Persistent HIV/hepatitis G co-infection provides significant survival benefit

The length of time that a person with HIV is infected with hepatitis G virus – more accurately known as GB Virus C (GBV-C) – has, for the first time, been clearly demonstrated to positively affect disease progression in a group of gay men not on antiretroviral therapy.

The study, whose findings were published in the March 4^th issue of the New England Journal of Medicine, looked retrospectively at a group of men in the Multicentre AIDS Cohort Study (MACS) over eleven years, and found that co-infection with GBV-C was significantly associated with prolonged survival five to six years after seroconversion. There was no such association 12 to 18 months after seroconversion.

"We found strong evidence that HIV-positive men who have persistent GBV-C infection survive longer than those who do not have GBV-C,” said senior investigator Jack Stapleton, M.D., of the University of Iowa and Iowa City Veterans Affairs Medical Centre. “The survival advantage is large, and depends on how long the GBV-C infection persists."

Although six studies have previously found that GBV-C does positively affect survival in HIV co-infected people, three other studies did not find this to be the case. This is likely to be because the latter three did not take into account the length of time of active GBV-C infection, as indicated by GBV-C viral load, but rather looked only at GBV-C antibodies. In the current study, antibodies against GBV-C – an indicator that there has been GBV-C infection in the past – were not found to have the same protective effect on disease progression. It was once thought that GBV-C caused hepatitis C, although it is now not associated with any known disease.

In the study, the investigators retrospectively analysed stored blood plasma samples of 271 men in the MACS cohort with a documented date of their HIV seroconversion, and analysed those who had blood taken at least twice after seroconversion. Two samples were taken at least five years apart. The cut-off date for analysis was January 1^st 1996, so that survival rates would not be affected by the use of HAART. In total, 231 men (85%) had evidence of active (n=107) or past (n=124) GBV-C infection.

Although survival rates did not differ significantly 12-18 months after HIV seroconversion (whether or not there was evidence of current, past or no GBV-C co-infection), GBV-C status five to six years after HIV seroconversion was strongly associated with subsequent survival. Of the 50 men with active GBV-C co-infection (as indicated by GBV-C RNA (viral load)) only nine had died after five to six years. Those who had only the antibodies to GBV-C co-infection (as indicated by the surface envelope glycoprotein E2) were 2.83 times (p=0.03) more likely to die: of 59 men, 23 died. Those with no evidence of current or past GBV-C infection were 3.85 times (p=0.002) more likely to die: of 29 men, 14 died.

Since most of the MACS cohort entered the study in 1985, follow-up of 10-11 years was possible before the cut-off date. The investigators found that 75% of those who had active GBV-C infection at both 12-18 months and five to six years after HIV seroconversion were still alive on January 1st 1996. In contrast, only 39% of those who had never been infected with GBV-C were still alive at this date.

Surprisingly, those who had once been infected and then cleared their GBV-C infection had the worst outcome: only 16% were still alive 10-11 years after HIV seroconversion. Nine percent of the cohort with active GBV-C infection(12 of 138) were found to have cleared their GBV-C infection between one and six years after HIV seroconversion, and very few developed antibodies. Since GBV-C and HIV both infect and replicate inside CD4 T cells, the reason for the poorer outcome in this group is something of a chicken-and-egg question. Was GBV-C clearance in these men due to the fact that HIV had already progressed and infected most of the available CD4 cells? Or was the progression of their HIV disease due to the loss of the protective effect of GBV-C? Further studies are needed.

Why these men with persistent GBV-C infection survived longer is still poorly understood. An editorial in the same issue of New England Journal of Medicine, by Drs. Pomerantz and Nunnari, suggests a variety of scenarios. One is that type 1 helper T (Th1) cytokines - like IL-2, which increases CD4 counts - are normal or elevated in those who are co-infected with HIV and GBV-C, whereas type 2 helper T (Th2) cytokines - including IL-4 and IL-10 - are increased, and Th1 cytokines decreased, in many people with HIV disease alone. Since the shift from Th1 to Th2 cytokines is associated with disease progression, GBV-C co-infection may somehow protect against that shift.

Additionally, since HIV and GBV-C infect and replicate inside the same cells, there could be a direct, or indirect, interaction between the two viruses, at various stages in the HIV lifecycle. The authors conclude that “it is highly unusual for there to be an interaction between viruses that appears to be beneficial to patients who are dually infected. A greater understanding of the interactions between GBV-C and HIV may point to therapeutic approaches that mimic the clinically protective effects of GBV-C in patients with HIV infection.”

Further information on this website

Do Hepatitis G/HIV co-infected patients do better on HAART? Debate revives - news story

Harmless hepatitis G slows HIV disease - news story

Viral co-factors affecting disease progression