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GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV)/HIV–Coinfected Patients Receiving HCV Treatment: Importance of the GBV-C Genotype

  1. Carolynne Schwarze-Zander1,4,a,
  2. Jason T. Blackard4,a,
  3. Hui Zheng7,
  4. Marylyn M. Addo5,
  5. Wenyu Lin4,
  6. Gregory K. Robbins6,
  7. Kenneth E. Sherman8,
  8. Dietmar Zdunek2,
  9. Georg Hess3 and
  10. AIDS Clinical Trial Group A5071 Study Team4
  1. 1Department of Internal Medicine I, University of Bonn, Bonn,
  2. 2Roche Diagnostics, Penzberg, and
  3. 3Roche Diagnostics, Mannheim, Germany;
  4. 4Gastrointestinal Unit,
  5. 5Partners AIDS Research Center, and
  6. 6Infectious Diseases Unit, Massachusetts General Hospital, and
  7. 7Harvard Center for AIDS Research, Harvard Medical School, Boston, Massachusetts;
  8. 8Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
  1. Reprints or correspondence: Dr. Raymond T. Chung, Gastrointestinal Unit, GRJ 825, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (rtchung{at}partners.org)
 
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Abstract

BackgroundPersistent GB virus C (GBV-C) coinfection leads to slower human immunodeficiency virus (HIV) progression. Despite the existence of multiple GBV-C genotypes, their relevance to the progression of HIV disease is unknown. We therefore investigated (1) the prevalence and genotype of GBV-C in hepatitis C virus (HCV)/HIV–coinfected patients and (2) the impact of HCV treatment on GBV-C RNA clearance

MethodsWe retrospectively studied 130 HCV/HIV-coinfected patients initiating HCV therapy. Anti-E2 enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction (PCR), and real-time PCR were used to detect and quantify GBV-C infection. GBV-C genotype was determined by sequencing the 5′ untranslated region

ResultsGBV-C infection (past or current) was identified in 111 (85%) of the patients. Ongoing GBV-C replication was detected in 40 patients. Coinfection with GBV-C genotype 2 was associated with significantly higher CD4+ cell counts. After 24 weeks of HCV therapy, GBV-C RNA clearance was observed in 50% of patients, although this was not associated with changes in HIV load or with CD4+ cell counts. Sustained GBV-C RNA clearance was observed in 31% of patients with GBV-C RNA detected at baseline

ConclusionsGBV-C coinfection was extremely common. GBV-C RNA clearance with HCV therapy was associated with neither short-term loss of HIV control nor impaired immune status. The association of GBV-C genotype 2 with higher CD4+ cell counts merits further study

GB virus C (GBV-C), which was first isolated in 1995, belongs to the Flaviviridae family and is the closest known relative of hepatitis C virus (HCV) [1, 2]. GBV-C was initially thought to induce hepatitis; however, subsequent investigations have failed to demonstrate GBV-C replication in hepatocytes or a causal association with hepatitis or other human diseases [3]. GBV-C viremia may persist for up to 16 years [4] and is diagnosed by the detection of viral RNA. In the majority of patients, viremia eventually resolves with the development of antibodies directed against the viral envelope protein E2 [5, 6] that appear to protect against GBV-C reinfection [7, 8]

Several groups have reported beneficial effects of GBV-C viremia on HIV disease, describing a slower progression of HIV disease to AIDS or death [9, 10]. Moreover, an association between GBV replication and lower plasma HIV loads and higher CD4+ cell counts has been demonstrated [11, 12], although these findings were not confirmed by other studies [13–15]

GBV-C, like HCV, has been shown to be sensitive to the antiviral actions of interferon (IFN) [16, 17]. IFNrelated clearance of GBV-C occurs in up to 60% of HCV- or HIV-infected patients [18]; however, very little is known about GBV-C RNA clearance in HIV/HCV/GBV-C triply infected patients treated with IFN or pegylated (PEG)–IFN plus ribavirin. With the increased survival conferred by the use of highly active antiretroviral therapy (HAART), complications of chronic HCV infection have emerged as an important cause of morbidity and mortality in HIV-infected individuals [19–21]. Indeed, several studies have shown an accelerated course of chronic HCV infection during HIV coinfection [22, 23]. Thus, the development of effective antiviral therapies for HCV in coinfected persons will be important for the long-term clinical management of HCV disease [24–26]. Nonetheless, the consequences of HCV therapy on the clearance of GBV-C have not been well characterized

Phylogenetic analysis has revealed at least 5 major GBV-C genotypes; they exhibit geographical clustering in West Africa (genotype 1), Europe and the United States (genotypes 1 and 2), parts of Asia (genotype 3), Southeast Asia (genotype 4), and South Africa (genotype 5) [27–34]. However, the clinical significance of GBV-C genotypes during HIV coinfection is unknown

Therefore, we sought to determine (1) the prevalence of GBV-C infection (past and current) and genotype distribution in a large cohort of HCV/HIV-coinfected patients and (2) the frequency of treatment-induced GBV-C RNA clearance in HIV/HCV/GBV-C triply infected patients and the potential effects of GBV-C RNA clearance on HIV disease. We hypothesized that distinct GBV-C genotypes may be cleared differentially by HCV therapy and that differences in GBV-C genotypes might influence important predictors of the progression of HIV disease

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Patients and Methods

Study design and patientsA total of 133 HCV/HIV coinfected patients was included in the study. All patients were enrolled as part of the prospective Adult AIDS Clinical Trials Group (ACTG) A5071 study evaluating the efficacy of IFNα-2a plus ribavirin versus PEG–IFN-α-2a plus ribavirin for chronic HCV infection in individuals coinfected with HIV [25]. By study design, an efficacy and safety assessment was performed for all patients at week 24 to determine whether they could continue to participate. HCV virologic responders (defined as those with an undetectable HCV RNA load at week 24) continued treatment until week 48. HCV virologic nonresponders at week 24 (57/67 patients in the IFN plus ribavirin arm and 37/66 patients in the PEG-IFN plus ribavirin arm) were asked to undergo liver biopsy, with continuation of treatment to week 48 for those with a ⩾2-point drop in the total hepatic activity index from baseline (i.e., histologic responders) [35]. Thus, all patients were treated for at least 24 weeks, although only virologic responders (n=39) and histologic responders (n=25) completed 48 weeks of treatment. All patients were monitored for an additional 24 weeks of follow-up after the completion of therapy. HCV RNA loads were assessed using the Roche Cobas Amplicor 2.0 assay (Roche Diagnostics), which has a lower limit of detection of 60 IU/mL. HIV RNA loads were assessed using the Roche Cobas Amplicor 2.0 assay (Roche Diagnostics), which has a lower limit of detection of 50 copies/mL

The presence of GBV-C RNA in serum was determined by reverse-transcription polymerase chain reaction (RT-PCR) before the initiation of HCV therapy (baseline). Three patients were excluded from further analysis because of a lack of available serum samples for GBV-C testing. Patients who were GBV-C RNA positive at baseline were further evaluated for the presence of GBV-C RNA at available follow-up visits, and patients who were GBV-C RNA negative at baseline were retested at the last available follow-up visit. All baseline and follow-up serum samples were also tested for the presence of E2 antibodies

Detection and quantification of GBV-C RNAViral RNA was extracted from 140 μL of serum by use of the QIAmp Viral RNA Mini Kit (Qiagen), in accordance with the manufacturer’s instructions. GBV-C RNA was detected by nested RT-PCR using primers corresponding to the 5′ untranslated region (UTR) [11]. RNA was transcribed and amplified using the antisense primer 5′-ATG CCA CCC GCC CTC ACC CGA A-3′ (nt 494–473, according to GenBank accession number AY196904) and the sense primer 5′-AAA GGT GGT GGA TGG GTG ATG-3′ (nt 67–87) in a OneStep RT-PCR device (Qiagen). Amplification conditions were an initial cycle for 59 min at 50°C and 10 min at 94°C; 35 cycles for 30 s at 94°C, 1 min at 55°C, and 1 min at 72°C; and extension for 20 min at 72°C. The first-round PCR product was then subjected to nested PCR using internal antisense primer 5′-CCC CAC TGG TCY TTG YCA ACT C-3′ (nt 362–341) and sense primer, 5′-AAT CCC GGT CAY AYT GGT AGC CAC T-3′ (nt 107–131). After 35 cycles for 30 s at 94°C, 30 s at 55°C, and 1 min at 72°C, PCR products were analyzed by agarose gel electrophoresis for the presence of a 256-nt band

The GBV-C load was quantified in all GBV-C RNA–positive samples by use of the LightCycler-RNA Master Hybridization System (Roche Diagnostics). Briefly, a 1-step RT-PCR was performed in glass capillaries. The following oligonucleotides were used in the PCR: 5′-CGG CCA AAA GGT GGT GGA TG-3′ (nt 61–80) and 5′-CGA CGA GCC TGA CGT CGG G-3′ (nt 246–228). For probing, a 5′-LCRed640–marked oligonucleotide (5′-CAA GGT GAC CGG GAT TTA CGA CCp-3′) and a 3′-fluorescein–marked oligonucleotide (5′-CTC TTA AGA CCC ACC TAT AGT GGC T-3′) were used. The lower limit of detection was 1000 genome equivalents (geq)/mL

Detection of E2 antibodyAs markers of GBV-C RNA clearance and prior exposure [8], serum E2 antibodies were detected using an immunoassay using recombinant E2 (μPlate Anti-Hgenv test; Roche Diagnostics), in accordance with the manufacturer’s instructions. Plates were incubated with diluted (1:20) serum, and E2 antibodies were detected using anti–human IgG peroxidase conjugate and ABTS substrate. Serum samples were tested in duplicate. In accordance with the manufacturer’s cutoff, an OD<0.10 was considered to be negative, and an OD⩾0.10 was considered to be positive

Phylogenetic analysisThe GBV-C genotype was determined by population-based amplification of the 5′ UTR region, as described elsewhere [36]. PCR products were gel purified and sequenced by use of the internal PCR primers as sequencing primers. Sequences were aligned with database reference using Clustal X (version 1.64b) [37]. The reference sequences used to confirm GBV-C genotype included the following GenBank accession numbers: 1A, U59543 and U59540; 1B, U59555 and U59549; 2A, U59520 and U59521; 2B, U59529 and U59533; 3, U59538 and U59539; and 4, AB018667 and AB021287. The statistical robustness and reliability of the branching order within the phylogenetic tree was confirmed by bootstrap analysis using 100 replicates. Bootstrap values >70% were considered to be statistically significant

Statistical analysisWe evaluated the associations between dichotomous variables, using Fisher’s exact test. Comparisons of continuous outcomes between 2 groups with small group sizes were evaluated using the Wilcoxon&amp;rank sum test, adjusted for ties. Associations between a continuous variable and any categorical variable with >2 groups were evaluated using the Kruskal-Wallis test. Results of both the Wilcoxon&amp;rank sum test and the Kruskal-Wallis test were considered to be robust because they were free of normal distribution assumptions. All P values were 2-sided. P<.05 was considered to be statistically significant

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Results

GBV-C infection statusOf the 130 patients with HCV/HIV coinfection, 111 (85%) had evidence of past or present GBV-C infection. E2 antibody was detected in 71 (64%) of these 111 patients. GBV-C RNA was detected in 40 (36%) of the 111 patients, and E2 antibodies were also detected in 11 of the 40. Demographic and biochemical profiles of the study population according to GBV-C status are shown in table 1. More men than women were GBV-C RNA positive, and more women than men had no evidence of GBV-C infection (defined as the absence of GBV-C RNA and a lack of E2 antibodies) (P<.001). Furthermore, younger patients were more often GBV-C RNA positive, whereas older patients were more likely to have signs of past GBV-C infection (P=.004). There were no significant differences in baseline CD4+ cell count, HCV load, or HIV load according to GBV-C infection status

GBV-C genotypingThe 5′ UTR (256 nt) could be amplified from 39 (98%) of 40 GBV-C RNA–positive patients. Seven (18%) of the 40 patients were infected with GBV-C genotype 1, 31 (79%) with genotype 2, and 1 (3%) with genotype 3 (figure 1). The 5′ UTR could not be amplified from 1 GBV-C–RNA positive patient

Figure 1
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Figure 1

Rooted phylogenetic tree based on the consensus GB virus C (GBV-C) 5′ untranslated region (256 nt) from 39 patients triply infected with HIV, hepatitis C virus, and GBV-C. The reference sequences used to confirm GBV-C genotype included the following GenBank accession numbers: 1A, U59543 and U59540; 1B, U59555 and U59549; 2A, U59520 and U59521; 2B, U59529 and U59533; 3, U59538 and U59539; and 4, AB018667 and AB021287. The nucleotide sequence divergence between isolates can be estimated using the 10% divergence bar shown. Relevant bootstrap values >70 (out of 100) are shown. Asterisks denote database reference sequences

Because previous studies did not explore the impact of different GBV-C genotypes on HIV disease, we were interested in further comparing demographic and clinical parameters between infections with GBV-C genotypes 1 and 2 (table 2). Patients with GBV-C genotype 1 infection were more likely to be nonwhite than were patients with genotype 2 infection (P=.031). At baseline, we noted significantly higher CD4+ cell counts in GBV-C RNA–positive patients infected with genotype 2 than in those infected with genotype 1 (534 vs. 308 cells/mL; P=.01). No significant differences in mean baseline HIV or HCV loads were found between GBV-C genotype 1– and genotype 2–infected patients. To further analyze CD4+ cell counts by GBV-C genotype, we adjusted for the potential confounding effects of race, HIV load, and ART use by including them in a multivariate linear-regression model; however, the difference in CD4+ cell counts between GBV-C genotype 1– and genotype 2–infected patients remained statistically significant (P=.015)

Figure 2
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Figure 2

Overview of GB virus C (GBV-C) infection, clearance, and relapse among hepatitis C virus (HCV)/HIV–coinfected patients enrolled in AIDS Clinical Trial Group A5071

Figure 3
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Figure 3

Comparison of baseline GB virus C (GBV-C) loads (in log10 genome equivalents [geq] per milliliter) between GBV-C sustained responders (SVR; n=11), nonresponders (NR; n=19), and relapsers (R; n=6). White circles indicate samples with GBV-C load measurements below the limit of detection of the assay (<103 geq/mL). P=.0128, by Kruskal-Wallis test, for a difference among the 3 groups

Table 1
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Table 1

Baseline characteristics for hepatitis C virus (HCV)/HIV–coinfected patients enrolled in AIDS Clinical Trial Group A5071

Table 2
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Table 2

Baseline characteristics for GB virus C (GBV-C) RNA–positive patients, by GBV-C genotype

The mean baseline viral load for GBV-C genotype 1–infected patients was 7.21 log10 geq/mL, whereas the mean for genotype 2–infected patients was 7.25 log10 geq/mL (P=.33). In contrast to genotype 1–infected patients, 9 (29%) of 31 genotype 2–infected patients had GBV-C RNA loads below the limit of detection of the assay of 103 geq/mL. Interestingly, none of the patients (0/7) with GBV-C genotype 1 infection had an HCV virologic response at week 24, whereas 10 (32%) of 31 patients with GBV-C genotype 2 infection had an HCV virologic response. However, this was not statistically significant (P=.156) (table 2)

GBV-C response to IFN therapyThe response of GBV-C to IFN therapy was determined in the 40 GBV-C RNA–positive patients (figure 2). After 24 weeks of treatment with IFN or PEG-IFN plus ribavirin, 19 (50%) of 38 HIV/HCV/GBV-C–infected patients with available data had undetectable GBV-C loads (table 3): 11 (73%) of 15 patients who received PEG-IFN plus ribavirin had undetectable GBV-C RNA loads at week 24 of treatment, whereas only 8 (35%) of 23 patients receiving standard IFN plus ribavirin had undetectable GBV-C RNA loads at week 24 (P=.045). There was a strong association between GBV-C RNA clearance and HCV virologic response: of 10 patients who achieved HCV virologic response at week 24, 9 (90%) also had undetectable GBV-C RNA loads at week 24 (P=.007). In particular, the magnitude of reductions in HCV RNA load from baseline to week 24 was significantly higher in GBV-C responders than in GBV-C nonresponders (−2.09 vs. −0.37 HCV RNA log10 IU/mL, respectively; P=.0009). Interestingly, GBV-C RNA clearance was associated with higher baseline CD4+ cell counts (591 cells/μL for GBV-C responders vs. 419 cells/μL for GBV-C nonresponders; P=.03). In addition, there was a trend toward higher rates of GBV-C RNA clearance for genotype 2 than for genotype 1 infection (P=.09). After 24 weeks of HCV therapy, no correlation was found between GBV-C RNA clearance and baseline GBV-C, HCV, or HIV loads (table 3), nor were changes (from baseline to week 24 of HCV therapy) in HIV load or CD4+ cell count significantly different between GBV-C responders and nonresponders

Table 3
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Table 3

GB virus C (GBV-C) response after 24 weeks of interferon (IFN) therapy

Of 19 patients who had cleared GBV-C after 24 weeks of HCV therapy, 6 (32%) had a recurrence of GBV-C RNA at a subsequent posttherapy follow-up visit (“GBV-C relapsers”). Two patients had similar GBV-C loads (±0.5 log10 copies/mL) before and after HCV treatment, whereas 1 patient had an increase in GBV-C viral load of >0.5 log10 copies/mL. In 3 patients, viral loads fell to below the limit of detection of the quantitative PCR (1×103 geq/mL) but were nonetheless detectable by qualitative PCR

Sustained clearance of GBV-C (defined as the following findings: GBV-C RNA positive at baseline, GBV-C RNA negative after 24 weeks of HCV treatment, and GBV-C RNA negative after 24 weeks of posttreatment follow-up) was observed in 11 (31%) of 36 HIV/HCV/GBV-C triply infected patients (figure 2). Interestingly, no patient developed E2 antibodies after clearance of GBV-C RNA. In contrast to GBV-C RNA clearance at week 24, sustained GBV-C RNA clearance was associated with a lower baseline GBV-C load (P=.0128 for the difference among the 3 groups) (figure 3)

At baseline, 90 patients were GBV-C RNA negative; however, E2 antibodies were detected in 71 (79%) of these patients. Sixty of these 90 patients were available for a reevaluation of GBV-C status at the 24-week follow-up visit (42–72 weeks after study entry) after the discontinuation of HCV treatment. No patient was newly infected or reinfected with GBV-C during this follow-up period, and no patient lost E2 antibody positivity (data not shown)

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Discussion

In the present study, we analyzed the frequency, genotype distribution, and subsequent clearance of GBV-C infection among 130 HCV/HIV-coinfected patients receiving IFN or PEG-IFN plus ribavirin for the treatment of HCV infection. The overall prevalence of GBV-C infection (E2 antibody positivity and/or GBV-C viremia) was 85% in our cohort, which is similar to data from other populations with frequent exposure to blood products (including injection drug use) and from HIV-positive patients [8, 10, 38, 39]. In agreement with other studies, we found a higher prevalence of GBV-C viremia among younger patients, whereas E2 antibodies were detected more frequently in older patients [40]. This may be explained by a potential protective effect of E2 antibodies against GBV-C reinfection [4–6]. However, in our study, we found 11 patients who were simultaneously positive for GBV-C RNA and E2 antibody. Similar results have been found in other HCV/HIV-coinfected patients [41, 42], and they may be attributable to altered immune responses in the setting of HCV/HIV coinfection [43] or reinfection with GBV-C in the presence of E2 antibodies [7]

GBV-C RNA was cleared in 50% of HIV/HCV/GBV-C triply infected patients treated with IFN (or PEG-IFN) plus ribavirin. Consistent with the high degree of sequence homology between GBV-C and HCV, treatment-induced clearance of GBV-C RNA at week 24 was strongly correlated with an HCV virologic response (table 3). Moreover, factors predicting clearance during treatment were similar for the 2 viruses: GBV-C RNA clearance was associated with PEG-IFN plus ribavirin treatment and a higher baseline CD4+ cell count. Nonetheless, additional factors—such as host genetic determinants and adaptive immune responses—are likely to influence GBV-C RNA clearance

At 24 weeks after treatment, sustained clearance of GBV-C was found in 31% of patients, whereas GBV-C RNA reappeared in another 19%. Sustained clearance of GBV-C was associated with baseline GBV-C load (figure 3) but not with CD4+ cell count, HCV virologic response, or HCV treatment arm. Although the factors that influence the sustained clearance of GBV-C are not known, studies in HCV/GBV-C–coinfected patients have shown a marginal effect or no effect of ribavirin on GBV-C sustained clearance [44, 45]. Moreover, the role of E2 antibody development in GBV-C RNA clearance remains unclear, because no patients with GBV-C relapse or a GBV-C sustained response developed E2 antibodies during the follow-up period. This may have been because of the efficient clearance of GBV-C by HCV therapy, but Van der Bij et al. [41] found, in a large HIV/GBV-C–coinfected cohort, that spontaneous resolution of GBV-C viremia was not necessarily followed by the appearance of E2 antibodies

Several studies have described a beneficial effect of GBV-C viremia on the progression of HIV disease. GBV-C replication has been associated with lower HIV loads and higher CD4+ cell counts [9–11, 46]. Several mechanisms of GBV-C interference with the progression of HIV disease have been proposed, including postentry inhibition of replication, alteration of T helper cytokine profiles, and changes in chemokine coreceptor expression [47–49]. However, a beneficial impact of GBV-C on the progression of HIV disease has not been confirmed in all studies [13, 14, 50]; thus, other virologic and immunologic factors may partially explain these divergent results

The existence of multiple GBV-C genotypes has led several authors to suggest that differences in GBV-C strains circulating within populations might affect the progression of HIV disease [50–52], although this has not been formally studied. We found no significant difference in baseline CD4+ cell count or HIV load according to GBV-C infection status. Nonetheless, important differences were observed based on the existing GBV-C genotype: GBV-C genotype 2 infection was associated with higher CD4+ cell counts, compared with genotype 1 infection. To our knowledge, until now there has been only a single report addressing the importance of genotype/subtype variations of GBV-C during HIV infection [51]. Those authors noted that CD4+ cell counts tended to be lower in patients infected with subtype 2a, compared with those infected with subtype 2b; however, other distinct genotypes were not circulating in the study population for further comparison. Therefore, it is possible that GBV-C genotype could at least partially account for the conflicting observations to date regarding the impact of GBV-C replication on the progression of HIV disease. In this respect, it is also interesting that GBV-C genotype 2 was marginally more sensitive to HCV therapy than was genotype 1 in our study (P=.09). Thus, given that an HCV virologic response and GBV-C RNA clearance may be linked and that GBV-C RNA persistence is associated with a decreased risk of death [41], it is tempting to speculate that GBV-C RNA clearance associated with HCV therapy might have an adverse effect on the progression of HIV disease

In summary, we have shown a high overall prevalence of GBV-C in a large cohort of HCV/HIV-coinfected patients receiving IFN or PEG-IFN plus ribavirin to treat chronic HCV infection. Importantly, GBV-C RNA clearance did not appear to be associated with short-term loss of HIV RNA control. It is possible that the effects of GBV-C on HIV are outweighed by effective ART, given that the majority of our study patients were receiving HAART. In accordance with the ACTG A5071 study design, only those patients with virologic response at week 24 and virologic nonresponders with histologic improvement were treated for the full 48 weeks; thus, long-term follow-up of the majority of these HIV/HCV-coinfected patients was not possible. Furthermore, it is not known whether the selected cohort was fully representative of the HCV/HIV-coinfected population. Thus, additional prospective studies with several years of follow-up data will be necessary to confirm our findings and to determine whether treatment-induced clearance of GBV-C has deleterious effects on long-term HIV progression in HAART-naive and -experienced patients. We also noted a significant association between GBV-C genotype and CD4+ cell count that suggested a differential impact of GBV-C genotype on important immunologic parameters. Although other unmeasured factors may potentially influence these results, the findings have important implications for understanding the relationship and molecular interactions of GBV-C and HIV and the consequences of GBV-C infection for the management of HCV/HIV-coinfected patients undergoing IFN-based antiviral therapy

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Acknowledgments

We are indebted to the following individuals for their participation in the AIDS Clinical Trial Group (ACTG) A5071 study: Paul Sax (Brigham and Women’s Hospital) and Mary Albrecht (Beth Israel Deaconess Medical Center), Harvard University, Boston, MA (ACTG site A0101); Mamta Jain and Michael Scott, University of Texas, Southwestern Medical Center, Dallas (ACTG site A3751); Alexandra Nesbit and Charles van der Horst, University of North Carolina, Chapel Hill (ACTG site A3201); Mary Shoemaker and Christine Hurley, University of Rochester, Rochester, NY (ACTG site A1101); Charles Gonzalez and Richard Hutt, New York University, Bellevue Hospital Center, New York (ACTG site A0401); Jane Norris and Debbie Slamowitz, Stanford University, Stanford, CA (ACTG site A0501); Kenneth E. Sherman, and Diane Daria, University of Cincinnati, Cincinnati, OH (ACTG site A2401); Peter Gordon and Jolene Noel-Connor, Columbia University, New York, NY (ACTG site A7802); Andrew Talal and Valery Hughes, Cornell Clinical Trials Unit, New York, NY (ACTG site A7803); Raymond Johnson and Greta Clement, Indiana University, Bloomington (ACTG site A2601); David Clain and Nidhir R. Sheth, Beth Israel Deaconess Medical Center, Boston, MA (ACTG site A2851); Nancy Hanks (University of Hawaii at Manoa) and Scott Souza (Queen’s Medical Center), University of Hawaii, Honolulu (ACTG site A5201); Gregory Fitz and M. Graham Ray, University of Colorado, Health Sciences Center, Denver (ACTG site A6101); Bradley Hare and Joann Volinski, San Francisco General Hospital, San Francisco, CA (ACTG site A0801); Margaret A. Fischl and Leslie Thompson, University of Miami, Coral Gables, FL (ACTG site A0901); Michael K. Klebert, Washington University, St. Louis, MO (ACTG site A2101); Joel Maslow and Rosanne Burke, University of Pennsylvania, Philadelphia (ACTG site A6201); Henry H. Balfour, Jr., and Jeffrey L. Meier, University of Minnesota, Minneapolis (ACTG site A1501); Cindy Leissinger and Carol deKernion, Tulane University, New Orleans, LA (ACTG site A9426); Patrick Lynch, Northwestern University, Evanston, IL (ACTG site A2701); and Tari Gilbert and Dee Dee Pacheco, Antiviral Research, University of California, San Diego (ACTG site A0701)

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Footnotes

  • ↵(See the editorial commentary by Berzsenyi and Roberts, on pages 407–9.)

  • ↵Presented in part: 1st International Conference on HIV and Hepatitis Co-Infection, Amsterdam, The Netherlands, 2–4 December 2004 (abstract C122)

    Potential conflicts of interest: none reported

    Financial support: National Institute of Allergy and Infectious Diseases, AIDS Clinical Trials Group (grants AI38858 and AI38855); Partners/Fenway/Shattuck Center for AIDS Research, National Institutes of Health (grant P30-AI42851)

  • ↵C.S.-Z. and J.T.B. contributed equally to the study

  • Received December 19, 2005.
  • Accepted February 10, 2006.
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  1. J Infect Dis. (2006) 194 (4): 410-419. doi: 10.1086/505713
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