Mutations That Confer Resistance to HCV Protease Inhibitors By
Liz Highleyman It is well known that use of HIV
protease inhibitors (PIs), especially as monotherapy, can lead to the emergence
of drug-resistant mutations.
The same is true for hepatitis C virus (HCV) PIs currently under development,
including telaprevir
(VX-950) and boceprevir
(SCH 503034). However, it remains to be seen whether exposure to HIV PIs might
compromise the efficacy of HCV PIs. In
a study presented at last month’s 42nd Annual Meeting of
the European Association for the Study of the Liver, mutations within the
HCV NS3 protease gene were investigated by direct sequencing using blood samples
from 38 HIV-HCV coinfected patients.
Subjects had genotype 1 HCV,
and had comparable demographic and clinical characteristics.
Half the patients were being treated with HIV
PIs at the time of sample collection, while the remainder where on PI-sparing
HAART regimens. Samples from the HIV positive patients were compared
with a pool of 250 control sequences obtained from Genbank. Results
- Comparison between HCV NS3 sequences
from HIV-HCV coinfected patients and control sequences showed that the amino acid
change that conferred resistance to telaprevir and boceprevir (aa 156/170) was
more frequent in HIV positive patients than in the control group (5 of 38 vs 2
of 250; P<0.0001).
- Patients taking HIV PIs showed
a mutation profile significantly different from that of the control group (3 of
19 vs 2 of 250; P=0.0028).
- HIV positive patients taking HAART
regimens without a PI exhibited a mutation profile similar to that of the control
group (0 or 19 vs 2 of 250; P=NS).
- The amino acid substitutions A156G
or A156T were observed in 3 HIV positive patients taking HIV PIs (15.7%), but
in no HIV positive subjects on PI-sparing HAART.
- The amino acid substitution at
position 170 of HCV NS3 was detected in 13.16% of patients taking HAART -- with
or without an HIV PI -- but not in the control group (5 of 38 vs 0 of 250; P<0.0001).
- However, this amino acid substitution
occurred with similar frequently in HIV positive patients taking PI-based and
PI-sparing HAART (2 of 19 vs 3 of 19).
- HIV and HCV load were comparable between individuals with and without
the amino acid substitution.
- Patients with at least 1 HCV NS3
mutation had a significantly lower CD4 cell percentage than subjects without these
amino acid changes (17.1% vs 25%; P=0.0481).
- The difference in CD4 cell counts
approached statistical significance (median 333 vs 568 cells/mm3; P=0.0598).
ConclusionIn
conclusion, the researchers wrote, “These results, albeit obtained in a small
cohort, may have implication for the treatment with HCV PI of HIV positive patients
coinfected with naturally selected resistant variants of HCV genotype-1.” Division
of Infectious Diseases, San Raffaele, Scientific Institute, Milan, Italy. 05/01/07 Reference
S Bagaglio, C Uberti-Foppa, L Alagna, and others. Mutations in the natural
strains of NS3 protease domain that confer resistance to anti-HCV protease inhibitors
in HIV/HCV coinfected patients. 42nd Annual Meeting of the European Association
for the Study of the Liver. April 11-15, 2007. Barcelona, Spain.
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