Specialist care needs to address the additional needs of special populations of patients, including PWID, persons coinfected with (or at risk for infection with) HIV, children and adolescents, and those with cirrhosis.
9.1. People who inject drugs
Injecting drug use is prevalent in many countries around the world, affecting people in low-, middle- and high-income countries. Approximately 67% of PWID are infected with HCV; 10 million of 16 million people in 148 countries.6 PWID are at increased risk of HCV-related disease and all-cause morbidity and mortality, and therefore require specialized care.38 Related guidance is summarized below, and in section 2.4 and . When caring for PWID, the central tenets of respect and non-discrimination should be followed, and additional adherence and psychological support given as required.
Screening
As an integral component of a comprehensive package of harm reduction interventions, WHO recommends targeted HCV screening of PWID as a population with a high prevalence of infection. Repeated screening is required in individuals at ongoing risk, and the possibility of reinfection after spontaneous clearance or successful treatment should also be considered. Those who have been previously infected should be retested using RNA testing, as the antibody remains positive after the first infection. HCV case-finding and treatment in specialist drug dependency services has also been shown to be cost–effective in high-income settings. The higher the treatment rates, the more cost-effective HCV case-finding becomes, as more of those identified will be treated, and a greater population impact could be seen.97 Screening for HBV and HIV is also recommended in PWID.
Care
Treatment of HCV in PWID requires integration of services, as other health-care needs are often also present. Dependency on opiates or other substances may be present and alcohol excess is also a common problem in PWID. Harm reduction strategies are required in order to prevent acquisition of other bloodborne viruses such as HBV and HIV. At all times, avoidance of discrimination or stigmatization of PWID is essential. Care should be given only with informed consent.
Drug dependency services may be required for the provision of opioid substitution therapy and sterile injection equipment. In addition, alcohol reduction strategies may be required and HIV treatment may also be necessary. Acceptability of services is a vital component of health care, and peer interventions may help with reducing injecting drug use and promoting safer injection practices.d Guidance on brief behavioural interventions is available as part of the WHO ASSIST package.
PWID are at risk of infection with HBV and should be vaccinated using the rapid vaccination regimen, as described in other WHO guidance.190 Needle and syringe programmes should also provide sterile needles and syringes with low dead space to PWID. It is also suggested that peer interventions be offered to PWID to reduce the incidence of viral hepatitis.
Treatment
Treatment for HCV infection is both efficacious and cost–effective in PWID164,191,192 and therefore WHO recommends that all adults and children with chronic HCV infection, including PWID, should be assessed for antiviral treatment. Treatment may also be effective as prevention, due to a reduction in transmission.97,98,99
Consideration must be given to potential drug–drug interactions – between both prescribed and non-prescribed drugs.e Methadone levels may be decreased in persons treated with PEG-IFN/RBV, for example. Although this interaction is usually subclinical, monitoring for symptoms of withdrawal is recommended.
Concurrent infection with HBV, HIV and/or TB is common in PWID and these require additional consideration, as discussed in Section 9.2.
9.2. Persons with HIV and HCV coinfection
Coinfection with HIV and HCV poses a challenge because of the large number of persons affected, the negative impact of HIV on the natural history of HCV infection, and the therapeutic challenges of dealing with interactions between the drugs used for treating HIV and HCV infections.
Both ART and treatment for HCV infection may slow the progression of HCV-related liver disease; therefore, treating both infections is a priority for persons with HIV/HCV coinfection.193 As the management of these infections is complex, it is advisable to provide treatment in an integrated fashion by clinicians familiar with the treatment of both infections.
Treatment of HCV infection
In HIV/HCV coinfected persons, there is more rapid progression of HCV-related liver disease, and treatment for HCV may slow the progression of hepatic fibrosis and/or delay the onset of clinical consequences of decompensated cirrhosis. Therefore, treatment of HCV is a priority for persons with HIV/HCV coinfection.
The decision to initiate treatment for HCV is more complex than in those with HCV monoinfection, as response rates are lower, risk of potential toxicities is higher and treatment is complicated by a high pill burden, overlapping toxicities, and interactions between drugs used for treating HCV and HIV. In general, clinical stabilization of HIV disease with ART is advisable prior to starting treatment for HCV, especially in persons with advanced immunosuppression (CD4 count <200 cells/mm3). In these situations, since HCV RNA suppression is greater in coinfected persons with CD4 counts higher than 450 cells/mm3,194 it may be preferable to initiate ART and delay therapy for HCV until CD4 counts increase as a result of ART.
HCV infection among persons with HIV coinfection can be treated with PEG-IFN/RBV. (For comments regarding response rates and duration of treatment, see
Section 7.1.) These persons can also be treated with PEG-IFN/RBV and boceprevir, telaprevir or simeprevir (for genotype 1 infection) and may also be treated with sofosbuvir/RBV or PEG-IFN/RBV/sofosbuvir. Persons coinfected with HCV/HIV treated with PEG-IFN/RBV with or without an additional agent (PI or sofosbuvir) who require treatment for HIV should receive compatible ART (Table 8.3).177
Persons with HIV require special consideration regarding the selection of an antiretroviral regimen. The safety profile in HCV/HIV-1 coinfected subjects treated with sofosbuvir is similar to that observed in HCV-monoinfected subjects. Elevated total bilirubin (grade 3 or 4) occurs extremely commonly in persons treated with sofosbuvir and atazanavir as part of the antiretroviral regimen. Tipranivir/sofosbuvir is not recommended but darunavir/ritonavir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir have been tested and no dose adjustment is currently recommended.
Simeprevir is not recommended to be used with several HIV treatment regimens, including cobistat, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz, nevirapine, delavirdine, etravirine and any HIV PI-containing regimen.196
Antiretroviral therapy in persons with HIV/HCV coinfection
In 2013, WHO updated its recommendations on the use of ART in adults, adolescents, pregnant women and children.197
and summarize the key recommendations on timing of ART and first-line ART regimens. These recommendations state that ART among people coinfected with HCV should follow the same principles as in HIV monoinfection. Initiating ART regardless of CD4 cell count was not recommended because of lack of evidence regarding the benefit of ART for persons with a CD4 count higher than 500 cells/mm3. The choice of ART for persons with coinfection is the same as for those with HIV alone. The principal recommendations of the 2013 consolidated guidelines are summarized in .197
Summary of recommendations for when to initiate ART in adults and adolescents.
Summary of first-line ART regimens for adults, adolescents, pregnant and breastfeeding women and children.
Potential harmful effects of antiretroviral (ARV) drugs include their hepatotoxic effects. Several studies have shown that hepatotoxicity as a result of ART may be worsened in the presence of concomitant HCV infection.198-200 However, the highest rates of hepatotoxicity have been observed with ARV drugs that are no longer commonly used or recommended, including stavudine (d4T), didanosine (ddI), nevirapine (NVP) or full-dose ritonavir (RTV, 600 mg twice a day).201 For most HIV/HCV-coinfected persons, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury.
Raised liver enzymes may be the result of ART-induced drug toxicity and/or opportunistic infections, making interpretation of liver enzyme elevations more problematic than for patients with HCV infection alone. ALT and AST should be monitored at 1 month after ART initiation and then every 3–6 months. A significant elevation of AST/ALT may prompt careful evaluation for other causes of liver impairment (e.g. alcoholic hepatitis, hepatobiliary disease), and may require short-term interruption of the ART regimen or specific drug suspected of causing the elevation.
Drug–drug interactions in persons with HIV/HCV coinfection
Assessment of potential drug–drug interactions is of critical significance in HIV-infected persons who are about to start HCV treatment (Table 8.3). Careful consideration of such interactions is important to avoid toxicity and to ensure efficacy of the regimens used to treat both HIV and HCV in order to avoid the development of ARV resistance and to increase the likelihood of SVR. Reported interactions are updated on a regular basis and therefore consultation with a frequently updated database is strongly recommended.f
Interactions between NRTIs have been reported in persons treated with dual IFN/RBV-based therapy. The use of ddI, d4T and AZT is associated with an increased risk of toxicities and these drugs are therefore contraindicated.202-205 Abacavir (ABC) can be used with RBV, but a theoretical interaction has been reported to be associated with decreased SVR rates in some206 but not all studies;207,208 some guidelines have recommended that the use of RBV should be weight based and dose adjusted. Tenofovir (TDF) and emtricitabine (FTC) or lamivudine (3TC)-based regimens are appropriate.
Additional drug–drug interactions must be considered when using other DAAs. If patients are commencing ART and DAAs are not being considered, standard first-line ART may be used (as long as this does not include zidovudine [AZT], d4T or ddI). Efavirenz may also be used but the dose of telaprevir must be increased. Boceprevir can be administered with raltegravir (RAL), TDF plus FTC; pharmacokinetic data also support the use of etravirine, rilpivirine and maraviroc as alternatives. Telaprevir can be used with either RAL or standard-dose RTV-boosted atazanavir; pharmacokinetic data also support etravirine, rilpivirine and maraviroc as alternatives.
Monitoring of therapy in persons with HIV/HCV coinfecion
IFN-based regimens are associated with a reversible CD4 decline (average 140 cells/mm3) and a high rate of treatment discontinuation due to side-effects (25% of patients in the APRICOT study).169 CD4 count monitoring is therefore recommended in coinfected persons on treatment. A higher risk of haematological suppression is also present in HIV-infected individuals; these are important dose-limiting side-effects, especially with co-administration of certain ARV drugs.
Monitoring during IFN and RBV treatment with or without PI therapy is therefore recommended at multiple time points (Table 8.2). Additional time points may be required for persons with evidence of side-effects and in persons at highest risk (for example, persons with cirrhosis and HIV, and those on PI therapy). Additional monitoring of liver function is recommended in persons with cirrhosis, including albumin, bilirubin and coagulation tests. Persons with evidence of neutropenia, thrombocytopenia and anaemia require 1–2-weekly monitoring.
9.3. Children and adolescents
WHO defines a child as an individual 19 years of age or younger and an adolescent as a person between the ages of 10 and 19 years. In countries where adults have a high prevalence of HCV infection, an increased prevalence in children can also be expected. In Egypt, for example, approximately 2% of children are infected.209 This rate is substantially higher in at-risk populations, such as those exposed to medical intervention. Iatrogenic transmission has been reported in hospitals34 and reduction of HCV transmission in health-care settings is a priority (strategies for reduction in HCV transmission as part of medical care are summarized in Table 2.3). Seroprevalence rates of 10–20% have been reported among children who have been treated in hospital for malignancy, renal failure requiring haemodialysis, extracorporeal membrane oxygenation and those who have undergone surgical procedures.210-215 Treatment is licensed for children older than 2 years of age. The product literature for PEG-IFNα2a reports that paediatric subjects treated with RBV combination therapy had a delay in weight and height increases after 48 weeks of therapy compared with baseline. However, by the end of 2 years of follow up, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight-for-age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment).
Screening
Targeted screening is indicated for children who have had medical interventions or who have received blood products in countries where screening of blood is not carried out routinely or where medical equipment is inadequately sterilized. Children born to mothers with HCV infection are also at risk; the risk of vertical (mother-to-child) transmission is approximately 5% and is substantially higher in infants born to HIV-infected mothers (17–25%).17,18
Care
Integrated health care is a key aspect of child health-care provision. Linkage with maternal and child health services, primary care, services for PWID and, where necessary, referral for HIV care and treatment are necessary.
Treatment
Treatment success rates are similar in adults and children, although fewer studies have been carried out in children. In particular, the use of DAAs has been inadequately studied in children as they were excluded from the phase III studies of these medicines.84,85 One systematic review reported on the virological outcomes and adverse effects of IFN/RBV treatment among children.153 This review included four RCTs and 31 non-randomized studies. The overall SVR rate for PEG-IFN and RBV was 30–100%, which is comparable to SVR rates seen in adults. Adverse effects were primarily flu-like symptoms and neutropenia.
9.4. Persons with liver cirrhosis
The spectrum of disease in those infected with HCV extends from mild fibrosis to cirrhosis and HCC. Between 15% and 30% of persons infected with HCV will go on to develop cirrhosis of the liver within 20 years and a proportion of these will progress to HCC. The risk is markedly increased in those who consume excess alcohol216 and in those coinfected with HBV and/or HIV, particularly those who do not have access to ART.60,61 Persons with compensated cirrhosis have the least time available for treatment, the most to lose and much to gain from achieving SVR. Treatment of HCV infection with IFN-containing regimens must be commenced before the onset of decompensated disease as it may precipitate liver failure and death if administered at this stage.
Regular clinical examination and monitoring of serum bilirubin, albumin and blood clotting profile (INR) is necessary in persons with cirrhosis on IFN-based treatment in order to detect decompensated disease. The treatment of such persons with IFN-containing regimens carries a higher risk of serious side-effects and the use of haemopoietic factors is recommended in settings where these are available.110
Assessment and follow up for the progression of disease and for evidence of HCC is an essential part of the care of persons with HCV-related cirrhosis. Compensated cirrhosis may also progress over time to decompensated cirrhosis associated with ascites, oesophageal and gastric varices, and eventually to liver failure, renal failure and sepsis, all of which are life-threatening. The diagnosis of decompensated liver disease is based on both laboratory and clinical assessment, and therefore a careful medical examination of patients must be made before starting treatment. Persons with cirrhosis (including those who have achieved a SVR) should be screened for HCC with six-monthly ultrasound examination and α-fetoprotein estimation, and should have endoscopy every 1-2 years to exclude oesophageal varices.110
9.5. Persons with HBV and TB coinfection
HBV and HCV coinfection
HBV and HCV coinfection may result in an accelerated disease course; HCV is considered to be the main driver of disease. Persons coinfected with HBV and HCV can be treated with antiviral therapy for HCV; SVR rates are similar to those of HCV-monoinfected persons.51,217 After HCV clearance, there is a risk of HBV reactivation and this may require treatment with concurrent anti-HBV antiviral therapy.199,g Telbivudine, in particular, may be associated with a higher risk of neuropathy if given with IFN-containing regimens.
TB and HCV coinfection
Severe concurrent infections such as TB should generally be treated before commencing therapy for HCV. WHO recommends regular screening of people living with HIV (including PWID) with a four-symptom screening algorithm to rule out TB. If the patient does not have any one of the following symptoms – current cough, fever, weight loss or night sweats – TB can be reasonably excluded, otherwise they should undergo further investigations for TB or other diseases. ART should be initiated with persons with HIV-associated TB as soon as possible, regardless of CD4 count. There are limited reported data on the co-management of persons coinfected with HCV, HIV and TB but such cases need sound clinical judgement in order to reduce the additive side-effects, pill burden and drug–drug interactions. Potential interactions can be checked online.g
9.6. Persons with renal impairment
Both ribavirin and PEG-IFN require dose adjustment in persons with renal failure, and baseline testing of renal function is required before initiating therapy. PEG-IFNα2a is cleared by the liver and PEG-IFNα2b via the kidneys. While a theoretical accumulation of PEG-IFNα2b could occur in persons with haemodialysis, no differences have been reported clinically.200,201 Sofosbuvir is excreted by the kidney; however, there are no data regarding the safety of this medication among persons with renal impairment.
In persons with end-stage renal disease (creatinine clearance 20–40 mL/min), a reduced dose of PEG-IFNα2a 135 μg once a week is recommended. The dose of RBV must also be decreased.
In persons with renal impairment receiving chronic haemodialysis, RBV may be administered at a dose of 200 mg daily or 200 mg every other day. Plasma RBV is removed by haemodialysis with an extraction ratio of approximately 50%.
