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The Mischievous Stethoscope

Is Hepatitis C treatment for the many not the few? Analysis of Special Populations

Hepatitis C is a clinically significant disease. As explored in the last article, it is of great public health importance. It afflicts more than 71 million people worldwide, accounting for 1 per cent of the global population. [1] The WHO 2030 elimination targets for Hepatitis C encompass three key aspects: (a) reduction of incidence (the number of new cases) by 90 per cent; (b) reduction of liver-related mortality by 65 per cent, and (c) 80 per cent of those eligible to be treated. Bearing these targets in mind, public health interventions have to be carried out in the realms of prevention and diagnosis. Screening and early diagnosis come hand in hand. Unlike prostate cancer, earlier detection of Hepatitis C and related liver conditions (such as cirrhosis) is vital for earlier administration of treatment and the reduction of associated side effects. This brings us to a core pillar of the grand scheme of things: treatment. Not only do we need to ponder about the timing of treatment, but the treatment modalities involved. We need to think about the merits and deficiencies of current drug treatments and whether they truly contribute to lowered liver-related mortality.


Drugs are a double-edged sword - they can get rid of the virus, but at the same time, they can ruin the liver since the liver is also responsible for detoxification and drug metabolism. Moreover, we have to think about the applicability of current treatment modalities in certain segments of the population. Recently, a study having investigated the pharmacokinetic effects of current drug combinations (pharmacokinetics = parameters such as drug distribution and absorption; basically the physiological parameters involved when a drug enters the body) indicated for Hepatitis C treatment in pregnant women, was published on Lancet Microbe. [3] The results were encouraging, since no clinically significant differences were found in drug exposure between pregnant and non-pregnant subjects. Naturally, as a phase 1 study, the sample size was small and its findings had to be verified in larger trials. However, it was nonetheless promising. The key issue at stake here is to see if a certain treatment modality can be applicable to most people.

Illustration of the life cycle of Hepatitis C in a hepatocyte and possible therapeutic targets (extracted from: https://www.researchgate.net/figure/Hepatitis-C-virus-HCv-lifecycle-and-potential-targets-for-direct-acting-antivirals_fig1_283480425)


For hepatitis C, there are numerous modalities (to be elucidated later, hence right here, I'm going to use letter symbols): Drugs A + B; Drugs C + D; Drugs E +F, and so forth. However, the most ideal scenario is to have, say, the combination Drugs A + B rendered to be applicable, either by adjusting the dose or treatment duration, to most people in the population. With adverse events in certain subgroups investigated, weighing exercises might result in the addition of additional drugs to suppress these reactions so that Hepatitis C can be better eliminated by the continual application of this combination. For instance, some patients might experience skin rashes during the treatment. It's good to know some patients do experience this side effect and we can make provisions beforehand. Having anticipated this, through the execution of studies and consolidation of research findings into national guidelines, we may choose to give corticosteroids and/or anti-histamines to suppress the skin reactions (like urticaria rash; if it's something like Stevens-Johnson Syndrome or DRESS, it's wise to stop the drug) instead of terminating Hepatitis C treatment.


With one treatment modality being predominant, we can do the maths much more easily. I know it is not decorous to talk about money and somewhat indelicate when discussed in dignified circles, but in medicine, money is crucial. Money determines if a treatment can be popularised. Hepatitis C treatment is extremely expensive. It was discovered that median originator prices were US$ 40,502 for sofosbuvir (a very popular drug in Hepatitis C regimens) and US$ 46,812 for sofosbuvir/ledipasvir (a drug combination commonly used in Hepatitis C). Generic pricing was found to be much cheaper. Sofosbuvir (12-week course, standard) costed US$ 28, while sofosbuvir/ledipasvir, US$ 58. [4] The stark differences between brand and generic pricing indicate it is better off having drugs made by a generic producer - the producer that synthesises the drugs based on the same chemical composition as the one discovered by the original brand, after the chemical patent expires. However, there must be a reason why a generic producer decides to synthesise a drug. There must be a market large enough for that drug or a particular drug combination. If it benefits only a slender segment of the community, the level of lucrativeness is not enticing enough to lure producers into manufacturing the product. If the drug combination/single drug serves an enormous proportion of the community, multiple generic producers can join in the competition. This results in a drastic drop in drug prices and benefits patients. Crucially, this reduces the healthcare gap between high-income and lower-income countries seen in the last article, since money does not play as great a role as it did before in treatment provision and even pre-exposure prophylaxis. Hepatitis C was found to be more common in MSM and sexual interaction was increasingly established as as a means of transmission for the disease. [5] Pre-exposure prophylaxis for Hepatitis C in the future, on par with HIV, is not a remote possibility.

This diagram shows the genome of Hepatitis C - the most significant of all are NS3, NS5A and NS5B. Non-structural proteins are used to aid the reproduction of the virus, with the key phases being genomic replication and viral assembly. For instance, NS5A is used for viral assembly and RNA replication. NS5B is an RNA polymerase involved in genomic replication. NS3 is a helicase which is used to unzip the genome for the aforementioned processes to occur. Many drugs used against Hepatitis C, also known as directly-acting antiviral (DAA) therapy, target them, therefore blocking viral reproduction. For example, ledipasvir blocks NS5A and sofosbuvir blocks NS5B. They are frequently used together. This diagram is extracted from: https://f6publishing.blob.core.windows.net/3b3053e8-259a-4f1d-998a-bea60c170433/WJH-7-831-g001.jpg.


In this article, I would like to focus on (a) patients with chronic kidney disease and (b) paediatric patients (defined as younger than eighteen years of age), and the applicability of DAA regimens to these populations.


Paediatrics:


Paediatrics is a fascinating subject. It is a discipline that requires the greatest of meticulousness and the installation, in one's knowledge bank, one extra section, since paediatrics concerns diseases of individuals who either (1) cry all the time and cannot tell you what exactly is wrong, or (2) are unable to express in clear wording what's going on. Moreover, in terms of drug administration, paediatric patients are mostly smaller (in lack of a better word) than their adult counterparts. There are considerable pharmacokinetic differences - this concerns the distribution of the drugs and metabolism. Liver function is less robust in children and the dose has to be adjusted according to body weight and age group. Paediatric patients are also more prone to congenital conditions which leads to diminished or augmented effects of the drug - both therapeutic and adverse. A tricky subject on its own, we are most interested in whether contemporary treatment regimens for Hepatitis C, especially DAA, work equally well in children and adolescents.


Hepatitis C in paediatric patients is not an absolute rarity. Although it was estimated in 2018 that the percentage of children (0-18 years old) suffering from Hepatitis C globally was 0.13 per cent (95% uncertainty interval: 0.08-0.16), this translated to 3.26 million paediatric patients. The prevalence of Hepatitis C in adults was also found to be significantly correlated with prevalence in counterparts aged 5-19 years. [6] The clinical significance of the disease is also illustrated by the impairment in the quality of life in paediatric patients living with Hepatitis C. It was showed that Hepatitis C infection in paediatric patients was associated with poorer cognitive performance in the patient relative to the normative population, higher caregiver stress and more serious concern over the patient's medical circumstances. Clinical depression was also seen in 2 per cent of the patient cohort. [7] Another study showed statistically significant improvement in health-related quality of life scores in caregivers from baseline to the end of the treatment, sustained throughout the 24 weeks of follow-up after the treatment. Adolescent scores in emotional functioning also improved during follow-up. [8] Such remarkable results remind us that administering treatment leads to improved patient and caregiver well-being and reinforces the idea of holistic medicine, where decisions have to be made in light of both the patient and their families.


Current evidence is encouraging. Studies have been performed on different age groups in assessment of whether adult regimens can be entirely replicated, or replicated with dosage modifications, on paediatric populations. Per current guidelines by the Food and Drug Administration (FDA) in the US and European Medicines Agency (EMA) in Europe, the sofosbuvir/ledipasvir regimen is approved for use in adolescents (12-17 years of age) and children, irrespective of age, weighing more than 35 kilograms. The approval only applies to the standard treatment duration of 12 weeks (24 weeks if the patient has compensated cirrhosis and genotype 1 infection). It is also only applicable to infections caused by Hepatitis C Virus (HCV) genotypes 1, 4, 5 and/or 6. [9]


A study was conducted on patients aged 6-11 years who were suffering from chronic Hepatitis C. Patients received ledipasvir/sofosbuvir with or without ribavirin (guanosine analogue, affecting purine metabolism) for 12 or 24 weeks. The doses were halved relative to the adult dosage, i.e. 45 mg of ledipasvir and 200 mg of sofosbuvir per dose. The overall sustained virologic response (SVR) was very remarkable, at 99 per cent (95% CI: 94-100%, n=91/92). The remaining patient relapsed during the 4th week of follow-up. The drug combination was also safe, where the most common adverse events were headaches and fever. One patient had three non-treatment-related severe (defined as grade 3/grade 4) adverse events. The pharmacokinetic parameters were comparable to adult studies, which further justifies use of the regimen in children. Having said that, there are multiple limitations identifiable from the study. The sample size is only 92 and while it is common for earlier trials to recruit a relatively small number of people, these results can only instil confidence if they are replicated in larger, preferably multi-centre phase 3 and phase 4 trials. Moreover, the majority of patients (n=88/92) have genotype 1 infection, while the slim minority have either genotype 3 or 4 infections. This is prone to data-skewing and lowered reproducibility and generalisability. Furthermore, most patients were treatment-naive (78%), i.e. never having received treatment before. This study therefore lacks any reliable assessment of the effects of prior treatment on the efficacy of DAA. [10]


In another study, patients aged 3-11 years were given sofosbuvir and ribavirin. They were suffering from chronic HCV infection as well. However, this study focused on the effects of the regimen on genotype 2/3 infections. The treatment durations were respectively 12 weeks for genotype 2 infections, and 24 weeks for genotype 3 infections. Adjustments to dosage were made according to patient body mass, with 17 kg as the cut-off. The results were again promising. 98 per cent of patients achieved SVR at week 12 of follow-up (95% CI: 90-100%, n=53/54) with the remaining patient having discontinued treatment owing to abnormal drug taste. The most common adverse events were headaches (29 per cent) and vomiting (32 per cent). A 3-year old patient was found to have ribavirin overdose and required hospitalisation. As with the aforementioned study, inherent defects were found to be the sample size as well as the large proportion of treatment-naive patients. [11]


There are several directions that current research can adopt. These include the assessment of paediatric populations found to have treatment-resistant genotypes, requiring drug substitution. Notorious examples include genotypes 3 with the Y93H mutation and 4r. It was discovered that in 2015 to 2018, 22.5 per cent of patients who experienced virological failures during DAA therapy had genotype 4 disease. Among them, 22.3 per cent were afflicted by genotype 4r. A Rwandan study also found that, after being given sofosbuvir/ledipasvir, SVR was achieved in 56 per cent of those who had genotype 4r infection, as compared to 93 per cent in general. [12-13] Notable studies done on treatment-resistant genotypes have only recruited adult patients. There may be a clinically significant difference in SVR when paediatric patients harbour such genotypic variants. This also affects subsequent drug choice since many Hepatitis C regimens such as grazoprevir/elbasvir, are not licensed for use in children. [14] These can be efficacious in children and adolescents. Further studies have to establish the corresponding evidence base for this demographic subgroup for licensing purposes. In C-WORTHY Part D study, Grazoprevir/elbasvir with ribavirin was administered to 41 patients of varying treatment durations (12-week duration, n=21; 18-week duration, n=20). 45 per cent in the 12-week group and 57.1 per cent in the 18-week group achieved SVR on the 12th week. No significant differences in SVR percentages were found in patients with RAS (resistance-associated substitutions). 43 per cent of the patients reported to have the NS5A RAS (n=7) achieved the corresponding SVR. 51 per cent did so for patients with the NS3 RAS (n=35). [15]


Future research can also investigate whether DAA therapy can be given to younger patients. This is not normally advocated due to the fact that young patients have high growth rates and their liver function is less well-established. This can lead to greater accumulation of toxins, contributing to hepatotoxicity and other side effects. Speeding up cirrhosis with drugs that are supposed to stop HCV-progression into cirrhosis is counter-intuitive. However, as done in trials with patients aged 6-11 years old, doses have been downward-adjusted according to age. This may be a valid solution in younger patients. Moreover, hepatoprotective agents can be considered. These include ursodeoxycholic acid and N-acetylcysteine. [16] With the combination therapy of DAA and such agents, liver health can be enhanced in both reducing the potential toxicities of drugs and eliminating HCV.


Chronic Kidney Disease:


Chronic kidney disease (CKD) and liver disease are closely related, where the former can be both a complication and risk factor of the latter. HCV can lead to glomerulonephritis and worsened treatment outcomes. [17] In the context of DAA treatment, sofosbuvir, a ubiquitous component in established regimens, use is recommended against in patients with an eGFR (glomerular filtration rate) below 30 mL/min/1.73m^2. This is attributable to the fact that sofosbuvir is renally processed and patients with poor renal function are prone to the accumulation of the metabolite GS-331007.


This has prompted the execution of studies regarding alternative treatment regimens for patients with CKD. In EXPEDITION-5, glecaprevir/pibrentasvir was given to patients with stage 3b/4/5 CKD for varying treatment durations. The majority (n=84) received 8 weeks of treatment. SVR12 (SVR on 12th week) was found to be 97 per cent (95% CI: 91.6-99.0%, n=98/101), with no significant difference found between patients with different stages of CKD. More importantly, none reported virological failure. [18] The C-SURFER Study investigated the effects of grazoprevir/elbasvir on patients with HCV genotype 1 infection and stage 4/5 CKD. The treatment duration was 12 weeks. SVR was achieved in 99 per cent of patients (95% CI: 95.3-100%, n=115/116), with the remaining patient suffering from relapse after 12 weeks from the end of treatment. [19] These studies proved that chronic kidney disease was no barrier to HCV treatment. Indeed, improvement in liver condition could also improve kidney health, owing to the possibility of HCV infiltration into the kidney parenchyma, leading to worsening of kidney function. However, avoiding sofosbuvir and other NS5B inhibitors does entail certain issues. Firstly, these regimens are not applicable to patients with moderate to severe hepatic impairment, as defined by the Child-Pugh Class. This is due to the addition of the NS3 protease inhibitor. Patients with HCV-induced hepatocellular carcinoma waiting for liver transplantation are therefore ineligible to use such regimens as bridging therapy. This is made worse if the patient also suffers from chronic kidney condition, since there is no appropriate regimen. Bridging therapy is considered vital given long waiting times to receive an appropriate liver since it reduces the likelihood of disease exacerbation in the interim. Sofosbuvir/ledipasvir is found to be efficacious in patients with decompensated cirrhosis and can be given. [20-22] Secondly, this brings us back to the argument of health economics. We seek to establish, as far as possible, one universal regimen so that generic drug providers are more willing to synthesise the drug. Increased competition between providers can bring drug prices to affordable levels so as to reduce health inequality and increase access to appropriate medicines for treatment. Given that sofosbuvir-related regimens are efficacious in a wide range of situations, it is natural for us to contemplate testing it in alternative populations, including those with end-stage CKD.


A recent non-randomised, multicentre, phase 2b trial was conducted in the US and New Zealand. [23] It aimed to investigate the effects of sofosbuvir/ribavirin and sofosbuvir/ledipasvir on patients with HCV genotype 1/3 infection and stage 4/5 CKD. The trial divided participants into three cohorts: (a) sofosbuvir 200 mg and ribavirin for 24 weeks (n=10); (b) sofosbuvir 400 mg and ribavirin for 24 weeks (n=10), and (c) sofosbuvir 400 mg and ledipasvir (90 mg) for 12 weeks (n=18). The primary efficacy end-point for all three cohorts was the rate of SVR12. The primary safety end-points were the incidence rates of adverse events, and laboratory, ECG, and vital sign abnormalities. Secondary efficacy end-points included the proportion of patients with SVR4 (SVR achieved by the 4th week of follow-up) and SVR24 (SVR achieved by the 24th week of follow-up), as well as the proportion of patients with virological failure. Pharmacokinetic parameters were also included in the analysis due to the projected effect on drug excretion and drug metabolite concentration by the patient's CKD. There were marked differences in SVRs between cohorts (a) & (b), and cohort (c). 40 per cent (95% CI: 12-74%) of cohort (a) achieved SVR4, relative to 60 per cent (95% CI: 26-88%) of cohort (b). Such results persisted by the 12th week, so that the rates of achieving SVR4 and SVR12 were identical. For cohort (c), all patients achieved SVR4 and SVR12 (95% CI: 82-100%). GS-331007 exposure was the highest in cohort (c). Creatinine clearance (CrCl), measured by the Cockcroft-Gault equation, results varied non-significantly during both the treatment period and follow-up (up to 12 weeks) in all cohorts. This was evidenced by the overlapping of confidence intervals and the relative stability of CrCl values. High proportions of all three cohorts experienced any adverse event (Cohort (a) - 100 per cent; Cohort (b) - 90 per cent; Cohort (c) - 72 per cent). All cohorts experienced similar rates of serious adverse events (range: 20-22 per cent). The most common adverse events in cohorts (a) and (b) were anaemia and headaches. Anaemia was observed in 30 per cent (n=3) of cohort (a) and 40 per cent (n=4) of cohort (b). Most patients with anaemia had haemoglobin levels below 10 g/dL (cohort (a): 70 per cent; cohort (b): 90 per cent). Headaches were observed in 40 per cent (n=4) of cohort (a) and none in cohort (b). In cohort (c), headaches (n=4; 22 per cent) and fatigue (n=4, 22 per cent) were the most common adverse events.


There are several points of note in this study. All recruited patients were not on dialysis, contrary to the cohorts receiving sofosbuvir-free therapies cited afore. This is welcomed since dialysis has the potential of affecting creatinine clearance values and blurs the impact of corporeal accommodation of higher concentrations of the metabolite GS-331007. Secondly, the cohort size, much more significantly than its sofosbuvir-free counterparts, is small to the extent that its results may be subjected to inadvertent statistical magnification. Thirdly, regarding cohort characteristics, most patients were male (n=26/38) and had genotype 1a disease (n=27/38). Gender differences in HCV disease severity and natural history are under-explored and it has not been decisively proven that gender-associated differences in DAA SVR rates are clinically insignificant. Moreover, genotypic inequality is likely to have skewed the results of the study. It is also impossible to appraise SVR rates in patients infected with other genotypes, let alone those with RAS's. Fourthly, the adverse events recorded in this study remind us that regular clinical evaluation and monitoring are of paramount significance when administering ribavirin-included therapies. It has long been established that ribavirin is associated with extravascular, haemolytic anaemia. [24] Ribavirin can inhibit ATP-dependent systems, leading to increased intracellular oxidative damage and impaired cellular energy metabolism. Morphological changes imposed on red blood cells (RBC) include the increase in phosphatidylserine exposure to the RBC membrane and assumption of an echinocytic form. Senescence amongst RBCs is encouraged, therefore shortening their half-lives and promotes removal in the splenic red pulp. Given 5 to 11 per cent of patients receiving ribavirin and any DAA experience clinically significant anaemia, regular follow-up is required. [24] Severe cases of anaemia also entail blood transfusions. This is another point of counter-intuition since blood transfusion can promote HCV transmission. This is even more evident in developing countries. Since none in cohort (c) experienced anaemia, ribavirin-free regimens may sound more attractive. At the same time, one patient in cohort (c) suffered from transient, prolonged QT interval shown on the ECG at week 4. Subsequent testing revealed normal results. One may dispel this as an anomaly. Nevertheless, cardiac changes pursuant to sofosbuvir/ledipasvir treatment are observed elsewhere. Ventricular tachycardia in patients having received sofosbuvir/ledipasvir for HCV infection was recorded in two Japanese cases. [25] These patients did not have QT interval abnormalities. The ventricular tachycardia events were also transient and did not recur. However, the patients reported normal kidney function. Whether cardiac issues would arise at higher frequency in patients with CKD remain unknown and should be explored in larger, multicentre studies. After all, long QT syndrome can lead to torsades de pointes, precipitating to ventricular tachycardia.


Concluding Remarks:


Hepatitis C treatment should be for the many, not the few. Sofosbuvir-associated regimens are found to be efficacious in many contexts, including in special populations such as children and adolescents, as well as patients with CKD. Recent advances in liver medicine have produced encouraging results, with SVR rates bearing the tendency of exceeding 90 per cent. Having said so, small cohort size and specific genotypic preponderance are endemic in many studies. Large, multicentre studies should be carried out to verify gathered findings to increase both accuracy and generalisability. Future research can also stress on expanding the age range of patients with chronic HCV infection eligible for receiving DAA therapy, investigating the applicability of sofosbuvir-free DAA regimens in paediatric populations, and cardiac adverse events in CKD patients receiving sofosbuvir/ledipasvir. Marching forward, reaching WHO's 2030 elimination targets is no longer a remote possibility.



References and Further Reading:


[1] Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Lancet. 2019;394(10207):1451-1466. doi:10.1016/S0140-6736(19)32320-7.


[2] World Health Organization. Global health sector strategy on viral hepatitis 2016-2021https://apps.who.int/iris/bitstream/handle/10665/246177/WHO-HIV-2016.06-eng.pdf;jsessionid=60A93ADD1A191FF6A0FA823314D24C43?sequence=1 (WHO, 2016).


[3] Chappell C, Scarsi K, Kirby B et al. Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study. The Lancet Microbe. 2020;1(5):e200-e208. doi:10.1016/s2666-5247(20)30062-8.


[4] Barber MJ, Gotham D, Khwairakpam G, Hill A. Price of a hepatitis C cure: Cost of production and current prices for direct-acting antivirals in 50 countries. J Virus Erad. 2020;6(3):100001. Published 2020 Jun 18. doi:10.1016/j.jve.2020.06.001.


[5] Jin F, Dore GJ, Matthews G, et al. Prevalence and incidence of hepatitis C virus infection in men who have sex with men: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(1):39-56. doi:10.1016/S2468-1253(20)30303-4.


[6] Schmelzer J, Dugan E, Blach S et al. Global prevalence of hepatitis C virus in children in 2018: a modelling study. The Lancet Gastroenterology & Hepatology. 2020;5(4):374-392. doi:10.1016/s2468-1253(19)30385-1.


[7] Rodrigue JR, Balistreri W, Haber B, et al. Impact of hepatitis C virus infection on children and their caregivers: quality of life, cognitive, and emotional outcomes. J Pediatr Gastroenterol Nutr. 2009;48(3):341-347. doi:10.1097/MPG.0b013e318185998f.


[8] Younossi ZM, Stepanova M, Balistreri W, et al. Health-related Quality of Life in Adolescent Patients With Hepatitis C Genotype 1 Treated With Sofosbuvir and Ledipasvir. J Pediatr Gastroenterol Nutr. 2018;66(1):112-116. doi:10.1097/MPG.0000000000001754.


[9] Indolfi G, Serranti D, Resti M. Direct-acting antivirals for children and adolescents with chronic hepatitis C. Lancet Child Adolesc Health. 2018;2(4):298-304. doi:10.1016/S2352-4642(18)30037-3.


[10] Murray KF, Balistreri WF, Bansal S, et al. Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11. Hepatology. 2018;68(6):2158-2166. doi:10.1002/hep.30123.


[11] Rosenthal P, Schwarz KB, Gonzalez-Peralta RP, et al. Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection. Hepatology. 2020;71(1):31-43. doi:10.1002/hep.30821.


[12] Pawlotsky JM. DAA failures in African patients with "unusual" HCV subtypes: Hey! Didn't you know there was another world?. J Hepatol. 2019;71(6):1070-1072. doi:10.1016/j.jhep.2019.09.021.


[13] Gupta N, Mbituyumuremyi A, Kabahizi J, et al. Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir-sofosbuvir (SHARED): a single-arm trial. Lancet Gastroenterol Hepatol. 2019;4(2):119-126. doi:10.1016/S2468-1253(18)30382-0.


[14] Excellence N. ELBASVIR WITH GRAZOPREVIR | Drug | BNF content published by NICE. British National Formulary. https://bnf.nice.org.uk/drug/elbasvir-with-grazoprevir.html. Published 2021. Accessed January 1, 2021.


[15] Gane E, Nahass R, Luketic V, et al. Efficacy of 12 or 18 weeks of grazoprevir plus elbasvir with ribavirin in treatment-naive, noncirrhotic HCV genotype 3-infected patients. [EASL abstract P0776] J Hepatol. 2015;62(Suppl 2):S621.


[16] Long LH, Xue CQ, Shi JF, Dong JN, Wang L. Efficacy of Hepatoprotective Agents With or Without Antiviral Drugs on Liver Function and Fibrosis in Patients With Hepatitis B: A Meta-Analysis. Hepat Mon. 2015;15(7):e29052. Published 2015 Jul 22. doi:10.5812/hepatmon.29052v2.


[17] Perico N, Cattaneo D, Bikbov B, Remuzzi G. Hepatitis C Infection and Chronic Renal Diseases. Clinical Journal of the American Society of Nephrology. 2009;4(1):207-220. doi:10.2215/cjn.03710708.


[18] Lawitz E, Flisiak R, Abunimeh M, et al. Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection. Liver Int. 2020;40(5):1032-1041. doi:10.1111/liv.14320.


[19] Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-1545. doi:10.1016/S0140-6736(15)00349-9.


[20] Chua JV, Kottilil S. Sofosbuvir and velpatasvir: a stellar option for patients with decompensated hepatitis C virus (HCV) cirrhosis. Ann Transl Med. 2016;4(Suppl 1):S8. doi:10.21037/atm.2016.08.56.


[21] Excellence N. ELBASVIR WITH GRAZOPREVIR | Drug | BNF content published by NICE. British National Formulary. https://bnf.nice.org.uk/drug/elbasvir-with-grazoprevir.html. Published 2021. Accessed January 1, 2021.


[22] Nehra V, Rizza SA, Temesgen Z. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection in adults. Drugs Today (Barc). 2018;54(7):407-421. doi:10.1358/dot.2018.54.7.2828188.


[23] Lawitz E, Landis CS, Flamm SL, et al. Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study. Lancet Gastroenterol Hepatol. 2020;5(10):918-926. doi:10.1016/S2468-1253(19)30417-0.


[24] Wu LS, Jimmerson LC, MacBrayne CE, Kiser JJ, D'Argenio DZ. Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus. CPT Pharmacometrics Syst Pharmacol. 2016;5(2):65-73. doi:10.1002/psp4.12058.


[25] Nirei K, Nakamura H, Matsuoka S et al. Ventricular Tachycardia as a Complication of Ledipasvir and Sofosbuvir Treatment for HCV Infection. Internal Medicine. 2017;56(7):787-790. doi:10.2169/internalmedicine.56.7948.

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