Unexpected Response Profiles Seen in Hepatitis C Virus-Infected Patients Treated with Sofosbuvir Plus Ribavirin: Five Case Reports

Introduction

Chronic hepatitis C virus infection is prevalent worldwide with annual global bioburden of 175 million chronic infections and more than 3.5 million deaths (10). Its tropism for liver worsens the disease with hepatic cirrhosis and progression to hepatocellular carcinoma (11). The therapeutics has evolved from conventional interferon-based therapies to the development of direct antiviral drugs. These interferon-free novel therapeutic strategies have competitively entered clinical setting since 2014–2015 because of the wide spectrum of side effects associated with interferon-based therapy (6).

This era of direct-acting antivirals (DAAs) has emerged with six to seven FDA-approved drugs. Sofosbuvir (SOF), a polymerase inhibitor is one among these DAAs, with a worldwide satisfactory success ratio (1). SOF is the center of attraction for its minimal side effects, oral administration, and high efficacy (4,7). SOF is a directed combination therapy, depending upon the verge of disease, genotype, and other parameters. This drug is effective in about 95% of hepatitis C virus (HCV) patients (9,14). Many cases of null response of HCV patients toward DAA have been recorded because of preexisting resistance mutations (2,5,12).

In this study, we reported a series of patients who have successfully undergone SOF treatment, but experienced an irregular and steeply high viral load around the middle of therapeutic period compared with the initially detected viral load. The viral loads were analyzed periodically after every 3 months, using the GenXpert technology. HCV was completely eradicated by the end of 24 weeks of treatment, but unusually experienced an increase in viral load during the initial therapy period. Further studies are needed to investigate such type of parameters in human body which are responsible to raise the viral load during treatment and then eradicate at end of treatment. We reported here the unusual response of five patients toward direct-acting antiviral drugs. The GenXpert polymerase chain reaction (PCR) analysis exhibited an increase in viral load during the treatment followed by complete elimination of virus after the completion of 6 months' therapy.

Reported Case-1

A 53-year-old woman was diagnosed with HCV-3a genotype on April 3, 2016. This was her first quantitative test for HCV conducted in response to her clinical symptoms and positive ELISA reports. Her first viral load was detected 1,587,669 IU/mL (Table 1). She had normal size of liver, but was suffering from spleenomegaly. Her liver functioning tests showed elevated liver enzymes—aspartate aminotransferase (AST) 60 IU/L (reference range <37 IU/L), alanine aminotransferase (ALT) 50 IU/L (reference range <42 IU/L), alanine phosphatase (ALP) 225 IU/mL (reference range <115 IU/mL), and bilirubin 0.7 mg/dL (reference range <0.2 mg/dL) (Table 2). After 3 months of treatment with sofosbuvir+ribavirin, her liver function tests (LFTs) and HCV test were taken to observe her health status. Her second viral load was elevated to 10 times and was detected 10,587,080 IU/mL (Table 1). She continued the same sofosbuvir-based regimen for another 3 months.

On October 7, 2016, at the end of 6 months' sofosbuvir-based treatment, HCV was not detected in her HCV quantitative PCR. Her body weight dropped during the treatment. Her platelet count also showed abnormal behavior with initial value 86,000 per microliter and a drop in platelet count in the middle of treatment to 37,000 per microliter, and then, a final raise to 72,000 per microliter. Her liver enzymes also showed peaked up values: AST 71 IU/L (reference range <37 IU/L), alanine aminotransferase (ALAT) 55 IU/L (reference range 42 IU/L), ALP 334 IU/mL (reference range <115 IU/mL), and bilirubin 1.4 mg/dL (reference range <0.2 mg/dL) (Table 2). The patient was not suffering from any other infection during this time period. The unusual viral peak up and then diminished viral response were observed (Table 1).

Reported Case-2

In July 2016, a 35-year-old female was referred to gastroenterologist at the hospital. The patient's blood report showed elevated level of liver enzymes: ALP 175 IU/L (normal range 30–115 IU/L), AST 45 IU/L (normal range 5–43 IU/L), and had HCV antibodies (Table 2). The patient was infected with HCV-3a and the viral load determined by PCR was 1,597 IU/mL. The time and route of transmission of the infection were not known. The Abdominal ultrasound report showed that the liver was moderately fatty, but normal in size. Similarly, there was no change in spleen size, however, pancreas size was abnormal and showed altered appearance. Combined therapy sofosbuvir+ribavirin was given to the patient for 24 weeks.

In October 2016, the patient completed 12 weeks antiviral treatment, but when PCR test was performed to check the treatment response, the results did not show any decrease in viral load. In fact, viral load was increased from 1,597 to 5,150 IU/mL, which indicated patient's resistance to therapy. However, the patient's viral load was undetected over a total time period of 6 months' treatment (Table 1).

Reported Case-3

In February 2016, a 27-year-old female with previous history of HCV infection was referred to the diagnostic laboratory for HCV PCR test. On February 5, 2016, the report of the patient showed a viral load of 95,140 IU/mL (Table 1). The HCV genotype of a patient was detected 3a. The patient had completed the interferon therapy. Her reports of liver enzymes showed an elevated level of AST 41 IU/L (reference range <37 IU/L), alanine aminotransferase (ALT) 55 IU/L (reference range <42 IU/L), ALP 125 IU/mL (reference range <115 IU/mL), and bilirubin 0.5 mg/dL (reference range <0.2 mg/dL) (Table 2). Her liver and spleen size were normal. Her hemoglobin level was 9.3 mg/dL, and platelet count was 195,000 per microliter. Sofosbuvir+interferon+ribavirin therapy was administered to her for 3 months, and after that, her viral load was raised unexpectedly instead of going down. On May 13, 2016, the viral load was detected 307,914 IU/mL. Her liver enzymes values and platelet count also showed an abrupt increase as shown in Table 2. The patient was advised the same regimen for 3 months further. On October 18, 2016, after 6 months' sofosbuvir treatment the patient was again tested for HCV, and the viral load was undetectable (Table 1).

Reported Case-4

A 52-year-old male patient with dark urine, nausea, fatigue, and severe jaundice visited the medical center with no previous history of HCV infection. His LFT showed ALT 53 IU/L, AST 16 IU/L, ALP 114 IU/L, and bilirubin 0.5 mg/dL (Table 2). PCR analysis showed 3a genotype and initial viral load 199,164 U/mL. The patient was treated with 6-month long regimen that comprised sofosbuvir+Viron+ribavirin. After the first month of treatment his viral load was increased to 4,441,196 IU/mL, and at the end of third month of treatment, high viral load of 2,235,839 IU/mL was detected in PCR analysis. On September 5, 2016, after receiving 6 months' therapy, viral load reached an undetectable level (Table 1). Mild change in ALP, ALT, ASP, bilirubin, Hb, and platelets during the course of treatment was also observed (Table 2).

Reported Case-5

In April 2016, a 32-year-old female came to a gastroenterologist. She was diagnosed with anti-HCV antibodies positive and then referred for PCR and detected with HCV-3a. Her initial viral load was determined by PCR (viral load = 12,351 IU/mL). She denied any type of blood transfusion in the last few years. However, she told that her husband was infected with both HCV and HBV. She was given combined therapy, that is, sofosbuvir+ribavirin+viron for 6 months. After 3 months when PCR was performed again for checking response to the therapy, a dramatic increase in viral load was seen. Viral load was increased 100-fold from 12,351 to 9,089,251 IU/mL (Table 1). However, the treatment was continued. Later on after 1 month, when PCR was performed again, there was rapid clearance of virus in the blood and viral load was reached to undetectable levels. This was a totally unusual response of patients toward the given therapy. The patient also showed variation in LFTs values.

Discussion

Treatment of HCV-infected patients with 6–8 weeks of sofosbuvir-based therapy has shown efficacy in a number of treated cases. Twenty-four weeks of treatment is a standard time period to eradicate the virus completely, but therapy can be extended further depending upon patient's response. The mentioned cases have shown drastic elevation in their viral load and liver function parameters. The adverse elevations observed during the treatment need serious consideration. The patients showed unexpected fairly high values of viral loads and all the liver function parameters; bilirubin, ALP, alanine aminotransferase, and AST. The above cases demonstrate severe upregulations and are fairly abnormal. All the cases showed a similar pattern of irregularities.

In the recommendations of a recently published report of the American Association for the Study of Liver Diseases (AASLD) suggested that if HCV viral RNA is detectable at week 4 of therapy, repetitive HCV quantitative PCR for the detection of viral titer is suggested after 2 further weeks of therapy (treatment week 6). If HCV viral titer has increased by greater than 10-fold (>1 log10 IU/mL) on repeat detection of viral load at week 6 (or thereafter), then, discontinuation of HCV treatment is recommended because of lack of treatment efficacy (8). According to AASLD, the recommended regimens for treatment naive patients with compensated cirrhosis are daclatasvir+sofosbuvir with or without ribavirin (24 weeks), whereas for treatment naive patients without cirrhosis, sofosbuvir+velpatasvir or daclatasvir+sofosbuvir for 12 weeks are recommended. Here in Pakistan, Sofosbuvir is the only available direct antiviral drug that the clinicians are bound to prescribe due to nonavailability of velpatasvir, daclatasvir, and other antiviral drugs. Different therapeutic options commonly practiced in Pakistan for genotype 3 are sofosbuvir+ribavirin for 24 weeks in the interferon ineligible patients and Peg-interferon+sofosbuvir+ribavirin for 12 weeks in interferon eligible patients. Herbal drug Viron is rarely being used along with sofosbuvir because of its antiviral properties (8).

The response of DAA drugs has not been properly studied in Pakistani population, however, the recent study suggested 94.4% rapid virological response in HCV patients treated with sofosbuvir+ribavirin (3). Being team members of a diagnostic and research center, we encounter almost 150 HCV patients for PCR diagnosis. Majority of the patients attain sustained virological response after the completion of the recommended DAA therapy, but we also find many patients unresponsive with a nonvirological response. We have already reported a worthy data regarding this failure response (13). However, these few caes with strange response dragged our attention. In these patients, the viral loads were seen to increase many times unexpectedly, during treatment (12 weeks). The therapy was further extended to 12 weeks and then in repeated HCV quantitative PCR for the detection of viral load, surprisingly, we observed that the virus was completely eradicated.

Before administrating the dosage and medication to patient, the metabolic and immune response, which varies from one person to another, should be taken into account. In addition to this, affectivity might vary with the life style of every other person. For instance, lack of activity, smoking, and unhealthy diet with high content of fats may matter much toward disease and response to treatment. The degree of unhealthy physical and metabolic status of the liver is again an important factor that influences the impact. One possible cause of this unusual response is the substandard quality of drugs; millions of people die worldwide because of ingestion of fake or counterfeit drugs. All patients were treated with combination therapy comprising DAA drug with ribavirin or interferon. Three patients were treated with Sofohil manufactured by Hilton Pharma, whereas two patients used Sovaldi made by Ferozsons Laboratories Limited. Currently, there are about 20 pharmaceutical companies manufacturing DAA, therefore, the drug regulatory authority must inspect the quality efficacy, and safety of medicines. Thus, clinicians should take into account all possible related parameters before recommending the treatment and thoroughly consider the conditions in between. Moreover, the undetectable values of virus after completing the 24-week therapy should be reevaluated during follow-up sessions.

Conclusion

Based on the present study, it might be concluded that if patients show persistent or increased HCV titer after 3 months, they should continue their therapy up to 6 months. For sure, the majority of the reports and studies are highlighting the safety of use and sustained virological response with DAA. However, these case series show unusual response to the treatment. The community of clinicians and researchers should consider fore-mentioned exceptions. Moreover, government officials and policy-makers must ensure the adequate provision of all antiviral drugs so that clinicians can adhere to the internationally recommended guidelines. A Global movement is needed to create generalized access to HCV treatment and its proper guidelines in low-income countries such as Pakistan.

Ethics Approval

This study was approved by the Ethics Committee of the University.