Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference
The European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel
Received 7 July, 2010
Revised 22 November, 2010
Accepted 24 November, 2010
Correspondence to Professor Dr. Jürgen K. Rockstroh, Department of Internal Medicine I, Bonn University, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. Tel: +49 228 287 16558; fax: +49 228 287 15034; e-mail: email@example.com
There is increasing awareness of an ongoing epidemic of acute hepatitis C virus (HCV) infection in HIV-infected MSM. The epidemiology has been reviewed in this journal recently ; however, there is a lack of guidance on the management of acute HCV infection in HIV-infected individuals. To address this issue, the European AIDS Treatment Network (NEAT) invited members of the European AIDS Clinical Society (EACS) hepatitis group, the European Association for the Study of the Liver (EASL), the European Study Group on Viral Hepatitis of the European Society of Clinical Microbiology and Infectious Diseases, the European AIDS Treatment group and other experts to draw up a consensus statement at a conference held in Paris, France, in May 2010. Four working groups prepared draft guidelines for consideration at the conference on case definition and diagnosis; transmission risk and epidemiology; pathogenesis and natural history; and acute HCV infection management in the HIV-infected population. A literature search using the PubMed database of the National Library of Medicine and abstract databases of the Conference on Retroviruses and Opportunistic Infections, the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Liver Meetings of the American Association for the Study of Liver Disease and EASL was utilized by all groups. Statements and recommendations were graded by the strength of recommendation and level of evidence (Table 1) . A consensus was reached if 80% or more of the participants were in favour.
Case definition and diagnosis of acute hepatitis C virus infection in HIV-infected patients
Acute HCV infection is defined as the first 6 months after exposure to HCV. This definition is arbitrary, as there is a lack of evidence on when ‘acute’ infection becomes ‘chronic’ and determining the precise timing of infection is usually problematic. As the majority of individuals with acute HCV infection are asymptomatic [3,4], clinical diagnosis has a low sensitivity. Differentiating between acute HCV infection and an exacerbation of chronic HCV infection clinically, virologically and immunologically is difficult in the absence of recent negative HCV-RNA and antibody results. A serological test does not exist to differentiate between acute and chronic infection [5–7].
One third to a half of individuals with acute HCV infection experience symptoms attributable to an acute illness [3,4], although symptoms are nonspecific. Eighty-eight percent individuals experience elevated alanine aminotransferases (ALTs) within 3 months of infection  with peak ALT levels higher than five times the upper limit of normal in 55% individuals . Patients in this study were sampled at 1–3 month intervals, so the rate of ALT elevation could be an underestimation. HIV-infected patients with chronic HCV develop hepatic flares with a rise of ALT higher than five times the upper limits of normal (ULN) in less than 2% , minimizing the possibility of classifying ‘chronic’ HCV infection as ‘acute’. The first marker of HCV infection is serum or plasma HCV-RNA detected through nucleic acid test (NAT) as early as 1 week postinfection . HCV antibody responses may be delayed or absent in HIV-infected individuals with two-thirds positive at 3 months and 5% remaining negative up to 1 year after infection . Fluctuations in HCV-RNA levels during the acute phase of HCV infection are characteristic in HIV-uninfected individuals and may be of value in suggesting a diagnosis of acute hepatitis C .
A definitive diagnosis of acute hepatitis C can be made by documented seroconversion from negative to positive in a test for HCV antibodies. Owing to the asymptomatic nature of the illness, seroconversion often occurs prior to diagnosis. Even if annual antibody screening is performed, a prior HCV antibody test may not have been performed within the previous 6 months. Owing to delayed and occasionally absent HCV antibody seroconversion, the window period in which HCV-RNA will be detectable in peripheral blood without the presence of anti-HCV antibodies cannot be used with accuracy to diagnose acute hepatitis C. Advanced serologic assays for HCV including HCV antigen tests improve the sensitivity of serological testing [12,13], but are inferior to testing for HCV-RNA (Table 2) [8,12].
Consensus recommendation: case definition acute hepatitis C virus infection
Preferred criteria (grade A, level II)
1. Positive anti-HCV immunoglobulin G (IgG) in the presence or absence of a positive HCV-RNA and a documented negative anti-HCV IgG in the previous 12 months.
2. Positive HCV-RNA and a documented negative HCV-RNA and negative anti-HCV IgG in the previous 12 months.
Alternative criteria (Grade B, Level III)
If historical data is lacking and relevant test results within the past year unavailable, acute hepatitis C may be diagnosed if the following criteria are met:
1. Positive HCV-RNA regardless of anti-HCV IgG with any of the following two conditions:
a. An acute rise in ALT greater than 10 times the ULN.
b. An acute rise in ALT greater than five times the ULN, with documented normal ALT within 12 months. In individuals with a previously high ALT, an acute rise to 3.5 times their previous ALT is acceptable .
2. Antihepatitis A virus IgM negative and antihepatitis B core IgM antibody negative, and exclusion of other causes of acute hepatitis.
No consensus (20 in favour, six against with three abstentions) was reached to include a history of transmission risk factors for acute HCV in the alternative case definition.
Epidemiology and transmission
Prevalence of hepatitis C virus infection
The prevalence of HCV infection in the HIV-infected is higher than in the uninfected population . Within the HIV-infected population, the highest prevalence is in those with a history of intravenous drug use (IVDU) or haemophilia and other bleeding disorders. The European AIDS cohort (EuroSIDA) reported a prevalence of anti-HCV antibody or HCV-RNA positivity of 33%, ranging from 6.6% in MSM to 75% in IVDUs . This is similar to other cohorts and cross-sectional studies in HIV-infected populations [17–26].
Incidence of acute hepatitis C
The most efficient means of HCV transmission is through parenteral exposure in IVDUs who share needles, syringes or other paraphernalia for drug use. Cases of sexual transmission of HCV infection in heterosexuals remain uncommon [27,28]. Since 2000, there have been reports from Europe, Australia and the USA of an increasing incidence of acute hepatitis C infection in HIV-infected MSM (Table 3) [22,23,26,29–32]. In Amsterdam, incidence has risen 10-fold from an estimated 0.08 per 100 person-years in 1984–1999 to 0.87 in 2000–2003 in HIV-infected MSM attending a sexually transmitted infection (STI) clinic .
Hepatitis C virus transmission in MSM
Studies in MSM have shown HIV infection and IVDU to be independently associated with the presence of HCV antibodies [29,33–35]. In early reports, evidence for sexual transmission was weak with conflicting evidence of an association with sexual risk behaviour [33–39].
Recent studies investigating factors underlying HCV transmission in HIV-infected MSM have provided further evidence for an association with certain sexual practices including fisting, using sex toys and group sex [29,36,37]. Noninjecting drug use is also associated, probably because of the influence on sexual behaviour, but transmission through sharing contaminated devices may also contribute. There is an association with bacterial STIs, notably syphilis and lymphogranuloma venereum. The mechanism of sexual transmission remains uncertain, but the association with traumatic sexual practices and ulcerative STIs affecting the mucosa of the rectum provides some clues. HCV-RNA has been detected in semen and more often in the HIV-infected individuals , although one study failed to detect HCV-RNA in the semen of most HIV-infected men even during acute HCV infection . Group sex may facilitate transfer of infected material . Other causes of disruption of the anorectal mucosa, including surgery, may contribute to the risk . There is no evidence that HIV-infected men are more susceptible to HCV infection due to immunological deficits, or that a more virulent HCV strain is being selected. Phylogenetic analyses of transmitted HCV strains show clustering consistent with transmission among a social and sexual network of HIV-infected MSM which extends nationally and internationally . Although the majority of patients present with two or more risk factors described above, cases of acute HCV infection are seen in MSM who report only unprotected anal intercourse. Although current outbreaks have been largely confined to HIV-infected MSM, cases have also been reported in HIV-uninfected individuals.
Public health implications
The recognition of ongoing transmission of HCV requires measures to reduce rates of transmission. This involves identification of undiagnosed HCV infection and ensuring appropriate risk-reduction advice is provided to the infected and those at risk.
Although unselected screening for acute hepatitis C in HIV-infected individuals may not be cost-effective in regions with a low prevalence , annual testing in populations at high risk may detect seroconversions in those with normal transaminases and permit improved estimation of the time of infection. Liver transaminases at routine visits with subsequent HCV-RNA testing in suspected patients will identify 90% of those with acute HCV . HIV-infected individuals with severe immunodeficiency may lose anti-HCV antibodies, but may regenerate antibodies after initiation of HIV therapy with subsequent immune reconstitution.
Consensus recommendation screening for acute HCV infection (grade A, level II, *grade C, level II)
1. All newly diagnosed HIV individuals should be screened for anti-HCV antibody .
2. HIV-infected MSM at risk for contracting acute hepatitis C infection should be screened at 6-month interval with ALT and annually with anti-HCV antibody.
3. HIV-infected patients with newly diagnosed STI or continued IVDU should be screened 3 months after diagnosis/last exposure.
4. A NAT test for HCV-RNA should be performed if a diagnosis of acute HCV infection is suspected.
The management of those diagnosed with acute HCV infection should include encouraging partner notification to identify potential sources of infection and those at risk of exposure. Screening for other sexually transmitted diseases is required.
Consensus recommendation risk-reduction advice (grade B, level II)
1. Although the mode of HCV transmission remains unclear, epidemiological studies suggest that the following risk behaviours be considered in risk-reduction advice: fisting, recreational drug use, group sex, use of sex toys, unprotected anal sex, sharing of paraphernalia (for IVDU and permucosal drug use) and sexual practices with risk for blood–blood contact or mucosal damage.
2. Information regarding risk of HCV transmission should be given to all HIV-infected individuals after HIV diagnosis and on an ongoing basis. Advice regarding risk factors for transmission must be given to all those newly diagnosed with HCV infection including risk-reduction.
Pathogenesis, natural history and implications for treatment of acute hepatitis C
Innate and adaptive immune responses
The immune response in acute hepatitis C, and correlates of spontaneous clearance, has been studied predominantly in HCV-monoinfected individuals and in chimpanzees. Acute hepatitis C infection induces a range of innate and adaptive immune responses. Single nucleotide polymorphisms near the interleukin (IL28B) gene, encoding for interferon-λ (IFNλ), provide strong evidence for an important role of the innate immune system in the natural defence against HCV [43–45]. Individuals with the rs12979860 CC genotype were more than three times likely to clear HCV-RNA compared with individuals with C/T and T/T genotypes . A similar association is observed in HIV/HCV-coinfected individuals . The frequency of the protective allele varies across ethnic groups with a lower frequency in those of African origin compared with European patients which could explain observed differences in spontaneous clearance between races . The cellular immune response is important for the outcome of acute hepatitis C. Clearance in HIV-uninfected individuals is associated with a broad, vigorous and sustained memory CD4+ and CD8+ T-cell response [46,47]. In one study, memory T-cell responses to nonstructural (NS4) protein correlated with HCV clearance , whereas in a comparative study of HIV-infected and uninfected individuals, HIV-infected patients had CD4+ T-cell IFNγ ELISpot responses against NS3-5 proteins, but were reduced in frequency, breadth and magnitude . Successful antiretroviral therapy can restore HCV-specific cellular immune responses . The importance of CD4/CD8 HCV antigen-specific responses in determining spontaneous clearance and patterns of viraemia after HCV acquisition has been demonstrated in HIV-negative  and HIV-coinfected individuals [52,53]. A lack of antigen-specific responses early in the course of acute infection determines progression to chronic HCV and may be associated with the pattern of viraemia observed . Spontaneous clearance was associated with early antigen-specific responses and rapid HCV clearance.
The role of humoral immune responses in acute hepatitis C is not well defined [52–58]. Evoked cellular and humoral immune responses after first acute HCV infection diminish following spontaneous resolution or successful antiviral therapy , although data are inconsistent.
Rates and predictors of spontaneous hepatitis C virus RNA clearance
The rate of and factors associated with spontaneous viral clearance in HIV-infected patients with acute hepatitis C have been studied in prospective cohorts. In the Johns Hopkins cohort  of predominantly black men with prior or current IVDU, HCV-RNA clearance was observed in 14% of HIV-uninfected and 7% of HIV-infected individuals with the lowest rate (5%) associated with CD4+ cell counts less than 200 cells/μl. Viral clearance was associated with nonblack ethnicity, younger age (<45 years) and hepatitis B surface antigen (HBsAg) positivity . In the EuroSIDA cohort, spontaneous HCV-RNA clearance was 23% in 1940 HCV antibody-positive individuals . Factors associated with spontaneous viral clearance were female sex, mode of transmission (sexual vs. IVDU), HBsAg positivity and region (other European regions vs. southern Europe/Argentina). Viral clearance was not associated with age, ethnicity or HIV-related variables .
Rates of spontaneous viral clearance in those with established HIV infection range from 0 to 40%, but due to small sample sizes, and the majority being MSM, factors associated with spontaneous viral clearance are not well defined [49,61–63]. Gilleece et al.  reported lower HCV-RNA titers and CD4+ T-cell count higher than 500 cells/μl were predictive of spontaneous clearance.
Consensus statement on the natural history of acute hepatitis C infection
1. Acute hepatitis C takes a chronic course more frequently in HIV-infected individuals (II).
2. Spontaneous clearance of acute HCV in HIV patients occurs in 0–40% (III) and is associated with the following factors:
a. Host genetic factors (e.g. IL28b-CC genotype*) and stronger adaptive immune responses (II).
b. Female sex, exposure group (sexual transmission vs. IVDU), HBsAg positivity, jaundice and higher peak ALT (II).
c. Early decline of HCV-RNA 4–8 weeks after presentation (III) *using the rs12979860 SNP.
Selection for early antiviral therapy
Ideally, only those who will not clear HCV spontaneously would be candidates for early antiviral treatment. However, delays in treatment could reduce efficacy. A positive HCV-RNA 12 weeks into acute hepatitis is associated with transition to chronic infection. Thus, treatment has been recommended in those with persistent HCV-RNA reactivity 12 weeks after onset of symptoms or 12 weeks after putative exposure, although there may be as much as 8 weeks difference between these time points. Low-level viraemia and viral load fluctuations are common in acute HCV and are incorporated in standard diagnostic criteria . The definition of 12-week HCV-RNA reactivity as a predictor of chronicity is supported by Gerlach et al. . In this study in HIV-negative patients, two of 24 cases that resolved still had HCV-RNA detectable 12 weeks after onset of hepatitis and none after 16 weeks. A limitation of this study was that the HCV-RNA assay used (Amplicor Monitor; Hoffmann–La Roche, Basel, Switzerland) had a sensitivity of 600 IU/ml, more than a log higher than currently available tests. In a recent study of acute posttransfusion hepatitis C  utilizing a more sensitive HCV-RNA assay (transcription-mediated amplification), 48% with resolved infection had HCV-RNA detectable at 12 weeks and 32% at 16 weeks after ALT elevation. However, 16% of patients progressing to chronic HCV had a negative HCV-RNA assay result 12 and 16 weeks after occurrence of hypertransaminasemia.
In a European cohort of 92 HIV-positive patients with acute HCV, the sensitivity and specificity of HCV-RNA determination at 4 and 12 weeks to predict the outcome of acute HCV was similarly strong . Eighty-five percent of individuals who did not reduce HCV-RNA by more than 2 log, 4 weeks after diagnosis, progressed to chronic hepatitis C defined as a positive HCV-RNA 24 weeks after the first positive HCV-RNA. Ninety-two percent of individuals who were HCV-RNA positive 12 weeks after diagnosis developed chronic hepatitis C. The observational setting and high cut-off of HCV-RNA assay used limits generalization of these data. The studies are summarized in Table 4 [64–66]. A robust study utilizing highly sensitive NAT assays is required to provide stronger conclusions on the predictive value of HCV-RNA measurements during acute hepatitis C.
Optimum interval between the onset of hepatitis and treatment initiation
If initiation of anti-HCV treatment is delayed for more than 1 year after onset, rates of sustained virological response (SVR) in HIV-uninfected persons are halved . A shorter delay (12 weeks) did not impair outcome in the HEPNET III cohort . In studies of acute HCV treatment in the HIV-infected individuals, most initiated treatment between 12 and 24 weeks into acute hepatitis and the length of time between the start of acute hepatitis and treatment initiation did not influence treatment response. This is exemplified in the Australian Trial in Acute HCV (ATAHC) in which SVR of greater than 75% was achieved in coinfected individuals with 24 weeks of combination therapy, with a median estimated duration of HCV infection before the start of therapy of 30 weeks, and greater than 24 weeks in over 80% .
Consensus recommendation on the monitoring and initiation of treatment in the course of acute hepatitis C infection
1. HCV-RNA levels should be measured at initial presentation and 4 weeks later (BII).
2. Treatment should be offered to the following individuals:
a. Patients without a decrease of 2 log10 of HCV-RNA at 4 weeks compared with initial HCV-RNA (BII).
b. Patients with persistent serum HCV-RNA 12 weeks after diagnosis of acute HCV (AII).
3. Patients showing spontaneous HCV-RNA clearance before and after 12 weeks should undergo serial HCV-RNA measurement for 48 weeks to confirm resolution (AIII).
Testing of retrospective samples may be useful to assess duration of viral infection. In cases of persistent HCV infection of duration greater than 12 weeks, initiation of treatment is recommended.
Management of acute hepatitis C in HIV-infected patients
In monoinfected acute hepatitis C, early therapy with standard IFNα or pegylated IFNα alone for up to 24 weeks is sufficient to obtain high rates of SVR (ranging from 71 to 98%) [64,69,70]. HIV-infected patients may be different due to a number of factors including high HCV viral loads, the proportion of genotype 1/4 infection and possible adverse impact of HIV-associated immune suppression.
There are several reports of cohorts studying treatment of acute hepatitis C in HIV-infected persons (Table 5) [3,48,62,63,71–75].
In these studies, patients were treated with pegylated IFNs at standard doses (α-2b, 1.5 μg/kg per week and α-2a, 180 μg/week). Ribavirin was used in 145 of 170 individuals: weight-adjusted dosing in 122 and fixed dose in 23 (800 mg/day in 19 and 1000 mg/day in four patients). Twelve of 25 individuals (48%) treated with pegylated IFN monotherapy showed an SVR compared with 96 of 159 (60%) with combination therapy (P > 0.05). Although the cumulative results of these studies do not establish the role of ribavirin, other evidence of breakthrough and nonresponse in patients treated with pegylated IFN alone are also suggestive [3,76]. In a report of a study of acute hepatitis C genotype 1 and 4, in HIV-infected patients, six of 12 (50%) stopped therapy due to lack of early virological response (EVR, fall in HCV-RNA of more than 2 log or undetectability by 12 weeks after start of antiviral therapy) when treated with pegylated IFN alone . The role of ribavirin in improving viral kinetic response has been demonstrated in the ATAHC study in which greater reductions in HCV-RNA were seen between weeks 8 and 12 of treatment in HIV/HCV-coinfected patients receiving combination therapy compared with pegylated IFN alone in monoinfected patients . This translated into comparable rapid virological response (RVR, undetectable HCV-RNA 4 weeks after start of therapy) and SVR (undetectable HCV-RNA 24 weeks after the end of antiviral therapy) rates.
Another treatment strategy suggested for acute hepatitis C is to start pegylated IFN and ribavirin, but then to discontinue the ribavirin in those with a fast decay of HCV-RNA (in this study defined as confirmed negative HCV-RNA at week 8 and 12). This treatment strategy may allow synergistic antiviral therapy in the beginning, yet limiting ribavirin-associated toxicities. Even though no disadvantages of this strategy have been reported thus far, SVR data are not yet available . Although 48 weeks of therapy for acute HCV in HIV-infected patients appeared more efficacious than 24 weeks in a single study , a preliminary report  in mostly genotype 1/4 acute infections showed SVR rates of greater than 70% with no statistically significant difference by length of therapy. Furthermore, as seen in Table 5, 24 weeks of therapy is associated with SVR rates of over 60% overall.
A lack of RVR predicting relapse is apparent from a study in monoinfected patients . Evidence for the use of viral kinetics in determining the chance of SVR and potentially the optimal length of therapy comes from the European Collaborative Cohort Study  in which 111 HIV-infected men with acute HCV achieved an overall SVR of 62%. Ninety-three percent of those with an RVR achieved a SVR, whereas only 9% not achieving complete EVR reached a SVR. Response rates were defined by an HCV-RNA below 615 IU/ml. It would be reasonable to aim for 24 weeks of therapy, with a longer duration of therapy reserved for those without RVR but having EVR.
Consensus recommendation on treatment of acute hepatitis C infection
1. Pegylated IFN and weight-based ribavirin is recommended for the treatment of acute hepatitis C in HIV-infected patients (grade A, level II).
2. Duration of treatment should be based on RVR [negative HCV-RNA at week 4 (evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA)], regardless of HCV genotype.
a. In patients with RVR, treatment duration should be 24 weeks (AII).
b. In patients without RVR, treatment duration of 48 weeks should be considered (BIII).
c. In non-RVR patients not achieving a 2 log10 drop in HCV-RNA at week 12, treatment can be discontinued (BIII).
When and which antiretroviral therapy to use in HIV-infected patients with acute hepatitis C virus
For information on CD4 strata for commencement of therapy and which antiretroviral components to use in HIV patients with acute hepatitis C commencing pegylated IFN and ribavirin therapy, the EACS guidelines should be consulted .
Consensus recommendation on the use of antiretroviral therapy in the setting of acute hepatitis C virus infection
In those with acute HCV and CD4 cell count higher than 350 cells/μl, HCV therapy can be commenced before starting HIV therapy (BIII).
Panel members and conflict of interest: The development of guidelines demanded commercial independence and avoidance of potential conflict of interests, which could influence statements and recommendations made. The organization and related expenses of the conference were therefore solely funded through NEAT. NEAT is a project funded by the European Union under the 6th Framework programme, contract “acronym: NEAT, number: LSHP-CT-2006-037570”. All conference participants were asked to declare any conflict of interest of themselves or their families.
The NEAT AHC panelists who were able to participate at the conference and vote on the statements/recommendations were:
Matthieu Albert, Institut Pasteur, France, no conflict of interest; Jose Benito, Hospital Carlos III, Madrid, Spain, no conflict of interest; Sanjay Bhagani Group leader “Management” (EACS), Royal Free Hospital, London, United Kingdom, no conflict of interest; Christoph Boesecke, Bonn University Hospital, Bonn, Germany, no conflict of interest; Katja Deterding (EASL), Medizinische Hochschule Hannover, Hannover, Germany, no conflict of interest; Stephanie Dominguez, Hôpital de la Pitié-Salpétière, Paris, France, no conflict of interest; Martin Fisher Group leader “Epidemiology and transmission risk factors”, Royal Sussex County Hospital, Brighton, United Kingdom, no conflict of interest; Arnaud Fontanet, Institut Pasteur, Paris, France, no conflict of interest; Diego Garcia (EATG)/(EACS), Foro Español Activistas en Tratamientos, Sevilla, Spain, no conflict of interest; Richard Gilson Group leader “Epidemiology and transmission risk factors”, University College London, London, United Kingdom, no conflict of interest; Marguerite Guiguet INSERM-UPMC UMR S943, Paris, France, no conflict of interest; Andy I.M. Hoepelman, University Medical Center, Utrecht, The Netherlands, educational grant Roche; Andrzej Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw, Poland, no conflict of interest; Christine Katlama, Hôpital de la Pitié-Salpétière, Paris, France, no conflict of interest; Josep Mallolas, Hospital Clínic, Barcelona, Spain, no conflict of interest; Emma Page Group leader “Case definition and diagnosis”, Chelsea and Westminster Hospital, London, United Kingdom, no conflict of interest; Lars Peters Group leader “Natural history and pathogenesis” (EACS), Copenhagen HIV Programme, Copenhagen, Denmark, no conflict of interest; Anton Pozniak, Chelsea and Westminster Hospital, London, United Kingdom, no conflict of interest; Maria Prins, Public Health Service, Amsterdam, the Netherlands, no conflict of interest; Massimo Puoti Group leader “Management” (EACS), A.O. Niguarda Cà Granda, Milan, Italy, no conflict of interest; Andri Rauch, University Hospital Berne and University of Berne, Inselspital, Bern, Switzerland, no conflict of interest; Alison Rodger, University College London, London, United Kingdom, no conflict of interest; Jürgen K. Rockstroh (EACS) Co-chair, Bonn University Hospital, Bonn, Germany, advisor of Essex and Roche pharmaceuticals; Vincent Soriano Group leader “Natural history and pathogenesis” (EACS), Hospital Carlos III, Madrid, Spain, no conflict of interest; Christoph Stephan, J. W. Goethe University Hospital, Frankfurt, Germany, no conflict of interest; Vincent Thibault, Hôpital de la Pitié-Salpétière, Paris, France, no conflict of interest; Cristina Tural (EACS), Hospital Germans Trias i Pujol, Badalona, Spain, no conflict of interest; Marc-Antoine Valantin, Hôpital de la Pitié-Salpétière, Paris, France, no conflict of interest; Thijs van de Laar, Public Health Service, Amsterdam, the Netherlands, no conflict of interest; Jan van der Meer, Academic Medical Center University of Amsterdam, Amsterdam, the Netherlands, no conflict of interest; Stefano Vella, Istituto Superiore di Sanita, Rome, Italy, no conflict of interest; Martin Vogel Group leader “Case definition and diagnosis”, Bonn University Hospital, Bonn, Germany, travel grants and speaker honoraria Roche and Essex pharmaceuticals; Stéphane de Wit, St. Pierre University Hospital, Brussels, Belgium, no conflict of interest.
The following NEAT AHC panelists were not able to participate at the conference and vote on the statements/recommendations. They were still involved in drafting statements/recommendations and reviewed and commented the final version of the manuscript:
Brigitte Autran, Hôpital Pitié-Salpêtrière, Paris, France, no conflict of interest; Bonaventura Clotet, Hospital Germans Trias i Pujol, Badalona, Spain, no conflict of interest; Mark Danta, UNSW St Vincent's Clinical School, Sidney, Australia, no conflict of interest; Maxime Journiac (EATG), EATG Brussels, Belgium, no conflict of interest; Gail Matthews, UNSW National Centre in HIV Epidemiology and Clinical Research, Sidney, Australia, no conflict of interest; Dirk Meyer-Olson, Medizinische Hochschule Hannover, Hannover, Germany, no conflict of interest; Mark Nelson Co-chair, Chelsea and Westminster Hospital, London, United Kingdom, no conflict of interest; Reinhold Schmidt, Medizinische Hochschule Hannover, Hannover, Germany, no conflict of interest; Heiner Wedemeyer (EASL), Medizinische Hochschule Hannover, Hannover, Germany, grant support for research, fees for lectures and consultancy: Roche, Merck, Transgene, Gilead, BMS, Novartis.
1. van de Laar TJ, Matthews GV, Prins M, Danta M. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 2010; 24:1799–1812.
2. The periodic health examination. Canadian Task Force on the Periodic Health Examination. Can Med Assoc J 1979, 121:1193–1254.
3. Matthews GV, Hellard M, Haber P, Yeung B, Marks P, Baker D, et al. Characteristics and treatment outcomes among HIV-infected individuals in the Australian Trial in Acute Hepatitis C. Clin Infect Dis 2009; 48:650–658.
4. Vogel M, Deterding K, Wiegand J, Gruner NH, Baumgarten A, Jung MC, et al. Initial presentation of acute hepatitis C virus (HCV) infection among HIV-negative and HIV-positive individuals-experience from 2 large German networks on the study of acute HCV infection. Clin Infect Dis 2009; 49:317–319, author reply 319.
5. Sagnelli E, Coppola N, Marrocco C, Coviello G, Battaglia M, Messina V, et al. Diagnosis of hepatitis C virus related acute hepatitis by serial determination of IgM anti-HCV titres. J Hepatol 2005; 42:646–651.
6. Coppola N, Pisapia R, Marrocco C, Martini S, Vatiero LM, Messina V, et al. Anti-HCV IgG avidity index in acute hepatitis C. J Clin Virol 2007; 40:110–115.
7. Coppola N, Pisapia R, Tonziello G, Masiello A, Martini S, Pisaturo M, et al. Improvement in the aetiological diagnosis of acute hepatitis C: a diagnostic protocol based on the anti-HCV-IgM titre and IgG Avidity Index. J Clin Virol 2009; 46:222–229.
8. Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D, McClure MO. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23:89–93.
9. Cicconi P, Cozzi-Lepri A, Phillips A, Puoti M, Antonucci G, Manconi PE, et al. Is the increased risk of liver enzyme elevation in patients co-infected with HIV and hepatitis virus greater in those taking antiretroviral therapy? AIDS 2007; 21:599–606.
10. Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol 1999; 31(Suppl 1):9–16.
11. McGovern BH, Birch CE, Bowen MJ, Reyor LL, Nagami EH, Chung RT, Kim AY. Improving the diagnosis of acute hepatitis C virus infection with expanded viral load criteria. Clin Infect Dis 2009; 49:1051–1060.
12. Nastouli E, Thomson EC, Karayiannis P, Main J, McClure M, Muir D. Diagnosing acute hepatitis C in HIV-infected patients: nucleic acid testing compared with antibody and antigen-antibody detecting methods. J Clin Virol 2009; 44:78–80.
13. Mederacke I, Wedemeyer H, Ciesek S, Steinmann E, Raupach R, Wursthorn K, et al. Performance and clinical utility of a novel fully automated quantitative HCV-core antigen assay. J Clin Virol 2009; 46:210–215.
14. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004; 18:2277–2284.
15. Balogun MA, Ramsay ME, Hesketh LM, Andrews N, Osborne KP, Gay NJ, Morgan-Capner P. The prevalence of hepatitis C in England and Wales. J Infect 2002; 45:219–226.
16. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 2005; 192:992–1002.
17. Larsen C, Pialoux G, Salmon D, Antona D, Le Strat Y, Piroth L, et al. Prevalence of hepatitis C and hepatitis B infection in the HIV-infected population of France, 2004. Euro Surveill 2008, 13.
18. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis 2002; 34:831–837.
19. Tedaldi EM, Hullsiek KH, Malvestutto CD, Arduino RC, Fisher EJ, Gaglio PJ, et al. Prevalence and characteristics of hepatitis C virus coinfection in a human immunodeficiency virus clinical trials group: the Terry Beirn Community Programs for Clinical Research on AIDS. Clin Infect Dis 2003; 36:1313–1317.
20. Anderson KB, Guest JL, Rimland D. Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA Cohort Study. Clin Infect Dis 2004; 39:1507–1513.
21. Strasfeld L, Lo Y, Netski D, Thomas DL, Klein RS. The association of hepatitis C prevalence, activity, and genotype with HIV infection in a cohort of New York City drug users. J Acquir Immune Defic Syndr 2003; 33:356–364.
22. Rauch A, Rickenbach M, Weber R, Hirschel B, Tarr PE, Bucher HC, et al. Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study. Clin Infect Dis 2005; 41:395–402.
23. Jin F, Prestage GP, Matthews G, Zablotska I, Rawstorne P, Kippax SC, et al. Prevalence, incidence and risk factors for hepatitis C in homosexual men: data from two cohorts of HIV-negative and HIV-positive men in Sydney, Australia. Sex Transm Infect 2010; 86:25–28.
24. Urbanus AT, van de Laar TJ, Stolte IG, Schinkel J, Heijman T, Coutinho RA, Prins M. Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. AIDS 2009; 23:F1–F7.
25. Frederick T, Burian P, Terrault N, Cohen M, Augenbraun M, Young M, et al. Factors associated with prevalent hepatitis C infection among HIV-infected women with no reported history of injection drug use: the Women's Interagency HIV Study (WIHS). AIDS Patient Care STDS 2009; 23:915–923.
26. Alary M, Joly JR, Vincelette J, Lavoie R, Turmel B, Remis RS. Lack of evidence of sexual transmission of hepatitis C virus in a prospective cohort study of men who have sex with men. Am J Public Health 2005; 95:502–505.
27. Marincovich B, Castilla J, del Romero J, Garcia S, Hernando V, Raposo M, Rodriguez C. Absence of hepatitis C virus transmission in a prospective cohort of heterosexual serodiscordant couples. Sex Transm Infect 2003; 79:160–162.
28. Vandelli C, Renzo F, Romano L, Tisminetzky S, De Palma M, Stroffolini T, et al. Lack of evidence of sexual transmission of hepatitis C among monogamous couples: results of a 10-year prospective follow-up study. Am J Gastroenterol 2004; 99:855–859.
29. van de Laar TJ, van der Bij AK, Prins M, Bruisten SM, Brinkman K, Ruys TA, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. J Infect Dis 2007; 196:230–238.
30. Ghosn J, Deveau C, Goujard C, Garrigue I, Saichi N, Galimand J, et al. Increase in hepatitis C virus incidence in HIV-1-infected patients followed up since primary infection. Sex Transm Infect 2006; 82:458–460.
31. Giraudon I, Ruf M, Maguire H, Charlett A, Ncube F, Turner J, et al. Increase in diagnosed newly acquired hepatitis C in HIV-positive men who have sex with men across London and Brighton, 2002–2006: is this an outbreak? Sex Transm Infect 2008; 84:111–115.
32. Ruf M, Cohuet S, Maguire H, Brant LJ, Ramsay M, Lattimore S, Delpech V. Setting up an enhanced surveillance of newly acquired hepatitis C infection in men who have sex with men: a pilot in London and South East region of England. Euro Surveill 2008; 13.
33. Bodsworth NJ, Cunningham P, Kaldor J, Donovan B. Hepatitis C virus infection in a large cohort of homosexually active men: independent associations with HIV-1 infection and injecting drug use but not sexual behaviour. Genitourin Med 1996; 72:118–122.
34. Buchbinder SP, Katz MH, Hessol NA, Liu J, O'Malley PM, Alter MJ. Hepatitis C virus infection in sexually active homosexual men. J Infect 1994; 29:263–269.
35. Ndimbie OK, Kingsley LA, Nedjar S, Rinaldo CR. Hepatitis C virus infection in a male homosexual cohort: risk factor analysis. Genitourin Med 1996; 72:213–216.
36. Schmidt A, Vogel M, Krznaric I, Rockstroh J, Radun D, Study Group on Sexual Risk Factors for Hepatitis C. The trouble with bleeding: why do HIV-positive gay men get hepatitis C? [abstract BPD 1/7] In: 12th European AIDS Conference; 11–14 November 2009; Cologne, Germany.
37. Danta M, Brown D, Bhagani S, Pybus OG, Sabin CA, Nelson M, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS 2007; 21:983–991.
38. Briat A, Dulioust E, Galimand J, Fontaine H, Chaix ML, Letur-Konirsch H, et al. Hepatitis C virus in the semen of men coinfected with HIV-1: prevalence and origin. AIDS 2005; 19:1827–1835.
39. Turner J, Aarons E, O'Farrell S, Price H, Ferns B, Copas A, Gilson R. Hepatitis C viral load in semen of HIV-positive men during acute and chronic hepatitis C infection [abstract O5]. In: Second Joint BHIVA /BASHH Conference; 20–23 April 2010; Manchester, UK.
40. van de Laar T, Pybus O, Bruisten S, Brown D, Nelson M, Bhagani S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009; 136:1609–1617.
41. Scott C, Day S, Low E, Sullivan A, Atkins M, Asboe D. Unselected hepatitis C screening of men who have sex with men attending sexual health clinics. J Infect 2010; 60:351–353.
42. Fox J, Nastouli E, Thomson E, Muir D, McClure M, Weber J, Fidler S. Increasing incidence of acute hepatitis C in individuals diagnosed with primary HIV in the United Kingdom. AIDS 2008; 22:666–668.
43. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461:798–801.
44. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138:1338–1345, 1345 e1–e7.
45. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461:399–401.
46. Post J, Ratnarajah S, Lloyd AR. Immunological determinants of the outcomes from primary hepatitis C infection. Cell Mol Life Sci 2009; 66:733–756.
47. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005; 436:946–952.
48. Schnuriger A, Dominguez S, Guiguet M, Harfouch S, Samri A, Ouazene Z, et al. Acute hepatitis C in HIV-infected patients: rare spontaneous clearance correlates with weak memory CD4 T-cell responses to hepatitis C virus. AIDS 2009; 23:2079–2089.
49. Danta M, Semmo N, Fabris P, Brown D, Pybus OG, Sabin CA, et al. Impact of HIV on host-virus interactions during early hepatitis C virus infection. J Infect Dis 2008; 197:1558–1566.
50. Valdez H, Anthony D, Farukhi F, Patki A, Salkowitz J, Heeger P, et al. Immune responses to hepatitis C and nonhepatitis C antigens in hepatitis C virus infected and HIV-1 coinfected patients. AIDS 2000; 14:2239–2246.
51. Aberle JH, Formann E, Steindl-Munda P, Weseslindtner L, Gurguta C, Perstinger G, et al. Prospective study of viral clearance and CD4(+) T-cell response in acute hepatitis C primary infection and reinfection. J Clin Virol 2006; 36:24–31.
52. Chen M, Sallberg M, Sonnerborg A, Weiland O, Mattsson L, Jin L, et al. Limited humoral immunity in hepatitis C virus infection. Gastroenterology 1999; 116:135–143.
53. Shimizu YK, Hijikata M, Iwamoto A, Alter HJ, Purcell RH, Yoshikura H. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses. J Virol 1994; 68:1494–1500.
54. Farci P, Shimoda A, Coiana A, Diaz G, Peddis G, Melpolder JC, et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000; 288:339–344.
55. Post JJ, Pan Y, Freeman AJ, Harvey CE, White PA, Palladinetti P, et al. Clearance of hepatitis C viremia associated with cellular immunity in the absence of seroconversion in the hepatitis C incidence and transmission in prisons study cohort. J Infect Dis 2004; 189:1846–1855.
56. Chapel HM, Christie JM, Peach V, Chapman RW. Five-year follow-up of patients with primary antibody deficiencies following an outbreak of acute hepatitis C. Clin Immunol 2001; 99:320–324.
57. Dowd KA, Netski DM, Wang XH, Cox AL, Ray SC. Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus. Gastroenterology 2009; 136:2377–2386.
58. Osburn WO, Fisher BE, Dowd KA, Urban G, Liu L, Ray SC, et al. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology 2010; 138:315–324.
59. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000; 284:450–456.
60. Soriano V, Mocroft A, Rockstroh J, Ledergerber B, Knysz B, Chaplinskas S, et al. Spontaneous viral clearance, viral load, and genotype distribution of hepatitis C virus (HCV) in HIV-infected patients with anti-HCV antibodies in Europe. J Infect Dis 2008; 198:1337–1344.
61. Gambotti L, Batisse D, Colin-de-Verdiere N, Delaroque-Astagneau E, Desenclos JC, Dominguez S, et al. Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001–2004. Euro Surveill 2005; 10:115–117.
62. Gilleece YC, Browne RE, Asboe D, Atkins M, Mandalia S, Bower M, et al. Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin. J Acquir Immune Defic Syndr 2005; 40:41–46.
63. Serpaggi J, Chaix ML, Batisse D, Dupont C, Vallet-Pichard A, Fontaine H, et al. Sexually transmitted acute infection with a clustered genotype 4 hepatitis C virus in HIV-1-infected men and inefficacy of early antiviral therapy. AIDS 2006; 20:233–240.
64. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003; 125:80–88.
65. Mosley JW, Operskalski EA, Tobler LH, Buskell ZJ, Andrews WW, Phelps B, et al. The course of hepatitis C viraemia in transfusion recipients prior to availability of antiviral therapy. J Viral Hepat 2008; 15:120–128.
66. Vogel M, Page E, Matthews G, Guiguet M, Dominguez S, Dore G, et al. Use of week 4 HCV RNA after acute HCV infection to predict chronic hcv infection [abstract 640]. In: 17th Conference on Retroviruses and Opportunistic Infections; 16–19 February 2010; San Francisco, California, USA.
67. Nomura H, Sou S, Tanimoto H, Nagahama T, Kimura Y, Hayashi J, et al. Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial. Hepatology 2004; 39:1213–1219.
68. Deterding K, Grüner N, Wiegand J, Buggisch P, Galle P, Spengler U, et al. Early versus delayed treatment of acute hepatitis C: the German HEP-NET Acute HCV-III Study – a randomized controlled trial [abstract 1047]. In: 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009); 22–26 April 2009; Copenhagen, Denmark.
69. Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 345:1452–1457.
70. Wiegand J, Buggisch P, Boecher W, Zeuzem S, Gelbmann CM, Berg T, et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET Acute-HCV-II Study. Hepatology 2006; 43:250–256.
71. Vogel M, Nattermann J, Baumgarten A, Klausen G, Bieniek B, Schewe K, et al. Pegylated interferon-alpha for the treatment of sexually transmitted acute hepatitis C in HIV-infected individuals. Antivir Ther 2006; 11:1097–1101.
72. Fierer D, Fishman S, Uriel A, Carriero D, Factor S, Mullen M, et al. Characterization of an outbreak of acute HCV infection in HIV-infected men in New York city [abstract 802]. In: 16th Conference on Retroviruses and Opportunistic Infections; 8–11 February 2009; Montreal, Canada.
73. Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS 2006; 20:1157–1161.
74. Kruk A. Efficacy of acute HCV treatment with peg-interferon a-2b and ribavirin in HIV infected patients [abstract TuPe1.1C01]. In: 3rd IAS Conference on HIV Pathogenesis and Treatment; 24–27 July 2005; Rio De Janeiro, Brazil.
75. Luetkemeyer A, Hare CB, Stansell J, Tien PC, Charlesbois E, Lum P, et al. Clinical presentation and course of acute hepatitis C infection in HIV-infected patients. J Acquir Immune Defic Syndr 2006; 41:31–36.
76. Vogel M, Bieniek B, Jessen H, Schewe CK, Hoffmann C, Baumgarten A, et al. Treatment of acute hepatitis C infection in HIV-infected patients: a retrospective analysis of eleven cases. J Viral Hepat 2005; 12:207–211.
77. Arends JE, Mudrikova T, Wensing MJ, Wind CM, van Baarle D, Hoepelman IM. High percentage of non-response with peginterferon-alfa-2a monotherapy for the treatment of acute hepatitis C in HIV infected patients [abstract H-222]. In: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12–15 September 2009; San Francisco, California, USA.
78. Matthews G, Grebely J, Hellard M, Yeung B, Marks P, Rawlinson W, et al. Differences in early virological decline in individuals treated within the Australian trial in acute HCV suggest a potential benefit for the use of ribavirin [abstract O60]. In: 45th Annual Meeting of the European Association for the Study of the Liver (EASL); 30 March–3 April 2010; Vienna, Austria.
79. Hare B, Marks K, Luetkemeyer A, Charlebois E, Glesby M, Talal A, et al. Kinetically guided PEG alfa-2a and RBV therapy for HIV+ adults with acute HCV infection [abstract 639]. In: 17th Conference on Retroviruses and Opportunistic Infections; 16–19 February 2010; San Francisco, California, USA.
80. Lambers F, van den Berk G, van der Meer J, Spijkerman I, Molenkamp R, Coutinho R, et al. Treatment outcome of acute HCV infection in HIV-infected MSM: effect of treatment length [abstract 641]. In: 17th Conference on Retroviruses and Opportunistic Infections; 16–19 February 2010; San Francisco, California, USA.
81. Calleri G, Cariti G, Gaiottino F, De Rosa FG, Bargiacchi O, Audagnotto S, et al. A short course of pegylated interferon-alpha in acute HCV hepatitis. J Viral Hepat 2007; 14:116–121.
82. Vogel M, Dominguez S, Bhagani S, Azwa A, Page E, Guiguet M, et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort. Antivir Ther 2010; 15:267–279.
83. Rockstroh J, Benhamou Y, Bhagani S, Bruno R, Garcia D, Mauss S, et al. European AIDS Clinical Society (EACS) Guidelines for the clinical management and treatment of chronic hepatitis B and C co-infection in HIV-infected adults: 2009
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International Journal of Std & AIDSSpontaneous clearance and treatment of acute hepatitis C infection in HIV-positive men with 48 weeks of interferon-alpha and ribavirinInternational Journal of Std & AIDS
acute hepatitis; hepatitis C; HIV; interferon; intravenous drug abuse; MSM; ribavirin
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