Treatment of acute hepatitis C in HIV-positive individuals: what are the challenges?
Hepatitis C (Risk factors)
Hepatitis C (Diagnosis)
Hepatitis C (Drug therapy)
Hepatitis C (Research)
Antiviral agents (Health aspects)
Rockstroh, Jurgen K.
|Publication:||Name: Journal of HIV Therapy Publisher: Mediscript Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Mediscript Ltd. ISSN: 1462-0308|
|Issue:||Date: March, 2009 Source Volume: 14 Source Issue: 1|
|Topic:||Event Code: 310 Science & research|
|Product:||SIC Code: 2834 Pharmaceutical preparations|
|Geographic:||Geographic Scope: Germany Geographic Code: 4EUGE Germany|
Since the original report of an increased incidence of acute hepatitis C virus (HCV) infections among HIV-positive men who have sex with men (MSM) in London at the beginning of 2000 , several groups have observed similar epidemics [2-13]. Worldwide, 700 cases have been reported to date (Figure 1). The epidemic appears to be ongoing [14,15]. The outbreaks have mainly been confined to large cities such as London, Berlin and Paris, and the impact is visible within existing large HIV-cohorts such as the Amsterdam, French PRIMO and Swiss HIV cohort [9,10,16], all of which noted an increase in sexually transmitted acute HCV infections after the year 2000.
Unfortunately spontaneous clearance of HCV, especially in the HIV-positive population, is infrequent and given the risk of progression to liver disease once chronic HCV infection is established the question arises: should acute infection be treated and, if so, what is the optimal management strategy? In the following review we describe important characteristics of the recent epidemic and discuss current data on the treatment of acute HCV infection in HIV-positive individuals.
SEXUAL TRANSMISSION OF HCV
The present epidemic is mainly characterised by sexually transmitted HCV infections and the majority of patients presenting to infectious disease clinics are HIV-positive. Sexual transmission of HCV has been reported previously; however, amongst heterosexual couples, it is regarded as an uncommon event [17,18]. Current studies on the epidemic of acute HCV among HIV-positive MSM have identified possible explanations for the increased rate of sexual transmission seen in this cohort [19-21]. First, high rates of concomitant sexually transmitted infections (STIs) were noted. Syphilis and lymphogranuloma venereum, both of which result in disturbance of mucosal integrity, were described most commonly. Secondly, high rates of frequent high-risk sexual behaviour, which is associated with an enhanced risk for mucosal damage, were observed [19,21]. For instance within the German cohort, frequent rectal bleeding after sexual intercourse was significantly more often reported among cases compared to controls. These observations reinforce the hypothesis that most of the sexual transmissions seen are indeed based on blood-to-blood transmissions (Figure 2).
[FIGURE 1 OMITTED]
DIAGNOSIS OF ACUTE HCV INFECTION
HCV infection is considered acute if the time between the suspected date of transmission and diagnosis is <6 months, whereas a chronic infection is established if the infection has been ongoing for 6 months or longer. The diagnosis of acute HCV infection is often hampered by the fact that acute HCV is usually asymptomatic with an acute rise in alanine transaminase (ALT), which goes unnoticed unless regular liver function tests are being performed. Therefore the majority of clinicians are initially faced with a positive anti-HCV test or HCV-RNA, carried out either for routine screening or due to a raised ALT, and are often unable to determine when exposure to HCV occurred and therefore whether HCV infection is acute or chronic. More importantly, relying on anti-HCV antibody testing alone may overlook a recent HCV infection as antibody response may be delayed in HIV-infected patients. Indeed, in a recent analysis of a UK cohort, 5% of individuals were still anti-HCV negative despite documented positive HCV-RNA for over 1 year. In order to differentiate between acute and chronic infection several propositions have been made. One definition adopted from Jaeckel et al.  proposes the use of ALT as a surrogate marker and deems the infection acute if there is a raised ALT >350 U/l compared with previously normal transaminases from the year before in conjunction with either a seroconversion of anti-HCV antibody or a history of relevant transmission risk, both within the past 4 months . Other groups have relied on retrospective testing of stored plasma samples  or a more generous timeframe for a past negative anti-HCV test .
In the routine clinical setting, a careful transmission risk history that tries to elucidate the probable time of transmission in conjunction with a review of the patient's liver transaminases within the past year is probably the best way to assess the time of infection. Of note, a rise in liver transaminase levels proved to be more sensitive in the detection of acute HCV infection than repeated testing of anti-HCV . Of 43 patients with acute HCV infection, 76% of patients showed an abnormal ALT >40 U/l at the time of first positive HCV-RNA and 88% of patients had a raised ALT either at the time of first positive HCV-RNA or 3 months later. On the other hand, a positive anti-HCV antibody test was found in only 25% of patients at the time of first positive HCV-RNA and in 63% of patients 3 months thereafter.
NATURAL COURSE OF ACUTE HCV
The recent outbreaks of acute HCV infections have enabled a more detailed description of the natural course of acute hepatitis C infection in HIV-infected individuals. Spontaneous resolution of infection, that is a negative HCV-RNA 24 weeks after the diagnosis, has been observed in 0-9 40% of untreated patients [2,23,24,26,27], which is much reduced compared to HCV-monoinfected individuals, where rates of between 20 and 50% are reported. Whereas earlier studies on acute HCV infection in HIV-positive individuals have reported clearance rates of 25% of untreated patients [23,26], newer studies on the diagnostics and natural course have reported lower rates of spontaneous clearance of between 13 and 16% of patients [3,25]. The differences in the rate of clearance observed may in part be explained by the fact that earlier trials focused on the treatment of acute HCV infection. This may have introduced a selection bias, leaving patients with good odds of spontaneous clearance untreated or per protocol inclusion criteria enrolling only patients with a good chance of spontaneous clearance.
Current data suggests that acute HCV infection most likely resolves within the first 12 weeks. For example, within the Chelsea and Westminster cohort all untreated patients who were HCV-RNA-negative 12 weeks after diagnosis remained negative thereafter; whereas all other patients who were still HCV-RNA-positive 12 weeks after the diagnosis remained positive during further follow-up. However, the time point of 12 weeks may not be so clear-cut. Within a pooled analysis of untreated patients within UK, German and French cohorts  a negative HCV-RNA 12 weeks after diagnosis was observed in 14/39 of the untreated patients (36%). However, during further follow-up, three patients who had been HCV-RNA-negative at week 12 were positive at week 24; and vice versa, four patients who had been HCV-RNA-positive at week 12 turned negative at week 24, so overall 15/39 patients had cleared the infection at week 24 (38%). During further follow-up between weeks 24 and 48, five additional patients who had been negative at week 24 turned positive and one more patient who had been positive turned negative with a total of 11/39 patients (28%) who had cleared HCV infection at week 48.
These observations of three different outcomes after acute infection: spontaneous sustained viral clearance; transient viral clearance followed by chronic infection; and chronic infection that persists  can be explained by differing immune responses to HCV infection. Initial clearance of HCV is associated with a strong and sustained HCV-specific CD4 T-cell response [30,31]. Loss of the virus-specific CD4 T cell response in patients who initially control the infection is immediately followed by recurrence of serum HCV-RNA . In those individuals that progress to chronic HCV, CD4 T cell responses are weak and short lived. Unfortunately these observations are further complicated by the fact that some of the viral breakthroughs observed are probably due to new infections rather than viral relapse as was demonstrated in a recent analysis of the Royal Free and Chelsea and Westminster cohorts in London .
TREATMENT OF ACUTE HEPATITIS C INFECTION
WHEN TO START THERAPY
Ideally only individuals who will not go on to spontaneously clear HCV should receive treatment. However, current data suggest that delaying the start of treatment for too long may eradicate the benefit of early treatment (increased rates of sustained virological response [SVR]) and treatment outcomes become similar to response rates observed in the setting of chronic HCV infection. For instance, a Japanese study found that delaying treatment for 1 year compared to 8 weeks after acute HCV infection in HIV-negative individuals reduced SVR rates from 86 to 40% . Kamal et al. investigated whether starting treatment at 8, 12 or 20 weeks after the diagnosis of acute HCV infection changed treatment outcome in HCV-monoinfected patients . Whereas a delay of therapy had no or little impact on the treatment outcome in HCV genotype 2 and 3 infection, patients with difficult-to-treat HCV genotype 1 infections with high levels of HCV-RNA showed a substantial loss of treatment response if treatment was started at week 20 compared to week 8 (42 vs. 75%, P=0.01). In the light of the present data the updated recommendations from the European AIDS Clinical Society (EACS) published in 2008 therefore recommend early therapeutic intervention in acute hepatitis C infection for HIV-positive individuals. Waiting for 12 weeks from the estimated date of exposure is recommended to allow spontaneous clearance. However, any further delay to treatment is discouraged in order to prevent reduced treatment response.
In case of uncertain time-point of infection, experts currently recommend waiting for 4 weeks after diagnosis of acute HCV infection. If the HCV-RNA level has dropped by more than 2 [log.sub.10] within these 4 weeks, a further watch-and-wait strategy is reasonable. However if a 2 [log.sub.10] drop has not occurred within this time or HCV-RNA levels have risen, commencement of treatment is recommended. For those who have shown a significant decrease in HCV-RNA at week 4, further HCV-RNA tests are recommended at weeks 8 and 12 (Figure 3). If, at week 12, HCV-RNA is still positive, treatment is recommended.
HOW TO TREAT
Most data available on the treatment of acute HCV infection in HIV co-infected individuals show SVR rates of 60-70% in individuals who have treatment initiated within 24 weeks of diagnosis and are treated with combined pegylated interferon and ribavirin [3,23,24,26]. However, due to the non-comparative designs of the studies, there are unanswered questions.
Is ribavirin necessary in the treatment of acute HCV infection? Studies in HCV monoinfected patients showed that the use of ribavirin in the setting of acute HCV infection is not necessary considering the very high rates of SVR reached with non-pegylated or pegylated interferon monotherapy [22,33,35-40]. This may differ in HIV-Figure infected patients as viral breakthrough or non-response has been observed in individuals undergoing pegylated interferon monotherapy [13,41]. On the other hand, in the analysis of the German cohort there was no evidence for an inferior treatment response in patients treated with pegylated interferon alone .
[FIGURE 3 OMITTED]
What duration of therapy is necessary to achieve SVR in the majority of individuals? In HCV monoinfected patients most trials have used a treatment course of 24 weeks and have achieved high rates of response in up to 98% of patients . Given these high rates of response, the question arises whether shorter treatment courses may offer a similar efficacy. A recent study in HCV monoinfected patients compared treatment durations of 8, 12 and 24 weeks using pegylated interferon [alpha]-2b (1.5 [micro]g/kg/week) monotherapy . Overall SVR rates were 67.6, 82.4 and 91.2%, respectively. Stratification by genotype led to relatively small subsets (13-16 per arm for genotypes 1 and 4, 2-3 per arm for genotypes 2 and 3), but gave interesting results. Patients with genotype 2 or 3 achieved an SVR of 100% irrespective of duration of therapy, suggesting that as few as 8 weeks would be sufficient in these patients. However, individuals with genotype 1 achieved an SVR of 38, 60 and 88% with 8, 12, and 24 weeks of therapy, respectively (P<0.05 for comparison between all groups), and in those with genotype 4, 12 and 24 weeks of therapy achieved significantly higher SVR rates than 8 weeks. However in HIV co-infected patients reduced SVR rates of 60-70% are reached after a 24-week treatment course. Would a longer duration of therapy improve treatment response? Within an analysis of the German cohort, patients who were treated for 48 weeks achieved higher SVR rates compared with those treated for 24 weeks only . The data is limited in terms of evidence because of the observational nature of the data and small patient groups; however, it stresses the necessity to study different treatment approaches within a randomised controlled trial. Only one pilot trial has investigated the possibility of a shorter treatment duration in HIV co-infected individuals  and in this study 12 weeks of pegylated interferon monotherapy was tested. However, although the infection resolved following treatment in three of four patients, two patients carried genotype 2 infections and the whole group was too small to generalise these results.
[FIGURE 4 OMITTED]
In an attempt to answer the above questions the steering committee of the European AIDS treatment network (NEAT) has decided to initiate a clinical study investigating the optimal treatment of acute HCV infection in HIV-positive individuals, the NEAT-002 study (Figure 4). Participants will be randomised to receive either combination pegylated interferon and ribavirin or pegylated interferon monotherapy for a duration of either 24 or 48 weeks. This trial is expected to start enrolling patients throughout Europe in the last quarter of 2009.
The higher SVR rates seen when treating acute HCV infection compared with chronic HCV infection offers physicians an exciting treatment alternative to this challenging virus. However, large randomised controlled trials on the best management strategy are lacking for HIV-positive patients. Until these are available, treatment approaches need to be based on best available evidence and thus follow the recommendations from the HCV-HIV International Panel. The upcoming NEAT 002 study offers a great opportunity to shed further light on this issue.
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MARTIN VOGEL *, EMMA PAGE ([dagger]), MARKNELSON ([dagger]), JURGEN K ROCKSTROH *
* University of Bonn, Germany
([dagger]) Chelsea and Westminster Hospital, London, UK
Correspondence to: Prof. Dr. med. Jurgen Rockstroh, Immunologische Ambulanz, Medizinische Klinik und Poliklinik I, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Email: firstname.lastname@example.org
Figure 2: Risk factors for the acquisition of acute HCV infection in HIV-positive men who have sex with men. Presented are odds ratios with a two-sided P-value < 0.05 in the bivariate (light grey) and multivariate (dark grey) analysis comparing patients with acquired acute HCV infection with HIV-positive controls. Multivariate Bivariate Nasally administered drugs (cocaine, 'speed' etc) 13.2 10.5 History of repeated major surgery last 5 years 9.1 Frequent group sex 7.7 At least 5 episodes of UAI within the 7.5 preceding year Frequent rectal bleeding from sexual intercourse 7.7 7.1 Frequent 'fisting' 5.9 Frequent use of sildenafil etc 4.1 Note: Table made from bar graph.
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