Harmless hepatitis-type virus seems to extend lives of HIV-positive individuals
Two independent studies appearing in The New England Journal of Medicine show that people with HIV who are co-infected with GB virus C (GBV-C) – a virus related to hepatitis C but not known to have any clinical manifestations – have significantly lower mortality rates than those infected with HIV alone.
In the first study, researchers at the Iowa City Veterans Affairs Medical Center and the University of Iowa College of Medicine tested 362 HIV patients for GBV-C viraemia between 1998 and 2000, with 144 patients (39.8%) testing positive. There were no significant differences with regard to clinical or demographic characteristics at the base-line testing, although there was a “trend toward a higher base-line CD4+ cell count” among those with GBV-C viraemia. Patients were followed for an average of 4.1 years, during which 41 (28.5%) of those with GBV-C viraemia died, compared to 123 (56.4%) who were not infected with the virus.
The adjusted relative risk of death for the GBV-C-negative group was 3.7 compared to those with GBV-C viraemia, regardless of base-line CD4+ cell count, mode of HIV transmission, age, race, sex, or prescribed treatments. The researchers also sought to determine whether GBV-C altered HIV replication. They took cultures of peripheral-blood mononuclear cells and infected them with HIV alone, GBV-C alone or both viruses simultaneously and found that when they tested them for p24 antigen, a marker for HIV growth, three days after infection, HIV replication in coinfected cells was inhibited by 23%.
Six days after infection, replication was inhibited by 49.4% in coinfected cells. They then injected GBV-C into cells that had already been infected with HIV for 24 hours to determine whether the introduction of GBV-C after HIV infection could impede viral replication and found that HIV replication was inhibited by 31.6% after three days and 58.1% six days after the introduction of GBV-C. Next, they infected cells that had been infected with GBV-C for 24 hours with HIV and found that replication was “almost completely halted by three and six days after infection” (by 87.4% and 99.0%, respectively).
When the researchers added uninfected peripheral-blood mononuclear cells to the cultures after six days they found that HIV had begun to replicate itself in the uninfected cells by the fourth day, “illustrating that GBV-C did not prevent the entry of HIV” into uninfected cells.
In the second study, researchers from the Department of Clinical Immunology at the Medizinische Hochschule in Hannover, Germany, tested 197 HIV-positive patients for GBV-C in 1993 and 1994 and found that 33 (16.8%) tested positive for GBV-C RNA and 112 (56.9%) had detectable antibodies for GBV-C. The remaining 52 (26.4%) had not been exposed to the virus. In 1996, 98 of the initial 197 patients were alive, and by March 2000, 74 of the patients were still alive. Those infected with GBV-C had a “significantly longer” duration of survival from both the date of his or her first positive HIV test and from the date of GBV-C testing than those who tested positive for antibodies to GBV-C and those who had not been exposed to the virus at all, although those who just tested positive for antibodies also survived “significantly longer” than those in the unexposed group.
The difference in survival was largely due to an increase in the amount of time it took those with GBV-C or viral antibodies to progress to AIDS. Even with the introduction of highly active antiretroviral therapy, those coinfected with GBV-C maintained a “significantly better” survival rate. Of those who died between 1998 and March 2000, only one was among those who tested positive for GBV-C RNA compared to 17 who tested positive only for antibodies to the virus. The researchers theorized that if GBV-C helped extend survival with HIV, its presence should “correlate with either higher CD4+ cell counts, because of a mechanism such as the normalization of the half-life of CD4+ cells, or a lower HIV load, because of an inhibition of HIV replication.”
The researchers found no correlation between GBV-C levels and CD4+ cell levels, but did find an inverse correlation between GBV-C viral load and HIV viral load, supporting the findings in the Xiang et al. study. The authors conclude, “[I]t is possible that GBV-C infection is a marker for the presence of other factors that result in the slower progression of HIV infection, but we think this effect probably results from an inhibition of HIV replication by GBV-C. The identification of mechanisms by which GBV-C inhibits HIV replication might lead to the development of new therapeutic approaches for HIV infection”.
A risky therapy?
GBV-C was first identified in 1995 by two teams of researchers, one from Abbott Laboratories and one from Genelabs Technologies. Although the virus is similar to hepatitis C and was originally thought to cause hepatitis, GBV-C appears to be harmless and “almost never cause[s] hepatitis.” The virus is transmitted through blood and sexual intercourse, “much like HIV, ” and although its overall prevalence is not known, it is found in roughly 2% of healthy blood donors and in 15% to 40% of those with HIV.
Dr. Isa Mushahwar, “one of the first” people to isolate the virus at Abbott, said that the study results were “very exciting, ” adding that the “ethical question becomes, should we infect the HIV-positive [with GBV-C]?” Such an experiment would require more studies and FDA approval, he said, “But if it helps and prolongs life … the question becomes, why not?”.
In an accompanying editorial, Drs. Valentina Stosor and Steven Wolinsky of Northwestern University Medical School write that the study by Xiang et al. did not clarify whether the two viruses “infect the same cell at the same time, nor did they determine the effect of GBV-C on the life cycle of HIV. … Thus, the mechanisms by which GBV-C might influence the replication of HIV and delay the development of AIDS are not immediately apparent, ” they write. “Until an underlying mechanism by which GBV-C can interfere with HIV replication is identified, a causal relation between coinfection and prolonged survival of persons with HIV infection can be neither inferred nor assumed, ” they conclude, adding that “any suggestion that the intentional infection of persons with GBV-C be explored as a therapeutic approach for HIV infection is premature”
Daniel Diekema, a member of the Iowa team, also called for caution, saying he “fervently hopes” that people with HIV will not seek to infect themselves with the virus as a means of HIV therapy. “We can never say for sure that the virus is harmless, ” he said. Jeffrey Drazen, editor of NEJM, said he almost did not publish the studies out of fear that they may “prompt” some people with HIV to infect themselves with GBV-C, but found the results “too tantalizing to ignore.” He added that the virus warrants more study because the mechanism by which it appears to inhibit HIV replication “probably isn’t as simple as its seems.”
Diekema added that although the virus itself may not be recommended as a therapy, it may prove beneficial by aiding drug development. “If this is going to lead to a new treatment – and that’s a big ‘if’ – it will be by way of understanding the basic mechanism by which the virus inhibits HIV replication.
Once that mechanism is determined, it could be exploited to develop new treatments, ” he said. Dr. Hans Tillman, one of the German researchers, acknowledged that the scientists “don’t have any clues how [the mechanism] works at the moment, ” but added that he is “quite confident” that they will have a better understanding of it within the next year.
Tillman also recommended that doctors test for GBV-C before prescribing interferon to treat hepatitis C in patients with HIV because interferon may “lead to clearance” of the “beneficial” GBV-C.
GB virus C / HIV coinfection was described as far back as 1997. Rates of HGV RNA detection in HIV-infected populations range from 11-41% and studies suggesting an effect on HIV-disease progression were first published in 1998 by Heringlake and colleagues, the same group whose results are published in this months report.
GBV anti-E2 antibodies were detected in 21% of HIV-infected patients in one study suggesting that a proportion of patients may clear the virus and remain aviraemic. Only those who remained viraemic showed any effect on HIV disease progression in those studies comparing GBV viraemic and GBV anti-E2 antibody positive subjects.
Scrub-typhus showed the same effect, only greater, in work published in the Lancet (Lancet, 2000 Aug 5;356(9228):475-9). In some people who become infected with certain strains of scrub-typhus after they have acquired HIV, their HIV viral load became undetectable.*
Xiang J et al. Effect of Coinfection with GB Virus C on Survival among Patients with HIV Infection. N Engl J Med 2001 345: 707-714.
Tillmann HL et al. Infection with GB Virus C and Reduced Mortality among HIV-Infected Patients. N Engl J Med 2001 345: 715-724.
Stosor V and Wolinsky S. GB Virus C and Mortality from HIV Infection. N Engl J Med 2001; 345:761-762, Sep 6, 2001.
Source: Kaiser Daily HIV/AIDS Reports