajira Basit
Isha Tyagi


Article Editor:
Janak Koirala


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/15/2019 4:28:41 PM

Introduction

First diagnosed in 1989, hepatitis C virus (HCV) is a major public health problem affecting 185 million people worldwide. The percentage of people who are seropositive for anti-HCV antibodies worldwide is estimated to have increased from 2.3% to 2.8% between 1990 to 2005. Most patients (80% to 85%) who become acutely infected cannot clear the virus and progress to chronic infection. The effects of chronic infection include cirrhosis, portal hypertension, hepatic decompensation with encephalopathy, and hepatocellular carcinoma. The landscape of treatment has evolved substantially since the introduction of highly active direct-acting antivirals (DAAs) in 2011. The goals of treatment aim at viral eradication, delay fibrosis progression, alleviate symptoms, prevent complications, minimize all-cause mortality, and ultimately maximize the quality-of-life.[1][2][3]

Etiology

HCV is a spherical, enveloped, positive-strand ribonucleic acid (RNA) virus that is approximately 55 nm in diameter. It is a member of the family Flaviviridae, yet distinct to be classified as a separate genus, Hepacivirus. The genome is approximately 9.6 kb in length. It encodes a polyprotein that is then processed into at least 10 proteins. These include three “structural” proteins, the nucleocapsid protein, core (C), and two envelope proteins (E1 and E2); two proteins that are essential for virion production (p7 and NS2); and five nonstructural proteins that are an essential part of the viral replication complex (NS3, NS4A, NS4B, NS5A, and NS5B). There is a very high level of virion turnover by the NS5B RNA polymerase with an absence of proofreading, resulting in the generation of viral mutants also known as "quasispecies."[4][5][6]

Epidemiology

Globally, it is estimated that more than 185 million people are living with HCV. As per the Centers for Disease Control estimates from 2013, approximately 2.7 to 3.9 million people are living with HCV worldwide. In developed nations, the HCV prevalence is typically 1% to 2%. The number of acute cases of HCV reported in the United States increased each year from 2009 to 2013. After adjusting, an estimated 29,718 acute HCV cases occurred in 2013. Of the three types of viral hepatitis (hepatitis A, B, and C), HCV accounted for the greatest number of deaths and the highest mortality rate, 5.0 deaths/100,000 population in 2013. HCV transmission requires that infectious virions contact susceptible cells that allow replication. HCV RNA can be detected in blood (including serum and plasma), saliva, tears, seminal fluid, ascitic fluid, and cerebrospinal fluid. Available data suggest that HCV may be transmitted during sexual intercourse, but this rarely occurs. Perinatal transmission frequency ranges from 0% to 4% in larger studies. But for most patients with HCV in the United States and Europe, the infection is acquired via intravenous drug abuse or poor medical practices in resource-limited areas of the world.[7]

As per the most updated classification, there are seven genotypes of HCV based on their nucleotide variability in HCV sequences recovered from multiple geographic regions. 

  • Genotype 1: the most widely dispersed worldwide, 60% to 70% of isolates from the United States are subtype 1a or 1b
  • Genotype 2: widely dispersed but most diverse in central and west Africa
  • Genotype 3: widely distributed but most diverse in Asia, linked to illicit drug use
  • Genotype 4: Northern Africa and the Middle East. 
  • Genotype 5: South Africa
  • Genotype 6: Southeast Asia. 
  • Genotype 7: Central Africa (Congo)

Pathophysiology

The Hepatitis C RNA virus enters the hepatocyte via endocytosis mediated by at least four co-receptor molecules. Following internalization in the cytoplasm, its positive-stranded RNA is uncoated and translated into ten mature peptides. These are then cleaved by both host proteases and virally encoded proteases known as NS3-4a serine proteases. These mature peptides then go on to reside on the endoplasmic reticulum, forming a replication complex which contains an important enzyme, the NS5B RNA dependent RNA polymerase. This enzyme catalyzes the positive RNA strand into its negative-strand intermediate which in turn serves as the template for new positive-strand synthesis. These are then packaged with core and envelop glycoprotein into mature virions which then exit the cell via exocytosis. HCV has no ability to integrate into the host's genome. The virus can be detected in plasma within days of exposure, often 1 to 4 weeks. Viremia peaks in the first 8 to 12 weeks of infection, and then plateaus or drops to undetectable levels (viral clearance); in the majority, 50% to 85% it persists. Persistent infection appears to be due to weak CD4+ and CD8+ T-cell responses which fail to control viral replication. When chronic infection is established, HCV does not appear to be cytopathic; it is the local inflammatory response that triggers fibrogenesis. Multiple external factors including alcohol consumption, HIV/HBV coinfections, Genotype 3 infection, insulin resistance, obesity, and non-alcoholic fatty liver disease are linked to accelerated fibrosis progression and cirrhosis. The severity of liver fibrosis is tightly correlated with the increased risk of hepatocellular carcinoma via facilitating genetic aberrations and promoting neoplastic clones.[8]

History and Physical

Although usually not associated with symptoms, acute HCV infection may cause malaise, nausea, and right upper quadrant pain, followed by dark urine and jaundice. This is clinically indistinguishable from any other acute viral hepatitis. Persistently infected individuals tend to be asymptomatic for the most part. Symptoms are nonspecific and include fatigue or malaise, intermittent right upper quadrant pain, and joint pain as well as a general feeling of being unwell with an overall reduced quality of life. It is challenging to relate these symptoms to HCV alone, as there could be a potential psychological basis due to the knowledge of having an underlying chronic disease. Ten percent to 20% of HCV-infected persons with cirrhosis will decompensate clinically within 5 years, as evidenced by the development of portal hypertension, esophageal varices, ascites, coagulopathy, encephalopathy, or hepatocellular carcinoma. At this stage, they could have physical signs indicating stigmata of chronic liver disease with caput medusae, spider angiomas, palmar erythema, asterixis, anasarca, and fluid thrill. Moreover, they may have signs and symptoms of other extrahepatic manifestations like mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, neurocognitive changes, insulin resistance, and B cell lymphoproliferative disorders. 

Evaluation

 The diagnosis of HCV infection is based principally on detection of antibodies to recombinant HCV polypeptides and by assays for HCV RNA. These are enzyme immunoassays that measure antibodies directed against NS4, core, NS3, and NS5 sequences. These cannot differentiate between past or current HCV infection. Direct testing for HCV RNA is necessary to distinguish between ongoing or prior infection in persons with HCV antibodies. HCV Rapid Antibody Test with rapid turnover can be important public health tools in nontraditional settings. There are three scenarios in which HCV RNA test should be considered upfront: (1) exposure within the past 6 months, (2) an immunocompromised host, and (3) suspicion for reinfection. Further evaluation consists of checking the viral genotype, which is still important in choosing the most optimal regimen and also for predicting the response to therapy. Other baseline evaluations include testing for HIV, hepatitis B surface antigen, susceptibility to hepatitis A and hepatitis B virus infections, and screening for other underlying causes of liver disease such as autoimmune liver disease, hemochromatosis, and Wilson disease. Before determining the HCV treatment strategy, the next step is to stage the disease, utilizing liver biopsy (gold standard) or approved imaging modalities with or without noninvasive biomarkers. Lastly, all of these patients should also undergo variceal screening and screening for hepatocellular carcinoma.[9][10][11]

Treatment / Management

Treatment can permanently eradicate HCV infection such that HCV RNA is no longer detectable in blood or liver with a decline in antibody titers and improved liver pathology. Before the development of the all-oral DAAs, the mainstay of therapy was injectable pegylated interferon and ribavirin. In addition to only having a cure rate of 40% to 60%, this form of treatment led to numerous adverse effects, including flu-like illness; hematological effects like neutropenia, thrombocytopenia, and severe anemia; and neurocognitive effects. With the advent of DAAs, immense progress has been seen toward shortening the duration of treatment from 48 weeks to 12 weeks, improving the adverse effects, increasing cure rates to 90% to 97%, and eliminating the need for injectable agents. Currently, three classes of DAAs include (1) second-generation protease inhibitors that inhibit the NS3/4 serine proteases, (2) the NS5A inhibitors which interferes with the structural protein NS5A, a crucial element in the formation of the replication complex and (3) the NS5B polymerase inhibitor which inhibits the enzyme responsible for transcription of a negative strand intermediate for future viral progeny. These three classes are used in different combinations to make a robust treatment regimen against the various genotypes of hepatitis C.[6][12][13]

The standard regimens are anywhere from 12 weeks to 24 weeks with or without ribavirin based on the genotype, treatment experience, and presence or absence of cirrhosis. With the current DAAs, it is the Genotype 3 infection which is the least responsive that is associated with rapid accelerated fibrosis progression and a higher incidence of hepatocellular carcinoma. Genotype 1, the most common genotype present in the United States, has four different treatments approved, two of these require only a single pill/day. For example, the combination of sofosbuvir and ledipasvir in a single pill and the combination of grazoprevir and elbasvir as a single pill. There are many more drugs in phase III and IV clinical trials which appear to have a pangenotypic potential such that will eliminate the need to check hepatitis C genotype. Defining each regimen for the various genotypes is beyond the scope of this chapter.

Pearls and Other Issues

Several other crucial issues are related to treating hepatitis C in special populations, for example, individuals who are co-infected with HIV and Hepatitis C. Many drug-drug interactions are encountered between the patient's antiretroviral therapy and the oral DAAs for Hepatitis C. With co-infected individuals with Hepatitis B, there have been case reports of Hepatitis B reactivation due to the phenomenon of viral interference. Treating Hepatitis C in patients with end-stage renal disease poses another challenge in itself although progress has been made and there are regimens for them. Numerous drug-drug interactions between Hepatitis C drugs and their immunosuppressive medications have been encountered in patients who are organ transplant recipients, requiring frequent blood level monitoring. Antiviral resistance is a new adverse event brought about by the use of DAA agents; it needs to be keyed in when selecting a regimen in previously treated individuals, and with some drugs (e.g., elbasvir), there is enough baseline resistance before exposure. The other challenging groups include the decompensated cirrhotics (CTP stage B or C) and the recurrent hepatitis C seen after liver transplantation. Details are beyond the scope of this summary.

Enhancing Healthcare Team Outcomes

Hepatitis C is a serious infection that has high morbidity and mortality. The infection is best managed by a multidisciplinary team that also includes nurses and pharmacists. The key is that many advances have been made in the treatment of hepatitis C, which can eradicate the virus, shorten the duration of treatment and hopefully prevent hepatocellular cancer.

Following treatment with the newer drugs, monitoring is still required to ensure compliance. Current short term data indicate that the drugs can eradicate the virus from the blood stream.


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Hepatitis C - Questions

Take a quiz of the questions on this article.

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A 54-year-old woman who is a known case of hepatitis C presents to her provider with a complaint of purplish, intensely itchy lesions on her forearm and ankles that developed a few days ago. The provider explains that it is likely due to the extrahepatic manifestation of hepatitis C infection. What is the prognosis of skin lesions in patients with hepatitis C?



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To which of the following has hepatitis C infection been linked?



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What is the most common cause of cirrhosis in North America?



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Of the following, which is true regarding hepatitis C infection?



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What percentage of patients with hepatitis C have no known risk factors?



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A 30-year-old woman tests positive for hepatitis C when she undergoes screening for blood-borne infection at a blood donation camp. She presents to her primary care provider with the results, asking about the natural course of the disease. What is the most common presentation of the patients infected with hepatitis C?



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A recent spike in the cases of hepatitis C prompts a health care team to carry out community-wide screening for the prevalence of hepatitis C. What does the screening test for hepatitis C measure for the diagnosis?



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Which of the following is false about complications of hepatitis C?



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Which of the following vasculitis syndromes is often associated with hepatitis C?



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A young 24-year-old male with a history of IV drug abuse has developed hepatitis C. He is started on Hepatitis C treatment with the new drugs. Which of the following tests are ideal to monitor during treatment?



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Which of the following regarding hepatitis C infection is true?



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A patient with persistent minimal elevation of liver enzymes is diagnosed with hepatitis C. Which of the following is true?



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The hepatitis C virus is rarely detected in?



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What percentage of patients acutely infected with hepatitis C develop chronic hepatitis C infection?



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Which of the following statements about hepatitis C is TRUE?



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What type of virus is hepatitis C?



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In what percentage of cases do needlestick exposures to hepatitis C result in transmission?



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Which statement about the prognosis of hepatitis C infection is FALSE?



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A 25-year-old male health care provider presents to emergency with a history of needle stick injury while drawing blood from a seropositive Hepatitis C patient about an hour ago. He is very anxious about the possible outcome. What is the protocol for the health care provider who sustains a needle stick injury from a hepatitis C infected patient with detectable HCV RNA?



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A patient was found to have Hepatitis C (HCV) antibodies. Which of the following is the most appropriate intervention at this time?



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Which of the following agents are used to treat chronic Hepatitis C infection?



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Which of the following renal disease is associated with hepatitis C infection?



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A public health team wants to investigate a recent outbreak of Hepatitis C in a homeless population. Which of the following is the most common route of transmission for hepatitis C?



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A patient with persistent minimal elevation of liver enzymes is diagnosed with hepatitis C. Which of the following is true?



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What is the most common cause of cirrhosis in the USA?



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A 46 year old woman is found to be positive for HCV antibody when she donated her blood at the blood bank. She does not have any risk factors that she can recall. Her liver enzymes are within normal ranges. How would one confirm if she has an ongoing hepatitis C infection or not?



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A 50-year-old male patient with hepatitis C cirrhosis presents to his primary care provider regarding liver transplantation. He read on the Internet that the waiting time for liver transplantation is long and that one should be included "early" to improve the chances of getting timely transplantation. The patient has a past history of illicit drug use in his twenties. He does not drink alcohol and otherwise in good health. Which of the following is least likely to be considered a contraindication for orthotopic liver transplantation?



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A 50-year-old homeless man with Hepatitis C presents to the hospital with abdominal pain and ascites for three days. On arrival, his vitals are BP 90/60 mmHg, temperature 100 Fahrenheit, pulse 90/min, RR 20/min. On examination, the patient has jaundice and has caput medusae over abdomen. Radiologic studies reveal the coarse texture of the liver and ascites. Ascitic tap and blood cultures are drawn and the empiric antibiotic course is started. Which of the following is a relative contraindication to starting ribavirin for hepatitis C in this patient?



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A 40-year-old African American male who is a known case of hepatitis C presents to his provider for initiating his anti-viral treatment. He was diagnosed 6 months ago and has had persistent viremia. Which of the following patient characteristics are associated with a favorable response to the treatment for hepatitis C?



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A 55-year-old South-East Asian immigrant woman is admitted to the hospital with the complications of cirrhosis. She had been in a usual state of health until a few months ago when she started experiencing fatigue and right upper quadrant pain. Her past history is significant for a blood transfusion for profuse bleeding associated with a complication of childbirth in her home country. She does not drink alcohol regularly. Which of the following is the most likely cause of her current liver disease?



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A 35-year-old man presents to his primary care provider with complaints of fatigue, intermittent right upper quadrant pain and joint pains for the last five months. Initially, he ignored the symptoms, but now he gets exhausted with minimal work. He used to have a very active lifestyle before the onset of these symptoms. On inquiry, the patient admits the occasional use of intravenous drugs with his friends for recreation, and they sometimes share needles. Due to this history of exposure, the primary care provider wants to rule out HIV, Hepatitis B, and Hepatitis C infection. Which of the following is the one best screening test for hepatitis C for this patient?



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A 40-year-old homeless women is recently diagnosed with hepatitis C. She has had no symptoms except for excessive fatigue for last two months. She wants to be counselled regarding the natural course of the disease. Which of the following best answers her question regarding the natural course of the disease?



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What group is the CDC recommending a one-time screen for hepatitis C?



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A male patient is newly diagnosed with hepatitis C infection. Which of the following lifestyle factors should he avoid to prevent liver fibrosis?



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A patient with male hepatitis C has been consuming alcohol despite being advised this could harm him. He says he only drinks half a bottle of beer every day. According to guidelines, the likelihood of liver fibrosis is high when patients consume how much alcohol every day?



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A female patient with is newly diagnosed with hepatitis C. Before starting treatment studies are sent to determine the hepatitis C genotype. On what will this provide information?



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A hospital quality care team wants to reduce the risk of transmission of hepatitis C in the health care workers caring for infected patients. Which of the following is a necessary precaution to follow while dealing with the patients infected with hepatitis C?



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A 38-year-old male with severe substance use disorder presents to the hospital with complaints of right upper pain, which he rates 10/10 for intensity. He has had multiple admissions in the past for malingering. However, this time, the provider also notices jaundice and mild fever. Further evaluation reveals positive results for HIV and hepatitis C. What percentage of patients acutely infected with Hepatitis C progress to chronic hepatitis C infection?



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A nurse trainee presents the emergency department with a complaint of needle stick injury while caring for a hepatitis C positive patient. The provider counsels her that she would only require monitoring for six months. What bodily fluid is least likely associated with the transmission of hepatitis C?



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Hepatitis C - References

References

Mashiba T,Joko K,Kurosaki M,Ochi H,Hasebe C,Akahane T,Sohda T,Tsuji K,Mitsuda A,Kimura H,Narita R,Ogawa C,Furuta K,Shigeno M,Okushin H,Ito H,Kusakabe A,Satou T,Kawanami C,Nakata R,Kobashi H,Tamada T,Ide Y,Yagisawa H,Morita A,Matsushita T,Okada K,Izumi N, Real-world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group. Hepatology research : the official journal of the Japan Society of Hepatology. 2019 May 11;     [PubMed]
Morales-Arraez D,Alonso-Larruga A,Diaz-Flores F,García Dopico JA,de Vera A,Quintero E,Hernández-Guerra M, Predictive factors for not undergoing RNA testing in patients found to have hepatitis C serology and impact of an automatic alert. Journal of viral hepatitis. 2019 May 11;     [PubMed]
Feld JJ, Extending a Helping Hand: Addressing Hepatitis C in Economic Migrants and Refugees. Annals of hepatology. 2018 Jan - Feb;     [PubMed]
Galati G,Muley M,Vigano M,Iavarone M,Vitale A,Dell'Unto C,Lai Q,Cabibbo G,Sacco R,Villa E,Trevisani F, Occurrence of hepatocellular carcinoma after direct-acting antiviral therapy for hepatitis C virus infection: literature review and risk analysis. Expert opinion on drug safety. 2019 May 8;     [PubMed]
Kamimura K,Sakamaki A,Kamimura H,Setsu T,Yokoo T,Takamura M,Terai S, Considerations of elderly factors to manage the complication of liver cirrhosis in elderly patients. World journal of gastroenterology. 2019 Apr 21;     [PubMed]
Parigi TL,Torres MCP,Aghemo A, Upcoming direct acting antivirals for hepatitis C patients with a prior treatment failure. Clinical and molecular hepatology. 2019 May 2;     [PubMed]
Mukhtar NA,Ness EM,Jhaveri M,Fix OK,Hart M,Dale C,Pratt C,Kowdley KV, Epidemiologic features of a large hepatitis C cohort evaluated in a major health system in the western United States. Annals of hepatology. 2019 Apr 17;     [PubMed]
Soi V,Daifi C,Yee J,Adams E, Pathophysiology and Treatment of Hepatitis B and C Infections in Patients With End-Stage Renal Disease. Advances in chronic kidney disease. 2019 Jan;     [PubMed]
Simoncini GM,Koren DE, Hepatitis C Update and Expanding the Role of Primary Care. Journal of the American Board of Family Medicine : JABFM. 2019 May-Jun;     [PubMed]
Maticic M,Zorman JV,Gregorcic S,Schatz E,Lazarus JV, Changes to the national strategies, plans and guidelines for the treatment of hepatitis C in people who inject drugs between 2013 and 2016: a cross-sectional survey of 34 European countries. Harm reduction journal. 2019 May 9;     [PubMed]
Lam JO,Hurley LB,Chamberland S,Champsi JH,Gittleman LC,Korn DG,Lai JB,Quesenberry CP Jr,Ready J,Saxena V,Seo SI,Witt DJ,Silverberg MJ,Marcus JL, Hepatitis C treatment uptake and response among human immunodeficiency virus/hepatitis C virus-coinfected patients in a large integrated healthcare system. International journal of STD     [PubMed]
Oraby M,Khorshed A,Abdul-Rahman E,Ali R,Elsutohy MM, A clinical study for the evaluation of pharmacokinetic interaction between daclatasvir and fluoxetine. Journal of pharmaceutical and biomedical analysis. 2019 Jul 15;     [PubMed]
Cunningham HE,Shea TC,Grgic T,Lachiewicz AM, Successful treatment of hepatitis C virus infection with direct-acting antivirals during hematopoietic cell transplant. Transplant infectious disease : an official journal of the Transplantation Society. 2019 Apr 10;     [PubMed]

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