Further evidence suggesting that early HIV treatment may be warranted for people with HIV and hepatitis C coinfection has emerged from a study of T-cell responses to hepatitis C published this week in PloS Medicine by a group of researchers from the Partners AIDS Research Center at Massachusetts General Hospital. Treatment before the CD4 count falls below 300 may increase the chance of sustained control of hepatitis C infection, the findings suggest.
HIV and hepatitis C coinfection is common in many parts of the world, and most studies into the effects of coinfection have shown a significantly faster course of liver damage caused by hepatitis C in coinfected people when compared with people infected with hepatitis C alone. The spectrum of liver damage caused by hepatitis C ranges from liver fibrosis through to end stage liver stage and liver cancer, and without treatment of hepatitis C liver damage tends to be progressive in HIV-positive people.
In order to examine immune system factors associated with spontaneous control of HCV and how that control is altered by HIV infection, the Massachusetts General Hospital researchers enrolled four groups of participants: 60 were infected with both viruses, and half of those had low HCV levels upon entering the study. The other two groups of 17 participants were infected with HCV only, with one group successfully controlling viral levels.
Spontaneous HCV control is known to rely on the activity of CD4 helper T cells specifically targeted against the virus, and destruction of CD4 cells by HIV underlies the immune deficiency that characterizes AIDS. Therefore the researchers measured participants' T cell response to HCV at the outset of the study and at two- to six-month intervals during the study period.
The results showed that those individuals able to maintain low HCV levels in spite of HIV coinfection had stronger virus-specific responses for both CD4 T cells and the CD8 "killer" T cells than did those with elevated HCV counts. Not surprisingly, participants infected only with HCV had even more powerful antiviral T cell responses. Eighty-six per cent of monoinfected HCV controllers showed HCV-specific lymphoproliferative responses, compared to 35% of coinfected HCV controllers (p=0.003) and 7% of coinfected persons with chronic HCV viremia (P=0.016).
About a quarter of those infected with both viruses who originally controlled HCV levels lost control during the two-and-a half-year study period, and their increased virus levels corresponded with an overall drop in CD4 T cells. None were able to reestablish viral control, highlighting the need for repeated HCV viral load testing in those who establish spontaneous control of HCV, the authors say.
None of the viral controllers who were infected with HCV alone had any increase in viral levels during the study period. Loss of protective responses and susceptibility to recurrent HCV infection may help to explain the higher rates of persistent HCV observed in subjects who are HIV/HCV coinfected, compared to those with HCV alone.
In analysing factors that might be associated with the loss of HCV control in those infected with both viruses, the researchers made a surprising discovery. The factor most powerfully associated with maintaining HCV control was not the CD4 T cell count upon entering the study but the lowest previously recorded or 'nadir' CD4 count. That finding suggests that, for individuals infected with both viruses, beginning antiretroviral treatment before CD4 levels drop too low to maintain HCV responses may be desirable.
“Maintenance of higher CD4 T cell counts, either through long-term non-progression of HIV or through antiretroviral treatment before CD4 T cell counts fell below 300 cells was the most important shared feature of these individuals.”
T-cell responses were not seen in individuals who had a nadir CD4 count below 300, regardless of the degree of immune reconstitution that had taken place when they began antiretroviral therapy, leading the authors to remark: “Our data suggest that the threshold CD4 T cell count that results in loss of adapative responses may be higher for HCV-specific responses than those for CMV.”
The researchers also found that, among those whose HCV levels rose, individuals who maintained some T cell responses had lower viral levels than did those with little or no T cell response. This suggests that the immune system retains a level of secondary immunity against HCV - the kind of 'memory' response against a previously encountered pathogen seen in many infections.
"Currently a nationwide trial is recruiting people for a study examining whether earlier treatment of HIV will improve hepatitis C treatment outcomes," lead auhtor Arthur Kim said. "Part of this study will investigate how earlier treatment may affect immune responses. It also will be important to follow the impact of loss of HCV control on liver disease, since this will probably have important consequences for patients with HIV." Kim is an instructor in Medicine at Harvard Medical School.
Kim AY et al. Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection. PloS Medicine 3 (12): e492, 2006.