The three considerations (boxes below) are existing formal WHO recommendations that address alcohol intake, fibrosis assessment and treatment response assessment.
Existing recommendation from the 2016 HCV treatment guidelines (2)
In resource-limited settings, it is suggested that aminotransferase/platelet ratio index (APRI) or FIB-4 be used for the assessment of hepatic fibrosis rather than other non-invasive tests that require more resources such as elastography or FibroTest.
(Conditional recommendation, low quality of evidence)
Note: This recommendation was formulated assuming that liver biopsy was not a feasible option. FibroScan®, which is more accurate than APRI and FIB-4, may be preferable in settings where the equipment is available and the cost of the test is not a barrier to testing.
All other considerations discussed in this chapter are based on good practice principles.
5.1. Clinical assessment of persons with HCV infection prior to treatment
Pretreatment evaluation of the risk of adverse events is based on the person’s clinical information, concomitant medications and knowledge of treatment regimen to be administered. Women of childbearing age may be offered pregnancy testing and are informed about the lack of available data on the safety and efficacy of DAAs during pregnancy. In addition, in 2016, WHO recommended an alcohol intake assessment before initiating treatment and a fibrosis assessment using noninvasive tests such as the APRI score or FIB-4 test (formula in ) to determine if there is cirrhosis (2). An online calculator is available at http://www.hepatitisc.uw.edu/page/clinical-calculators. and summarize the cut-off values for the detection of significant fibrosis and cirrhosis, and the sensitivity and specificity of the APRI score and FIB-4 test when using these cut-offs. This information will allow clinicians to decide on the appropriate treatment duration of the pangenotypic regimen of their choice based on the absence or presence of cirrhosis. The treatment duration of the recommended pangenotypic regimens sofosbuvir/daclatasvir and glecaprevir/pibrentasvir depends on the absence or presence of cirrhosis.
Low and high cut-off values for the detection of significant fibrosis and cirrhosis.
Sensitivity and specificity of APRI and FIB-4 for the detection of advanced fibrosis and cirrhosis.
5.1.1. Drug–drug interactions
Drug–drug interactions (DDIs) for DAA regimens vary both in number and clinical significance, depending on the medicines prescribed. Commonly prescribed medicines that may lead to DDIs include proton pump inhibitors, statins, antidepressants and antiretrovirals (ARVs) for HIV (now recommended for all HIV-infected persons, regardless of CD4 count) (130). The association between recommended pangenotypic regimens and efavirenz is either contraindicated (in the case of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir) or requires dose adjustment (in the case of sofosbuvir/daclatasvir). summarizes the DDIs between WHO-recommended HIV ARV medicines and HCV medicines. Where DDIs are likely, ARV substitutions may be considered before initiating HCV therapy. Prescribers may consult the University of Liverpool webpage on hepatitis drug interactions (http://www.hep-druginteractions.org/) prior to prescribing, as details of interactions are frequently updated. This website includes details of interactions with prescribed and non-prescribed medicines.
Drug–drug interactions between antiretrovirals and direct-acting antivirals.
5.1.2. Monitoring for treatment toxicity
In general, DAAs are well tolerated by persons with HCV infection, with only minor side-effects. The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend a monitoring schedule that includes baseline, week 4 and week 12 after the end of treatment (131, 132). The Guidelines Development Group proposed to simplify this schedule as the most common adverse events of DAAs are minor and include fatigue, headache, insomnia and nausea. The Guidelines Development Group proposed that the frequency of routine laboratory monitoring be limited to a baseline and end-of-treatment specimen (see summary monitoring schedule framework for the treatment of persons with HCV infection based on expert opinion in ).
Monitoring framework before and during DAA treatment.
Additional laboratory monitoring is necessary in persons treated with ribavirin. Ribavirin is taken with food and causes a predictable, dose-dependent haemolytic anaemia. It is contraindicated in persons with anaemia or those with blood disorders such as thalassaemia. Finally, HIV coinfection, HBV coinfection (see
sections 5.2.1 and 5.2.2), cirrhosis or renal impairment, potential DDIs and ill-health may also necessitate more frequent monitoring than proposed in .
5.1.3. Monitoring for treatment response
In 2017, WHO recommended that following completion of DAA treatment, SVR should be assessed at 12 weeks after the end of treatment using HCV RNA NAT (3).
5.2. Clinical considerations for specific populations
5.2.1. Persons with HIV/HCV coinfection
Persons with HIV/HCV coinfection generally have more rapid disease progression than monoinfected persons (133, 134). Even among persons in whom ART leads to successful control of HIV infection (i.e. undetectable HIV viral load), the risk of hepatic decompensation among coinfected persons is higher than among persons with HCV monoinfection (135, 136). For these reasons, since 2014, the WHO Guidelines listed persons with HIV/HCV coinfection among those to be prioritized for HCV treatment (1).
HCV treatment outcomes with DAAs are comparable in persons with HIV/HCV coinfection to those with HCV monoinfection (137). Because DAAs are safe and effective for people with HIV/HCV, there is no longer any need to consider them as a special or difficult-to-treat population. However, there are important DDIs with pangenotypic HCV regimens and ART. Therefore, checking for DDIs between HIV and HCV medications needs to be emphasized (see also
section 5.1.1 and ).
5.2.2. Persons with HBV/HCV coinfection
There are no global prevalence data on HBV/HCV coinfection, but various studies have reported that 3–18% of people who are HBsAg positive are also HCV infected (138). HBV/HCV coinfection is more likely among PWID and persons living in areas where both viruses are endemic (138). Coinfection with HBV and HCV increases the risk for HCC, although the reasons for this are not well understood (139, 140).
In 2016, the FDA issued a warning about the risk of HBV reactivation during DAA treatment (defined as >1000 IU/mL increase in HBV DNA or detection of HBsAg in a person who was previously negative) based on 29 case reports (95). Even though HBV reactivation appears rare, individuals may be considered for HBV testing before initiating HCV treatment (131, 141). Persons with HBV/ HCV coinfection may be assessed for eligibility for HBV treatment and, if needed, started on HBV treatment before starting HCV treatment (131, 141). Persons with advanced disease may be considered for monitoring at regular intervals for HBV reactivation during HCV treatment. The risk of reactivation among persons who are anti-HBc positive but HBsAg negative is very low (142–144).
5.2.3. Persons with cirrhosis
The risk of cirrhosis is increased in those who consume excess alcohol (145), and in those coinfected with HBV and/or HIV (133, 135, 136, 139), particularly those who are not receiving ART (146). To determine if fibrosis or cirrhosis is present, WHO recommends the use of non-invasive tests such as the APRI score or the FIB-4 test (see
section 5.1) (2).
Management of compensated cirrhosis
Assessment and follow up for progression of disease and evidence of HCC is an essential part of the care of persons with HCV-related cirrhosis. Persons with cirrhosis (including those who have achieved SVR) may be considered for HCC screening with six-monthly ultrasound examinations and/or alpha-fetoprotein estimation (131, 141), and endoscopy every 1–2 years to exclude oesophageal varices (147).
Management of decompensated cirrhosis
Diagnosis of decompensated liver disease is based on both laboratory and clinical assessment. A proportion of persons with decompensated liver disease will deteriorate on treatment and currently there are no predictors to identify these persons. Therefore, treatment of persons with decompensated cirrhosis ideally takes place in centres with the expertise to manage complications and where access to liver transplantation is available.
Daclatasvir, velpatasvir and sofosbuvir have been studied in persons with decompensated cirrhosis and their use has been demonstrated to be generally safe and effective. In contrast, regimens that include an HCV protease inhibitor (e.g. glecaprevir/pibrentasvir) are not approved for use in persons with decompensated liver disease.
5.2.4. Persons with chronic kidney disease
Glecaprevir/pibrentasvir have been shown to be effective and safe in persons with chronic kidney disease and HCV infection with all six major HCV genotypes (63). However, in 2018, there is limited availability in LMICs of this regimen, hence as an interim measure where genotype appropriate, consideration could be given to those combinations previously recommended in the WHO 2016 HCV treatment guidelines (2) and listed in Web annex 5 as safe in persons with grades 4 and 5 chronic kidney disease.
Sofosbuvir-based regimens do not have the safety and efficacy data to support their use in persons with chronic kidney failure grades 4 and 5, i.e. severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2).
5.2.5. Persons with TB/HCV coinfection
Persons at increased risk of infection with HCV may also be at increased risk of infection with TB. Therefore, the clinical evaluation of persons being considered for HCV treatment can include screening for active TB. A four-symptom screening algorithm exists to rule out active TB (148). If the person does not have any one of the following symptoms – current cough, fever, weight loss or night sweats–TB can be reasonably excluded; otherwise, the person must undergo further investigations for TB or other diseases.
Most of the DAAs interact with metabolic pathways in the liver, which increases or decreases the level of DAAs when co-administered with commonly used rifamycins such as rifabutin, rifampin and rifapentine (149–151). Therefore, concurrent treatment of HCV infection and TB must be avoided. Active TB involves a risk of secondary transmission and that can be life-threatening in a shorter time frame than HCV. Thus, TB is usually treated before HCV. In persons with HCV infection treated for TB, the risk of antimycobacterial-induced hepatotoxicity is higher than in those with TB monoinfection, although the risk of severe hepatotoxicity is rare (152). Monitoring liver function tests detects hepatotoxicity early.
Concurrent treatment of HCV infection and multidrug-resistant TB is particularly complicated because of many DDIs between DAAs and second-line antimicrobials. There are limited data on the management of persons coinfected with HCV, HIV and TB. Specialist referral may be needed to reduce the additive side-effects, pill burden and DDIs.
5.2.6. Retreatment of persons with failure of DAA therapy
With DAAs, SVR rates generally exceed 90% across all HCV genotypes (76). Even if all of the 71 million persons with HCV infection were to gain access to DAA therapy, an estimated 2–5 million of them would not be expected to achieve SVR, and would need effective retreatment. Persons who do not achieve SVR after DAA treatment have limited options for retreatment. An appropriate, highly effective initial treatment regimen helps avoiding the dilemma of limited retreatment options. Examination of adherence and potential DDIs may guide decisions when persons fail DAA therapy.
Currently, there is one pangenotypic regimen approved for the retreatment of persons who have been previously treated with any combination of DAAs. This is the FDC of sofosbuvir, velpatasvir and the protease inhibitor voxilaprevir (153, 154). In two clinical trials of sofosbuvir/velpatasvir/voxilaprevir, more than 300 persons, 46% with cirrhosis, were treated for 12 weeks. The triple DAA regimen was highly effective for persons who did not reach an SVR with DAA-containing regimens. SVR rates ranged from 93% to 99%, with the lowest rate in persons with genotype 3 infection and cirrhosis (155). Sofosbuvir/velpatasvir/voxilaprevir cannot be used in persons with Child–Pugh Class B or C cirrhosis or renal failure. The combination of glecaprevir/pibrentasvir has been approved for retreatment in patients who have failed sofosbuvir-containing regimens and those who have failed treatment with either a protease inhibitor or an NS5A inhibitor (but not both). In the absence of these regimens, expert consultation suggests that extending the initial DAA therapy to 16 or 24 weeks, while at the same time reinforcing adherence, may be an alternative option for retreatment.
