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Safe co-administration of raltegravir, pegylated-interferon and, ribavirin in HIV individuals with hepatitis C virus-related liver damage

Moreno, Anaa; Quereda, Carmena; Fortún, Jesúsa; Bárcena, Rafaelb; Pérez-Elías, María Ja; Casado, José La; Rodríguez-Sagrado, Miguel Ac; Mateos, María Ld; Blesa, Carlosb; Moreno, Santiagoa

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doi: 10.1097/QAD.0b013e328336e9b3
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Raltegravir (RAL), the first approved HIV-1 integrase-inhibitor, combines rapid and potent antiretroviral activity with a lack of interference with the hepatic cytochrome P450-3A4 [1,2], an advantage that makes it useful in certain settings, such as liver transplantation [3,4]. The low rate of hepatitis C virus (HCV) and/or hepatitis B virus-coinfected patients in pivotal trials of RAL [5,6] has precluded the availability of information on its potential use in patients with viral hepatitis-related liver damage, specially cirrhotic individuals. Moreover, to date, there are no data on the safety of RAL with pegylated-interferon (peg-IFN) and ribavirin (RBV). We report for the first time the safe co-administration of highly active antiretroviral therapy (HAART) including RAL with peg-IFN/RBV in five HIV individuals with HCV-related liver damage: low-grade fibrosis (n = 1), compensated cirrhosis (n = 1), decompensated cirrhosis (n = 2), and a severe form of HCV recurrence following liver transplantation (n = 1).

Table 1 summarizes the most relevant HIV-related features of the cohort. All individuals were men, with a median age of 47 years (42–54), and prior AIDS in one (20%). Reasons for RAL use were virological failure (P1 and P2), HAART related toxicity (lactic acidosis due to HAART with 3NRTI leading to treatment interruption in P3, and gastrointestinal intolerance to ritonavir in P4), and the prevention of anaemia due to azidothymidine (AZT) and RBV in P5. Median baseline CD4 cell counts and HIV-RNA were 130 cells/ml (95–1109) and 2.24 log10 copies/ml (1.7–5.0). The median time on RAL-HAART was 95 weeks (23–127); RAL was stopped in P4 (death during HCV therapy) and P5 (simplification to ATRIPLA after 34 weeks of HCV therapy). P1 stopped didanosine prior to HCV therapy, and in P3 maraviroc replaced T-20 after 7 weeks. There were no HIV-RNA rebounds during RAL-HAART, and the median CD4 cell count at the end of follow-up rose to 274 cells/ml (122–796).

Table 1
Table 1:
Baseline and evolutive HIV and HAART features.

Table 2 summarizes data regarding baseline HCV-related liver damage and outcomes of HCV therapy. HCV genotype was 1 in three cases and 3a in two. Median baseline HCV-RNA was 7.0 log10 IU/ml (4.46–7.83). Overall, four individuals (80%) had severe HCV-related liver damage: a severe form of HCV recurrence 33 days after liver transplantation in P3, and three cases of cirrhosis, with prior decompensation episodes in two (spontaneous bacterial peritonitis and variceal bleeding in P1, ascites and hepatic encephalopathy in P4). In P2, Fibroscan (EchoSens, Paris, France) performed prior to HCV therapy showed F2 (8.6 kPa). Only one patient did not complete HCV therapy (P4) due to spontaneous bacterial peritonitis and pancolitis leading to death after 36 weeks of therapy. This patient started peg-IFN/RBV with the lowest HCV-RNA (29 400 IU/ml) and had achieved a rapid virological response at week 4. He was referred to the liver transplant unit at the beginning of therapy, but had not entered the waiting list at the time of death. Despite an overall early viral response rate of 100%, only patients with genotype 3a reached a sustained viral response (SVR) (40%). Among patients not reaching SVR, P1 entered the waiting list for liver transplantation in October 2009, and remains alive with the same RAL-HAART, and P3 maintains liver enzymes within normal ranges and low HCV-RNA (<50 000 IU/ml). Peg-IFN and RBV dose adjustments were performed in both individuals with decompensated cirrhosis. Haematopoietic growth factors were used in two individuals (40%), human recombinant erythropoietin (EPO) and granulocyte colony-stimulating factor in P3 and EPO in P4.

Table 2
Table 2:
Baseline and evolutive outcomes of hepatitis C virus therapy.

Our data support the feasibility of RAL use in patients with advanced HCV-liver damage, and also during therapy with peg-IFN/RBV. During the past years, there has been many literature on the considerations to take into account when treating HIV/HCV-coinfection, specially for the additive toxicity of RBV and nucleoside reverse transcriptase inhibitors (NRTI) such as zidovudine, didanosine, and stavudine [7,8]; to our knowledge, this is the first report on the safety of RAL while receiving HCV therapy in HIV-coinfection, and also following liver transplantation. In our patients, complications observed during HCV therapy were not attributable to RAL use, and were similar to those already reported among non-HIV cirrhotic patients, such as severe bacterial infections [9] and haematological toxicity leading to peg-IFN and/or RBV dose adjustments [10]. Even considering the risks associated to HCV-therapy in HIV-infected patients with cirrhosis, the impact of SVR on liver-related complications and mortality [11] should be taken into account when considering therapy, especially in patients with favourable prognostic factors, such as low baseline HCV-RNA and/or genotype 3 [12]. On the contrary, the use of haematopoietic growth factors in the patient undergoing liver transplantation was not unexpected, as the rate of haematological side effects in this population is high [13].

In conclusion, RAL showed a good safety profile in patients with HCV-related liver damage, including those with hepatic insufficiency, and was safely combined with peg-IFN/RBV therapy.


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