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Clinical Impact of GB Virus C Viremia on Patients with HIV Type 1 Infection in the Era of Highly Active Antiretroviral Therapy

  1. Wang-Huei Sheng1,
  2. Chien-Ching Hung1,
  3. Ruei-Jiuan Wu1,
  4. Jann-Tay Wang1,
  5. Pei-Jer Chen2,
  6. Shan-Chwen Chang1, and
  7. Jia-Horng Kao2
  1. 1Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
  2. 2Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  1. Reprints or correspondence: Dr. Chien-Ching Hung, Dept. of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Rd., Taipei, Taiwan (hcc0401{at}ha.mc.ntu.edu.tw).
 
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Abstract

Background. The influence of GB virus C (GBV-C) viremia on clinical outcomes of patients with human immunodeficiency virus type 1 (HIV-1) infection remains controversial in the era of highly active antiretroviral therapy (HAART).

Methods. A prospective observational study was conducted to describe the epidemiology of GBV-C viremia and assess its clinical impact on treatment responses to HAART in 385 HIV-1–infected patients during the period from January 1999 through June 2004.

Results. A total of 59 patients (15.3%) had detectable GBV-C RNA viremia during a median observation of 3.6 years (range, 1.0–7.0 years); 47 patients (12.2%) had GBV-C viremia at enrollment, and 12 (3.1%) acquired GBV-C infection during follow-up. Thirty-two (68.1%) of the 47 patients with baseline GBV-C viremia had persistent GBV-C viremia. Compared with patients with clearance of GBV-C viremia (n = 15) and patients without detectable GBV-C viremia (n = 326), patients with persistent GBV-C viremia were more likely to be men who have sex with men (81.3% vs. 60.4%; P = .02), tended to have lower baseline plasma HIV RNA load (HIV RNA load ≥5 log10 copies/mL, 31.3% vs. 49.4%; P = .05), and had a higher proportion of isolated anti—hepatitis B core antibody (37.5% vs. 17.2%; P = .005). There was no statistically significant difference in terms of virologic, immunologic, and clinical responses to HAART; occurrence of hepatic events; and mortality among the 3 groups.

Conclusions. Persistent GBV-C viremia is significantly associated with male-male sex in HIV-infected patients with advanced immunodeficiency, and persistent GBV-C viremia does not confer short-term benefit in patients receiving HAART.

GB virus C (GBV-C) is an RNA virus that belongs to the Flaviviridae family and is closely related to hepatitis C virus (HCV) [1]. GBV-C infection may persist for decades without causing apparent clinical illness or death [2]. Like HIV, GBV-C can be transmitted through parenteral, sexual, or mother-to-child route; thus, exposure to GBV-C is common in HIV-infected patients [3–6]. Previous studies indicated that 14%–45% of HIV-infected patients have GBV-C coinfection [4–15].

GBV-C is a lymphotrophic virus that could replicate in CD4 cells [16]. Clearance of GBV-C viremia depends on host immunity; 60%–75% of immunocompetent persons clear GBV-C spontaneously, and the clearance usually coincides with the development of antibodies against the GBV-C surface envelope glycoprotein E2 [17]. In immunocompromised hosts, such as patients with HIV infection, GBV-C viremia may persist for several years [7]. In the special clinical context of coinfection with HIV and GBV-C, several reports have found that GBV-C may provide clinical benefit by delaying the progression of HIV infection [8–11]. Persistent GBV-C viremia has been shown to be associated with prolonged survival among HIV-infected patients, and the loss of GBV-C RNA might lead to poor prognoses [10, 13, 14]. Accordingly, GBV-C viremia is dynamic, and the presence of GBV-C at diagnosis does not necessarily represent long-term interaction between GBV-C and HIV [10, 13, 14].

Although HAART has been in use for a decade, clinical data on interactions of GBV-C and HIV in patients receiving HAART are limited [12, 14, 18, 19]. To our knowledge, all of the published studies have not included follow-up examinations for GBV-C viremia while patients were receiving HAART. In this study, we aimed to describe epidemiology of GBV-C infection and to assess the impact of persistent GBV-C viremia on the immunologic, virologic, and clinical responses to HAART in HIV-infected patients receiving HAART during the period from 1999 through 2004.

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Materials and Methods

Patients. Patients who received a new diagnosis of HIV infection at the National Taiwan University Hospital (Taipei) from 1 January 1999 through 30 June 2004 were enrolled for GBV-C RNA testing after providing written informed consent. Demographic and clinical data were obtained from medical records using a standard case record form. To determine whether there was persistent GBV-C viremia after the initiation of HAART, 2 serum samples from the same patients were obtained (1 prior to initiation of HAART, and the other at the end of this study, at least 1 year separating the previous test, or at their last visits). Serum samples were stored at -70°C until use. To better assess the long-term impact of GBV-C on HIV-infected patients, subjects who were observed for <12 months were excluded from the study. HAART, defined as the combination of at least 3 antiretroviral agents containing protease inhibitors or nonnucleoside reverse-transcriptase inhibitors, has been provided without charge to all patients with HIV infection since April 1997. The end date of observation of this study was 31 December 2005. This study was approved by the Institutional Review Board at National Taiwan University Hospital.

Liver biochemical tests values, including serum aminotransferase and bilirubin levels, blood CD4 cell count, and plasma HIV RNA load (PVL), were determined every 3–4 months. PVL was quantified using a RT-PCR assay (Roche Amplicor, version 1.5; Roche Diagnostic Systems) with a detection limit of 400 copies/mL (2.60 log10 copies/mL), and the CD4 cell count was determined using FACFlow (Becton Dickinson). An ultrasensitive HIV PVL test with a lower detection limit of 50 copies/mL was performed if the previous HIV PVL was <400 copies/mL. Hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and anti—hepatitis B core antibody (anti-HBc) were checked at the time of enrollment by using EIAs (Abbott Laboratories). HBV DNA was extracted from 200 µL of serum samples of patients with isolated anti-HBc at enrollment by using the High Pure Viral Nucleic Acid Kit (Roche Molecular Biochemicals), and RT-PCR was performed using a LighterCycler instrument (Roche Molecular Biochemicals) in accordance with the manufacturer's instructions. It was estimated that the sensitivity corresponded to ∼103 copies/mL. Antibodies to HCV were assayed using a third-generation EIA (AxSYM HCV III; Abbott Laboratories).

Definitions. Hepatitis flare was defined as a serum aspartate aminotransferase (AST) or an alanine aminotransferase (ALT) level of ≥5 times the upper limit of normal (at National Taiwan University, these values are 31 and 41 U/L, respectively), and hyperbilirubinemia was defined as a total serum bilirubin level ≥2.0 mg/dL (upper limit of normal, 1.0 mg/dL), with>50% of conjugated bilirubin without evidence of hemolysis. Isolated anti-HBc pattern was defined as serum that tested positive for anti-HBc antibody but negative for both HBs antigen and anti-HBs antibody.

Assessment of virologic and immunologic responses to antiretroviral therapy and HIV progression. Virologic response to HAART was assessed by the proportion of patients achieving an undetectable PVL at 6 months, 12 months, 24 months, and from the last available PVL data following initiation of HAART. Any virological failure was defined as failure to achieve an HIV PVL <400 copies/mL during the 6 months after initiation of HAART or as repeatedly detectable PVL, after initial suppression, to undetectable levels. Immunologic response was assessed by the increment of CD4 cell count at 6 months, 12 months, 24 months, and from the last available CD4 cell count data following initiation of HAART and by the proportion of patients achieving an increase of CD4 cell count by 100 and 200 cells/µL or greater during the follow-up period. HIV progression was assessed as relapse or new development of AIDS-defining illness [20] 1 month after initiation of HAART.

GBV-C RNA detection and determination of nucleotide sequences. RNA was purified using 200 µL of serum or plasma from each sample using the QIAamp Viral RNA Mini Kit (Qiagen) in accordance with the manufacturer's instructions. RT-PCR products were amplified using nested PCR. The primers used in the nested RT-PCR were as follows: 5′-GGC CAA AAG GTG GTG GAT GG-3′ (outer-forward), 5′-ATT GAA GGG CGA CGT GGA CC-3′ (outer-reverse), 5′-GTG ATG ACA GGG TTG GTA GG-3′ (inner-forward), 5′-GTA CGT GGG CGT CGT TTG CC-3′ (inner-reverse). PCR products were sequencing on a 48-capillary 3730 DNA analyzer (GeneAmp PCR System 9700&2700; Applied Biosystems). The lower limit of detection for this GBV-C RNA assay used was ∼100 copies/mL [21]. All PCR products were confirmed as a portion of the 5′-UTR of GBV-C sequences as assessed on http://www.ncbi.nlm.nih.gov/BLAST.

Statistical analysis. All statistical analyses were performed using SPSS software; version 11.0 (SPSS). Categorical variables were compared using χ2 or Fisher's exact test, and a 2-sample t test was used for the comparison of continuous variables, with correction of unequal variances when appropriate. Noncategorical variables were compared using the Wilcoxon rank sum test. The significance level was set at .05, and all P values were 2-tailed. The survival probabilities were also estimated by the method of Kaplan-Meier. Equality of survival distributions was evaluated by the log-rank test. A multivariate Cox regression analysis, including categories of sex, age, risk factors for HIV infection, initial CD4 cell count, duration of HAART, initial HIV load, initial HBs antigenemia, and HCV infection and GBV-C status (persistent GBV-C viremia, clearance of GBV-C, or without GBV-C viremia), for mortality were performed. Patients who were lost to follow-up were included in the analyses, but the data were censored at the time of the last visit.

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Results

There were 442 patients with newly diagnosed HIV-infection at the National Taiwan University Hospital during the study period. Fifty-seven patients (10.6%) observed for <12 months were excluded, and 385 were thus enrolled for analysis. No significant differences in terms of age, sex, risk factors for HIV infection, initial CD4 cell count, and HIV PVL were found between excluded patients and enrolled patients (data not shown). Forty-seven (12.2%) of 385 HIV-infected patients had detectable GBV-C viremia at baseline. After a median follow-up of 3.6 years (range, 1.0–7.0 years), 32 (68.1%) of the 47 patients had persistent GBV-C viremia, and 15 patients (31.9%) cleared GBV viremia, with a clearance rate of 8.48 per 100 person-years. In addition, 12 other patients acquired new or reemerging GBV-C infection, with an incidence of 0.92 cases per 100 person-years.

To study the impact of persistent GBV-C viremia on clinical, virologic, and immunologic response to HAART and hepatic outcomes in HIV-infected patients, 12 patients with newly acquired or reemerging GBV-C viremia were excluded for further analysis. Therefore, 32 patients with persistent GBV-C viremia (the persistent GBV-C viremia group), 15 patients with clearance of GBV-C (the GBV-C clearance group), and 326 patients without GBV-C viremia (the non—GBV-C group) were compared. The baseline demographic and clinical characteristics of the 3 groups of patients are summarized in table 1. There were no significant differences regarding age, sex, baseline CD4 cell count, AIDS-defining opportunistic illness at baseline, baseline serum alanine aminotransferase level and total bilirubin level among these groups. However, patients in the persistent GBV-C viremia group included a higher proportion of men who have sex with men (81.3% vs. 60.4%; P = .02) and tended to have a lower baseline HIV-RNA plasma viral load than did those without GBV-C viremia (proportion of patients with HIV PVL ≥5 log10 copies/mL, 31.3% vs. 49.4%; P = .05). There were no statistically significant differences regarding baseline HBsAg positivity and HCV infection among the 3 groups (table 1). Detectable HBV DNA was found in 5 (7.2%) of 69 patients with isolated anti-HBc (occult HBV infection), and all of them were in the non—GBV-C group. Patients in the persistent GBV-C viremia group had a higher proportion of isolated anti-HBc antibodies than did those in the GBV-C clearance group and non—GBV-C group (37.5% vs. 6.7% [P = .04] and 37.5% vs. 17.2% [P = .005], respectively). GBV-C viremia was detectable in 11 (16.4%) of 67 patients with HBs antigenemia, compared with 48 (15.1%) of 318 patients without HBsAg (P = .78). However, GBV-C viremia was detectable in 10 (28.6%) of 35 patients with anti-HCV antibody, compared with 49 (14.0%) of 350 patients without anti-HCV (P = .02). There were no statistically significant differences regarding the duration of HAART, the initial HAART regimen, and patients switches to a PI during HAART (table 1).

Figure 1
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Figure 1

Kaplan-Meier survival estimates of the mortality among patients with or without GB virus C (GBV-C) viremia (P = .66, by the log-rank test).

Table 1
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Table 1

Clinical characteristics of HIV-infected patients with persistent GB virus C (GBV-C) viremia (group 1), those with clearance of GBV-C (group 2), and those with non—GBV-C viremia (group 3).

The comparisons of hepatic, immunologic, virologic, and clinical outcomes among the 3 groups are shown in table 2. There were no differences in new episodes of hepatitis and hyperbilirubinemia, the extent to which CD4 counts increased, development of new opportunistic illnesses, and the proportion of patients achieving undetectable HIV PVL and ever-developing virological failure after initiation of HAART. A total of 21 patients (5.5%) died, including 2 (6.3%) of 32 in the persistent GBV-C viremia group, 2 (13.3%) of 15 in the GBV-C clearance group, 1 (8.3%) of 12 in the newly acquired GBV-C viremia group, and 16 (4.9%) of 326 in non—GBV-C group. Seventeen patients died of HIV-related opportunistic infections, 2 died of end-stage liver disease, and 2 died of malignancies. Kaplan-Meier survival estimates of the patients with or without GBV-C viremia are shown in figure 1; there was no significant difference among the groups (P = .66, by the log-rank test). Multivariate Cox regression analysis showed that only injection drug use (hazard ratio [HR], 6.17; 95% CI, 1.34–17.25; P = .007) and baseline CD4 cell count (HR, 0.996; 95% CI, 0.49–1.00; P = .05) were significantly associated with survival, and baseline HBs antigenemia was of borderline significance (HR, 2.42; 95% CI, 0.95–6.49; P = .07). Status of GBV-C viremia did not correlate with mortality (P = .57).

Table 2
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Table 2

Hepatic, immunologic, virologic, and clinical outcomes of HIV-infected patients with persistent GBV-C viremia (group 1), those with clearance of GBV-C (group 2), and those with non—GBV-C viremia with or without GBV-C viremia (group 3).

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Discussion

In this prospective, observational study, we found that 12.2% of HIV-infected patients in Taiwan had concurrent GBV-C viremia, and we were unable to demonstrate the benefits of persistent GBV-C virema on clinical progression of HIV disease and short-term survival of patients receiving HAART. The prevalence of GBV-C viremia among HIV-infected patients ranges from 14% to 42% in Western countries, with higher rates occurring among men who have sex with men and injection drug users, probably because of increased risk for GBV-C exposure [4–7, 14]. In this study, GBV-C viremia was detected in 12.2% of HIV-infected patients, which is a much higher rate than in healthy blood donors (2.2%) and in the general population (3.4%–5.0%) in Taiwan [22–24]. Compared with Western studies, the slightly lower prevalence of GBV-C viremia in Taiwanese HIV-infected subjects might be explained by the lower proportion of injection drug users (<5%). Consistent with other reports [25, 26], we also found that persistent GBV-C viremia occurred more commonly among men who have sex with men.

In this study, we found that patients with persistent GBV-C viremia had a lower baseline HIV PVL than those without GBV-C by 0.5 log10. Previous studies suggested that HIV-infected patients with GBV-C coinfection who received single or dual nucleoside reverse-transcriptase inhibitors had a more favorable outcome, with delayed progression to AIDS, compared to those with HIV infection alone [5, 7–11, 27]. Long-term persistence of GBV-C viremia is probably a key component of the beneficial outcome of GBV-C and HIV coinfection [10, 11] because of the interference with HIV replication within lymphocytes [28]. In addition, GBV-C could immunologically delay progression of HIV infection through induction of various cytokines and other soluble factors [29] or by maintaining an intact T-helper-1 cytokine profile [30].

In the HAART era, controversies exist regarding the beneficial effects of GBV-C viremia on HIV progression and responses to HAART [12, 14, 18, 19, 31]. The differences among the findings of our study and the findings of the published studies may originate from differences in patients recruited, study design, definitions of virologic and immunologic responses to HAART, and persistence of GBV-C coinfection. In our study, we assessed the impact of persistent GBV-C viremia, whereas in the others [12, 18, 19], only baseline GBV-C viremia was assessed. The baseline immunologic or virologic status of HIV infection may affect the impact of GBV-C viremia after the initiation of HAART. In the studies by Rodriguez et al. [18], only 46.4% of the patients with GBV-C viremia who had depleted CD4 counts (60 cells/µL) achieved a virological response to HAART that was defined as <400 copies/mL at the final follow-up visit. In the study by Antonucci et al. [19], who enrolled a significantly higher proportion of injection drug users with higher CD4 counts (325 cells/µL), the time to achieve initial virological suppression or an increase of CD4 count by 200 cells/µL after HAART did not differ between patients with and those without baseline GBV-C viremia [19]. In our study, which assessed the responses to HAART at different time points, we did not find such additional beneficial effects of persistent GBV-C viremia. The reduction of PVL following HAART was as much as ≥2 log10 copies/mL after 12 months of HAART in our study (table 2); this is significantly higher than the 0.5–log10 copies/mL difference between patients with GBV-C viremia and patients without GBV-C viremia at baseline [27]. The benefit in terms of HIV progression and reduction of HIV PVL in our patients with GBV-C viremia may be masked by HAART.

In line with a previous report [32], our data suggested that GBV-C did not increase the risk of hepatitis flares or hyperbilirubinemia among HIV-infected patients, even in those with concurrent chronic HBV or HCV infection. However, isolated anti-HBc was more common among patients with persistent GBV-C viremia than those without persistent GBV-C viremia for which the reason remains unclear. Several possibilities may be speculated. First, GBV-C infection might result in the emergence of isolated anti-HBc by altering the immune response to HBV infection. Second, like HCV, GBV-C might suppress HBV replication, leading to the presentation of isolated anti-HBc and the lack of circulating HBsAg and anti-HBs [33]. Third, this association might reflect increased susceptibility to persistent GBV-C infection in patients with prior HBV infection.

There were several limitations of this study. First, patients with a short observation duration (<12 months) were not included in this analysis. Second, we did not test for anti-E2 antibody in these patients. It is likely that a large proportion of those without GBV-C RNA viremia may have had past infection (recovery from GBV-C viremia). Last, our sample size is small. Because HAART already significantly decreases morbidity and mortality in HIV-infected patients, whether persistent GBV-C viremia may confer marginal survival benefit in addition to HAART requires additional large studies with longer durations of follow-up.

In conclusion, persistence of GBV-C RNA in HIV-infected patients receiving HAART is common in Taiwan, and male-male sex may serve as an important transmission route. We were unable to demonstrate beneficial effects of persistent GBV-C infection on the virologic, immunologic, and clinical responses to HAART in HIV-infected patients.

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Acknowledgments

Potential conflicts of interest. All authors: no conflicts.

  • Received July 19, 2006.
  • Accepted October 12, 2006.
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  1. Clin Infect Dis. (2007) 44 (4): 584-590. doi: 10.1086/511037
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