Throughout the course of the AIDS epidemic, many co-factors have been investigated as possible causes of faster disease progression. But recent studies have suggested that there may be a co-factor that actually benefits people with HIV.
The hepatitis G virus (HGV, also known as GB virus C) is commonly found in people co-infected with HIV and hepatitis C. HGV, first identified in 1995, is a blood-borne virus that doesn't seem to cause liver disease or have any effect on hepatitis C, although its long-term effects are unknown. But researchers soon began noticing the effect of HGV on HIV infection.
A study from Japan published in 1998 found that HIV-positive people with hemophilia who were also HGV-positive had slower HIV disease progression than those who were HGV-negative, although the results were not statistically significant. Another 1998 study from England found that people with HIV were less likely to clear HGV than those who were HIV-negative, but did not look at the effect of HGV on HIV infection. Then, a study published in 1999 found slower HIV disease progression in 23 people who were also HGV-positive compared to those who were HGV-negative. A study from Japan published in 2000 found that HGV infection benefited people with HIV - for people with hemophilia and HIV, the risk of progression to AIDS was 40% lower if they were also HGV-positive, regardless of age, viral load, CD4 count or CCR5 genotype.
Last September, two studies published in The New England Journal of Medicine received considerable attention. The first study, from Iowa City, followed 362 people with HIV, 40% of whom tested positive for HGV. After four years, 28% of those with HGV had died, compared to 56% of those who did not have HGV. This increased survival remained significant even when adjusted for beginning CD4 count, age, sex, race and mode of HIV infection.
But the difference was not as great when HAART was brought into the picture. Of those who entered the study before 1990, 33% with HGV died, compared to 72% without HGV. But of those who entered after 1995, when HAART became available, only one person died. So this study couldn't tell whether or not HGV infection offered any survival benefit if HAART was used.
This study also looked at HGV's effect on HIV in the test tube (in vitro). If cells were infected with both HIV and HGV at the same time, HIV replication was slowed down by 49% after six days. If cells were infected with HGV after HIV infection, HIV replication was slowed down by about the same degree, 58%. But if cells were first infected with HGV and then with HIV, replication was slowed down by an impressive 99% six days after infection. HGV infection did not affect the CD4, CXCR4 or CCR5 receptors that HIV uses to enter a cell, so the authors of the study conclude that HGV interferes with HIV replication at some point after entry into the cell.
The second study, from Germany, followed 197 people with HIV from 1993 to 2000. Among the 17% who tested positive for HGV, survival was significantly longer, even in those on HAART. The researchers also found slower progression to AIDS, higher CD4 counts and lower HIV viral loads in people co-infected with HGV. More surprisingly, those with higher HGV viral loads had lower HIV viral loads, although a higher HGV viral load was not associated with higher CD4 counts.
A study presented at February's Conference on Retroviruses and Opportunistic Infections looked at the disease history of 80 asymptomatic injection drug users with HIV from 1989 to 1997. Seventeen people were positive for HGV, and were comparable to those without HGV in terms of HIV viral load, CD4 count, years since HIV infection, and time on antiretrovirals. But at the end of follow-up, those with HGV had a better AIDS-free survival rate, lower viral loads and higher CD4 counts than those who were HGV-negative. The most striking finding was that 73% of the HGV-positive group had viral loads below 400, compared to only 39% of the HGV-negative group.
More importantly, this study proposed a new theory as to how HGV infection might slow HIV disease progression. It found that Th1 cytokines (IL-2 and IL-12) remained stable only in the HGV-positive group, and that Th2 cytokines (IL-4 and IL-10) rose only in the HGV-negative group. The authors suggest that HGV may interfere with the classic shift from a Th1 to Th2 pattern that is seen in many people with disease progression.
What does this mean for people with HIV? Nothing right now. No one is suggesting that anyone with HIV attempt infection with HGV, since the long-term effects of that infection are unknown. In addition, these studies only show an association between HGV infection and slower HIV disease progression - we don't know if it's actually HGV that is causing the slower progression or if there's something else that people with HGV have in common. However, a German study that looked at receptor mutations known to slow HIV disease progression (CCR5, CCR2, and SDF1) found no differences between people with and without HGV, and concluded that HGV infection was an independent predictor of better survival and slower disease progression.
If HGV does slow HIV disease, we don't know how it does this -- is it acting as an antiviral or is it stimulating the immune system to better respond to HIV? The in vitro results would seem to indicate that HGV is somehow able to inhibit HIV replication, but more research is needed to find the answer. If we can find out exactly what, if anything, HGV infection does to people with HIV, it could lead to new treatment strategies and entirely new approaches to slowing HIV disease progression. Stay tuned.
Mark Milano is a longtime AIDS treatment activist and a treatment educator at ACRIA.