Monitoring for toxicity CLINICAL CONSIDERATIONS

8.1 Monitoring for toxicity

The side-effect proile of IFN and PEG-IFN includes depression, fatigue, lu- like symptoms, neutropenia, thrombocytopenia, anaemia, thyroid imbalance hyper- or hypothyroidism, lowered absolute CD4+ T cell count in HIV-positive persons, alopecia, arthralgia, anorexia, pneumonitis, and ophthalmological disorders including retinopathy, retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction an eye examination is recommended prior to starting IFN therapy. There may also be marked interactions with other medications in patients with co-morbidity. RBV can cause haemolytic anaemia and is teratogenic. The addition of the PIs boceprevir or telaprevir for genotype 1 infection substantially increases the eficacy of treatment but also increases the likelihood of side-effects. Telaprevir may cause skin reactions, which range from mild to severe, as well as anal discomfort and itching. Boceprevir is associated with dysgeusia an altered sense of taste and may also occasionally be associated with rash. Simeprevir is associated with photosensitivity. In addition, an increased incidence of neutropenia, anaemia and thrombocytopenia has been observed in patients receiving triple with boceprevir or telaprevir rather than dual therapy. Persons with cirrhosis are at high risk of serious adverse events 40–57, particularly anaemia and infection. 171,172 Monitoring during treatment with IFN and RBV with or without PI therapy is therefore recommended at multiple time points Table 8.2. Monitoring at additional time points is required for persons with evidence of side-effects and in persons at highest risk for example, persons with cirrhosis and HIV coinfection, and those on PI therapy. Additional monitoring of liver function is recommended in persons with cirrhosis, including albumin, bilirubin and coagulation international normalized ratio [INR]. Patients with evidence of neutropenia, thrombocytopenia and anaemia require 1–2-weekly monitoring. HCVHIV coinfection In persons with HCVHIV coinfection, IFN-based treatment is associated with a reversible CD4 decline average 140 cellsmm 3 and a high rate of treatment discontinuation due to side-effects 25 of patients in the APRICOT study. 169 A serious concern was that liver failure occurred and was fatal in 614 patients. This was associated with cirrhosis with Child–Pugh scores of 5 or more at baseline and didanosine ddI-containing regimens. 185 For this reason, ddI and stavudine d4T are contraindicated in patients receiving IFNRBV therapy. More recent studies have shown fewer side-effects as such combinations are now avoided. Depression rates as high as 40 have been recorded when treating patients coinfected with HIV and HCV with IFN therapy. There are also reports of marked weight loss. 186 Severe anaemia, thrombocytopenia and neutropenia are important dose-limiting factors when treating coinfected patients. Persons coinfected with HCVHIV treated with PEG-IFNRBV with or without a PI or sofosbuvir who require treatment for HIV should receive compatible ART Table 8.3. 177 It is recommended that treating practitioners check potential interactions online as these are frequently updated http:www.hep- druginteractions.org. TABLE 8.3 Drug–drug interactions in HIV and HCV treatment Source: adapted from http:www.hep-druginteractions.org HIV NRTIs Boceprevir Telaprevir Peg-IFN alfa Ribavirin Abacavir Didanosine Emitricitabine Stavudine Zidovudine HIV Protease Inhibitors Boceprevir Telaprevir Peg-IFN alfa Ribavirin Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelinavir Ritonavir Saquinavir Tipranavir HIV NNRTIs Boceprevir Telaprevir Peg-IFN alfa Ribavirin Delavirdine Efavirenz Etravirine Nevirapine Rilpivirine HIV EntryIntegrase Boceprevir Telaprevir Peg-IFN alfa Ribavirin Elvitegravircobicistat Maraviroc Raltegravir No clinically signiicant interaction expected No clinically signiicant interaction predicted Potential interaction These drugs should not be co-administered TABLE 8.4 Dose modiications recommended in the product literature for pegylated interferon and ribavirin Liver cirrhosis The CUPIC study 171,172 found a very high risk of side-effects in treatment- experienced patients with compensated cirrhosis treated with PEG-IFN, RBV and either boceprevir or telaprevir. Among patients who received at least 16 weeks of treatment, 40 of patients developed a serious adverse event and 11.7 had to cease therapy. Six patients died; ive from severe infection and one from oesophageal variceal haemorrhage. Hepatic decompensation occurred in 2.4 of patients manifesting as ascites, encephalopathy or variceal bleeding.

8.2 Dose modification