Session 23
Oral Abstracts
HIV/HCV Co-Infection
Tuesday, 4 - 6:15 pm
Presentation Time: 5:30 pm
Room 3000
|
116
DNA Polymorphisms Affect Severity of Disease and Response to Therapy in Subjects Co-infected with HCV and HIV
M Peters*1, J Anderson2, R Chung3, M Koziel4, K Sherman5, R Apple6, and ACTG 5071 team and NIAID – AIDS Clinical Trials Group, Bethesda, MD
1Univ. of California, San Francisco, USA; 2Statistical and Data Analysis Ctr. (SDAC), Harvard Sch. of Publ. Hlth., Boston, MA, USA; 3Harvard Med. Sch., Massachusetts Gen. Hosp., Boston, USA; 4Harvard Inst. of Med., Boston, MA, USA; 5Univ. of Cincinnati Med. Ctr., OH, USA; and 6Roche Molecular Systems, Alameda CA, USA
Background: Host factors may
play a role in the severity of HCV. We aimed to assess the role of DNA polymorphisms in 18 genes (coding region or
promoter) involved in inflammation on the severity of HCV and on the response
to treatment in HIV/HCV subjects receiving interferon (IFN) or PEG-IFN + ribavirin, in a randomized, multicenter,
open label trial in 133 co-infected subjects.
Methods: DNA was obtained from 81 subjects who had consented
to genetic analysis; 25 single nucleotide polymorphisms were tested and
reported as homozygous for wild type or variant, or heterozygous. Allelic
frequencies were compared: between 81
co-infected subjects and 2000 normal controls; with respect to entry liver
histology (HAI); and between HCV
responders (at 24 weeks or sustained 6 months after therapy) and
non-responders. Multivariable models previously showed PEG,
white race, Karnofsky score of 100, and low fibrosis to be jointly associated
with 24-week virologic response in A5071. Multivariate analysis of sustained
virologic response was confined to 43 PEG-IFN
subjects because few IFN sustained virologic responders consented to testing.
Results: Variant allelic
frequencies were 16-fold higher for ICAM-1 in HIV/HCV subjects than in controls
and >2-fold higher for IgE Fc receptor, IL4-receptor and P selectin. No
response was associated with v ICAM1 (p
<0.01 for 24 weeks and <0.03 for sustained virologic response), wild type
CCR5 promoter (p <0.09 for sustained virologic
response) and wild type CCR5 (p <0.02 at 24 weeks and <0.001 for
sustained virologic response). Total HAI
score correlated with wild type ICAM1 (p
<0.08) and v CCR5 promoter (p <0.02). Classification and
regression trees were used to identify factors jointly predicting 24 week virologic
response, sustained virologic response, and fibrosis score and ranked in order
of importance in the table below.
Predictors
of 24w VR
|
Predictors of SVR
(n
= 43 receiving PEG)
|
Predictors of Fibrosis
|
|
Genotype non-1
|
Genotype non-1
|
v CCR5
promoter
|
|
No ART at
entry
|
v CCR5
|
wt TGFb
|
|
Receipt PEG
IFN
|
|
HIV detectable
|
|
v IL4R
|
|
wt IL-13
|
|
low HCV RNA at entry
|
|
|
Conclusions: In HIV/HCV
co-infected individuals, host genetic factors appear important in development
of fibrosis and in response to therapy. Allelic variations in proteins critical
to the inflammatory response may alter the hepatic response to HCV as well as
the severity of chronic disease.
Keywords: Hepatitis C; cytokines; DNA polymorphisms
