Why Is There More Rapid Progression of Liver Fibrosis in HIV-Infected Patients With Chronic Hepatiti

[Guest guest]

More: 15th Conference on Retroviruses and Opportunistic Infections (CROI)

Selection from: CROI 2008: Management of HIV Infection in Special Populations

CROI 2008: HIV/Hepatitis Virus Coinfections CME

V. Soriano, MD, PhD

Disclosures

At least 90 of 1150 abstracts presented at this year's 15th Conference on

Retroviruses and Opportunistic Infections (CROI) addressed different aspects of

coinfection between HIV and viral hepatitides. There was 1 oral abstract session

in which some of the most relevant studies were presented.

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Why Is There More Rapid Progression of Liver Fibrosis in HIV-Infected Patients

With Chronic Hepatitis C?

It is well established that progression to cirrhosis occurs more rapidly in

patients with chronic hepatitis C who are coinfected with HIV compared with

hepatitis C virus (HCV)-monoinfected individuals. In the absence of treatment,

half of coinfected patients will show liver cirrhosis after an average of 25

years following HCV acquisition.[1] This observation is somewhat paradoxical

because liver damage in chronic hepatitis C is mainly immune-mediated.

Hypothetically, immunodeficiency might ameliorate HCV-related immune lesions.

Histologic studies, however, have demonstrated that while inflammatory responses

in the liver of coinfected patients might be lower, hepatic fibrosis is

enhanced.

Researchers from the Mount Sinai School of Medicine in New York, NY,

investigated whether HIV could infect hepatic stellate cells, which are the

specialized macrophages that produce collagen and are the major determinants of

the fibrotic process. The authors found that HIV can enter stellate cells

throughout endocytosis independent of CD4 receptors. HIV can also replicate

within these cells, activating collagen production.[2] Thus, suppression of HIV

replication with antiretroviral therapy (ART) could reverse this deleterious

effect of HIV on liver fibrosis progression. Following this rationale, recent US

Department of Health and Human Services guidelines have recommended considering

earlier initiation of ART in HIV/HCV- coinfected patients.[3] What is less clear

is why liver cirrhosis is not seen more frequently in HIV-infected individuals

in the absence of classical etiologic factors, such as hepatitis B, hepatitis C,

or alcohol injury.

Researchers from s Hopkins Medical Institute in Baltimore, land,

presented an alternative explanation for the rapid liver fibrosis progression

seen in HIV/HCV- coinfected patients. It is believed that the destruction of the

mucosa-associated lymphoid tissue characteristically occurring soon after HIV

infection might favor bacterial translocation from the lumen of the

gastrointestinal tract to the bloodstream.[4] In the portal system, this may

cause repeated episodes of infection and inflammation in periportal spaces, with

secondary hepatic fibrosis.[5] In line with this hypothesis, the Hopkins authors

showed that plasma levels of lipopolysaccharide (LPS), LPS-binding protein,

soluble CD14, and endotoxin core antibodies were more elevated in coinfected

patients who progressed to cirrhosis than those who did not.[6] Thus, as

outlined in Figure 1, bacterial translocation in HIV could favor liver damage in

HIV/HCV- coinfected patients.

Finally, possible involvement of CD4+ T regulatory (Treg) cells was postulated

by Spanish researchers.[7] Both HIV and HCV infections may alter the Treg cell

population, which would modulate viral persistence by inhibiting specific T-cell

responses. The authors found that HIV but not HCV induces upregulation of highly

activated Treg cells. This upregulation increases with CD4 depletion, which

hypothetically might contribute to the accelerated course of liver disease in

coinfected patients.

Other factors contributing to the more rapid progression of liver fibrosis seen

in HIV/HCV- coinfected individuals were also examined. Of note, prolonged

exposure to protease inhibitors (PI),[8] nucleoside/tide reverse transcriptase

inhibitors (NRTIs),[9] or both[10] were found to be associated with more severe

liver fibrosis. Conversely, some allelic interleukin-10 polymorphisms were

associated with milder liver fibrosis.[11] The mechanism by which PIs could

worsen liver fibrosis might involve the metabolic abnormalities typically linked

to this drug class, such as insulin resistance and hyperlipidemia,[10] while

liver damage associated with NRTI use could be due to mitochondrial toxicity.[9]

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This year's CROI certainly focused attention on the issue of hepatitis

coinfection in patients with HIV disease and on the importance of diagnosis,

monitoring, and appropriate treatment of such patients. For those particularly

interested in HIV and viral hepatitis coinfection, consider attending the 4th

International Workshop on HIV and Hepatitis Coinfection, to be held in Madrid,

Spain, June 19-21, 2008. Certainly important advances will also be reported

there.

This activity is supported by an independent educational grant from

GlaxoKline.

http://www.medscape.com/viewarticle/571288?src=mp & spon=20 & uac=31238BR

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