Usefulness of Sofosbuvir and Daclatasvir combination in the treatment of HCV infection in childhood cancer patients: Experience from a tertiary care hospital

Objective: To determine the usefulness of Sofosbuvir-Daclatasvir combination in the treatment of hepatitis c virus infection in paediatric cancer. Method: The retrospective study was conducted at the Oncology Department of the National Institute of Child Health, Karachi, and comprised medical charts of patients who received sofosbuvir and daclatasvir from January 2018 to January 2022. Eﬃcacy was documented by clearance of hepatitis C virus ribonucleic acid as rapid viral response, early viral response and sustained viral response at weeks 4, 12 and 24, respectively. Drug eﬃcacy was determined by monitoring and recording adverse eﬀects. Chemotherapy protocol for the treatment of patients concomitantly receiving direct acting antivirals was modified while looking at drug-drug interactions. The total duration of direct acting antiviral therapy was 12 weeks. Data was analysed using SPSS 24. Results: Of the 804 patients with diﬀerent malignancies, 132(16.4%) were found positive for hepatitis C virus. Of them, 28(21.21%) patients were started on direct acting antivirals; 17(60.71%) boys and 11(39.28%) girls. The overall mean age was 9.93±6.12 years. The diagnosis was pre-B acute lymphoblastic leukaemia in 18(64.28%) cases, 16(57.14%) were on maintenance chemotherapy, and 18(64.28%) had genotype 1. Pre-and post-treatment mean alanine transaminase levels were 328.00±324.00IU and 36.00±29.00IU, respectively ( p =0.003). Pre-and post-treatment mean serum bilirubin levels were 3.13±3.95mg/dl and 0.61±0.21mg/dl ( p =0.022). Rapid viral response was achieved in 26(92.85%) children, while early viral response and sustained viral response were achieved in all 28(100%) patients. Minor side eﬀects were noted in 4(14.28%) patients and chemotherapy was continued in all 28(100%) cases as per the designed protocol. Conclusion: The sofosbuvir-daclatasvir combination was found to be eﬀective in hepatitis C virus treatment in paediatric cancer patients.


Introduction
Chronic hepatitis C virus (HCV) infection in paediatric patients is mostly asymptomatic, but in cases of comorbidities like malignancies, it becomes challenging because of rapid course of progression to liver fibrosis.There is a significant need of transfusion of blood products in cancer patients either due to disease consequences or due to myelosuppression secondary to chemotherapeutic agents. 1,2There can be complications associated with such transfusion, especially the transmission of viruses, including hepatitis B, hepatitis C and human immunodeficiency virus (HIV), if appropriate screening protocols are not followed.While in high-income countries (HICs), there is decreased incidence of infection transmission with the utilisation of proper screening procedures, the situation is alarming in low-and middle-income countries (LMICs).The prevalence rates for HCV infection in cancer patients ranges from 1.50% to 32%. 3,4As severe adverse effects are expected with the recommended interferon-ribavirin treatment, this combination is not to be given simultaneously with chemotherapy.Direct acting antivirals (DAAs) were introduced in 2013 and after the emergence of new generations of drugs, the eradication rate of HCV infection has been reported between 90% and 95% with very few side effects. 5,6][9][10][11] A study about the concomitant use of DAAs in adult patients on cancer chemotherapy reported 95% eradication of HCV infection and no significantly increased side-effects except some drug-drug interactions. 12The concomitant use of these drugs with chemotherapy in children, however, has not been studied.Keeping in view the severity of HCV infection in cancer patients, the current study was planned to determine the efficacy of sofosbuvir-daclatasvir

Patients and methods
The retrospective study was conducted at the Oncology Department of the National Institute of Child Health, Karachi, and comprised medical charts of patients who received sofosbuvir (SOF) and daclatasvir (DAC) from January 2018 to January 2022.After approval from the institutional ethics review board, data was retrieved from medical records.Clinical and laboratory data of children with different malignancies who received sofosbuvirdaclatasvir combination was recorded in a proforma.The potential drug-drug interactions of DAAs and chemotherapeutic agents were checked online (www.hepdruginteractions.org). 13OF was safe with chemotherapeutic agents, while DAC had theoretical interaction with a few agents, including methotrexate with increase chances of haematological toxicities.Dexamethasone, on the other hand, enhances enzyme CYP3A4 metabolism, decreasing the DAC concentration.Serum concentration of dactinomycin was reported to be increased when combined with DAC.While looking at these interactions, chemotherapy protocols of patients concomitantly receiving DAAs were modified (Annexure) in line with studies where rapid viral response (RVR) was one of the most important tools to predict DAA treatment outcomes. 11,14,15nexure: The subjects represented a special immunocompromised paediatric population being treated for their underlying malignancy for whom there was no standard of care related to DAA therapy.As such, they were evaluated with quantitative HCV PCR and genotype assessment.Besides, the facility of conducing these tests was available at the study site, and these were done free of cost to the patients.Dose of once daily 200mg and 400mg SOF was prescribed to patients aged ≤5-11 years and >11 years, respectively.Once daily dose of DAC 30mg and 60mg was given to patients aged ≤5-11 years and >11 years, respectively.Laboratory investigations were recorded at week 1 and 2, followed by 2 weekly assessments till completion of 12 weeks of DAA therapy.After initiation of DAAs, quantitative HCV PCR analysis was performed at weeks 4, 12 and 24.As was the case in previous paediatric studies, 11,16,17 patients in the current study were given 12-week DAA therapy while keeping an eye on their serial RVR, EVR and ETR levels.These children with cancer had no concomitant chronic liver disease, therefore fibrosis-4 index (Fib-4) or aspartate aminotransferase-to-platelet ratio index (APRI) or fibroscan were not utilised.
Data was analysed using SPSS 24.Descriptive statistics were calculated for qualitative and quantitative variables.Qualitative variables were presented as frequencies and percentages.Quantitative variables were presented as mean and standard deviation.Data normality was tested and Shapiro-Wilk test was used for pre-treatment (baseline) and post-treatment biochemical parameters, including alanine transaminase (ALT), which was earlier known as serum glutamic-pyruvic transaminase (SGPT), AST, which was earlier known as serum glutamic-oxaloacetic transaminase (SGOT), and serum creatinine.For normally distributed data, paired T test was used, while nonparametric Wilcoxon sign rank test was used if the variables did not meet the assumption of normality.P<0.05 was taken as significant.

Open Access J Pak Med Assoc
Hepatomegaly was present in 10(37%) patients.There were 3(10.7%)patients who did not complain of any specific symptoms and only had deranged laboratory parameters.
Mean haemoglobin (Hb) level, mean platelets and white blood cell (WBC) counts, absolute neutrophil count (ANC) value and serum creatinine level were in normal range prior to initiation of SOF-DAC combination and there were no significant changes post-treatment (p>0.05).Posttreatment values for both the mean ALT and mean serum bilirubin levels showed significant decline (Table 2).
Of the 24(85.71%)children who had ALT value >50mg/dl prior to DAA therapy, 20(83.33%)achieved a significant (p<0.05)reduction and the levels came down to the desirable level of <50mg/dl, resulting in uninterrupted chemotherapy scheduling.
RVR was achieved in 26(92.85%)children, and only 2(7.14%) patients had RNA load <12.00IU, while EVR and SVR were achieved in all 28(100%) patients.Minor side effects were noted in 4(14.28%)patients; 2(50%) had generalised body ache, 1(25%) developed headache in the first two weeks of treatment, and 1(25%) experienced pruritus while on SOF-DAC therapy.All 4(100%) patients were treated symptomatically, and chemotherapy was continued in all 28(100%) cases as per the designed protocol.Treatment was well tolerated, and no drug-drug interaction was reported.

Discussion
To the best of our knowledge, the current study is the first to evaluate the usefulness of DAA in paediatric oncology population.Standard of care anti-HCV therapy is not defined in patients with cancer.In addition, there are no guidelines for the timing of DAA administration with respect to the individual anti-cancer treatment schedule in patients with HCV and cancer.
HCV infection affects millions of people worldwide and the main mode of its transmission is the use of contaminated medical material.9][20] For the oncology population, in some regions of Europe and Asia, HCV antibodies have been reported in up to 2.8% of patients with solid tumours and 30% of those with haematological malignancies. 21,22e management of HCV-infected patients was compromised in the past, likely due to difficulties in treating them concomitantly with chemotherapy and older HCV therapy, such as interferon.With the arrival of DAAs, their treatment standards have changed as the virological clearance rate is documented even in cancer patients   having HCV infection.Torres HA et al. 23 showed that the SVR rates, regarded as indicating HCV cure, are now similar in HCV-infected patients with and without cancer.
The current study provided some insight into the usefulness of DAA therapy in immunocompromised paediatric cancer patients with concomitant HCV infection.There are recent similar studies done in adult cancer patients with liver disease. 24In the paediatric population, encouraging results regarding the use of DAAs including the SOF-DAC combination are available, indicating their positive efficacy and favourable safety profiles. 15,25thing, however, has been published for this special subset of patients with childhood cancer that is likely to receive multiple injectable medications and repeated blood transfusions during the illness and treatment.In the current study, there were 5 children aged <5 years.This is because the most common underlying malignancy was ALL.
As reported earlier, 26 hepatitis flare occurs in 26% to 45% of HCV-infected cancer patients in the absence of liver infiltration by tumour or use of hepatotoxic drugs other than chemotherapeutics, and can lead to liver dysfunction that necessitates discontinuation or dose reduction of potentially life-saving chemotherapy.In our study, ALT levels were abnormal in 24(86%) patients; of them, 6(25%) had levels >500mg/dl and if they were not started on DAAs, chances of chemotherapy completion were bleak.In these circumstances, with the use of DAA therapy, the parameters normalised signifying the fact that these alterations were secondary to HCV infection.When the liver functions improved, it was possible to continue with the chemotherapy.Hence, chances of their disease remission also enhanced.In addition to this huge benefit, the use also helped in the prevention of progressive liver damage in terms of the development of chronic liver disease (CLD) and liver cirrhosis.
The guidelines issued by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) 27 mentioned that a ≥10-fold increase in ALT values from baseline, especially with signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalised ratio (INR) at any time during treatment should prompt discontinuation of DAA therapy.In the current series, none was observed.Once the LFT normalises, patients do not have to wait for another 24 weeks to resume chemotherapy.
In order to maintain the balance of treating HCV infection while also taking care of their primary disease and without subjecting them to unnecessary exposure to adverse events (AEs) during the initial 4 weeks of therapy, patients were closely monitored.RVR is one of the most powerful tools for predicting treatment response 14 and RVR in the current study was achieved in 93% of the children.
AEs were earlier reported with simultaneous use of antineoplastic agents [28][29][30] and were largely attributed to chemotherapy.This issue together with the possibility of drug interactions poses a challenge while managing children with cancer.It is therefore crucial to monitor patients and recognise any serious AE timely.It is also important to note that when AEs occur, they usually appear within the first 2-4 weeks of concomitant therapy. 24In the current patients, only a few AEs were observed while no toxic effect was observed that required discontinuation of either agent.
It is significant that the primary disease of all the current subjects remained in remission after completion of DAA therapy.Therefore, HCV infection and its treatment should not be considered contraindications to cancer treatment.HCV-targeted DAA can be used concomitantly with selective anti-neoplastic agents.However, a dedicated, multidisciplinary approach with close monitoring is mandatory.
The current study has limitations, including the sample size which was too small to allow meaningful generalisation of the findings.Also, the patients were in the less intensive phase of chemotherapy when DAAs were used.Further prospective trials of DAAs and chemotherapeutic agents in HCV-infected paediatric oncology population are required.

Conclusion
The SOF-DAC combination was found to be effective in HCV treatment, and it may be used in patients with selected chemotherapy drugs with due monitoring and modification of treatment protocols.

Phase of chemotherapy: Continuation phase Age: 4 years and above First 2 weeks: No
Chemotherapy, Monitor CBC, LFTS, Cr, PT, INR WK 2-4: Monitor CBC, ANC, Cr, LFTs Vinblastine @50% dose WK 4: PCR Results, Monitor CBC, ANC, LFTs, Cr, PT, INR PCR Negative patients: Vinblastine @ 100% dose PCR Positive patients: -With normal labs (CBC, ANC, LFTs, and Cr): Vinblastine @75% dose -With abnormal labs: Hold chemotherapy for 1 week & repeat labs WK 5 -12: PCR Negative patients: Monitor CBC, ANC, LFTs, Cr.Vinblastine @ 100% dose, Repeat PCR AFTER 12 WEEKS OF DAA PCR Positive patients: -With normal labs: Vinblastine @75% dose.Repeat PCR AFTER 12 WEEKS OF DAA -With Abnormal labs: No chemo, Monitor CBC, ANC, LFTs, Cr, PT,INR, albumin Repeat PCR AFTER 12 WEEKS OF DAA After WK 12: PCR Negative Patients will receive chemotherapy as per standard of care treatment protocol PCR Positive patients: -With normal labs: Vinblastine @ 75% doses, discuss DAA replacement option with hepatologist -With Abnormal labs: No chemo, discuss DAA replacement option with hepatologist Patient category: Wilm's Tumor (WT) Phase of chemotherapy: Continuation phase Age: 4 years and above First 2 weeks: NO CHEMOTHERAPY, Monitor CBC, LFTS, Cr, PT, INR WK 2-4: Monitor CBC, ANC, Cr, LFTs Vincristine @50% dose WK 4: PCR Results, Monitor CBC, ANC, LFTs, Cr, PT, INR PCR Negative patients: Vincristine @ 100% dose, Doxorubicin @ 50% dose, No Dactinomycin Usefulness of Sofosbuvir and Daclatasvir combination in the treatment of HCV infection …… PCR Positive patients: -With normal labs (CBC, ANC, LFTs, and Cr): Vincristine @75% dose, Doxorubicin @25% dose, No Dactinomycin -With abnormal labs: Hold chemotherapy for 1 week & repeat labs -With Abnormal labs: No chemo, discuss DAA replacement option with hepatologistData analysed related to paediatric cancer patients of either gender aged 3-18 years who were in remission and having baseline HCV polymerase chain reaction (PCR) data available.Data of patients with relapse of primary disease, patients who were not in remission and whose records were incomplete was excluded.Also excluded was data of patients who had concomitant hepatitis B virus (HBV) infection.

Table - 3
: Efficacious impact of DAAs on bilirubin and ALT levels.