Immune Activation Contributes to HIV Disease Progression in HIV/HCV Coinfected Women

		SUMMARY: HIV/HCV coinfected women with detectable hepatitis C virus (HCV) in their blood had a higher percentage of activated CD8 T-cells, as well as a significantly higher risk of progression to AIDS, according to a study described in the March 15, 2010 Journal of Infectious Diseases. Increased immune activation may help explain more the rapid HIV disease progression seen in some studies of coinfected patients.

By Liz Highleyman

Considerable research has shown that HIV/HCV coinfected individuals tend to experience more rapid liver disease progression than HIV negative people with hepatitis C alone. The effect of HCV on HIV disease progression is less clear, however, as studies have produced conflicting results.

A growing body of evidence indicates that increased CD4 and CD8 T-cell immune activation is a risk factor both for HIV disease progression and for non-AIDS conditions such as cardiovascular disease. Additive immune activation due to 2 co-existing infections may further increase the risk.

Andrea Kovacs from the University of Southern California Keck School of Medicine and colleagues analyzed the risk of new onset clinical AIDS and AIDS-related deaths among 1307 HIV positive women with and without hepatitis C.

The study included 813 HIV positive/HCV negative women, 87 HIV/HCV coinfected women with undetectable HCV viremia (blood viral load), and 407 HIV/HCV coinfected women with detectable HCV.

The researchers assessed percentages of activated CD4 and CD8 T-cells, as determined by expression of CD38 and HLA-DR markers, in blood samples from 592 study participants with available data, and looked at the association between immune activation and disease progression over a median duration of 5.2 years.

Most of the 592 participants with immune activation data were African-American or Hispanic, the mean age was about 37 years, about half had a history of injection drug use (though < 20% were active users during follow-up), the average CD4 cell count was 439 cells/mm3, and the average CD8 cell count was 964 cells/mm3. Among the HCV positive women, most (80%) had HCV genotype 1, and only 19 received interferon treatment (without ribavirin).

Results

	Overall, among the 1307 women without AIDS at baseline, 495 progressed to AIDS, including 162 who died of AIDS-related causes during 10 years of follow-up.
	HIV/HCV coinfected women with detectable HCV had a significantly higher percentage of activated CD8 T-cells than HIV positive women without HCV (P < 0.001).
	Coinfected women also had a significantly higher incidence of AIDS-related illness or death compared with HCV negative women (P < 0.001).
	Coinfected women with HCV viremia were more likely to develop bacterial pneumonia, wasting syndrome, and encephalopathy (brain disease).
	The risk of progression to AIDS-defining conditions or AIDS-related death was nearly 3 times higher among coinfected women with the highest third of CD38+/HLA-DR+ CD8 cells (> 43%) compared to those with the lowest third (< 26%) (hazard ratio 2.94; P < 0.001).
	This magnitude of difference was not observed between HIV positive/HCV negative women with the highest and lowest CD8 cell activation levels (hazard ratio 1.87; P = 0.16).
	In contrast, CD4 T-cell activation predicted progression to AIDS or AIDS-related death similarly in both HIV/HCV coinfected women and those with HIV alone.
	Increased percentages of CD38-/HLA-DR+ and CD38-/HLA-DR- CD8 cells and CD38-/HLA-DR- CD4 cells -- that is, T-cells lacking the CD38 marker -- were associated with a 50%-70% lower risk of AIDS for both coinfected women with HCV viremia and HCV negative women.
	HCV viremia was associated with progression to AIDS independent of CD4 count, HIV viral load, use of antiretroviral therapy (ART), and injection drug use.
	HCV viral load was associated with CD4 and CD8 T-cell activation independent of HIV viral load.
	HIV/HCV coinfected women had nearly twice the risk of developing AIDS as HCV negative women even if they never had a CD4 cell count < 200 cells/mm3.

Based on these findings, the investigators stated, "HCV positive viremic women with HIV coinfection who have high levels of T-cell activation may have increased risk of AIDS."

"These data suggest that the increased risk of HIV disease progression among HCV coinfected women with high levels of CD8 activation may be due to immune dysfunction," they elaborated in their discussion. "Our finding of increased incidence of AIDS-defining conditions in relation to high levels of immune activation suggests that there is impaired T-cell function in HCV positive viremic women that may potentially put them at higher risk of HIV disease progression compared with HCV negative women."

In conclusion, the authors wrote, "our study demonstrates that HIV coinfected HCV positive viremic women are at increased risk for AIDS-defining conditions compared with HCV negative women, possibly because of high levels of activation of T-cells, especially CD8 T-cells, which indicates increased immune dysregulation in this population of women. Lower levels of activation of both CD8 and CD4 T-cells and activation of CD8 T-cells expressing only HLA-DR is protective against AIDS."

"Earlier treatment of HIV and HCV infection may be beneficial" for coinfected individuals, they suggested.

Maternal, Child, and Adolescent Center for Infectious Diseases & Virology and Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA; Department of Medicine, University of California, San Francisco, CA; San Francisco Veterans Affairs Medical Center, San Francisco, CA; Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL; Division of Infectious Diseases, Georgetown University, Washington, DC; Department of Medicine, State University of New York Downstate College of Medicine, Brooklyn, NY; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.

3/19/10

Reference
A Kovacs, R Karim, WJ Mack, and others. Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus. Journal of Infectious Diseases 201(6): 823-834 (Abstract). March 15, 2010.