Patients and Methods

ATAHC is a multicenter, prospective, longitudinal cohort study of patients with recently acquired HCV infection. Study patients were recruited through a variety of mechanisms, including direct recruitment from primary and tertiary care sites. Patients were also recruited through new HCV case notifications via enhanced surveillance systems operating in the major Australian states. Recently acquired HCV infection is defined in these systems by the detection of anti-HCV antibody in a person who has had a negative result of an anti-HCV antibody test recorded within the past 24 months or by the first detection of anti-HCV antibody and clinical hepatitis diagnosed within the past 12 months. Eligibility criteria for ATAHC were devised to be consistent with these definitions; therefore, the study could include patients with both acute HCV infection (estimated duration of infection, <6 months) and early chronic HCV infection (estimated range of duration of infection, 6-18 months) (figure 1). Study recruitment commenced in June 2004, and enrollment was open to both HIV-uninfected and HIV-infected individuals. Inclusion criteria for the study were recently acquired HCV infection, as defined by the first positive result of testing for anti-HCV antibody within 6 months before enrollment and either (i) acute clinical HCV (jaundice or alanine aminotransferase [ALT] level >10 times the upper limit of normal), with exclusion of other causes of acute hepatitis within 12 months before the initial positive result of anti-HCV antibody testing, or (ii) a negative result of anti-HCV antibody testing in the 24 months before the initial result positive for anti-HCV antibody. Patients were required to have tested positive for anti-HCV antibody at screening, and all patients with detectable HCV RNA were assessed for HCV treatment eligibility. Exclusion criteria for the treatment arm included receipt of investigational drugs within previous 6 weeks; positive results of serological testing for anti-hepatitis A virus IgM, hepatitis B surface antigen, or anti-hepatitis B core IgM; other causes of liver disease; and other standard laboratory-based exclusion criteria for IFN therapy. Heavy alcohol intake or active use of illicit drugs were not exclusion criteria; however, drug and alcohol assessment was performed to assess treatment suitability. Clinicians were advised to defer treatment for at least 12 weeks after diagnosis of AHC to allow for potential spontaneous HCV clearance.

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Figure 1

Potential mechanisms for entry into study through the clinical hepatitis definition (A) or the antibody (Ab) seroconversion definition (B). A, Estimated duration of infection calculated as the time from 6 weeks before clinical diagnosis of hepatitis (“X”) to screening. Acute clinical hepatitis was defined by jaundice or alanine aminotransferase level 110 times the upper limit of normal with exclusion of other causes of acut hepatitis. B, Estimated duration of infection calculated as the time from the midpoint between the last negative result of anti-hepatitis C virus (HCV) Ab testing (first “X”) and the first positive result of anti-HCV Ab testing (second “X”). m, months.

Study treatment and virological assessment. Treated HCV-monoinfected patients received 180 µg of PEG-IFN-α2a weekly for 24 weeks. In view of concerns regarding the efficacy of monotherapy for HIV-infected individuals and after the first 2 HIV-HCV-coinfected patients treated with PEG-IFN monotherapy did not respond to treatment, the study protocol was amended to mandate combination therapy with PEG-IFN and RBV for 24 weeks for all HIV-HCV-coinfected patients. HCV RNA assessment was performed at all scheduled study visits (at screening; baseline; weeks 4, 8, 12, 24, 36, and 48; and every 12 weeks through week 144), initially with a qualitative HCV-RNA assay (Versant TMA assay; Bayer; lower limit of detection, 50 copies/mL [∼10 IU/mL]) and, if results were positive, testing was repeated using a quantitative HCV RNA assay (Versant HCV RNA 3.0; Bayer; lower limit of detection, 3200 copies/mL). HCV genotyping (Versant LiPa2; Bayer) was performed for all patients at screening. Risk behavior, including injection behavior, was assessed at screening and every 12 weeks through follow-up. Additionally, at screening, the investigator was specifically requested to identify the most likely mode of HCV acquisition on the basis of the patient's clinical history and risk exposure.

Statistical methods and study definitions. Evaluation of HCV treatment response was done on the basis of intention-to-treat (ITT) analyses of all HIV-HCV-coinfected patients who enrolled between June 2004 and June 2006 and who commenced combination therapy with PEG-IFN and RBV. The primary end point was HCV RNA clearance, as defined by a negative result of qualitative HCV RNA assessment at ⩾24 weeks after treatment (SVR). Other HCV treatment outcomes included undetectable levels of HCV RNA at week 4 (rapid virological response [RVR]), week 12 (early virological response), and week 24 (end-of-treatment response). Secondary study end points included changes in ALT level from baseline to weeks 24 and 48 and changes in hemoglobin level, neutrophil count, platelet count, CD4 cell count, and HIV RNA level from baseline to week 24.

The following definitions were set before study commencement. Duration of HCV infection was defined as the time from the estimated date of HCV infection to screening. The estimated time of HCV infection was calculated for acute clinical HCV cases as 6 weeks before the onset of symptoms or peak ALT level >400 IU/L (whichever occurred first). For asymptomatic HCV cases, the estimated time of HCV infection was calculated as the midpoint between the last negative result of anti-HCV antibody testing and the first positive result of anti-HCV antibody testing (figure 1). Individuals with an estimated duration of infection of <6 months were characterized as having “acute” HCV infection, whereas individuals with an estimated duration of infection of 6-18 months were characterized as having “early chronic” HCV infection.

All study patients provided written informed consent before any study procedures were performed. The study protocol was approved by St. Vincent's Hospital, Sydney, Ethics Committee (the primary study committee), as well as by local ethics committees at all study sites, and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation/Good Clinical Practice guidelines.

Results

Baseline characteristics. A total of 103 patients were enrolled in the study overall between June 2004 and June 2006, of whom 27 (26%) were HIV infected. Baseline characteristics of the HIV-infected and HIV-uninfected patients are given in table 2. Notable differences existed between the HIV-infected and HIV-uninfected groups. All HIV-infected patients were male, compared with 62% of HIV-uninfected patients. HIV-infected patients were more likely to be older (mean age, 40 years vs. 30 years), to be infected with HCV genotype 1 (60% vs. 42%), and to have a higher HCV RNA level at baseline (median, 65,187 IU/mL vs. 30,769 IU/mL). Clinical presentation of acute HCV was remarkably similar between HIV-infected and HIV-uninfected patients, with approximately half (46%-48%) experiencing an acute HCV illness and with a similar maximum mean ALT level (981 IU/mL vs. 937 IU/mL). Of 27 HIV-infected patients, 25 had documented HCV antibody seroconversion. The mean duration of infection before screening was shorter for the HIV-infected group than for the HIV-uninfected group (22 weeks vs. 39 weeks). For the HIV-infected patients, the mean baseline CD4 cell count was 614 cells/mm³, and 59% were receiving HAART.

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Figure 2

Treatment response rates in HIV-infected patients treated with pegylated IFN and ribavirin in the Australian Trial in Acute Hepatitis C, by intention-to-treat analysis. ETR, end-of-treatment response; EVR, early virological response; RVR, rapid virological response; SVR, sustained virological response.

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Table 1

Studies of outcomes of treatment for acute hepatitis C virus (HCV) infection among HIV-infected individuals.

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Table 2

Baseline characteristics of HIV-infected and -uninfected patients enrolled in the Australian Trial in Acute Hepatitis C between June 2004 and June 2006.

There were significant differences in the risk factors for HCV transmission between HIV-uninfected and HIV-infected groups. IDU was identified as the most likely source of infection for 81% of HCV-monoinfected patients, compared with 44% of HIV-infected patients. In contrast, sexual transmission was the most likely source of infection for 56% of the HIV group (of whom 38% were with a known HCV-infected sex partner and 62% were with partner(s) of unknown status), compared with only 8% of the HCV-monoinfected group. Even among the HIV-infected group that had IDU as a risk factor for HCV transmission, patterns of drug use were different from those among the HIV-uninfected group. For the HIV-infected group, the mean age at first injection was older (31 years vs. 22 years), and the most frequent drug injected was methamphetamine (58%) or amphetamine (42%), as opposed to heroin (55% of HCV-monoinfected cases)

Treatment uptake. Of 27 HIV-infected patients enrolled, 22 (81%) commenced HCV treatment. Of the 5 untreated patients, one received a diagnosis of malignant melanoma and died from this disease 6 months after enrollment, and the remaining 4 had low HCV RNA levels at screening (10-615 IU/mL for 2 patients and <3000 IU/mL for 2 patients). Two of these cases subsequently cleared, one progressed to chronic HCV infection, and the fourth was lost to follow-up at week 12, with a detectable HCV RNA level at that time point.

Treatment response. The first 2 coinfected patients were treated with PEG-IFN monotherapy within the same protocol as the HCV-monoinfected patients. Both of the patients had infection with HCV genotype 1a and a high HCV RNA level at baseline. Neither achieved a >1-log reduction in HCV RNA at week 4, and both remained positive for HCV RNA at week 12. Treatment was ceased and, for one patient, was recommenced some months later with combination therapy, again unsuccessfully. Subsequent to these results, the treatment protocol for HIV-infected individuals was amended to 24 weeks of PEG-IFN and RBV combination treatment for all patients as the initial therapy. Twenty HIV-coinfected patients were treated with PEG-IFN and RBV and reached the 48-week SVR time point.

Treatment responses are given in figure 2; 95%, 90%, and 80% of patients had undetectable HCV RNA levels (<10 IU/mL) by ITT analysis at early virological response, end-of-treatment response, and SVR, respectively. One patient was lost to follow-up at week 36; for this patient, RVR was achieved, with HCV RNA levels <10 IU/mL at all time points before week 36. It is highly likely, therefore, that this patient would have achieved SVR, to yield a potential SVR rate of 85%. Of the 3 patients treated with PEG-IFN and RBV who had virological nonresponse (HCV RNA level detectable at week 48), one did not have early virological response and withdrew from treatment at 12 weeks. Heavy alcohol intake was a significant factor in this case. The second patient achieved an initial reduction in HCV RNA level to <615 IU/mL at week 4 but continued to have positive results of qualitative testing. The HCV RNA level increased thereafter to 3589 IU/mL by week 24. The third patient relapsed after treatment completion, with an HCV RNA level of 61,581 IU/mL at week 48, having had a negative result for HCV RNA at the end of therapy. Viral sequencing supported viral breakthrough in the second patient and viral relapse in the third patient, instead of reinfection. By ITT analysis, SVR was achieved in 100% (9/9) of patients infected with a non-1 genotype and in 64% (7/11) of patients infected with HCV genotype 1. All 3 virological failures were in cases of infection with HCV genotype 1a. SVR rates did not appear to be reduced among patients with a longer period of estimated infection and was observed for 77% of patients with an estimated duration <24 weeks and for 86% of patients with an estimated duration of infection >24 weeks.

Rapid and early virological response rates. HCV RNA qualitative data for week 4 was available for 16 (80%) of the patients. In this group, the RVR rate was 44% (35% by ITT analysis if unavailable results are included). Although the numbers are small, genotype appeared to have little impact on RVR, with RVR among 50% of patients infected with genotype 1 and 30% of patients infected with a genotype other than genotype 1. All 7 patients with RVR subsequently achieved SVR, which yielded a positive predictive value for RVR in this analysis of 100%. SVR was achieved by 6 of 9 patients without an RVR (negative predictive value, 33%).

Safety and tolerability. Therapy was generally well tolerated, with a median drop in hemoglobin level of 2.1 g/dL by week 24. Four patients experienced serious adverse events—in one patient, severe depression developed that required hospitalization. Only 1 patient required a dose modification because of neutropenia, and 80% of patients received >80% of injections. The median CD4 cell count decreased by 237 cells/mm³ at week 24, to 393 cells/mm³ (range, 189-689 cells/mm³), but by week 48 had rebounded to a median of 515 cells/mm³. HIV RNA level remained suppressed in all patients receiving HAART and decreased by a median of 0.7 log₁₀copies/mL among those not receiving HAART. All 3 HCV virological failures were observed in patients receiving HAART and with HIV RNA levels <50 copies/mL.

Discussion

This analysis of HCV treatment outcomes for HIV-HCV-coinfected patients in this study highlights and expands on several important areas of research in this field. First, baseline characterization of these individuals demonstrates that, compared with the HCV-monoinfected patients recruited into the study contemporaneously, HIV-infected patients with recently acquired HCV infection represent a significantly different group of individuals. HIV-HCV-coinfected patients were older, were more often infected with HCV genotype 1, and were considerably more often infected through sexual transmission. Differences were also seen in patterns of drug use among those who did inject. Despite these differences, AHC presented with a similar clinical picture for HIV-uninfected and HIV-infected patients. The shorter duration from the estimated time of infection to screening observed for the HIV-infected group may reflect a heightened awareness of the current epidemic of acute HCV infection within the HIV treatment community.

The recognition of sexual exposure as an important possible route of HCV transmission among the HIV population has been widely reported in recent years, accompanied by a rapid increase in the number of AHC cases diagnosed among HIV-infected individuals from across Europe [1, 3, 4, 11]. Our study is the first to simultaneously enroll HCV-monoinfected individuals, using the same sites and protocol, to demonstrate that, not only is the occurrence of sexually transmitted AHC also occurring within the HIV-infected population in Australia, but also that this group of patients has distinctly different characteristics from those of HCV-monoinfected individuals who acquire AHC in the same time frame. A case control study from the United Kingdom that involved 111 HIV-infected MSM with AHC identified a number of high-risk sexual behaviors potentially associated with acquisition of infection [6], but further exploration of the mechanisms of permucosal transmission is still required. Phylogenetic analysis of patients in the UK case study identified at least 7 HCV transmission clusters, supporting the role of permucosal transmission among HIV-infected networks. Phylogenetic analysis of patients recruited in ATAHC, from within both IDU and sexual networks, will help examine the extent of clustering and, importantly, any interaction between HIV-infected and HIV-uninfected populations.

Second, our study found an extremely high rate of treatment success in this HIV-infected population after a 24-week course of PEG-IFN and RBV for acute and early chronic HCV infections. An SVR rate of 80% seen among HIV-HCV-coinfected patients by ITT analysis is similar to that seen for treatment of AHC among HCV-monoinfected patients [20-23] and is one of the most successful SVR rates reported for HIV-infected patients to date (table 1). Although based on a relatively small sample size, our study is still one of the largest reported for this setting. The excellent treatment response seen in our HIV-infected group is especially encouraging, given the high proportion of patients with negative HCV-related prognostic markers at baseline (i.e., infection with genotype 1 and high baseline level of HCV RNA). Of particular note in our study is the inclusion of patients with both acute HCV infection (as defined by an estimated duration of infection <6 months) and early chronic HCV infection (as defined by an estimated duration of HCV infection of 6-18 months). In fact, the median estimated duration of infection before the actual start of treatment was 30 weeks among all patients and was >24 weeks in 80% of patients. Although the numbers involved are small, there was no suggestion that the SVR rate was decreased among those with early chronic infection (SVR 86%), compared with those with acute HCV infection (SVR 77%). There are very few data on treatment outcomes in early chronic HCV infection, either for HCV-monoinfected or HIV-coinfected patients; thus, our data are not only novel but also are encouraging in that 24 weeks of PEG-IFN and RBV treatment appears to be adequate for the majority of patients in this group, including those with HCV genotype 1 infection.

Monitoring of early virological responses to predict HCV treatment outcome is increasingly common. RVR has been shown in chronic HCV infection to be a useful predictor of treatment outcome, both for HIV-uninfected patients [24, 25] and HIV-infected patients [26, 27]. The utility of RVR for acute HCV infection has been less well studied. Kamal et al. [22] reported an overall RVR rate of 86%, with a positive predictive value of 88% and a negative predictive value of 98%. In our study, although limited by the small sample size, RVR was shown to be an excellent predictor of SVR, with 100% positive predictive value. These data suggest that RVR is an important predictor of SVR for AHC, as well as chronic HCV infection.

In summary, this report of HIV-infected patients within our study establishes that sexual or “permucosal” transmission of AHC within HIV-infected populations is a global phenomenon. It also suggests that HCV infection in HIV-infected individuals can be successfully treated with 24 weeks of combination therapy with PEG-IFN and RBV, not only for acute HCV infection but also for early chronic HCV infection. These findings support the importance of regular HCV testing among HIV-infected MSM, with consideration given to commencement of early treatment for recently acquired HCV infection.

ATAHC Study Group

Protocol steering committee members. John Kaldor (National Centre in HIV Epidemiology and Clinical Research [NCHECR]), Gregory Dore (NCHECR), Gail Matthews (NCHECR), Pip Marks (NCHECR), Andrew Lloyd (University of New South Wales [UNSW]), Margaret Hellard (Burnet Institute, Victoria), Paul Haber (University of Sydney), Rose Ffrench (Burnet Institute, Victoria), Peter White (UNSW), William Rawlinson (UNSW), Carolyn Day (University of Sydney), Ingrid van Beek (Kirketon Road Centre), Geoff McCaughan (Royal Prince Alfred Hospital), Annie Madden (Australian Injecting and Illicit Drug Users League, Australian Capital Territory), Kate Dolan (UNSW), Geoff Farrell (Canberra Hospital, Australian Capital Territory), Nick Crofts (Burnet Institute, Victoria), William Sievert (Monash Medical Centre, Victoria), and David Baker (East Sydney Doctors).

NCHECR ATAHC research staff. John Kaldor, Gregory Dore, Gail Matthews, Pip Marks, Barbara Yeung, Brian Acraman, Kathy Petoumenos, Janaki Amin, Carolyn Day, Anna Doab, and Therese Carroll.

Burnet Institute research staff. Margaret Hellard and Oanh Nguyen.

Immunovirology laboratory research staff. UNSW Pathology: Andrew Lloyd, Suzy Teutsch, Hui Li, Alieen Oon, and Barbara Cameron; South Eastern Area Laboratory Services Microbiology: William Rawlinson, Brendan Jacka, and Yong Pan; Burnet Institute Laboratory, Victoria: Rose Ffrench, Jacqueline Flynn, and Kylie Goy.

Clinical site principal investigators. St. Vincent's Hospital, NSW: Gregory Dore; The Alfred Hospital, Infectious Disease Unit, Victoria: Margaret Hellard; Royal Adelaide Hospital, South Austrailia: David Shaw; Royal Prince Alfred Hospital: Paul Haber; Royal Melbourne Hospital, Victoria: Joe Sasadeusz; Princess Alexandra Hospital, Queensland: Darrell Crawford; Kirketon Road Centre: Ingrid van Beek; Nepean Hospital: Nghi Phung; Westmead Hospital: Jacob George; Holdsworth House GP Practice: Mark Bloch; East Sydney Doctors: David Baker; John Hunter Hospital: Brian Hughes; Fremantle Hospital: Lindsay Mollison; The Alfred Hospital, Gastroenterology Unit, Victoria: Stuart Roberts; Monash Medical Centre, Victoria: William Sievert; St. Vincent's Hospital, Victoria: Paul Desmond.