Monitoring guidance for the detection of adverse events to HCV treatment has largely been based on the experience of interferon and ribavirin therapy.
A technical report on monitoring during treatment was carried out as part of the guidelines development process in 2014 (web Appendix 5, 2014). Newer interferon-free regimens are much better tolerated by patients, as they have fewer adverse events and thus less need for early discontinuation of therapy.
Therefore, the frequency of routine laboratory monitoring may be reduced;
however, there remains the need for laboratory monitoring in patients with cirrhosis, those with significant comorbidities and those treated with ribavirin therapy. Although this approach is being evaluated, no data are yet available to allow for absolute recommendations. A summary monitoring schedule framework for the treatment of patients that is based on expert opinion is shown in Table 8.4. If blood parameters become abnormal on therapy, increased monitoring and dose adjustment may be required.
Time DAA alone DAA + ribavirin DAA + pegylated interferon +
ALT: alanine aminotransferase; DAA: direct-acting antiviral; FBC: full blood count
TABLE 8.4 Framework for the frequency of monitoring patients undergoing HCV therapy based on type of regimen
8.2.1 Regimens containing DAAs
New DAA regimens appear to be well tolerated by patients in both clinical studies and “real-world” observational studies. Certain regimens have been shown to be safe for use in patients with decompensated liver cirrhosis and those who have undergone liver transplantation. However, close monitoring is required in these patients and it is recommended that such regimens be undertaken only in units with the expertise to manage these patients and treat complications if they arise.
Daclatasvir
The common adverse reactions associated with this drug are fatigue, headache and nausea, seen in studies that have either used the drug in combination with sofosbuvir with or without ribavirin (197), or with interferon and ribavirin (210).
Clinical judgement based on the patient’s clinical details such as presence of HIV coinfection, cirrhosis or renal impairment, potential DDIs and clinical well-being during treatment may necessitate more frequent monitoring than the schedule illustrated in Table 8.4. Indirect hyperbilirunaemia can occur in patients taking regimens containing protease inhibitors (simeprevir, paritaprevir and asunaprevir), especially if combined with ribavirin. This is usually transient and decreases with continued treatment.
Ombitasvir/paritaprevir/ritonavir and dasabuvir
SAEs with this regimen occurred in <2.5% of cases and the treatment discontinuation rate was <2% in phase 3 clinical studies. Pruritus was the most common side-effect attributable to this regimen; however, patients also experienced fatigue, nausea and insomnia in regimens in which ribavirin was co-administered.
Asymptomatic serum ALT elevations, without an increase in serum bilirubin, were noted in the first four weeks of treatment but resolved without intervention or need for DAA discontinuation. This was most common in patients using estrogen therapy concomitantly. Transient unconjugated bilirubinaemia was noted in patients also receiving ribavirin, related to the inhibition of OATP1B1 and OATP1B3 bilirubin transporters by ritonavir. An increase in total bilirubin was observed more often in patients with liver cirrhosis.
Simeprevir
A reduction in the efficacy of treatment with simeprevir was observed in persons infected with HCV genotype 1a who had NS3 Q80K polymorphism.
The simeprevir drug label therefore includes a recommendation to screen for the presence of this variant polymorphism prior to beginning therapy and to consider alternative therapy if the Q80K strain is detected. This test is expensive and not widely available in LMIC.
Patients taking simeprevir may experience mild-to-moderate rashes and photosensitivity, which may be more pronounced in people of east Asian ancestry. Phase 3 clinical studies showed that rates of SAEs were low (≤6%) when simeprevir was used with either interferon or sofosbuvir (101, 211). Some limited data from real-life cohorts suggest that patients with an eGFR <46 mL/min/1.73 m2 who are treated with sofosbuvir and simeprevir may be more likely to develop adverse events (119). Common adverse effects are fatigue, headache, nausea, insomnia and pruritus.
Sofosbuvir with or without ledipasvir
Both drugs have been well tolerated by patients, both in clinical study and “real-life” settings. Sofosbuvir with interferon and ribavirin for 12 weeks appears to be reasonably well accepted by patients, with low rates of discontinuation in clinical studies. In all these regimens, fatigue, headache, insomnia and nausea are the most common adverse events reported. Recent evidence has emerged of significant bradyarrhythmias associated with sofosbuvir in patients also taking amiodarone and therefore it is contraindicated in these patients. Sofosbuvir is renally excreted and is also not recommended in those with eGFR <30 mL/
min/1.73 m2 or those with end-stage renal failure.
8.2.2 Regimens containing interferon
Therapy with interferon causes a number of side-effects, some of which can be life threatening. Patients should be regularly assessed, and warned to be
vigilant for features of depression, irritability, severe fatigue, sleeping disorders, retinopathy and skin reactions. It is advised to discuss important side-effects with the family, as patients may tend to underreport or to ignore early signs of depression. Dose reduction or treatment cessation should be considered, as well as the administration of antidepressants if there is depression.
Haematological side-effects include neutropenia, thrombocytopenia, lymphopenia and anaemia. These parameters should be assessed at weeks 1, 2 and 4 of therapy. Depending on the clinical situation, lengthening the intervals between assessments from 4- to 8-weekly can be considered thereafter. The dose of interferon should be reduced if the neutrophil count falls below 750/
mm3, or the platelet count falls below 50 000/mm3. Treatment should be stopped if the neutrophil count falls below 500/mm3 or the platelet count below 25 000/mm3. When the neutrophil or platelet counts rise from those levels, treatment can be restarted at a lower dose. These interruptions should be as brief as possible and a switch to interferon-free regimens, if available, should be considered in patients who cannot tolerate interferon.
8.2.3 Regimens containing ribavirin
Most of the recommended regimens do not require the addition of ribavirin. However, in certain situations, particularly when treating persons with cirrhosis, ribavirin may be required to optimize efficacy, shorten treatment duration and thereby cost, and possibly reduce the risk of selection of resistance-associated variants (RAVs).
Administration of ribavirin is complicated because it should be taken with food and causes a predictable, dose-dependent haemolytic anaemia. Therefore, it should not be administered to patients with anaemia or those with blood disorders such as thalassaemia. Moreover, patients with cirrhosis, cardiovascular disease, pulmonary disease, renal impairment and all those older than 60 years of age need close monitoring when treated with ribavirin-containing regimens. Dose reductions may be required (see text bow below). Careful clinical evaluation of patients before and during treatment is important to identify those in need of closer monitoring.
Dose adjustment of ribavirin
Anaemia is a common, predictable side-effect of ribavirin therapy and dose adjust-ment is often required. Patients whose haemoglobin (Hb) level falls below 10 g/
dL should have their ribavirin dose reduced from 800–1200 mg/day (depending on the patient’s weight and HCV genotype) to 600 mg/day. A patient whose Hb level falls below 8.5 g/dL should discontinue ribavirin therapy. For patients with a history of stable cardiovascular disease, dose reduction of ribavirin is required if the Hb decreases by ≥2 g/dL during any 4-week period. In addition, for these patients, if the Hb remains <12 g/dL after 4 weeks on a reduced dose, the patient should dis-continue combination therapy.
The dose of ribavirin in patients with renal failure must also be adjusted; patients with an eGFR <50 mL/min/1.73 m2 should not be treated with ribavirin and those on dialysis must have the dose lowered to 200 mg per day or take it three times per week. Increased monitoring is required in this group.
Among patients with decompensated cirrhosis, ribavirin dosing should either be weight-based or started at an initial dose of 600 mg and increased as tolerated.
Ribavirin is teratogenic and thus cannot be used during pregnancy. Women of childbearing age must avoid pregnancy by using at least two reliable forms of contraception. Ribavirin also has a long half-life; thus, pregnancy must be prevented for at least 6 months after the end of ribavirin therapy. Providers have a responsibility to ensure that their patients and male partners can access and use reliable contraception.