Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort
Law, W Phillipa,b; Duncombe, Chris Ja,b; Mahanontharit, Apichab; Boyd, Mark Aa,b; Ruxrungtham, Kiatb,d; Lange, Joep MAb,c; Phanuphak, Praphanb,d; Cooper, David Aa,b; Dore, Gregory Ja
From the aNational Centre in HIV Epidemiology and Clinical Research (NCHECR), The University of New South Wales, Sydney, Australia, the bHIV-Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand, the cInternational Antiviral Therapy Evaluation Centre (IATEC), University of Amsterdam, Amsterdam, The Netherlands and the dFaculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Correspondence to Dr Gregory J. Dore, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Darlinghurst, Sydney 2010, Australia.
Tel: +61 2 9385 0900; fax: +61 2 9385 0920; e-mail: firstname.lastname@example.org
Received: 12 December 2003; revised: 24 February 2004; accepted: 16 March 2004.
Objective: To examine the impact of viral hepatitis co-infection on HIV disease outcomes following commencement of combination antiretroviral therapy in a developing country setting.
Methods: HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of Thai HIV-infected patients enrolled in eight HIV-NAT randomized controlled trials of antiretroviral therapy (n = 692). Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum.
Results: Mean age was 32.3 years, 52% were male, 11% had CDC category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV co-infection was 8.7, 7.2 and 0.4%, respectively. Median HIV RNA reductions (log10 copies/ml) were approximately 1.5 for HIV, HIV-HBV, HIV-HCV subgroups from week 4 up to week 48. Mean increases in CD4 cell count were significantly lower among HIV-HBV and HIV-HCV subgroups at week 4 (HIV, 62 × 106 cells/l; HIV-HBV, 29 × 106 cells/l; HIV-HCV, 33 × 106 cells/l), however, by week 48 CD4 cell increases were similar (HIV, 115 × 106 cells/l; HIV-HBV, 113 × 106 cells/l; HIV-HCV, 97 × 106 cells/l). Cox regression analyses showed that HIV-HBV or HIV-HCV co-infection were not associated with a CD4 cell count increase of 100 × 106 cells/l over 48 weeks. Estimated progression to AIDS event or death at week 48 was 3.3% (95% confidence interval, 2.0–5.1%) for HIV, 6.7% (2.5–14.6%) for HIV-HBV, and 8.0% (2.2–20.5%) for HIV-HCV subgroups (P > 0.05).
Conclusions: An early delayed CD4 count recovery among HIV/viral hepatitis co-infected patients was not sustained, and was not associated with increased HIV disease progression.
Improved survival and reduced incidence of opportunistic infections among people with HIV in the era of highly active antiretroviral therapy (HAART)  has increased the contribution of co-morbidities such as chronic liver disease to overall morbidity and mortality [2–5]. Co-infection with HIV and hepatitis B (HBV) or C virus (HCV) has therefore become an increasingly important field of HIV research and clinical management.
HIV increases the risk of HBV-related liver disease progression , however, contrasting findings have been reported on the effect of HBV on HIV natural history. A lack of an association between HIV-HBV co-infection and HIV disease progression has been reported in several studies [7–11], whereas others have found accelerated HIV disease progression and reduced survival [12–14]. The impact of HIV-HBV co-infection on CD4 cell count recovery following initiation of HAART has had limited evaluation .
Similarly, HIV increases HCV-related liver disease progression and the effect of HCV on HIV disease progression is unclear. Some studies have reported no effect of HIV-HCV co-infection on HIV disease progression and survival [7,16,17], whereas others have found increased HIV disease progression and reduced survival [12,18]. The Swiss HIV Cohort Study demonstrated delayed CD4 cell count recovery following initiation of HAART and increased clinical progression in persons with HIV-HCV co-infection . Daar et al. found an association between higher HCV viral load and increased progression to AIDS , while more advanced liver disease has also been linked to increased HIV disease progression .
Due to the remaining uncertainty in relation to the impact of chronic viral hepatitis on HIV natural history, we conducted a study among a prospective cohort of Thai HIV-infected patients enrolled in antiretroviral therapy randomized clinical trials through the HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration in Bangkok. The relative lack of HIV natural history studies among Asian populations, in particular those examining chronic viral hepatitis co-infection was a further incentive for the study.
The study population included all HIV-infected adults participating in randomized controlled trials of antiretroviral therapy at HIV-NAT, Bangkok, Thailand, who initiated therapy between December 1996 and March 2001. Patients were recruited from the HIV outpatient clinic of Chulalongkorn Hospital. In accordance with trial protocols, clinical and laboratory data were collected at screening (within 4 weeks of antiretroviral therapy commencement), baseline (just prior to antiretroviral therapy commencement), and at weeks 4, 8, 12, 24, 36 and 48.
Clinical and laboratory data
Data collected from patients at baseline were: age, gender, risk group for HIV infection, past or present occurrence of HIV-related illnesses as classified according to the Centers for Disease Control and Prevention (CDC) 1993 guidelines , weight, CD4 and CD8 cell counts, HIV viral load, prior antiretroviral therapy use, liver function profile, and past or present occurrence of symptoms and signs related to hepatitis.
In addition, at each subsequent scheduled visit, clinical data on CDC and non-CDC adverse events, and laboratory data were collected. Standard laboratory testing included full blood count, serum chemistries, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, CD4 and CD8 cell counts, and plasma HIV viral load. HBV (HBsAg) and HCV (anti-HCV antibody) testing was performed retrospectively on baseline blood samples stored at −70°C by Cobas Core enzyme-linked immunosorbent assays (EIA; Roche Diagnostic Systems, Branchburg, New Jersey, USA). Co-infection with HBV was defined as the detection of HBsAg at baseline and at week 48. Co-infection with HCV was defined as the detection of anti-HCV antibody at baseline.
The commencement of trial antiviral therapy was regarded as the start of observation. Changes in CD4 cell count and HIV RNA level over the initial 48 weeks of trial antiretroviral therapy were the main outcome measures, with comparisons between three subgroups: (1) HIV monoinfection (HBsAg-/anti-HCV-); (2) HIV-HBV co-infection (HBsAg+/anti-HCV-); and (3) HIV-HCV co-infection (anti-HCV+/HBsAg-). HIV disease progression was also examined across these subgroups, with comparison of progression to a CDC class C (AIDS-defining) event and death during the 48-week study period. An additional analysis was performed to assess the impact of lamivudine therapy status on CD4 cell count changes within the HIV-HBV subgroup.
Differences between groups were analysed using Student's t test or ANOVA for normally distributed continuous data, and Wilcoxon or Kruskal–Wallis test for data that were not normally distributed. Chi-square tests, where appropriate, were used for categorical data. Differences between groups were considered to be significant at P < 0.05, and are two-sided. HIV RNA levels were log10 transformed. As the plasma HIV RNA levels were measured with different assays with varying lower limits of quanitification (LLQ) across the separate randomized controlled trials included in this study, those levels below the LLQ of the assay were assigned the corresponding cut-off values in the analyses. Survival analyses were performed for development of AIDS-defining event or death, and for CD4 cell and HIV RNA response following the initiation of antiretroviral therapy.
All protocols were approved by the institutional review board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. All patients gave written, informed consent.
A total of 692 patients from eight randomized controlled trials were included in the study, representing almost all patients who commenced trial combination antiretroviral therapy at HIV-NAT between December 1996 and March 2001. Patients from a study investigating the effects of the steroid nandrolone decanoate on weight in HIV wasting syndrome were not included. All patients received at least two nucleoside reverse transcriptase inhibitors (NRTIs), while 135 received a protease inhibitor (PI)-containing regimen and 215 received a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen. Of those who received a PI-containing regimen, 50 patients received low dose ritonavir in addition to the main protease inhibitor component of the antiretroviral regimen.
The prevalence of HBV, HCV, and HBV/HCV co-infection was 8.7% (60 of 692), 7.2% (50 of 692), and 0.4% (three of 692), respectively. Baseline demographic and clinical characteristics by hepatitis status are shown in Table 1. Patients with HIV-HCV co-infection were most likely to be male (72%), and more likely to report injecting drug use as their HIV risk factor (10%). HIV-HBV co-infected patients were most likely to have a prior AIDS diagnosis (25%). Patients with HIV-HBV and HIV-HCV co-infection were more likely to have a past history of signs and symptoms related to hepatitis (12 and 10%, respectively). Other demographic and clinical parameters were similar across groups, including mean age, weight, HIV viral load, and trial antiretroviral therapy regimen.
Median CD4 cell counts at baseline were 256, 270 and 317 × 106 cells/l/mm3 for HIV, HIV-HBV and HIV-HCV subgroups, respectively (P > 0.05). Median HIV RNA levels (log10 copies/ml) at baseline were 4.4, 4.3 and 4.5 for HIV, HIV-HBV and HIV-HCV subgroups, respectively (P > 0.05).
HIV viral load suppression
Median HIV RNA reductions (log10 copies/ml) were approximately 1.5 for all three subgroups from week 4 up to week 48 (Fig. 1). Neither HIV-HBV (P = 0.73) nor HIV-HCV co-infection (P = 0.35) was associated with the likelihood of achieving undetectable HIV viral load following the initiation of antiretroviral therapy. Undetectable HIV viral load during follow-up was associated with absence of prior antiretroviral therapy (P = 0.003), undetectable HIV RNA at baseline (P = 0.001), CD4 cell count increase of greater than 100 × 106 cells/l (P = 0.0001), and CD8 increase of greater than 200 × 106 cells/l (P = 0.03).
CD4 cell increase
Mean increases in CD4 cell count were significantly lower among HIV-HBV and HIV-HCV subgroups at week 4 (HIV, 62 × 106 cells/l; HIV-HBV, 29 × 106 cells/l; HIV-HCV, 33 × 106 cells/l) and week 8 (HIV, 71 × 106 cells/l; HIV-HBV, 52 × 106 cells/l; HIV-HCV, 45 × 106 cells/l) following commencement of antiretroviral therapy, however, by week 48 CD4 cell increases were similar (HIV, 115 × 106 cells/l; HIV-HBV, 113 × 106 cells/l; HIV-HCV, 97 × 106 cells/l) (Fig. 2). Cox regression analyses showed that being HIV-HBV or HIV-HCV co-infected did not significantly decrease the likelihood of increasing CD4 cell count by 100 × 106 cells/l over 48 weeks of antiretroviral therapy (Table 2). The proportions of patients with a CD4 cell count increase of 100 × 106 cells/l by week 48 was 72, 70 and 66% for HIV, HIV-HBV and HIV-HCV subgroups, respectively. However, achieving a CD4 cell count increase of 100 × 106 cells/l was associated with detectable HIV RNA at baseline (P = 0.01), absence of prior antiretroviral therapy (P = 0.0001), CD8 increase of greater than 200 × 106 cells/l (P = 0.0001), and undetectable HIV RNA after commencement of trial antiretroviral therapy regimen (Table 2).
Within the HIV-HBV subgroup mean CD4 cell increases at week 48 were 114 × 106 cells/l among subjects with (n = 44) and 111 × 106 cells/l among subjects without (n = 16) lamivudine-containing antiretroviral therapy regimens.
Progression to AIDS-defining events and deaths
Sixty (9%) of 692 patients experienced a new AIDS-defining event, and five patients died during the study period. Three deaths were from AIDS-related causes and none from a liver-related cause. Estimated progression to new AIDS-defining event or death at week 48 was 3.3% [95% confidence interval (CI), 2.0–.1] for HIV, 6.7% (95% CI, 2.5–14.6) for HIV-HBV, and 8.0% (95% CI, 2.2–20.5) for HIV-HCV subgroups (log rank P > 0.05). Cox regression models confirmed the lack of independent association between either HIV-HBV or HIV-HCV co-infection, and HIV disease progression (Fig. 3).
Chronic viral hepatitis appears to have a limited impact on antiretroviral therapy responses among Thai patients with HIV infection. HIV viral load reductions were similar among patients with and without viral hepatitis co-infection. Early delayed CD4 cell count recovery was seen in patients with viral hepatitis co-infection, particularly those with HIV-HCV co-infection, but follow-up to 48 weeks showed similar CD4 cell count increases and no difference in HIV disease progression.
Some methodological limitations should be considered in relation to these findings. HIV-HBV and HIV-HCV co-infection was based on serological status rather than HBV DNA and HCV RNA detection. No systematic assessment of liver disease outcomes was conducted in our study. Liver biopsy for patients with HIV and viral hepatitis co-infection is not standard of care in Thailand. There were no liver disease-related deaths among our cohort, but longer term follow-up will be required to examine the contribution of chronic viral hepatitis to liver disease-related and overall mortality. Longer follow-up is also required to further assess the impact of hepatitis co-infection status on HIV disease progression.
Among HIV-NAT patients commenced on trial antiretroviral therapy, there was an early delayed CD4 cell count recovery in those with HIV-HCV co-infection. Studies in Australia  and Switzerland  have demonstrated similar findings, however, in these studies an approximately 40 × 106 cells/l lower CD4 count increase was maintained through 24 months. Direct HCV pathogenicity on lymphocytes has been suggested as the mechanism for this effect , and earlier treatment of HCV in people with HIV proposed as a consequence . Among HIV-NAT patients the CD4 cell increase among HIV-HCV co-infected patients was 25–30 × 106 cells/l lower from week 4 to 12, but by week 48 was less than 20 × 106 cells/l and no longer significantly different from HIV mono-infected patients. Furthermore, a CD4 cell count increase of 100 × 106 cells/l was not associated with HIV-HCV co-infection. Other studies have shown no impact of HIV-HCV co-infection on either CD4 cell recovery or HIV disease progression . Delayed CD4 cell recovery in patients with HIV-HCV co-infection is not related to differences in virological control as shown in our study and by others [19,24,25]. Differences in study populations may explain the contrasting findings on antiretroviral therapy responses among HIV-HCV co-infected patients from different settings. For example, the proportion of HIV-HCV co-infected patients who have injecting drug use acquired HIV infection varies across studies. The small minority of HIV-HCV co-infected patients who acquired HIV through injecting drug use in our study is a major strength as it reduces the potential confounding of CD4 cell response by injecting drug use status.
HIV-NAT patients with HIV-HBV co-infection also had an early but non-sustained delayed CD4 cell recovery. One other study has examined CD4 cell recovery and HIV disease progression in HIV-HBV co-infected patients. This study showed no delayed CD4 cell recovery and no difference in HIV disease progression over 24 months in comparison with HIV mono-infected patients . Lamivudine has clearly demonstrated anti-HBV activity in HIV-HBV co-infected populations . However, there was no differential CD4 cell response in HIV-HBV co-infected patients with and without lamivudine-containing antiretroviral therapy regimens. The impact of new antiretroviral therapy agents with dual HIV and HBV activity such as tenofovir [27–29] on both HIV and HBV outcomes among HIV-HBV co-infected patients is an important area of further research.
Although HIV-HBV and HIV-HCV co-infection do not have a major effect on antiretroviral therapy responses among Thai patients, the risk of hepatotoxicity was increased three-fold among viral hepatitis co-infected patients in this cohort . Thus, close monitoring of liver function tests is required in HIV-HBV and HIV-HCV co-infected patients following commencement of antiretroviral therapy.
The lack of a major impact of HIV-HCV co-infection on antiretroviral therapy responses, the low liver disease-related morbidity and mortality in the HIV-NAT cohort, and continuing sub-optimal HCV treatment responses in HIV-HCV co-infection , mean that HCV-specific treatment is probably a low priority for HIV-HCV co-infected patients in Thailand and other similar settings. The relationship between more advanced immune deficiency and more rapid liver disease progression in HIV-HCV co-infected patients , and recent evidence that HAART without specific HCV treatment reduces liver disease-related mortality , highlights the priority that immune restoration and maintenance should take in HIV-HCV co-infected patients. This strategy is particularly important for settings such as Thailand where HAART is increasingly accessible, but HCV treatment remains expensive. However, the priority of HCV treatment in HIV-HCV co-infected patients in settings such as Thailand should be regularly reviewed to consider changes in liver disease-related mortality, and pricing and effectiveness of HCV therapies.
The low rates of HIV disease progression and overall mortality in the HIV-NAT cohort demonstrate that introduction of effective antiretroviral therapy in resource-limited settings can provide profound improvements in individual outcomes for people with HIV, including those with co-morbidities such as chronic viral hepatitis.
The authors gratefully acknowledge the support of clinical trial sponsors Boehringer Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squibb, the efforts of clinical trial nurses, and in particular the participation of all patients involved in randomized controlled trials at HIV-NAT. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Aging, and is affiliated with the Faculty of Medicine, The University of New South Wales.
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