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Comment on: Unboosted fosamprenavir is associated with low drug exposure in HIV-infected patients with mild-moderate liver impairment resulting from HCV-related cirrhosis.

Sir, We have read with great interest the article by Gatti et al. concerning the use of unboosted fosamprenavir in HIV-infected patients with mild–moderate liver impairment resulting from HCV-related cirrhosis. Their results show a low overall exposure to amprenavir in cirrhotic patients, supporting the recommendation of the summary product characteristics of fosamprenavir to boost the drug with ritonavir 100 mg once daily even in cirrhotic patients. The low plasma concentration of amprenavir in three of five cirrhotic patients on unboosted fosamprenavir was attributed to the absence of ritonavir, but the authors reported that all the patients, including those with a low Ctrough of amprenavir below the minimum target concentration of 400 ng/mL, had an undetectable HIV load. Might adherence to fosamprenavir have been an issue? We would like to report our experience in 18 HIV-infected patients on different fosamprenavir dosages and a backbone of two nucleoside reverse transcriptase inhibitors, who underwent therapeutic drug monitoring to evaluate amprenavir plasma concentrations. Seven patients were HCV/HIV co-infected and 11 patients were HIV mono-infected. Of the seven co-infected patients, three were cirrhotic (Child–Pugh score A for one patient and Child–Pugh score B for the remaining two) and four had chronic hepatitis. All of the three cirrhotic patients were on fosamprenavir at a dosage of 700 mg twice daily. Two patients with chronic hepatitis were on fosamprenavir 700 mg twice daily boosted with ritonavir 100 mg twice daily, one patient was on fosamprenavir 1400 mg twice daily and one patient was on fosamprenavir 1400 mg daily boosted with ritonavir 100 mg once a day. Of the 11 monoinfected patients, 4 were on fosamprenavir 1400 mg twice daily, 4 were on fosamprenavir 1400 mg daily boosted with ritonavir 100 mg once a day and 3 were on fosamprenavir 700 mg twice daily boosted with ritonavir 100 mg twice daily. Pharmacokinetic analysis was performed between 6 and 18 months of continuous fosamprenavir intake, at a time when all the patients were virologically suppressed (HIV-RNA ,50 copies/mL). Trough concentrations were measured in plasma samples by an HPLC method. In five patients, Ctrough of amprenavir was under the minimum target concentration of 400 ng/mL. Only one patient had chronic hepatitis; she was on fosamprenavir 700 mg twice daily boosted with ritonavir 100 mg twice daily. Of the other four patients, two were on fosamprenavir 700 mg twice daily boosted with ritonavir 100 mg twice daily, one was on fosamprenavir 1400 mg twice daily and one was on fosamprenavir 1400 mg daily boosted with ritonavir 100 mg once a day. The three patients with liver cirrhosis had a Ctrough of amprenavir higher than the minimum target concentration of 400 ng/mL (701 ng/mL for the patient with a Child–Pugh score A; 980 and 1130 ng/mL for the two patients with a Child–Pugh score B). After being informed of the results of the pharmacokinetic studies, the patients with a Ctrough under the minimum target concentration of 400 ng/mL admitted incomplete adherence to the antiretroviral regimen. It may be that the cirrhotic patients included by Gatti et al. were selective drug takers with a full control of viral replication (HIV-RNA ,50 copies/mL). Finally, we think that caution should continue to be used in employing fosamprenavir boosted with ritonavir 100 mg once daily even in cirrhotic patients, as it has been shown that chronic viral hepatitis impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir leading to increased hepatotoxicity in HIV-infected people with chronic viral hepatitis on a ritonavir-based antiretroviral therapy regimen.