Raltegravir in Patients With End Stage Liver Disease and in Transplant Recipients
Raltegravir in Patients With End Stage Liver Disease and in Transplant Recipients
This phase I/II, multi-center study is designed to determine the pharmacokinetic profile of
 Raltegravir in patients with end stage liver disease and to assess drug-drug interaction when
 Raltegravir is combined with immunosuppressive therapy in liver transplant recipients.
HIV infected patients with stable plasma HIV-RNA below 50 copies per mL and severe liver
 dysfunction will be switched from their antiretroviral regimen to a combination of
 raltegravir (one 400 mg pill twice daily) and two fully active molecules among nucleosi(ti)de
 analogs and enfuvirtide for a first period of at least 3 months and a second period of at
 least 3 months after liver transplantation, if need be, when a steady state of the
 anticalcineurin will be reached. Pharmacokinetic parameters of raltegravir will be calculated
 during severe liver dysfunction period and after liver transplantation. Pharmacokinetic
 parameters of cyclosporine (or tacrolimus if contra indication to cyclosporine) will be
 compared when administrated alone or combined with raltegravir. Patients will be followed up
 according to standard of care. This study will be divided in two distinct periods (1 and 2)
 lasting 3 months each. Period 1 will start from the inclusion in the study and will generally
 include the switch to raltegravir. Period 2 will start from liver transplantation.
Inclusion Criteria:

 -  Age ≥ 18

 -  Documented HIV-1 infection, hepatitis B or C co-infection is allowed

 -  Plasma viral load at screening visit below 50 copies per mL for at least 6 months

 -  Patient with severe liver failure (Meld Score ≥ 15 and/or refractory ascites and/or
 haemorrhage of digestive tract and/or hepatic encephalopathy) for taking part into
 period 1

 -  Patient eligible for the liver transplant waiting list or immediate post
 transplantation for taking part into period 2

 -  Abstinence from alcohol intake for at least 6 months (WHO norm)

 -  Withdrawal from intravenous drug use for at least 6 months (methadone substitution is
 permitted)

 -  No ongoing class C opportunistic infection (1993 CDC classification)

 -  Patient whose clinical and immunovirological condition allows triple therapy with
 raltegravir + 2 NRTI or raltegravir + NRTI + enfuvirtide

 -  Patient whose HIV population, according to cumulative genotypes carried out on viral
 RNA together with treatment history (if available and interpreted as per the ANRS-AC11
 algorithm version no.19) does not present a profile of mutations associated with
 resistance to raltegravir and is sensitive to at least two fully active* agents
 selected among nucleoside/nucleotide reverse transcriptase analogs NRTI (abacavir,
 lamivudine, emtricitabine, tenofovir) or enfuvirtide

 *An ARV agent is considered to be fully active if the cumulative genotypes do not show
 any mutation associated with resistance or any mutation associated with "possible
 resistance"

 -  Patient not having experienced viral escape during treatment combining 3TC, FTC or
 raltegravir

 -  Patient registered with or covered by a social security scheme

 -  For women of child-bearing potential, use of a barrier contraceptive method during
 sexual intercourse and negative pregnancy test (plasma ß-HCG ) at screening visit

 -  Informed consent form signed at screening visit at the latest

 Exclusion Criteria:

 -  More than two virological failures during antiretroviral treatment

 -  Currently receiving treatment with an agent in development (apart from an
 authorization for temporary use)

 -  Plasma viral load at screening visit ≥ 50 copies per mL during at least the last 6
 months

 -  Pregnant women, or women liable to become pregnant, breast-feeding women, no
 contraception, or refusal to use contraception

 -  All conditions (including but not limited to alcohol intake and drug use) liable to
 compromise, in the investigator's opinion, the safety of treatment and/or the
 patient's compliance with the protocol

 -  Patient not having any effective options for NRTI +/- enfuvirtide (defined in the
 inclusion criteria)

 -  Ongoing treatment with interferon-alpha or ribavirin for hepatitis C

 -  Concomitant medication including one or more agents liable to induce UGT1A1 and reduce
 raltegravir concentrations:

 -  anti-infective agents: rifampicin/rifampin

 -  psychotropic/antiepileptic agents: phenytoin, phenobarbital, carbamazepine

 -  steroidal anti-inflammatory drug: dexamethasone