Several
studies presented at the 8th International Congress on Drug Therapy in HIV Infection
in Glasgow looked at liver toxicity associated with antiretroviral therapy in
HIV positive patients with hepatitis C virus (HCV). Following is a brief summary
of some of this data.
I.
Aguilar and colleagues reported on the incidence of severe liver-related adverse
events (SLEs) in a retrospective cohort study of 388 patients who started HAART
regimens that included lopinavir/ritonavir (Kaletra); 61% were coinfection with
HCV, while 6.7% had HBV. SLEs were defined as decompensation of pre-existing chronic
liver disease and Grade 3-4 liver enzyme elevations (i.e., plasma AST or ALT values
> 5 times the upper limit of normal if baseline levels were normal, or >
3.5 times the baseline values when they were abnormal). There were 6 reported
SLEs, all in patients coinfected with HCV; all occurred within the first 6 months
after starting lopinavir/ritonavir. This represented 0.72 events per 100 patient-years
(95% CI 0.36-2.98) overall, and 1.21 events per 100 patient-years (95% CI, 0.60-5.86)
in HIV-HCV coinfected patients. The only factors associated with SLEs at 6 months
were baseline liver enzyme elevation (100% vs 56%; P = 0.03) and HIV-HCV coinfection
(100% vs 60.3%; P = 0.05). The authors concluded that, "The incidence of
SLEs in HIV patients receiving a HAART regimen including lopinavir/ritonavir was
very low, even in coinfected patients…Lopinavir/ritonavir can be considered
a safe and well-tolerated option in HIV patients with hepatotropic virus coinfections."
In
a related study, P. Cote and colleagues reported on 35 HIV-HCV coinfected patients
with suppressed HIV and without Grade 3/4 ALT and AST elevations who started treated
with lopinavir/ritonavir. Twenty patients completed 48 weeks of therapy. At 48
weeks, HIV viral load decreased by 2.58 log copies/mL and mean CD4 cell count
increased by 66 cells/mm3. Mean ALT increased from 58 to 71 U/L (P = 0.46), while
AST remained unchanged at 53 U/L. Grade 3/4 liver enzyme elevations occurred in
3 out of 11 patients (27%) with HCV genotype 3 and 1 of 24 patients (4%) with
other genotypes (P = 0.115). Six patients reported non-serious adverse events.
The researchers concluded that, "HIV-HCV patients treated with [lopinavir/ritonavir]
experience significant immunological improvement and HIV viral load decrease with
minimal perturbation of baseline HCV viral load. Hepatotoxicty incidence was low."
C.
Koegl and colleagues followed an ongoing cohort of HIV positive patients starting
twice-daily ritonavir-boosted fosamprenavir (Lexiva). Among the first 40 patients
evaluated, 10 (25%) were coinfected with HCV. The median time on fosamprenavir/ritonavir
was 12.1 months (range 0.1-36.6 months). The median decrease in gamma-glutamyl
transferase (GGT) was 84.0 U/L in HIV-HCV coinfected patients (P = 0.02) and 4.5
U/L in HCV negative individuals (P = non-significant). The median changes in ALT
were 5.0 (P = non-significant) and 4.5 U/L (P = 0.02), respectively. The researchers
wrote that in this cohort, "we observed relatively stable ALT values and
a significant decrease in GGT in HIV-HCV coinfected patients after switching to
a fosamprenavir/ritonavir-containing regimen. Our data confirm the safety of fosamprenavir/ritonavir
in both HIV mono[infected] and in HIV-HCV coinfected patients." Tipranavir/ritonavir
P.
Garcia-Gasco and colleagues reported on the safety of ritonavir-boosted tipranavir
(Aptivus) in heavily treatment-experienced patients with and without chronic hepatitis
B or C. This retrospective study included 50 participants who started tipranavir/ritonavir
as part of a salvage regimen; 12 were coinfected with HCV and 4 were HBV surface
antigen positive. Liver fibrosis (by FibroScan) was observed in 14 patients (28%).
ALT -- but not AST -- increased during tipranavir/ritonavir therapy. No cases
of Grade 3/4 liver toxicity occurred. There was no association between HCV RNA,
HBsAg, or significant liver fibrosis and risk of liver toxicity. A univariate
analysis showed an association between longer prior protease inhibitor exposure
and liver toxicity, but this was not confirmed in a multivariate analysis. "A
mild-moderate increase in ALT, as well as in cholesterol and triglycerides, is
frequently seen during tipranavir/ritonavir therapy," the researchers concluded.
"HBV [or] HCV coinfection does not seem to increase the risk of liver toxicity
of tipranavir/ritonavir." Atazanavir/ritonavir
F.
Gatti and colleagues evaluated the influence of liver cirrhosis on atazanavir
(Reyataz) pharmacokinetics in 12 HIV-HCV coinfected patients treated with atazanavir/ritonavir.
Patients were classified using FibroScan into groups with no cirrhosis (liver
stiffness < 12 kPA; n = 5) or cirrhosis (liver stiffness >/= 12 kPa; n =
7). All patients had HIV RNA < 50 copies/mL. The researchers found that atazanavir
trough concentrations and 0-24 hour area under the curve (AUC) were slightly higher
in patients with cirrhosis, and observed an inverse correlation between AUC and
liver stiffness.
NNRTI
Concentrations and Cirrhosis
Finally,
P. Barreiro and colleagues reported on the influence of liver fibrosis on levels
of antiretroviral drugs in 268 HIV-HCV coinfected patients. Plasma drug levels
were measured in patients receiving nevirapine
(Viramune), efavirenz (Sustiva),
lopinavir/ritonavir, or atazanavir
with or without ritonavir at standard doses for more than 12 weeks. Liver fibrosis
staging was measured using FibroScan; the distribution of Metavir scores was 39%
F0-F1, 16% F2, 11% F3, and 34% F4. Drug concentrations were higher in patents
with cirrhosis compared to non-cirrhotics for efavirenz (median 3.4 vs 1.9 mg/mL;
P < 0.01) and nevirapine (median 6.6 vs 5.8 mg/mL; P = 0.33). Efavirenz levels
were above the toxicity threshold (> 4 mg/mL) more often in cirrhotics than
in non-cirrhotics (31% vs 3%; P < 0.001). The same trend was observed for nevirapine
plasma levels > 8 mg/mL (50% vs 27%; P = 0.27). Plasma levels of protease inhibitors
did not differ significantly based on presence or absence of cirrhosis. "Liver
clearance of NNRTIs, particularly of efavirenz, seems to be impaired in cirrhotics,
[which] translates into higher plasma drug levels," the researchers concluded.
"These patients might benefit from therapeutic drug monitoring to avoid drug
overexposure."
12/05/06
References
I
Aguilar, S Vergara, A Rivero, and others. Low incidence of severe liver events
(SLE) in HIV patients with and without hepatitis C or B coinfection receiving
lopinavir/ritonavir (LPV/r). 8th Congress on Drug Therapy in HIV Infection (HIV8).
Abstract P107.
P
Cote, C Cooper, JG Baril, and others. Safety assessment of lopinavir/ritonavir
(LPV/r) in HIV+ and hepatitis C (HCV) co-infected patients. HIV8. Abstract P312.
C
Koegl, E Wolf, A Eberhard, and others. Fosamprenavir/ritonavir (FPV/r): decrease
of liver enzymes in patients co-infected with hepatitis C. HIV8. Abstract P108.
P
Garcia-Gasco, J Garcia, E Poveda, and others. Safety of tipranavir in heavily
antiretroviral-experienced HIV-infected patients with and without chronic hepatitis
B/C. HIV8. Abstract P112.
F Gatti, P Nasta, A Loregian, and others. Influence
of liver cirrhosis on atazanavir pharmacokinetics. HIV8. Abstract P285.
P
Barreiro, S Rodriguez-Novoa, P Labarga, and others. Influence of the stage of
liver fibrosis on plasma levels on antiretroviral drugs in HIV-infected patients
with chronic hepatitis. HIV8. Abstract PL6.2.
