Acute hepatitis C

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Acute hepatitis C Anurag Maheshwari, Stuart Ray, Paul J Thuluvath

Symptomatic acute hepatitis C occurs in only about 15% of patients who are infected with hepatitis C virus (HCV). Acute hepatitis C is most often diagnosed in the setting of post-exposure surveillance, or seroconversion in high-risk individuals (eg, health-care professionals or injecting drug users) previously known to be seronegative. Although transmission via transfusion and injecting drug use has declined in developed countries, unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries. Clinically, acute hepatitis C can increase concentrations of alanine aminotransferase to ten times the upper limit of normal but almost never causes fulminant hepatic failure. Diagnosis of HCV infection in the acute phase is difficult since production of antibodies against HCV can be delayed by up to 12 weeks, and about a third of infected individuals might not have detectable antibody at the onset of symptoms. Therefore, testing for HCV RNA by PCR is the only reliable test for the diagnosis of acute infection. Symptomatic patients with jaundice have a higher likelihood of spontaneous viral clearance than do asymptomatic patients, and thus should be monitored for at least 12 weeks before initiating antiviral therapy. By contrast, asymptomatic patients have a much lower chance of spontaneous clearance, and might benefit from early antiviral therapy. Antiviral therapy for 12 weeks is generally effective in treating patients who are HCV RNA negative after 4 weeks of treatment; lengthier courses could be needed for those who relapse or fail to show early virological clearance.

Introduction Infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma around the world. HCV is a small (50 nm), single-stranded RNA virus that belongs to the Flaviviridae family. HCV is transmitted mainly by parenteral routes such as blood transfusion, injecting drug use, contaminated medical equipments, tattoos, and rarely sexually or perinatally. HCV entry into hepatocytes is assumed to be a multistep process that requires sequential interactions between cellular factors and viral proteins. Replication depends on viral and host proteins, and occurs in association with intracellular membranes. The rate of HCV replication in an infected person is very high: up to a trillion particles are produced each day. Despite major advances in our understanding of hepatitis C biology, the distinct mechanisms of the HCV life cycle have not been fully elucidated. Clearance of the virus—either spontaneously or by treatment—is thought to represent a cure, and leads to normalisation of liver enzymes and possibly slow regression of early fibrosis. Treatment is an important consideration, because spontaneous clearance is seen in only a third of infected individuals. WHO estimates that about 170 million (3% of world population) people are infected with HCV, with the highest prevalence reported from Egypt and the lowest from Sweden (table 1).1–10 An estimated 2·7–3·4 million people are infected with HCV in the USA alone.11,12 Acute infection with HCV leads to symptomatic hepatitis in only a minority of patients, and only 15% of all symptomatic cases of acute liver disease in the USA are thought to be due to acute hepatitis C.13 Studies suggest that spontaneous clearance of virus is higher in symptomatic than in asymptomatic acute HCV infection; pooled data from various studies suggest that higher sustained viral clearance rates could be achieved www.thelancet.com Vol 372 July 26, 2008

Lancet 2008; 372: 321–32 Division of Gastroenterology and Hepatology (A Maheshwari MD, P J Thuluvath FRCP) and Division of Infectious Diseases (S Ray MD), Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence to: Dr Paul J Thuluvath, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 1830 E Monument Street, Suite 430, Baltimore, MD 21205, USA [email protected]

with short courses of antiviral treatment in the early stages of chronic infection. Here, we examine the recent developments in the epidemiology and management of acute HCV infection.

Epidemiology There is a paucity of data in most countries because of the subclinical presentation of acute hepatitis C. The estimated incidence of new cases of hepatitis C in the USA is about 38 000 per year, but only 6300 (17%) present with symptomatic acute hepatitis. These data were derived from the US Centers for Disease Control and Prevention (CDC) Sentinel Counties Study,14 using a mathematical derivation of incidence from prevalence data (catalytic model). Armstrong and colleagues13 used a catalytic model to estimate past incidence of hepatitis C infection in the USA, and concluded that the incidence of acute HCV infection rose from 0–44 cases per 100 000, before 1965, to its peak in the 1980s (100–200 per 100 000). Since the 1990s there has been a decline in the incidence of acute hepatitis C in the USA (figure 1) and western Europe. Those born between 1940 and 1965 had the highest risk for HCV infection, with incidence reaching a peak between the age of 20 to 35 years.13 The falling incidence of acute infections with HCV is attributed to improved blood donor screening, needle exchange programmes, and education among injecting drug users. As the incidence of HCV by transfusion and injecting drug use has fallen, other modes of transmission, including needle-stick injuries among health-care workers, sexual and perinatal transmission have gained importance. Comparative estimated rates of transmission of hepatitis B virus (HBV), HCV, and HIV by self-reported needle stick, perinatal, and sexual routes are shown in figure 2. A CDC report suggested that the risk of HCV transmission is about six times higher per needle-stick 321

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Prevalence Middle East and Australasia China1,2

3·0–3·2%

India1,3

0·9–1·8%

Indonesia1

2·1%

Saudi Arabia1,4

0·4–1·8%

Pakistan1,5

2·4–6·5%

Japan1,6

0·6–2·3%

Taiwan7

4·4%

Iran8

0·2%

Australia1

0·3%

New Zealand1

0·3%

Philippines1

3·6%

Thailand1,9

0·9–5·6%

North and South America 1·8%

USA1 Brazil1

1·1%

Mexico1

0·7%

Venezuela1

0·9%

Argentina1

0·6%

Chile1

0·9%

Canada1

0·5%

Europe UK1

0·02%

Spain1

0·7%

France1

1·1%

Germany1

0·1%

Italy1

0·5%

Russia1

2·0%

Sweden1

0·003%

Poland1

1·4%

Ukraine1

1·2%

Romania1

4·5%

Africa Egypt1,10

18·1–22·0%

Libya1

7·9%

Sudan1

3·2

Democratic Republic of the Congo1

6·4%

Zimbabwe1

7·7% 1·7%

South Africa1 Rwanda1

17·0%

Table 1: Prevalence of hepatitis C infection

exposure than is the risk of HIV infection (1·8% vs 0·3%).16 However, more recent studies from Japan and Italy have reported considerably lower rates of transmission by needle-stick exposure (0·2–0·4%).19,20 Deep injury, injury with a hollow-bore needle, and HIV co-infection of the source seem to be associated with greater risk of needle-stick transmission. Perinatal transmission is the major mode of acquisition of HCV infection in children. The prevalence of HCV infection in pregnant women is estimated to be 1% (range 0·1–2·4%),21 and the rate of mother-to-infant transmission is 4–7% per pregnancy in women with detectable viraemia. High viral loads 322

(>106 copies per mL) are associated with increased risk of vertical transmission, and co-infection with HIV increases the risk of transmission by about 15–22%, probably because of the higher viral load.22,23 Interestingly, transmission to female infants may be twice as frequent as transmission to male children, for unknown reasons.23 Taken together, these data indicate that the HCV epidemic in the USA is continuing and that there is more to learn about the mechanisms of transmission of the virus. The role of elective caesarean section for the prevention of vertical transmission is debatable and results have been conflicting in monoinfected patients.23,24 An elective caesarean section is recommended in women coinfected with HIV, since transmission rates in this cohort are higher than in those monoinfected with HCV; elective surgery in these patients has been shown to reduce transmission by up to 60%, and is cost effective.25,26 Sexual transmission of HCV can occur, although with much lower frequency than that of HIV or HBV. Long-term partners of HCV-infected patients have higher rates of HCV infection than the general population, although this could in part be due to sharing of sharp implements (eg, razors, toothbrushes, etc) or other modes of infection such as medical procedures or undisclosed injecting drug use.27,28 Some studies have reported very low intra-spousal transmission of HCV among monogamous couples29 and the CDC, on the basis of current evidence, does not recommend the use of barrier precautions among heterosexual monogamous couples to prevent HCV transmission. Other studies have shown increasing prevalence of HCV infection in populations with sexually transmitted diseases, HIV coinfection, and increasing number of sexual partners.30 Studies of men who have sex with men have suggested an increase in sexual transmission of HCV infection in cohorts with high-risk sexual practices. However, when adjusted for other confounding factors such as concomitant HIV infection or injecting drug use,31–35 no independent association of sexual transmission of HCV with high-risk sexual practice was seen. HIV infection, however, seems to facilitate the sexual transmission of HCV infection. In Europe, there have been reports of recent outbreaks of acute HCV infection in HIV-positive men who have sex with men, associated with traumatic sexual practices such as fisting, bleeding during sex, or concomitant infection with sexually transmitted diseases.36–39 The prevalence of HCV infection in the developing world varies widely both between countries (eg, China2 and India3; table 1) and within individual countries (eg, Pakistan1,5 and Thailand1,6). Consistently high prevalence rates (about 22%) have been reported from Egypt.10 There is a paucity of robust epidemiological data, however, from most developing countries. The highly variable prevalence rates among developing countries are in part a reflection of different modes of HCV transmission. Variations www.thelancet.com Vol 372 July 26, 2008

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140

New infections (100 000)

120 100 80 Decline in injecting drug users 60 40 Decline in transfusion recipients

20 0 1960

1965

1970

1975

1980

1985

1989

1992

1995

1998

2001

Year

Figure 1: Incidence of hepatitis C infection in the USA over time15

60 50 Risk of infection (%)

within individual countries could result from the heterogeneity of the studied population or methodological variations. Blood transfusions from unscreened donors and unsafe therapeutic procedures are the major modes of transmission in the developing world. The use of paid blood donors is a major source of HCV infection, much as it was in developed countries a few decades ago. Current data suggest that paid donors account for up to 63% of the blood supply in many developing nations.40 Obstacles to voluntary, unpaid blood donations include cultural beliefs,41 lack of regulatory oversight or enforcement,42 and lack of infrastructure.43 There are several countries that do not screen blood donors for HCV and, even in countries that do mandate screening, the procedures are often not done routinely because of financial constraints. A study from Pakistan revealed that only 23% of blood banks screened their blood supply for antibodies against HCV.44 A survey done in 2000 among blood bank directors from India showed that, although 95% of donors were screened for HIV, only 6% were screened for HCV.45 In sub-Saharan Africa, only South Africa and Zimbabwe consistently screen blood donors for HCV.46 These alarming data suggest that the silent epidemic of HCV will continue to remain a major health hazard in the developing world in the foreseeable future. The risk of HCV infection through unsafe medical practices is substantial and leads to a steady number of new infections in the developing world.47 WHO calculates that unsafe health-care devices account for 2·3 million new HCV infections per year and 200 000 HCV-related premature deaths,48 mostly in developing countries. The re-use of injection equipments and the unnecessary administration of medications via injectable routes are important causes of HCV transmission in these countries. WHO estimates that about 40% of injection-related equipment is reused in developing countries.49 Moreover, a recent review reported that 70% of injections in Tanzania, 85% of those in Russia, and 82% of those in Indonesia are unnecessary.47 Contaminated injection equipment has been identified as a major risk factor in areas of high prevalence such as Egypt10,50 and India,51 where multiple injection therapies were used for treatment of schistosomiasis and visceral leishmaniasis, respectively. However, transmission via this route is not restricted to the developing world: a US report of HCV transmission via contaminated radiopharmaceutical agent used for myocardial perfusion studies highlights the ease of viral transmission in the absence of adequate precautions.52 Cross-contamination of the radio-pharmaceutical agent led to infection of 16 patients with HCV; 15 of these patients developed symptomatic hepatitis, 11 developed jaundice, and one died from sepsis complicating acute liver failure. The source of contamination was traced to a single vial of

40

HCV HBeAg+ HBeAg– HIV

30

50% 40%

25%

25%

20

15% 16% 8%

10 1·8%

5%

12%

10%

5%

5% 1·2%

0·3%

3%

0 Needle-stick exposure

Perinatal/event Sexual: high risk/year Categories of exposure

Monogamous/year

Figure 2: Risk of viral transmission from various routes16–18

technetium99m Sestamibi prepared by a nuclear pharmacy 12 h after radiolabelling white blood cells from a patient who was co-infected with HIV and HCV. Although injecting drug use accounts for most newly diagnosed HCV infections in developed countries,53,54 its effect in developing countries is unclear because of a paucity of data. The effect of other modes of transmission (eg, cosmetic procedures, religious or cultural practices such as tattooing, body-piercing, acupuncture, or circumcision) have been studied, but the data have been controversial, and the contribution of these modes to the spread of HCV infection remains uncertain.50 In the absence of an effective vaccine, efforts should be focused on preventive strategies to reduce HCV transmission, including universal screening of blood and blood products, proper sterilisation of medical and dental equipment, mandatory use of disposable needles, avoidance of unnecessary injections or procedures, and needle-exchange programmes for injecting drug users. Additionally, health workers (especially in developing countries) and the public should be educated about the risk of infection from unsafe practices, and individuals at risk should be counselled and tested for HCV. Treatment of HCV, however, is unlikely to have a major effect on the epidemiology of HCV since most infected individuals in 323

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the world remain undiagnosed and have no access to expensive medications.

Immunobiology of acute hepatitis C Up to a third of patients with acute HCV infection can clear the virus spontaneously; rates of spontaneous clearance are higher among those with jaundice. A study of injecting drug users showed that the presence of HCV antibodies as a marker of past infection was strongly associated with clearance of infection on re-exposure.55 The immune responses that result in successful clearance, however, are not well defined. The interval from acute infection to seroconversion varies from 6 to 8 weeks in healthy patients,56,57 but can be longer in sicker patients infected via blood transfusion.58 However, there have also been case series of spontaneous clearance of viraemia without seroconversion,59 suggesting that some patients can clear HCV without developing antibodies against HCV; these data need further corroboration before one can speculate on their implications. Humoral immune responses seem to have little effect on viral clearance; no specific antibody responses have been found to predict the outcome of infection.60 Antibody responses during acute infection are restricted mainly to the IgG1 subclass, rarely neutralise HCV ex vivo before the establishment of chronicity, and are seen in low titres.58,61 One attempt to neutralise HCV ex vivo before inoculation of a chimpanzee showed both neutralisation of the identical strain of HCV and the propensity for HCV to escape such responses by virtue of extreme envelope gene diversity.62 Studies of acutely infected human beings have shown persistence of infection is associated with mutations in the same genomic region.63,64 Although these results do not suggest a critical role for humoral responses in the outcome of natural infection, they cannot directly address pre-existing (eg, vaccine-induced) antibody responses. Cellular immune responses seem to have an important role in determining the outcome of acute HCV infection. Studies in human beings and chimpanzees suggest that clearance of viraemia is associated with vigorous CD4+ and CD8+ cellular responses.65–68 The secretion of cytokines such as interleukin 2, interferon γ, and tumour necrosis factor α by CD4+ T lymphocytes activates antiviral mechanisms that could have a role in HCV clearance. Taken together,69 these data suggest that viral clearance occurs more frequently in patients with acute HCV infection whose peripheral blood mononuclear cells display a Th1 phenotypic profile (type-1 like T-helper profile associated with secretion of interleukin 2 and interferon γ), compared with those who express a Th2 phenotypic profile (type 2-like T-helper profile associated with secretion of interleukin 4 and interleukin 10). A vigorous HCV-specific CD4+ Th1 response, especially against the non-structural proteins of the virus, was associated with viral clearance and 324

protection from disease progression in some studies.70 CD8+ T cells might be involved in direct killing of infected cells, and might assist viral clearance by secretion of cytokines such as tumour necrosis factor α and interferon γ. These roles are supported by data from studies of chimpanzees, in which CD4+ or CD8+ T cells were depleted during acute infection.71,72 However, despite the detection of HCV-specific CD8+ responses in peripheral blood, HCV often persists, suggesting that the generation of cellular responses alone is insufficient to eliminate the virus.73 This situation could be particularly true when the CD8+ T-cell response is intense, but narrowly focused74 or not sustained.75 A related study76 showed that persistence was associated with high rates of mutation in targeted T-cell epitopes, suggesting a role for immune escape in persistence of infection that had been seen much earlier in chimpanzees.77 Analysis of a cohort of women infected with HCV from a single source found that the HLA-B27 allele occurred more frequently in those with spontaneous viral clearance than in those with chronic infection,78 and a more recent study described a potential mechanism for this effect.79 Although some studies of immune responses in patients undergoing antiviral therapy suggested that enhanced CD8+ T-cell activity, along with a Th1 cytokine profile, might be associated with a favourable outcome,80,81 other studies indicate that the magnitude and breadth of anti-HCV T-cell responses before therapy are not predictive of treatment outcome, and that successful viral suppression is associated with a decrease in these responses, perhaps because antigenic stimulation is removed.82–84 Natural killer (NK) and NK T cells clearly have a role in host antiviral responses, although their role in viral clearance is not yet clear.85 Activation of adaptive immunity depends on sensing of the virus by innate immune mechanisms, and work to elucidate these mechanisms in HCV infection has been provocative. The innate immune system recognises pathogen-associated molecular patterns via sensors such as the toll-like receptors (TLRs). The discovery that the HCV NS3/4A protease can interfere with the activation and nuclear translocation of interferon regulatory factor 3 (IRF3)86 suggested that HCV might interfere with TLR signalling, because IRF3 is an important downstream signal of TLR3, which senses double-stranded RNA. Subsequent work showed that the inhibition of signalling via TLR3 was mediated in that experimental system by cleavage of a key human adaptor molecule, by the viral NS3/4A protease.87 Even more provocative was the finding that HCV RNA (which is partially double-stranded) could trigger IRF3 activation in a TLR3-independent manner, and that the viral NS3/ 4A protease could interfere with that recognition, leading to the discovery that retinoic acid inducible gene I (RIG-I) is an important sensor for doublestranded RNA in the cytoplasm,88 and that NS3/4A can cleave an essential human adapter molecule in the www.thelancet.com Vol 372 July 26, 2008

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RIG-I signalling pathway.89–94 Viral interference with innate immune recognition might contribute to the progressive loss of adaptive immune response to HCV during early chronic infection, and might provide a rationale for treatment based on inhibition of the viral protease.

%

10 –1 5%

%

Spontaneous clearance

0 –9

Chronic infection

Asymptomatic infection (85–90%)

85

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Symptomatic hepatitis (10–15%)

2% –5 25

Acute HCV infection is asymptomatic in most patients; its natural history and chronicity rate varies much between the populations studied. European studies, including a cohort of 458 children95 who underwent cardiac surgery during early childhood, and two cohorts of women infected by HCV-contaminated immunoglobulin in Ireland96 and Germany,97 showed persistent viraemia in 55% of infected patients on follow-up. Similar rates of persistence were also noted in a retrospective study from Australia, where 51 (54%) of 95 patients admitted for acute non-A, non-B hepatitis were later found to be positive when their stored sera was tested for anti-HCV antibody.98 However, higher rates of persistence have been noted in US studies of injecting drug users, asymptomatic blood donors, and patients with transfusion-associated hepatitis. Persistence of virus has been defined as detectable HCV RNA for more than 6 months from the time of presumed infection, and is usually asymptomatic. Two prospective studies of injecting drug users who showed seroconversion during follow-up, reported persistent viraemia in 79% (722/919)99 and 86% (37/43)100 of patients followed for median periods of 8·8 years and 6 years, respectively. In a cohort of 103 patients with transfusion associated hepatitis C followed for up to 25 years, persistent viraemia was seen in 77% of patients.101 In another long-term prospective study of 248 asymptomatic blood donors,102 viral persistence was reported in 86%. These studies suggest that chronicity rates might depend on the mode of infection, and the age at which patients acquire infection. Only 10–20% of all acutely infected patients are believed to develop jaundice,103 although more recent European studies of injecting drug users have reported a higher incidence of jaundice (40–70%). A study of acute HCV infection in 16 elderly patients reported symptomatic acute hepatitis in 15 (94%) and jaundice in 11 (69%).43 The syndrome of acute hepatitis is often preceded or accompanied by symptoms of fatigue, myalgia, low-grade fever, right upper quadrant pain, nausea, or vomiting. Since acute hepatitis C is encountered infrequently, there are only limited data on the incidence of these symptoms. European studies104,105 of acute hepatitis C at tertiary referral centres report high frequencies of symptoms including jaundice (71%), influenza-like illness (64%), dark urine and clay coloured stools (36%), nausea or vomiting (35%), and pain in the right upper quadrant of the abdomen (26%). However, these studies could be affected by referral bias, since they were designed to

Incubation period 2–12 weeks

48 –7 5

Clinical features of acute HCV infection

HCV exposure

Chronic infection

Figure 3: Outcome of HCV infection14,100,104,109

identify HCV infection from a cohort of symptomatic patients. Other series from Japan,106 Egypt,81 and the USA107 that have prospectively followed injecting drug users or people with needle-stick injury have reported a lower incidence of symptoms, including jaundice (0–10%), and could be more indicative of the overall scenario. A recent case-control study in HIV-positive men who have sex with men also confirmed low rates of symptomatic disease, only 7·2% of cases presenting with jaundice.108 The possible outcomes of acute HCV infection are shown in figure 3, and are dependent on many host and viral factors. Acute hepatitis can occur 2–12 weeks after exposure (mean 7 weeks) and last for 2–12 weeks.110 It can be severe and prolonged but is almost never fulminant. Although concentrations of alanine aminotransferase greater than ten times the upper limit of normal are uncommon,111,112 some recent studies of symptomatic HCV infection have reported increases of up to 20 times,104,105 and yet other studies have used increases of ten times normal as a criterion for diagnosis of acute HCV infection.81,113,114 Evidence exists to suggest that patients who develop jaundice tend to have a higher rate of spontaneous clearance of HCV infection than do those with asymptomatic infection.100,104,115 The presence of jaundice might be an indicator of an effective host immune response that leads to spontaneous viral clearance, although this association is not uniform.74 Other factors that might contribute to spontaneous clearance include being infected with HCV genotype 3,116 being female,104 having a low peak viral load,100 being white by ethnic origin,100 and having a rapid decline in viral load within the first 4 weeks of diagnosis.115 By contrast, being of black ethnic origin and having a co-existent HIV infection99 could lead to viral persistence. One should note that these observations were made on the basis of small studies, and although these observations need to be corroborated in larger studies, such studies could be difficult to do because of the infrequent occurrence of symptomatic acute infection. Extrahepatic 325

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A

Alanine aminotransferase Antibodies against HCV

Titre

HCV RNA present

Normal

B

HCV RNA

HCV RNA

Titre

HCV RNA present

Normal 0

1

2

3 4 Months

5

6

1

2

3

4

Years Time after exposure

Figure 4: Serological pattern of acute HCV infection with (A) recovery15 and (B) progression to chronic infection15

manifestations of hepatitis C—eg, cryoglobulinaemia, vasculitis, porphyria cutanea tarda, and membranous glomerulonephritis—have not been reported as part of the acute hepatitis C syndrome.

Diagnosis of acute HCV infection There is no definitive pathological test to diagnose acute HCV infection. An identifiable exposure to HCV, recent seroconversion, marked increases in concentrations of liver enzymes with previous documentation of normal concentrations, and exclusion of other causes of acute liver diseases are usually used as circumstantial evidence of acute HCV infection. However, acute exacerbation of chronic HCV infection, and other conditions such as alcoholic hepatitis and drug-induced liver dysfunction, are confounding factors that can make a diagnosis of acute HCV hepatitis difficult. The only method to conclusively diagnose acute HCV infection is to document seroconversion in a previously seronegative individual. Seroconversion is most frequently documented in the setting of needle-stick exposure, when the exposed individual is followed prospectively, or during surveillance of high-risk individuals. Detection of antibodies against HCV by immunoassay is an unreliable way to identify acute HCV infection, 326

since the absence of antibodies does not preclude infection in the acute setting. The appearance of antibodies against HCV could be delayed in as many as 30% of patients at the onset of symptoms,117 particularly in immunocompromised hosts, because they could be incapable of mounting an effective antibody response. Acute HCV infection can be followed by spontaneous resolution or chronic infection. The serological patterns associated with spontaneous resolution and those associated with chronic infection are shown in figure 4. HCV RNA levels could fluctuate (and on occasion be undetectable) for up to a year after infection, necessitating serial measurements of HCV RNA concentrations for a year after documented or confirmed acute infection. Rarely, successful viral clearance might occur in the absence of antibody production, or with rapid antibody loss.59,109 As many as 10% of acutely infected patients might eventually lose HCV serological markers,118,119 making the HCV antibody test insensitive for diagnosis of acute HCV infection. Similarly, the recombinant immunoblot assay test that is used to confirm a positive test for antibodies against HCV is also insensitive to acute HCV infection because production of these antibodies can also be delayed. IgM antibodies against HCV have not proven useful in the diagnosis of acute HCV infection, because their concentrations remain fairly constant in both acute and chronic infection.120 Qualitative and quantitative methods for detection of HCV RNA—including reverse transcriptase (RT) PCR, branched DNA (bDNA) assays, and transcriptionmediated amplification (TMA)—are the most sensitive means to document viraemia, and should be used when clinical suspicion of acute infection is high despite a negative HCV antibody test. The lower limit of detection varies by the method used. bDNA assays such as the Bayer bDNA assay (Bayer Laboratories) have a lower limit of detection at 615 IU/mL; endpoint PCR detection assays such as the Cobas Amplicor v2.0 (Roche Diagnostics) and NGI SuperQuant (National Genetics Laboratory, CA) have detection limits of 50 IU/mL and 100 IU/mL, respectively. The newer real-time PCR detection assays, such as the Cobas TaqMan assay (Roche Diagnostics) and Abbott Real-Time HCV assay (Abbott Laboratories), have lower limits of detection (15 IU/mL and 10 IU/mL, respectively). The Bayer TMA assay (Bayer Laboratories) can detect HCV at limits of 5 IU/mL. The newer assays are extremely reliable (sensitivity and specificity both >95%), and have allowed viral detection among those with fluctuating viraemia that were previously classified as relapsers. Detection of HCV RNA without detectable antibodies suggests acute infection, especially when it is followed by seroconversion. However, detecting HCV RNA by PCR is not cost effective in a low-risk population, and is not recommended as a screening test for chronic infection.109 There are no specific guidelines for post-exposure surveillance. The CDC recommends testing for www.thelancet.com Vol 372 July 26, 2008

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antibodies against HCV and measuring alanine aminotransferase concentrations at baseline, testing for HCV RNA by PCR at 4–6 weeks after exposure, and again for antibodies against HCV and alanine aminotransferase concentrations at 4–6 months.16 These guidelines are based on data from 2001, and predate our current knowledge of treatment outcomes of acute HCV infection. At our institution, infection control guidelines recommend testing for antibodies against HCV at baseline, 3 months, and 6 months, and for HCV RNA at baseline, 4 weeks, and 3 months. These guidelines are for screening only and further testing after an initial positive test is at the discretion of the treating clinician. Since early treatment is associated with excellent outcomes, doing an additional test for HCV RNA at 8 weeks after initial exposure is reasonable.113

Treatment of acute HCV infection Although large trials exist to guide treatment of patients with chronic HCV infection, this is not the case for acute HCV infection (table 2). Published studies show considerable heterogeneity of trial design, inclusion criteria, patient characteristics, treatment onset relative to date of exposure or onset of symptoms, and treatment method. Moreover, serious concerns135,136 have been raised about the reliability of data from two large randomised, controlled trials113,114 of treatment of acute hepatitis C, which were done in various centres across Egypt, Germany, and the USA. Despite many requests, the investigators have not disclosed the demographic breakdown of the various centres to address concerns about the feasibility of recruitment of such a large population within a short period of time. Because of this controversy, our recommendations are made discounting these two trials. The endpoint of most studies has been the probability of achieving sustained virological response (SVR), which by consensus is defined as lack of detectable viraemia 24 weeks after the end of treatment. For all practical purposes, absence of HCV RNA by a sensitive assay, 6 months after discontinuation of treatment, could be considered to indicate cure, since relapse rates are extremely low. In a meta-analysis, Alberti and colleagues137 examined the outcome of 369 treated and 201 untreated patients from 17 studies. The pooled data showed an SVR rate of 62% (range 37–100%) in the treated patients, compared with 12% (0–20%) in untreated individuals (p<0·05). In another study, Licata and colleagues138 examined 12 cohort studies reporting data from 162 treated and 81 untreated patients, and found that the likelihood of SVR was 70·5% (25–97·7%) in the treated group, compared with 35·3% (5·8–37·5%) in the untreated group. Studies have shown that the treatment of acute HCV hepatitis is beneficial and cost effective.130 There was no evidence of clinically significant flare-ups of hepatitis during treatment, even in patients with substantial increases in the www.thelancet.com Vol 372 July 26, 2008

concentrations of alanine and aspartate aminotransferases at the time of treatment initiation. Tolerability of therapy was generally acceptable and dropout rates low in most reported studies. Despite the absence of large randomised controlled trials, to conclude that early treatment could reduce the chronicity of HCV infection is reasonable.

Spontaneous clearance Spontaneous clearance of HCV occurs at a high rate in patients with symptomatic HCV hepatitis. In a small study,115 eight (67%) of 12 symptomatic patients cleared their infection spontaneously; the mean time from onset of first symptoms to HCV RNA negativity was 34·7 (SD 22·1 days). In another study, Gerlach and co-workers104 reported the natural history of 60 patients who presented to two large referral centres between 1993 to 2000; 51 of these 60 patients had symptomatic hepatitis. Although spontaneous viral clearance was observed in 24 (52%) of the 46 untreated patients with symptomatic acute hepatitis, none of the nine asymptomatic patients cleared the virus spontaneously. All patients who spontaneously cleared the infection had undetectable levels of HCV RNA 4 months after the onset of symptoms. Presence of symptoms or jaundice in these patients might suggest robust antiviral cellular immunity.

Optimum timing of treatment Several studies have now shown considerably higher rates of SVR with the treatment of acute HCV infection than with the treatment of chronic infection. However, the optimum timing of treatment is critical to avoid unnecessary treatment of those who will clear the infection spontaneously, while offering prompt therapy to achieve the highest possible SVR for those who will not clear the infection spontaneously. The evidence suggests that it is prudent to wait for at least 12 weeks before initiating antiviral treatment in patients with acute hepatitis C, especially when they present with symptomatic hepatitis C.113,133 There are only limited data on the optimum timing for treatment of individuals undergoing post-exposure surveillance (eg, after needle-stick injury); these patients are more likely to be asymptomatic and are therefore less likely to clear the virus spontaneously.106

Duration of treatment Data from Japanese investigators106 suggest that a course of daily interferon for 4 weeks could be efficacious, with an SVR rate of 87%; prolongation of therapy for 20 weeks for those who relapsed achieved SVR rates of 100%. The investigators also suggest that an undetectable viral load after 1 week of treatment predicts SVR, but this observation needs further corroboration. In a multicentre German study, 89 patients with acute hepatitis C105 were treated with pegylated 327

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Treated patients Treatment regimen

Duration of therapy

ETR

SVR

Omata et al121

25

Interferon beta, total 52 MU

30 days

90%

..

Viladomiu et al122

28

Interferon alfa, 3 MU three times a week vs no treatment

12 weeks

73%

..

Tassapoulos et al123

24

Interferon alfa, 3 MU three times a week vs no treatment

6 weeks

75%

..

Hwang et al124

33

Interferon alfa, 3 MU three times a week vs no treatment

12 weeks

81%

44%

12 weeks

73%

22%

..

40%

100%

90%

Lampertico et al125

45

Interferon alfa, 3 MU three times a week vs no treatment

Takano et al126

90

Interferon beta at varying doses (total 8·4–336 MU)

Vogel et al127

24

Interferon alfa, 10 MU daily

Calleri et al128

40

Interferon beta, 3 MU three times a week vs no treatment

Gursoy et al129

36

Interferon alfa, 3 MU three times a week vs 6–10 MU three times a week

12 weeks

Jaeckel et al130

44

Interferon alfa, 5 MU daily for 4 weeks then three times a week

24 weeks

Gerlach et al104

26

Variable regimen of monotherapy or combination

14–52 weeks

..

81%

Rocca et al131

13

Variable regimen of monotherapy or combination

24–48 weeks

..

92%

Nomura et al106

30

Interferon alfa, 6 MU daily for 4 weeks and 6 MU three times a week for relapsers

4 weeks followed by 20 weeks for relapsers

..

4–8 weeks Until normal alanine aminotransferase activity restored 4 weeks

25% 56–65% 100%

8 weeks

26–50% 98%

100% (including relapsers)

Delwaide et al132

28

Interferon alfa-2b, 5 MU daily

89%

75%

Kamal et al81

40

Pegylated interferon monotherapy vs pegylated interferon plus ribavirin

24 weeks

90–95%

80–85%

Sanantonio et al133

16

Pegylated interferon alfa-2b 1·5 μg/kg weekly

24 weeks

94%

94%

Broers et al134

14

Pegylated interferon alfa-2b 1·5 μg/kg weekly

24 weeks

..

57%

Wiegand et al105

89

Pegylated interferon alfa-2b 1·5 μg/kg weekly

24 weeks

82%

71%

Kamal et al113

129

Pegylated interferon alfa-2b 1·5 μg/kg weekly

24 weeks

88–97%

76–95%

Kamal et al114

131

Pegylated interferon alfa-2b, 1·5 μg/kg weekly

79–94%

68–91%

8, 12, or 24 weeks

ETR=end of treatment response. SVR=sustained virological response.

Table 2: Trials comparing therapies for acute hepatitis C

interferon alfa-2b for 24 weeks. The SVR rate for the entire cohort was 71% and for those who adhered to therapy was 89% (70/89 patients). Psychiatric side-effects that resulted in termination of treatment were reported by six (7%) patients; one participant committed suicide. A smaller Swiss study134 also showed poor adherence, with high dropout rates among injecting drug users. These studies underscore the poor tolerability of interferon with prolongation of treatment beyond 12 weeks, and highlight the morbidity associated with therapy. The genotype of the infecting strain of HCV could also have a role: higher relapse rates, in patients treated for 3 months with pegylated interferon, were reported for those infected with HCV genotype 1.139 There is increasing evidence from chronic HCV trials to suggest that early virological responders (ie, those who are HCV RNA negative after 4 weeks) could attain very high SVR with short periods of treatment. In acute HCV infection, a reasonable strategy would be to treat early responders for 12 weeks, and reserve 24 weeks of treatment for relapsers or those who fail to show early virological clearance.

Optimum treatment regimen Despite increasing evidence to suggest that treatment for acute hepatitis C is very efficacious, the optimum drug regimen remains unclear. Early Japanese studies126 328

used interferon beta, whereas European and American studies have used interferon alpha. With the advent of newer pegylated interferons, and evidence of improved efficacy in patients with chronic HCV infection, clinicians now use pegylated interferon as first-line therapy; high SVR rates have been reported.81,133 Although daily induction therapy has been tried,130 the benefits of such therapy remain unproven, since there are no trials that compare daily interferon with weekly pegylated interferon. Moreover, studies with pegylated interferons have shown efficacy rates comparable with standard interferon.133 The combination of interferons with ribavirin has not been tested extensively. The few studies that used ribavirin found it to be well tolerated, but response rates were not significantly higher than with monotherapy.81,104,131 The use of ribavirin in combination with interferon might be considered in patients with low response rates to treatment, such as those co-infected with HIV or those infected with HCV genotype 1, although this strategy remains unproven. There have been very few studies of acute HCV infection in patients co-infected with HIV, and the response to therapy has varied from 59%140 to 90%.141 Current data do not allow us to make firm recommendations with regard to the optimum treatment regimen or duration of therapy in HIV-positive patients who develop acute HCV infection. www.thelancet.com Vol 372 July 26, 2008

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Conclusion Acute hepatitis C is an under-recognised clinical entity with only a few patients developing symptomatic hepatitis. The presence of antibodies against HCV is unreliable in the diagnosis of acute infection and RT PCR should be used in all patients who are suspected of having acute HCV infection. Symptomatic patients are more likely to spontaneously clear the virus than are asymptomatic patients; however, about 70% of asymptomatic patients will develop chronic hepatitis C. On the basis of published data, antiviral therapy could be delayed for 3 months from the date of exposure or onset of symptoms, but these observations need further corroboration. Antiviral treatment with pegylated interferon monotherapy for 12–24 weeks is effective in achieving SVR rates over 80%. Longer duration (24 weeks) of treatment and the addition of ribavirin could be considered in those infected with HCV genotype 1, those with high viral loads, and those who relapse after short durations of treatment. The incidence of acute HCV infections is decreasing in developed countries, but could be increasing in developing countries because of unsafe medical practices. Such a situation is likely to lead to an increased incidence of chronic liver disease and hepatocellular carcinoma. Current treatment strategies are expensive and therefore not available or affordable for most developing countries. Moreover, interferon-based treatment is associated with significant side-effects. Therefore, intervention strategies must focus on reducing the risk of transmission, especially in developing countries. Better markers to differentiate acute and chronic HCV infection, predictors of spontaneous HCV clearance after exposure, cost-effective oral medications with few side-effects, and the development of an effective vaccine against HCV should be the goals of future research. Conflict of interest statement AM declares that he has no conflict of interest. SR has received research grants from Roche Laboratories. PJT has received research grants from Roche, Wyeth, Sanofi, Johnson & Johnson, SciClone, and Ribapharm, and has received honoraria from Axcan and Gilead. References 1 WHO. Hepatitis C—global prevalence (update). Wkly Epidemiol Rec 1999; 49: 421–28. 2 Xia GL, Liu CB, Cao HL, et al. Prevalence of hepatitis B and C virus infections in the general Chinese population from a nationwide cross-sectional seroepidemiologic study of hepatitis A, B, C, D and E virus infections in China, 1992. Int Hepatol Comm 1996; 5: 62–73. 3 Chowdhury A, Santra A, Chaudhuri S, et al. Hepatitis C virus infection in the general population: a community-based study in West Bengal, India. Hepatology 2003; 37: 802–09. 4 El-Hazmi MM. Prevalence of HBV, HCV, HIV-1, 2 and HTLV-I/II infections among blood donors in a teaching hospital in the central region of Saudi Arabia. Saudi Med J 2004; 25: 26–33. 5 Khattak MF, Salamat N, Bhatti FA, Qureshi TZ. Seroprevalence of hepatitis B, C and HIV in blood donors in northern Pakistan. J Pak Med Assoc 2002; 52: 398–402. 6 Moriya T, Koyama T, Tanaka J, et al. Epidemiology of hepatitis C virus in Japan. Intervirology 1999; 42: 153–58.

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