No influence of GB virus C replication on the prognosis in a cohort of HIV-1-infected patients
Birk, Markusa,b; Lindbäck, Stefana; Lidman, Christera
Departments of aInfectious Diseases and bClinical Virology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Sponsorship: Financial support was obtained from the Swedish Physicians against AIDS Research Fund.
Received: 2 May 2002; revised: 22 May 2002; accepted: 8 July 2002.
Co-infection with GB virus C (GBV-C) in HIV-1-infected individuals could have a beneficial influence on disease outcome. We followed 157 HIV-1-infected patients with seroconversion dates defined within ± 1 year for a median of 7 years. Of these patients, 36 (23%) were positive for GBV-C RNA. Life-table analyses showed no significant difference in outcome variables between patients with or without GBV-C viraemia. Endpoints were CD4 T lymphocyte count of 200 cells/μl or less, AIDS diagnosis and AIDS-related death.
In 1995, a previously unknown virus was isolated, which belongs like hepatitis C virus to the Flaviviridae and was named GB virus C (GBV-C) . It is transmitted vertically from mother to child  and horizontally by blood or blood products [3,4] or by sexual contact [5,6]. The initial association with non-A–E hepatitis could not be confirmed. At present, GBV-C is not known to cause any disease. The prevalence in the healthy population is approximately 1–4% [3,7]. Substantially higher prevalence rates have been reported in homosexual men , intravenous drug users (IDU) , and HIV-1-infected patients [10,11].
Recently, some studies indicated a beneficial effect of co-infection with GBV-C on the outcome of HIV-1 infection [10–12]. In contrast, it has been proposed that co-infection with hepatitis B or C virus correlates with a reduced survival rate  in HIV-1-infected individuals.
In 1997, we published a study , which showed a highly significant difference in disease progression and death from AIDS between homo/bisexual men and IDU. This difference was proposed to be caused by the transmission route determining the initial immune response.
In the present study, we focused on the impact of co-infection with GBV-C on the immunological and clinical outcome in this cohort.
We identified all HIV-1-infected homo/bisexual men and IDU seen at our department before May 1995, with dates of seroconversion defined within plus or minus one year. A total of 188 patients was detected; however, five patients declined to participate and in 26 patients no suitable serum/plasma samples were available. This resulted in 157 study subjects. The 31 excluded patients did not differ significantly with regard to age, sex, risk group, or antiretroviral treatment (data not shown). The Ethics Committee at the Huddinge University Hospital approved the study.
The date of HIV infection (start date) was calculated as the midpoint between the last negative HIV test and the first positive HIV test. The date for the CD4 cell count being 200/μl or less was calculated from multiple CD4 cell count data. AIDS diagnosis was used according to the CDC definition from 1993 . In order to diminish the effect of antiretroviral treatment on disease progression, the data of the follow-up were censored from May 1995, when highly active antiretroviral therapy was introduced in Sweden.
Viral RNA was isolated from 140 μl plasma/serum using the Qiagen QIAamp Viral RNA Kit (Qiagen, Heidelberg, Germany) according to the recommendations of the manufacturer. The RNA was amplified with nested reverse transcriptase–polymerase chain reaction using primers from the 5′-non-coding region, as previously described .
The endpoints were a CD4 cell count of 200 cells/μl or less, AIDS diagnosis, and death from AIDS. The mortality of non-HIV-related causes (e.g. accident, overdose) was censored. The JMP software (SAS Institute, Cary, NC, USA) was used for statistical analyses. Analysis of variance and Student's t-test were used for parametric variables, the Wilcoxon rank sum test was used for non-parametric variables, and the chi-square and Fisher's exact test were used for categorical data. We used Kaplan–Meier life-table analysis and proportional hazard analysis for time to event data. A P value of 0.05 or less was considered to be significant.
Serum/plasma samples were available in 157 patients, and the samples were drawn 0.75 years (median, range −0.4–4.9) after the first positive HIV test. The median age at HIV diagnosis was 32 years (range 20–69), and the median follow-up time was 7.0 years (range 1–12). GBV-C RNA was detected in 36 out of 157 patients (23%). There was no significant difference (P = 0.7) in the rate of GBV-C viraemia between homosexual men (10/49, 20%) and IDU (26/108, 24%). The GBV-C RNA-positive patients (n = 36) and GBV-C RNA-negative patients (n = 121) were similar with regard to female sex (n = 12, 33% and n = 29, 24%; P = 0.3), the use of Pneumocystis carinii pneumonia (PCP) prophylaxis (n = 11, 34% and n = 26, 23%; P = 0.2) and the use of zidovudine treatment (n = 17, 53% and n = 58, 51%; P = 0.8).
In life-table analyses we did not find any significant difference between GBV-C RNA-positive and -negative patients in the time to a first CD4 lymphocyte count below 200 cells/μl (P = 0.9), the time to AIDS diagnosis (P = 0.4) or the time to death from AIDS (P = 0.6) (Fig. 1a–c). The GBV-C status (positive or negative) was not associated with any of the three outcome variables in multiple proportional hazard analyses, including age, risk behaviour, zidovudine treatment and PCP prophylaxis as regressors (data not shown).
In the present study, we followed up a cohort of 49 homo/bisexual men and 108 IDU for a median of 7 years after seroconversion. All patients were seen in our clinic before May 1995, their time-point of HIV-1 infection could be determined within one year, and the patients were followed closely clinically and in the laboratory before effective antiretroviral treatment was introduced. Our study setting probably thus demonstrates the natural course of HIV infection in the 1990s before the introduction of highly active antiretroviral therapy. All these factors are of importance and may explain the conflicting results on prognosis, which have been reported from other studies [10–12].
We chose GBV-C RNA as a marker for active co-infection/replication. We did not perform serological studies of GBV-C in our study because the value of serology is disputable in the sense of co-infection/replication. Furthermore, in previous studies the positive influence of GBV-C on the HIV prognosis was most marked among patients with active replication, i.e. positive GBV-C RNA [10–12].
We found a prevalence of 23% GBV-C co-infection. Comparable prevalence rates have been reported previously in HIV-positive patients [16,17]. In our patients there was no significant difference in GBV-C viraemia between homo/bisexual men and IDU. The different prognosis of HIV-1 infection in the homo/bisexual men and IDU of our cohort cannot thus be explained by differences in GBV-C co-infection rates.
In conclusion, we found neither a positive nor a negative influence of GBV-C co-infection on the immunological and clinical outcomes of HIV-1 infection. Controlling for known prognostic factors such as age, sex, year of seroconversion, antiretroviral therapy and PCP prophylaxis did not affect the results for all three endpoints (CD4 cell count ≤ 200 cells/μl; AIDS; AIDS-related death). The role of GBV-C co-infection still seems to be controversial [18–20]. More studies are needed to confirm the significance of GBV-C co-infection in the pathogenesis of HIV infection.
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© 2002 Lippincott Williams & Wilkins, Inc.
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