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Clinical, virological and epidemiological basis for the treatment of chronic non-A, non-B hepatitis
s19
Clinical, virological and epidemiological basis for the treatment of chronic non-A, non-B hepatitis
H.J. Alter
Non-A, non-B hepatitis is the most common serious complication of blood transfusion and also occurs in a sporadic form whose routes of transmission are currently unknown. While generally mild in its acute presentation, nan-A, ~n-l3 hep &is frequently progresses to cbroniu hepatitis which zzy eventuate in cirrhosis and hepatocellti carcinoma. The disease is caused by a smail, enveloped RNA vinrs now designated hepatitis C vim, whichhassimitities to the flaviviruses. Studies using the recently developed antibody assay have indicated that hepatitis C virus is the predominant agentof both transfusion-associated and sporadicnon-A, non-I3hepatitis. In 50435%of transfusion-associated cases, a donor can he found who is positive for antibodies to the hepatitis C virus. Current dataindicrtte thattheseantibodiesare prwnt in ap pwx.0.5%~fblooddonorsintheUnitedStatesaadEurope,l~S%bJapanand6%in~,as~Uasin60-&0%~fhaemqhiiiac~and intravetrous drugabusersandapprox.20%of dialysis patieats. Withchangesin dwor selectionandtraw fwian pr&ces, heinch&m of td non-A, IIM-Bhepatiti ham&d&d fromratesof 5-10% prickto 1985to estimatedcwent ratesof 2-496. Tireintr&cGon of theanti-HCVtestshouldeffti an acwitional5O% reductku in m-assoejated WSA, non-Bhepatitis. In addition to thesepreventiveuwsur~, &f&w tbwapyuow am at handin ti form of a-interferon.The efficacyof otheraMviralagentsandthe potentialfor combiuatjun therapies also needtotleexpIOred.
InCloning of the hepatitis C vinrs (HCV) has transfomxd the field of non-A, non-B hepatitis (NANBH) and provided major insights into its =mtion, transmissian and chronic sequelae (I). Each of these aspects will have considerable impact on bothprevention and treatment smtegies. For the 5rst time, transmissionpatternscan be
genomidy assessed. Similarly, hatment ~dn now be better defined in terms of anti-HCV positive vs. antiHCV-negative dwase, each of which mayhave different treatment outcomes. We are moving in the direction of diagnostic precision and uf unders!anding the moIecular basis of NANBHinfection,Visualization of the HCVpar-
ticleand elucidationof its structureare ~IDSOSI certainto follow, aud the fieldof non-A, non-H hepatitis will move stateOfclinicalobservationto a statesimilar to that for the hepatitisI3 virus (HBV) where the
tracedby scrologiwtassays(Z), the diagnosisof NANEN can be directlyestablishedratherthan inferredby se~o-
from tbe mne
Iogical ex&sion,
molecular biiology, phw characteristics, tissrre distribution and disease manifestations are known in intricate
and disease
-ations
such as that
with hepatoceilularcarcinomacan be serdogicallyand Corrqondh~~r
U.S.A.
Dr. H.J. Alter. bparttnent of TransfusionMedicine,
National
Imtitutcs
ofHe&h,
9MHlRdviIk
pike, Bethesda,MD
H.J. ALTER
sive whole.
observed in NANBH, including: a monophasic, single peak with subsequent full recovery; a polyphasic. fluctuating pattern that is characteristic of NANBH; and a plateau pattern, wherein the ALT does not reach very
NANBH was recognized in 1975 when it became apparent that most cases of transfusion-associated hep atitis were serologically unrelated to either the hepatitis A virus (HAV) or HEW (1). The term ‘non-A, non4 refleeted uncenainty about the nature of this agent and the fact that the diagnosis was based on the serological exdusion of known hepatotrophic agents. Although a great deal of clinical information has been acamuleted over the ensuing decade, the exclusionary nature of the diaguosis of NANBH did not change. Indeed, it is remarkable
high levels in the acute phase, but where persistent ALT elevation is the rule. In the latter cases, the acute phase merges imperceptibly into the invariable chronic outcome. The development of chronic hepatitis is also very frequent in those patients with the polyphasic (fluctuating) ALT pattern and it is this chronic hepatitis that constitutes the primary problem in HCV infection. Hence, while acute NANBH infection is seemingly benign, it takes on major clinical significance because of its predisposition to evolve into chronic disease. Multiple prospective studies indicate that 3040% of patients with NANBH develop chronic hepatitis, with the average occurrence in a composite of eight studies being apptox. 50% (2). Chronic hepatitis is defined by ALTele-
how much has been learned about NANBH despite the absence of a visualized panicle or a specific serological as-
vations persisting for more than a year after the onset of hepatitis. Liver biopsies obtained in the wake of per-
detail. The therapeutic effectiveness of a-interferon is at a unique stage, when, for the first time, treatment, biology, physiology and serology ere being integrated into a cohe-
first
say. Using only setum alanine
aminoimlsferas8 (ALT),
liver biopsies and the chimpanzee model, have fairly precisely deened the clinical
sistent biochemical
abnomxdities
reveal mild chronic ac-
investigators spcttum of
tive hepatitis (CAH) in the majority of cases, but the bis-
NANBH and have developed a physical model of the agent, including size characteristics and the lipid ~nterd
chronic persistent hepatitis, severe CAH and cirrhosis. In addition to evidence of hepatoeellular inflammation with varying degrees of piecemeal necrosis, the histologkal lesions are characterized by bile duct proliferation and mi.
of its membrane. These have led to inactivation strategies and other intervention measures which have greatly reduced blood transmission. The acute disease associatedwith the non-A, non-B
tologieal spectrum also includes chronic lobular hepatitis,
cmvesicular steatasis. In mild cases, it may be dlult to distinguish the lesions from alcoholic hepatitis or liver dis-
hepatitis virus (hereafter designated HCV) infection is generally mild or inapparent. Only 25% of prospectively followed patients with transfusion-associated NANBH (TA-NANBH) are icteric and/or symptomatic, and less than 10% are severely ill. Symptoms when present are typical of viral hepatitis and indistinguishable from infection with HAV or HBV. Fulminant hepatitis is extremely rare in prospectively followed patients with TA-NANBH. However, in compilations of patients presenting with fulminant hepatitis, NANBH is frequently cited as the cause (1). I believe this primarily reflects the imprecision of the diagnosis and it will now be important to reassess these fulminant cases using specific methods for the detection of
ease of obesity. We development of cirrhosis has been noted in every seriesthat includes histological analysis; almost uniformly, 20% of patients who are biopsied have histological evidence of cirrhosis (2). Furthermore. in patients who undergo serial biopsies. the progression barn CAH to cirrhosis has been repeatedly documented. In
HCV. Serological assayswill not help in patients who succumb to their fulminant hepatitis because anti-HCV development is considerably delayed. However, the poly merare chain reaction (PCR) may detect viral nucleic acid in serum and in situ hybridization or immunohistological studies may be utilized in stored or freshly obtained liver biopsies. These methods ate not well developed et pres-
quency of cirrhosis on biopsy contrastswith the much lower frequency of clinically apparent cirrhosis. While hop atic failure and typical end-stage liver disease clearly occur in the wake of TA-NANBH, th& occutteuce is ICIatively rate as compared with the number of casea of cirrhosis projected from the incidence of NANBH, the tie-
ent but are almost certain to become available in the near future. Several patterns of transaminase elevation have been
studies in Italy and Japan, where acute and chronic phase biopsies were obtained, histological progression from acute post-transfusion hepatitis to CAH to cirrhosis has been proven (2). The combination of biochemical and histological abnormalities suggests that at least 10% of patients with NANBH develop cirrhosis (20% of 50%). This high fre-
queucy of chronic biochemical changes and the frequency of c:rrhosis on liver biopsy. Hence, the cirrhosis generally appears to be indolent es compared with the image of cirrhosis occurring in the setting of alcoholism. There are
s21 several possible explanations for this. Firstly, alcoholic patients are generally not biopried uutil they present with physical manifestations of pmtal hypertension. They are less likely to be involved in prospective studies where biopsies are obtained solely on the basis of persistent biochemical abnormalities. Little is known about the duration of cirrhosis in alcoholic patients before po~al hypertensive sequelae become manifest. Secondly. the alcoholic patient continuously subjects the liver to to.& insults which may speed progression to cirrhosis and from cirrhosis to end-stage liver disease. In contrast, cirrhosis in the NANBH patiad evolves from a single infectious watt and the subsequent chmmc, !ow$rsde hepatocelluiar damage may not equate with the massive inflammatory onslaughts of repetitive bouts of atcoholism and hence may run a more indolent and slowly progressive course. Indeed, the evolution of NANBH
has been shown to be
extremely slow. Studies in Japan, which retrospectively related various stages of chronic liver disease to a history of prior transfusion,
demonstrated
period 10 the development the mean interval
an inordinately
of clinically mxtifest
from transfusion
long
disease:
to the diagnosis
of
chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) were appmx. 10, 20 and 30 years, respectively. This delayed development of clinical disease could acwunt far the discrepancy between the number of cirrhosis cases and liver fatalities projected from prospective studies, and the number actually observed. Acquired immunodeficiency syndrome (AIDS) lookback swJics have shown that a very high pmpation of transfused individuals die of the disease for which they are transfused or an intercurrent illness and hence die before they develop cliical evidence of their human immunodeficiency virus (HIV) infection. The same is undoubtedly true for HCV infection. such that many transfused HCV-infected patients dieof other causes before they dev&p cirrhosis or before their cirrhosis becomes sufficiently extensive to result in the clinical stigmata associated with impaired parml flow and decreased protein production. IO essence, chronic hepatitis and cirrhosis are frequently documented in NAN&H infection by biochemical and histologicaI criteria, but the clinical correlate of these changes wars less than expected because of the slowly cvolvinS nature of the disease and the probability of death from intercurrent causes. Nonetheless, end-stage liver disease dca OFcur as a result of HCV infection, as dues HCC (1.3). The relationshin of NANBH to HCC had been occasionally recognized in cally recognized by the alcoholic patiems with cumnce has now heen
c*“o reports and mure systematiabsence of HBV marken in nonHCC. The probability of this ccvastly strengthened by the finding
of anti-HCV antibody in a high proportion (@l-80%) of HBV negative patients with HCC. The strength of this serological association was one of the majo. surprises of the recent application of UCV serology. While causality has not been established. i: is probable ‘&at tiCV, like HBV, is directly or indirectly aswiated with the development of liver cell cancer. This may be through a specific oncogettic effect. through the mutagenic effect of the regenerative process which accompanies cirrhosis, through a cofactor mechanism, or through any combination of the above. Whatever the mechanism, HCV may be one of the primary aetiological agents in the development of HCC, particularly in Japan where HCV infection and HCC are both very prevalent. Hence, the problem of NANBH infection resides in iu chronic manifestations which now clearly include both cirrhosis and HCC. It is these chrmtic sequelae which served as the impetus and rationale for treatment with a.interfcron and other antiviral agents. If the progression to cirrhosis and HCC cat be prevented in patient with CAH or other pre-cinhotlc
chronic liver tiiasc,
will clearly he justlfipd. At present,
Tim treatment
the dtuarian
of treat-
ment necessary to prevent these sequelae or the most oppatune time to initiate treatment are unknown.
NNt-A,ltOlt-B:tk* Many of the physical characteristics of the NANBH agent have been deIineated even in the absence of an identified particulate stmcture attdlor any semlogical or other direct means of viral idanitication. Tbir bar been made possible by infectivity studies performed io the chimpanzee, the mdy animal model for NANEtH. The swceptibiity of the chimpanzee to NANBH infection was estab&hed in I!+76 and, i&ed. served as the East proof that NANBH was caused by a bansmtibk agent (4). The chimpanzee develaped only a mild form of hepatitis, but the combination of and mild histological changes of hepamceIhtler inQammation made this a reasonable and us&l infeztivity tttc&I. The value of the chiipattzee model was further enhanced when chamctciistic ultmsmtctwal chat= were noted in the cytoplasm of infected hepataytes. There were a variety of such changes, but mast charaa.zristic were cytophwnfc tubular structure comistiug of doubk-unit membraoes sunmmdfug an eIecuondense cena. The preseuce of these tures in animals 6th mild evidence of hepatitis amfumed the transmirsion of NANBH. Independent studies. perfunned at the National Institutes of Health (NIH), the Centers for Disease Cotnml (CDC) and in Japan, revealed that the agent character-
ALTcIevatIo~
H.J. ALTER
sz2 ized by the presence of cytoplasmic tubular structures was sensitive to chloroform and hence contained essential lip id in its membrane (4,J). We now know that this chlorofrxt-sensitive. tubular forming agent induces anti-HCV antibody in infected individuals and hence represents the hepatitis C virus. This agent is the predominant and possibly the sole cause of NANBH. However, a second NANBH agent has been suggested by chimpanzee crosschallenge studies, by a short incubation form of NANBH which follows the administration of clotting factor concentrates, and by experiments which suggest that there is a chloroform-resistant agent that can also transmit hepatitis to the chimpanzee (4,5). The existence of a second agent can now be better ascertained “sin8 the sane moIec,der approaches which discovered and charanetied HCV (6). Following the characterization of HCV as chloroformstnstive, filtration studies were performed to determine its size. Initial studies indicated that the agent is less than 80 nm in diameter
(5) and subsequent
studies revealed
that the egettt could pass through a 50 em filter, but was trapped by a 30 nm filter (7). Overall, it was estimated that the particle was 30-60 nm in diameter. NANBH
is thus small and
(8). The ability to detect antibody allowed ior e series of epidemiological studies which are described in the next section. By the use of overlapping clones, the genetic structure of HCV has been identified. It appests toconsist of appmx. 10 CC0 base pairs which code for structural and non-structural proteins in a single large open reading frame which is post-transcriptionally cleaved. Both the physical and genomic characteristics of HOI have many similarities to the tlavivintses, supporting the earlier supposition of Bradley et al. (5). However, there is ooly a small degree of homology between HCV end known flaviviruses and at this point HCV is considered ‘fiavi-Ike’ mtltcr than deftnitively ktongin~ it, that vim, class. Although the entire gemme has been sequenced and although its general physical characteristin are known, HCV has never been visualized. This is consistent with the low level of circulating vints infetred from infectivity titres in the chimpanzee model. However, the availability of e serological marker end PCR should alIov; for coacen. tration of the agent in gradients tion.
and its ultimate visualize-
Tbe agent of
lipid-encapsidated.
These
physical cbaracteristies considerably narrow the field of candidate virus families to which the agent of NANBH might belong. These include the small RNA viruses formally designated toga and now designated alpha and flavi, the small DNA viruses of the hepadna group, incomplete agents such as delta, unconventional viruses and viraids. Dr. Bradley at the CDC first suggested that the NANBH agent was most similar to the togaviruses (5) and that contention is now being supponed by the work at the Cbiron Corporation which finds that HCV has properties similar to, but not identical to. the flavivirures (Houghton M, Personal communication). Thus, even prior to the cloning of HCV, a remarkable and essentially correct estimete of the agent’s structure and texonomic classification was established. In 1989, the Chiron Corporation, in collaboration with the CDC, culminated 6 years of intensive effort by cloning HCV (6). This was achieved by extracting nucleic acid from litres of highly infectious chimpanzee plasma and then generating a c-DNA library. The c-DNA was then insened into an expression vector, yGT-11, which was initially used to infect Escherichia cob and subsequently to infect yeast. Tbe expressed proteins were screened with plasma from a patient with chronic NANBH. Reactive clones were assessed by radioautography. Through this screening process, a clone was identified which expressed a protein specific for NANBH. This antigen wes combined with that of two related clones and became the foundation of un immunoassay to detect antibody to HCV
NmA, ntcm.B: qMem&gy
utd sue&y
The availability of a serological marker has allowed for semprevalence studies, epidemiological studies and a better deGiticm of the sequence of events in HCV infection. When
the anti-HCV
essay was developed,
it was first
evaluated in chimpanzees and clearly distinguished chimpanzees with NANBH infeztkm from those with HBV or HAV infection and from uninoculated cotttrols. It was then evaluated against the NM NANBH panel consisting of sere proven to transmit NANBH and appropriate disease and normal controls. The Cbimn assay was the reliably and reproducibly break this caled panel (8).
to
tint
finally. the assay wes evaluated in transfusion recipiettts with biopsy-proven NANBH and in the donots to these patients (9). These studies showed that anti-HCV was very frequently present in patients who developed chronic NANBH (80-100%) and less frequently present in those with acute, self-limiting disease (15-6096). In general, the more certain the clinical diagnosis of NANBH, the more likely anti-HCV positivity. It eppeers that antiHCV will decline and ultimately disappear in cases where the infection is not persistent. In OUT NIH studies, all 15 patients with chronic NANBH were anti-HCV positive, es were three of five (60%) with transient NANBH (9). The antibody has been shown to persist for a mean of greater then 6 years in the chronic cases and to disappear in each of the acute ceses though this disappearance wes dekyed. and in one case
took more than 9 years. The development of anti-HCY antibody is generally delayed with a mean interval pustexposure of about 18 weeks in the transfusion setting.
Some cases may take close able antimy.
toa year
to manifest detect-
Late samples are essential for proper diagnosis. An analysis of the donor-recipient nnship rend-HCV veals an anti-HCV positive donor in SO-85 positive GMS. In the NW study, surrogate markers (ALT, anti-HBc) detected 50% of the anti-HCV positive donors (9). Hence, implementation of anti-WV testing
*
furblwd ¬ screeningtill be veryeffectiveandclearIy superiorto surrogatetesting,thou@ the latter may be retained as adjunctive protective measures not only for HCY, but also for HBY and HIV infections, A summary of the epidemiological trends which have emerged as the result of anti-HCV testing is as follows: (i) sporadic (community-acquired) NANBH is dsle to the
same agentas TA-NANBH (10); (ii) sexualand contact transmissianmay occur,but are rare comparedto HFW and HIV infect&s (10); (iii) anti-HCV is found in 60-W% of haemophiliaw and intnwenous drug abusers, lS-20% of dialysispatientsand only 4% of malehome~xuals (II); (iv) in pruspetiivestud&, morethan80%of well characterizedTA-NANBH cases are HCV-related and 5Q-85% have an identified anti-HCVpositivedonor (9); Iv) anti-HCVis found more frequentlyin chronic thanin rcsolviugNASH and probablyindicatesactive viralreplicationand ongoinginfectivityratherthan convalescence(9); (vi) the deveiopment of auti-HCVafter transfusionis delayed(meanapprox.20 weeks},the iuterval from exposureto detectionmay exceed 1 year; and {vii) anti-HCY prevalent in donors is 0.3% in Canada, 0.5% in Europe, 0.6% in the U.S.A., 1.5% in Japan and 6% in Afrka (12). A variable number of cases classifiedas PJANIWare an@-HCV ntgative. One explanation for this is an error in tie &Gal diagnais. T3e diagnosis of NANBH is often
imprecisebecauseit is based on clinicaland serologM e~~lusi01~Anti-HCVnegativecases may representnonviralhepato&luhrinjuryor incidentalhepaticithnmation relwd to viruses not geneMy consideredto be hepatotrq3hic.Tl~emorecertainthe clinicaldiagnosis,especiallywhen established by biopsy, the more likely the case will be anti-HCV positive. A seco~~Ipossbk re85oa for anti-HCV negativity is that anti-HCV sroconversion may havt been misEedBecky of inadequate sampling, particularly the lack of late samples to detect the often delayed semnversion. Thirdly, the case may be due to HCV despite a negative a&HCV assay.This assay rep resentsa tit generation test and may not be positive in all instances of HCV infection.As PCR, in situhybridization
and immunofluorescence technique are refined,a pro-
portion of anti-HCV negative cases will undoubtedly be shown to be HCV related. Lastly, the abw of antiHCV in NANBH cases mayindicatethe presenceof orte or more additional agentsof thisdisease.Thereis a need to exar;;i;;e uneq’;ivocal cases of NANBH which are h&iHCV negative by PCR and in situ hybridization. If still HCV negative, rhesc: will be fertile cases for investigation by the same molecular approachesthatuncweredHCV. WhileHCV is unequivocally transmittedby parentera routes,including tmsfusion andintravenousdrugabuse, its other modes of spread are pxly defirred. The large number of sporadic hepatitis cases in which there is no identified percut8neous bland source strongly suggests non-parentera transmission patterns. nti2 first presump tion wodd favour sexual transmission, but the data for this are currently mt. Afthough v control stndi~ by the CDC suggest WetosexuaIspread,sexualpartners of
patientswith trau$rtsiun-associated hepatitisand hetem sexualcontactsof iatravenousdrugabuMs havenot been shownto be at increasedriskfromMY infection (1I). In addition,the prevakace of HCV is relativelylow in male homosexL&(4%), a populationat tik for all formsof sexuaIlytransmitted diseases; an exm of 60% of male homosexuaJs havebeeninfectedwithHBV andHIV. Few data are currentlyavailableon materno-foetaltraasmission, but the low prevalenceof anti-HCVin infantsaud youngchildren mitigates a@st such spread as playing a prominent role in dissemination of this disease. The p”ibility of insect transmission is intriguing since the agent has characteristics in common with -borne infectious agents; however, there is w c3irect evidem;e: for this. Stud& whiib will more precEseIy define these transmissionpatternsareinprogress,Weareju8tattbetbresholdof understpnttingthe~ofpvANBHiafection and considerable data in this regard are expected to accrue in the next few years.
Nm-A, nom-B: tk Remarkable adivances haveoccurred ~II the prevention of NAPJBH and other transfusion-t viral dis-
eases. Maq of t&e advances preceded the recent developmentof a speciGctest to detectcarriersof HCV and relate to measures intr0duc4 prinhl~r to prevent tran&&on-trmsxn&ed AIDS. ForGtou4y, aIT meafllres introduced to prevent HIV t prevent HBV and HCV transmi&oa because of the overlap in these hi@ risk donor populations. The dedining incidence of these
* ’ 11 also
transfusion-transmitted dise~ in part reflects advances in serology, but IIN& m ~&MS 8 basicchangeh the reauitulentofd4wrsandinMoodtr=ftEwprac9ice.
H.J. ALTER
S24
The threat of AIDS has forced an assessmentof transfusion practice and has engendered in both physician and patient a heightened awareness of the infectious and sometimes mortal risks of blood transfusion. This has led to a more judicious use of blood products and the elimination of some, but not all, unwarrantedtransfusions.There is still a need to better define the indications for transfusion and to control the overutilization of some blood cornponenrs. In tandem with the more appropriate use of blood has been a dramatic increase in the use of autoI+ gous Mod, both by pre-deposit and by intra-operative salvage. In some institutions, 15% of the blood utilized is of autologous otigin and many patients sustain major surgery without the use of any homologousbled products. The other area of major change has been in the selection and screeningof blood donors. In the United States, there are now no paid donors except those that contribute
plasma which can be effectively inactivated. Donors are provided with extensive information on high-risk behaviow and are asked to self-excludethemselves if they fall into any of the designated categories. In addition, direct questioning regarding risk behaviour is being introduced and donors musl sign consent forms which hold them responsiblefor having understood the information provided and for self-exclusion where appropriate. tistly, donors
rates by an additional 50% so that the overall incidence will he l-29. This is a remarkable decline from rates in
our institution in the 196os,which exceeded3U%, Not mentioned in the above analysis is the increasing utilization of viral inactivation procedures. Among those at greatest risk for blood-transmitted viral disease have been recipients of clotting factor concentrates. In excess of 60% of patients with haemopbilia have been infected with HBV, HCV and HIV and many have experienced the dire consequences of these infections (15). At present, howevw, virt~@ all clotting factor cuncentrat= undergo a viral inactivation procedure, usually heat or lipid mlvents which render the product free of viral contaminants. These measures are so effective that it is -nticipated that newly treated haemophiliacs till not W at any increased risk of hepatitis or AIDS as the resuIt of plasma concentrate administration. Future resolution of the NANBH problem may reside in additional inacGvation procedures which destroy nucleic acid, but not cell
membranesand hena allow treatment of cellular camp the bid. The ultimate goal will be to inactivate all blood products to elimioate residual virw tiat has slipped through the emensive historical and serologM donor screen. These combined measures will approach the previously unimaginable goal of zero risk of transmis-
nents in
are gi’-cn an opportunity to confidentially exclude their blood unit even after donation if circumstances prevented the donor’s forthright responses to the administered ques-
sion of infection by blood transfusion. These advances in the prevention of transfusion-transmitted NANBH will have little impact on sporadic (cam-
tions,
munity-acquired)
These conceptual changes have been supplemented by the introduction of specific assays for detection of antiHIV-l and anti-HTLV-1 and, in many areas, by surrogate assays(ALT, anti-HBc) for the detection of NANBH vi-
dent, except for decreasingthe pool of NANBH virus carriers. The prevention of sporadic NANBH will depend upon elucidation of the mechanisms of non-parented transmission of this agent. Studies are in progress to assess the &at&e rules of SeKual,maternu-fuetal and XCtor-borne transmission and appropriate prevention will
muscarriers. In lhe future, specifictests for anti-EKV wil! be universallyintroduced for donor screeningNo comprehensive study of NANBH incidence has been reported since these multiple intervention meaSures
NANBH which is transfusion-indepen-
depend upon the outcome of these studies. While the ultimate solution to the problem of NANBH
have been sequentially introduced. However, there is indirect evidence that NANBH incidence has markedly declined since 1986 as assessed by cases reported to state health departments and the CDC, by the general observation of those administering blood and by as yet incomplete
resides in prevention, fur the first time there is now B treatment option. As outlined in this symposium, initial studies with a-interferon are very encouraging, demonstrating that this drug can reduce hepatocellular inflammation and in some cases normalize serum ALT and re-
prospective studies where such cases have now become
verse the histological changes which accompany chronic hepatitis, A spectrum of responses to drug therapy have been noted, including treatment failures and partial and wmplete remissions. Relapses often mur when therapy is stopped, but it is clear that some NANBH patients
rare. Earlier praspective studies revealed transfusion-associated hepatitis incidences in the range of 7-12% prior to 1980(1). mark& ly varied incidences, depending on geographic location,
Studies Fran 1980-1985 have showi
with general levels between 5-10% (13,14). Although the lrue current incidence is unknown, it is my estimate that post-transfusion NANBH rates are now between 2-4% in the U.S. A. I would further project that the introduction of the specific assay for HCV will reduce these
treated with a-interferon sustain prolonged complete remission which far exceeds the spontaneousresolution rate.There are manyunresolvedissues,including the ap propriate indications for treatment, dosage, duration of therapy and optimal times to initiate therapy, but tha
BASIS FOR THE TREATMENT OF CIIRONIC NANBH are questicm which can be readily addressed in appropriate ctinical trials. Of particular importance is the need to determine if early therapy would be the key tu the prevmion
of cirrhosis
S25 ploration is the rde of orher antiviral agents. particularly those shown to be efficacious against RNA viruses, and
and perhapsI-KC,Also requiringex-
References 1 Dienstag JL. Non-A, non-B hepatitis. I. Recognition. epidemidogy. and clinical features. Gastrwntcrology 1933; 85: 439-62. 2 Alter HI. Chronic consequences of non-A. non-B hepatitis. In: &elf LB, Lewis JH, eds. Current Perspectives in Hepatology. New York: Plenum Publishing, 1989; 83-97. 3 Kiyawa K, Akaiane Y, Nagata A, et al. Hepwltular car& noma after non-A, non-B posttransfusion hepatitis. Am J Gxitroenrerol 1s; 79: 777-81. 4 Dimstag IL. Non-A, non-Blqxds. It. Experimental transmis*o, putative virus agents and markers aad prcvcatia. Gas_ cnterology 1m; 85: 743-60. 5 Bradley DW, McCaustland KA, Cook EH. Schabk CA, Ebert JW, Maynard JE. Posttransfusion non-A, non-8 lqatitis in chixparuecs: physidemical evidence she tubule-forming agent is a small, enveloped vines. Gastrocnterolugy 1935; 88: 773-9. 6 Cho4 Q-L, Kuo G, Weiner AJ, Qverby LR, Bmdky DW. lfoughton M. Is~htion of a cDNA ckm detived from a Mm% born mm-A. ~ton-5 viral hepatitis gnome. S&net IQE9; 224: 359-U. 7 Alter HJ, Prince AM Transfusion-tiated non-A, non-B hcp atitk an assessment of the causative agent ancl its clinical impact.
Transfus Mcd Rev 1988; 2: 288-93. 8 Kuo G. Chow Q-L, Alter HI, et a1. An assay fw dcculating antibodies 10 a major eiioIo@c virus of human non-A non-B hepatitis. Science 1989: 244: X2-4. 9 Alter HJ, Purcell PH. S!tih JW, et al. Detection of antibody to hepatitis C tin15 in prospectively followed transfusion receipients xith acute and chronic non-A, non-8 heparitis. N En@ d Med 198% 321: 1494-5#. 10 Alter HJ. Colemaa PJ, Altlwnder J, ef al. Irnpoti= of heterosexual activity in the 1mnsmission of hepatitis B and non-A, nonB hepatitis. JAMA 1989; 262: 1201-S. 11 Esteban JI. Esteban R, Viladorniu L. Hepatitis C virus antibodiesamongriskgroPpsinSpain.Lancetl~ii:294-6. 12~~An&HCVCIi~TriaIs:~oftbe%xecdiags, First lntern@n~I SvmpDsium Hcphtis c vuw, Rome,
Italy.
ScptcmbEr f445,1989.
Clinical, virological and epidemiological basis for the treatment of chronic non-A, non-B hepatitis
H.J. Alter
Non-A, non-B hepatitis is the most common serious complication of blood transfusion and also occurs in a sporadic form whose routes of transmission are currently unknown. While generally mild in its acute presentation, nan-A, ~n-l3 hep &is frequently progresses to cbroniu hepatitis which zzy eventuate in cirrhosis and hepatocellti carcinoma. The disease is caused by a smail, enveloped RNA vinrs now designated hepatitis C vim, whichhassimitities to the flaviviruses. Studies using the recently developed antibody assay have indicated that hepatitis C virus is the predominant agentof both transfusion-associated and sporadicnon-A, non-I3hepatitis. In 50435%of transfusion-associated cases, a donor can he found who is positive for antibodies to the hepatitis C virus. Current dataindicrtte thattheseantibodiesare prwnt in ap pwx.0.5%~fblooddonorsintheUnitedStatesaadEurope,l~S%bJapanand6%in~,as~Uasin60-&0%~fhaemqhiiiac~and intravetrous drugabusersandapprox.20%of dialysis patieats. Withchangesin dwor selectionandtraw fwian pr&ces, heinch&m of td non-A, IIM-Bhepatiti ham&d&d fromratesof 5-10% prickto 1985to estimatedcwent ratesof 2-496. Tireintr&cGon of theanti-HCVtestshouldeffti an acwitional5O% reductku in m-assoejated WSA, non-Bhepatitis. In addition to thesepreventiveuwsur~, &f&w tbwapyuow am at handin ti form of a-interferon.The efficacyof otheraMviralagentsandthe potentialfor combiuatjun therapies also needtotleexpIOred.
InCloning of the hepatitis C vinrs (HCV) has transfomxd the field of non-A, non-B hepatitis (NANBH) and provided major insights into its =mtion, transmissian and chronic sequelae (I). Each of these aspects will have considerable impact on bothprevention and treatment smtegies. For the 5rst time, transmissionpatternscan be
genomidy assessed. Similarly, hatment ~dn now be better defined in terms of anti-HCV positive vs. antiHCV-negative dwase, each of which mayhave different treatment outcomes. We are moving in the direction of diagnostic precision and uf unders!anding the moIecular basis of NANBHinfection,Visualization of the HCVpar-
ticleand elucidationof its structureare ~IDSOSI certainto follow, aud the fieldof non-A, non-H hepatitis will move stateOfclinicalobservationto a statesimilar to that for the hepatitisI3 virus (HBV) where the
tracedby scrologiwtassays(Z), the diagnosisof NANEN can be directlyestablishedratherthan inferredby se~o-
from tbe mne
Iogical ex&sion,
molecular biiology, phw characteristics, tissrre distribution and disease manifestations are known in intricate
and disease
-ations
such as that
with hepatoceilularcarcinomacan be serdogicallyand Corrqondh~~r
U.S.A.
Dr. H.J. Alter. bparttnent of TransfusionMedicine,
National
Imtitutcs
ofHe&h,
9MHlRdviIk
pike, Bethesda,MD
H.J. ALTER
sive whole.
observed in NANBH, including: a monophasic, single peak with subsequent full recovery; a polyphasic. fluctuating pattern that is characteristic of NANBH; and a plateau pattern, wherein the ALT does not reach very
NANBH was recognized in 1975 when it became apparent that most cases of transfusion-associated hep atitis were serologically unrelated to either the hepatitis A virus (HAV) or HEW (1). The term ‘non-A, non4 refleeted uncenainty about the nature of this agent and the fact that the diagnosis was based on the serological exdusion of known hepatotrophic agents. Although a great deal of clinical information has been acamuleted over the ensuing decade, the exclusionary nature of the diaguosis of NANBH did not change. Indeed, it is remarkable
high levels in the acute phase, but where persistent ALT elevation is the rule. In the latter cases, the acute phase merges imperceptibly into the invariable chronic outcome. The development of chronic hepatitis is also very frequent in those patients with the polyphasic (fluctuating) ALT pattern and it is this chronic hepatitis that constitutes the primary problem in HCV infection. Hence, while acute NANBH infection is seemingly benign, it takes on major clinical significance because of its predisposition to evolve into chronic disease. Multiple prospective studies indicate that 3040% of patients with NANBH develop chronic hepatitis, with the average occurrence in a composite of eight studies being apptox. 50% (2). Chronic hepatitis is defined by ALTele-
how much has been learned about NANBH despite the absence of a visualized panicle or a specific serological as-
vations persisting for more than a year after the onset of hepatitis. Liver biopsies obtained in the wake of per-
detail. The therapeutic effectiveness of a-interferon is at a unique stage, when, for the first time, treatment, biology, physiology and serology ere being integrated into a cohe-
first
say. Using only setum alanine
aminoimlsferas8 (ALT),
liver biopsies and the chimpanzee model, have fairly precisely deened the clinical
sistent biochemical
abnomxdities
reveal mild chronic ac-
investigators spcttum of
tive hepatitis (CAH) in the majority of cases, but the bis-
NANBH and have developed a physical model of the agent, including size characteristics and the lipid ~nterd
chronic persistent hepatitis, severe CAH and cirrhosis. In addition to evidence of hepatoeellular inflammation with varying degrees of piecemeal necrosis, the histologkal lesions are characterized by bile duct proliferation and mi.
of its membrane. These have led to inactivation strategies and other intervention measures which have greatly reduced blood transmission. The acute disease associatedwith the non-A, non-B
tologieal spectrum also includes chronic lobular hepatitis,
cmvesicular steatasis. In mild cases, it may be dlult to distinguish the lesions from alcoholic hepatitis or liver dis-
hepatitis virus (hereafter designated HCV) infection is generally mild or inapparent. Only 25% of prospectively followed patients with transfusion-associated NANBH (TA-NANBH) are icteric and/or symptomatic, and less than 10% are severely ill. Symptoms when present are typical of viral hepatitis and indistinguishable from infection with HAV or HBV. Fulminant hepatitis is extremely rare in prospectively followed patients with TA-NANBH. However, in compilations of patients presenting with fulminant hepatitis, NANBH is frequently cited as the cause (1). I believe this primarily reflects the imprecision of the diagnosis and it will now be important to reassess these fulminant cases using specific methods for the detection of
ease of obesity. We development of cirrhosis has been noted in every seriesthat includes histological analysis; almost uniformly, 20% of patients who are biopsied have histological evidence of cirrhosis (2). Furthermore. in patients who undergo serial biopsies. the progression barn CAH to cirrhosis has been repeatedly documented. In
HCV. Serological assayswill not help in patients who succumb to their fulminant hepatitis because anti-HCV development is considerably delayed. However, the poly merare chain reaction (PCR) may detect viral nucleic acid in serum and in situ hybridization or immunohistological studies may be utilized in stored or freshly obtained liver biopsies. These methods ate not well developed et pres-
quency of cirrhosis on biopsy contrastswith the much lower frequency of clinically apparent cirrhosis. While hop atic failure and typical end-stage liver disease clearly occur in the wake of TA-NANBH, th& occutteuce is ICIatively rate as compared with the number of casea of cirrhosis projected from the incidence of NANBH, the tie-
ent but are almost certain to become available in the near future. Several patterns of transaminase elevation have been
studies in Italy and Japan, where acute and chronic phase biopsies were obtained, histological progression from acute post-transfusion hepatitis to CAH to cirrhosis has been proven (2). The combination of biochemical and histological abnormalities suggests that at least 10% of patients with NANBH develop cirrhosis (20% of 50%). This high fre-
queucy of chronic biochemical changes and the frequency of c:rrhosis on liver biopsy. Hence, the cirrhosis generally appears to be indolent es compared with the image of cirrhosis occurring in the setting of alcoholism. There are
s21 several possible explanations for this. Firstly, alcoholic patients are generally not biopried uutil they present with physical manifestations of pmtal hypertension. They are less likely to be involved in prospective studies where biopsies are obtained solely on the basis of persistent biochemical abnormalities. Little is known about the duration of cirrhosis in alcoholic patients before po~al hypertensive sequelae become manifest. Secondly. the alcoholic patient continuously subjects the liver to to.& insults which may speed progression to cirrhosis and from cirrhosis to end-stage liver disease. In contrast, cirrhosis in the NANBH patiad evolves from a single infectious watt and the subsequent chmmc, !ow$rsde hepatocelluiar damage may not equate with the massive inflammatory onslaughts of repetitive bouts of atcoholism and hence may run a more indolent and slowly progressive course. Indeed, the evolution of NANBH
has been shown to be
extremely slow. Studies in Japan, which retrospectively related various stages of chronic liver disease to a history of prior transfusion,
demonstrated
period 10 the development the mean interval
an inordinately
of clinically mxtifest
from transfusion
long
disease:
to the diagnosis
of
chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) were appmx. 10, 20 and 30 years, respectively. This delayed development of clinical disease could acwunt far the discrepancy between the number of cirrhosis cases and liver fatalities projected from prospective studies, and the number actually observed. Acquired immunodeficiency syndrome (AIDS) lookback swJics have shown that a very high pmpation of transfused individuals die of the disease for which they are transfused or an intercurrent illness and hence die before they develop cliical evidence of their human immunodeficiency virus (HIV) infection. The same is undoubtedly true for HCV infection. such that many transfused HCV-infected patients dieof other causes before they dev&p cirrhosis or before their cirrhosis becomes sufficiently extensive to result in the clinical stigmata associated with impaired parml flow and decreased protein production. IO essence, chronic hepatitis and cirrhosis are frequently documented in NAN&H infection by biochemical and histologicaI criteria, but the clinical correlate of these changes wars less than expected because of the slowly cvolvinS nature of the disease and the probability of death from intercurrent causes. Nonetheless, end-stage liver disease dca OFcur as a result of HCV infection, as dues HCC (1.3). The relationshin of NANBH to HCC had been occasionally recognized in cally recognized by the alcoholic patiems with cumnce has now heen
c*“o reports and mure systematiabsence of HBV marken in nonHCC. The probability of this ccvastly strengthened by the finding
of anti-HCV antibody in a high proportion (@l-80%) of HBV negative patients with HCC. The strength of this serological association was one of the majo. surprises of the recent application of UCV serology. While causality has not been established. i: is probable ‘&at tiCV, like HBV, is directly or indirectly aswiated with the development of liver cell cancer. This may be through a specific oncogettic effect. through the mutagenic effect of the regenerative process which accompanies cirrhosis, through a cofactor mechanism, or through any combination of the above. Whatever the mechanism, HCV may be one of the primary aetiological agents in the development of HCC, particularly in Japan where HCV infection and HCC are both very prevalent. Hence, the problem of NANBH infection resides in iu chronic manifestations which now clearly include both cirrhosis and HCC. It is these chrmtic sequelae which served as the impetus and rationale for treatment with a.interfcron and other antiviral agents. If the progression to cirrhosis and HCC cat be prevented in patient with CAH or other pre-cinhotlc
chronic liver tiiasc,
will clearly he justlfipd. At present,
Tim treatment
the dtuarian
of treat-
ment necessary to prevent these sequelae or the most oppatune time to initiate treatment are unknown.
NNt-A,ltOlt-B:tk* Many of the physical characteristics of the NANBH agent have been deIineated even in the absence of an identified particulate stmcture attdlor any semlogical or other direct means of viral idanitication. Tbir bar been made possible by infectivity studies performed io the chimpanzee, the mdy animal model for NANEtH. The swceptibiity of the chimpanzee to NANBH infection was estab&hed in I!+76 and, i&ed. served as the East proof that NANBH was caused by a bansmtibk agent (4). The chimpanzee develaped only a mild form of hepatitis, but the combination of and mild histological changes of hepamceIhtler inQammation made this a reasonable and us&l infeztivity tttc&I. The value of the chiipattzee model was further enhanced when chamctciistic ultmsmtctwal chat= were noted in the cytoplasm of infected hepataytes. There were a variety of such changes, but mast charaa.zristic were cytophwnfc tubular structure comistiug of doubk-unit membraoes sunmmdfug an eIecuondense cena. The preseuce of these tures in animals 6th mild evidence of hepatitis amfumed the transmirsion of NANBH. Independent studies. perfunned at the National Institutes of Health (NIH), the Centers for Disease Cotnml (CDC) and in Japan, revealed that the agent character-
ALTcIevatIo~
H.J. ALTER
sz2 ized by the presence of cytoplasmic tubular structures was sensitive to chloroform and hence contained essential lip id in its membrane (4,J). We now know that this chlorofrxt-sensitive. tubular forming agent induces anti-HCV antibody in infected individuals and hence represents the hepatitis C virus. This agent is the predominant and possibly the sole cause of NANBH. However, a second NANBH agent has been suggested by chimpanzee crosschallenge studies, by a short incubation form of NANBH which follows the administration of clotting factor concentrates, and by experiments which suggest that there is a chloroform-resistant agent that can also transmit hepatitis to the chimpanzee (4,5). The existence of a second agent can now be better ascertained “sin8 the sane moIec,der approaches which discovered and charanetied HCV (6). Following the characterization of HCV as chloroformstnstive, filtration studies were performed to determine its size. Initial studies indicated that the agent is less than 80 nm in diameter
(5) and subsequent
studies revealed
that the egettt could pass through a 50 em filter, but was trapped by a 30 nm filter (7). Overall, it was estimated that the particle was 30-60 nm in diameter. NANBH
is thus small and
(8). The ability to detect antibody allowed ior e series of epidemiological studies which are described in the next section. By the use of overlapping clones, the genetic structure of HCV has been identified. It appests toconsist of appmx. 10 CC0 base pairs which code for structural and non-structural proteins in a single large open reading frame which is post-transcriptionally cleaved. Both the physical and genomic characteristics of HOI have many similarities to the tlavivintses, supporting the earlier supposition of Bradley et al. (5). However, there is ooly a small degree of homology between HCV end known flaviviruses and at this point HCV is considered ‘fiavi-Ike’ mtltcr than deftnitively ktongin~ it, that vim, class. Although the entire gemme has been sequenced and although its general physical characteristin are known, HCV has never been visualized. This is consistent with the low level of circulating vints infetred from infectivity titres in the chimpanzee model. However, the availability of e serological marker end PCR should alIov; for coacen. tration of the agent in gradients tion.
and its ultimate visualize-
Tbe agent of
lipid-encapsidated.
These
physical cbaracteristies considerably narrow the field of candidate virus families to which the agent of NANBH might belong. These include the small RNA viruses formally designated toga and now designated alpha and flavi, the small DNA viruses of the hepadna group, incomplete agents such as delta, unconventional viruses and viraids. Dr. Bradley at the CDC first suggested that the NANBH agent was most similar to the togaviruses (5) and that contention is now being supponed by the work at the Cbiron Corporation which finds that HCV has properties similar to, but not identical to. the flavivirures (Houghton M, Personal communication). Thus, even prior to the cloning of HCV, a remarkable and essentially correct estimete of the agent’s structure and texonomic classification was established. In 1989, the Chiron Corporation, in collaboration with the CDC, culminated 6 years of intensive effort by cloning HCV (6). This was achieved by extracting nucleic acid from litres of highly infectious chimpanzee plasma and then generating a c-DNA library. The c-DNA was then insened into an expression vector, yGT-11, which was initially used to infect Escherichia cob and subsequently to infect yeast. Tbe expressed proteins were screened with plasma from a patient with chronic NANBH. Reactive clones were assessed by radioautography. Through this screening process, a clone was identified which expressed a protein specific for NANBH. This antigen wes combined with that of two related clones and became the foundation of un immunoassay to detect antibody to HCV
NmA, ntcm.B: qMem&gy
utd sue&y
The availability of a serological marker has allowed for semprevalence studies, epidemiological studies and a better deGiticm of the sequence of events in HCV infection. When
the anti-HCV
essay was developed,
it was first
evaluated in chimpanzees and clearly distinguished chimpanzees with NANBH infeztkm from those with HBV or HAV infection and from uninoculated cotttrols. It was then evaluated against the NM NANBH panel consisting of sere proven to transmit NANBH and appropriate disease and normal controls. The Cbimn assay was the reliably and reproducibly break this caled panel (8).
to
tint
finally. the assay wes evaluated in transfusion recipiettts with biopsy-proven NANBH and in the donots to these patients (9). These studies showed that anti-HCV was very frequently present in patients who developed chronic NANBH (80-100%) and less frequently present in those with acute, self-limiting disease (15-6096). In general, the more certain the clinical diagnosis of NANBH, the more likely anti-HCV positivity. It eppeers that antiHCV will decline and ultimately disappear in cases where the infection is not persistent. In OUT NIH studies, all 15 patients with chronic NANBH were anti-HCV positive, es were three of five (60%) with transient NANBH (9). The antibody has been shown to persist for a mean of greater then 6 years in the chronic cases and to disappear in each of the acute ceses though this disappearance wes dekyed. and in one case
took more than 9 years. The development of anti-HCY antibody is generally delayed with a mean interval pustexposure of about 18 weeks in the transfusion setting.
Some cases may take close able antimy.
toa year
to manifest detect-
Late samples are essential for proper diagnosis. An analysis of the donor-recipient nnship rend-HCV veals an anti-HCV positive donor in SO-85 positive GMS. In the NW study, surrogate markers (ALT, anti-HBc) detected 50% of the anti-HCV positive donors (9). Hence, implementation of anti-WV testing
*
furblwd ¬ screeningtill be veryeffectiveandclearIy superiorto surrogatetesting,thou@ the latter may be retained as adjunctive protective measures not only for HCY, but also for HBY and HIV infections, A summary of the epidemiological trends which have emerged as the result of anti-HCV testing is as follows: (i) sporadic (community-acquired) NANBH is dsle to the
same agentas TA-NANBH (10); (ii) sexualand contact transmissianmay occur,but are rare comparedto HFW and HIV infect&s (10); (iii) anti-HCV is found in 60-W% of haemophiliaw and intnwenous drug abusers, lS-20% of dialysispatientsand only 4% of malehome~xuals (II); (iv) in pruspetiivestud&, morethan80%of well characterizedTA-NANBH cases are HCV-related and 5Q-85% have an identified anti-HCVpositivedonor (9); Iv) anti-HCVis found more frequentlyin chronic thanin rcsolviugNASH and probablyindicatesactive viralreplicationand ongoinginfectivityratherthan convalescence(9); (vi) the deveiopment of auti-HCVafter transfusionis delayed(meanapprox.20 weeks},the iuterval from exposureto detectionmay exceed 1 year; and {vii) anti-HCY prevalent in donors is 0.3% in Canada, 0.5% in Europe, 0.6% in the U.S.A., 1.5% in Japan and 6% in Afrka (12). A variable number of cases classifiedas PJANIWare an@-HCV ntgative. One explanation for this is an error in tie &Gal diagnais. T3e diagnosis of NANBH is often
imprecisebecauseit is based on clinicaland serologM e~~lusi01~Anti-HCVnegativecases may representnonviralhepato&luhrinjuryor incidentalhepaticithnmation relwd to viruses not geneMy consideredto be hepatotrq3hic.Tl~emorecertainthe clinicaldiagnosis,especiallywhen established by biopsy, the more likely the case will be anti-HCV positive. A seco~~Ipossbk re85oa for anti-HCV negativity is that anti-HCV sroconversion may havt been misEedBecky of inadequate sampling, particularly the lack of late samples to detect the often delayed semnversion. Thirdly, the case may be due to HCV despite a negative a&HCV assay.This assay rep resentsa tit generation test and may not be positive in all instances of HCV infection.As PCR, in situhybridization
and immunofluorescence technique are refined,a pro-
portion of anti-HCV negative cases will undoubtedly be shown to be HCV related. Lastly, the abw of antiHCV in NANBH cases mayindicatethe presenceof orte or more additional agentsof thisdisease.Thereis a need to exar;;i;;e uneq’;ivocal cases of NANBH which are h&iHCV negative by PCR and in situ hybridization. If still HCV negative, rhesc: will be fertile cases for investigation by the same molecular approachesthatuncweredHCV. WhileHCV is unequivocally transmittedby parentera routes,including tmsfusion andintravenousdrugabuse, its other modes of spread are pxly defirred. The large number of sporadic hepatitis cases in which there is no identified percut8neous bland source strongly suggests non-parentera transmission patterns. nti2 first presump tion wodd favour sexual transmission, but the data for this are currently mt. Afthough v control stndi~ by the CDC suggest WetosexuaIspread,sexualpartners of
patientswith trau$rtsiun-associated hepatitisand hetem sexualcontactsof iatravenousdrugabuMs havenot been shownto be at increasedriskfromMY infection (1I). In addition,the prevakace of HCV is relativelylow in male homosexL&(4%), a populationat tik for all formsof sexuaIlytransmitted diseases; an exm of 60% of male homosexuaJs havebeeninfectedwithHBV andHIV. Few data are currentlyavailableon materno-foetaltraasmission, but the low prevalenceof anti-HCVin infantsaud youngchildren mitigates a@st such spread as playing a prominent role in dissemination of this disease. The p”ibility of insect transmission is intriguing since the agent has characteristics in common with -borne infectious agents; however, there is w c3irect evidem;e: for this. Stud& whiib will more precEseIy define these transmissionpatternsareinprogress,Weareju8tattbetbresholdof understpnttingthe~ofpvANBHiafection and considerable data in this regard are expected to accrue in the next few years.
Nm-A, nom-B: tk Remarkable adivances haveoccurred ~II the prevention of NAPJBH and other transfusion-t viral dis-
eases. Maq of t&e advances preceded the recent developmentof a speciGctest to detectcarriersof HCV and relate to measures intr0duc4 prinhl~r to prevent tran&&on-trmsxn&ed AIDS. ForGtou4y, aIT meafllres introduced to prevent HIV t prevent HBV and HCV transmi&oa because of the overlap in these hi@ risk donor populations. The dedining incidence of these
* ’ 11 also
transfusion-transmitted dise~ in part reflects advances in serology, but IIN& m ~&MS 8 basicchangeh the reauitulentofd4wrsandinMoodtr=ftEwprac9ice.
H.J. ALTER
S24
The threat of AIDS has forced an assessmentof transfusion practice and has engendered in both physician and patient a heightened awareness of the infectious and sometimes mortal risks of blood transfusion. This has led to a more judicious use of blood products and the elimination of some, but not all, unwarrantedtransfusions.There is still a need to better define the indications for transfusion and to control the overutilization of some blood cornponenrs. In tandem with the more appropriate use of blood has been a dramatic increase in the use of autoI+ gous Mod, both by pre-deposit and by intra-operative salvage. In some institutions, 15% of the blood utilized is of autologous otigin and many patients sustain major surgery without the use of any homologousbled products. The other area of major change has been in the selection and screeningof blood donors. In the United States, there are now no paid donors except those that contribute
plasma which can be effectively inactivated. Donors are provided with extensive information on high-risk behaviow and are asked to self-excludethemselves if they fall into any of the designated categories. In addition, direct questioning regarding risk behaviour is being introduced and donors musl sign consent forms which hold them responsiblefor having understood the information provided and for self-exclusion where appropriate. tistly, donors
rates by an additional 50% so that the overall incidence will he l-29. This is a remarkable decline from rates in
our institution in the 196os,which exceeded3U%, Not mentioned in the above analysis is the increasing utilization of viral inactivation procedures. Among those at greatest risk for blood-transmitted viral disease have been recipients of clotting factor concentrates. In excess of 60% of patients with haemopbilia have been infected with HBV, HCV and HIV and many have experienced the dire consequences of these infections (15). At present, howevw, virt~@ all clotting factor cuncentrat= undergo a viral inactivation procedure, usually heat or lipid mlvents which render the product free of viral contaminants. These measures are so effective that it is -nticipated that newly treated haemophiliacs till not W at any increased risk of hepatitis or AIDS as the resuIt of plasma concentrate administration. Future resolution of the NANBH problem may reside in additional inacGvation procedures which destroy nucleic acid, but not cell
membranesand hena allow treatment of cellular camp the bid. The ultimate goal will be to inactivate all blood products to elimioate residual virw tiat has slipped through the emensive historical and serologM donor screen. These combined measures will approach the previously unimaginable goal of zero risk of transmis-
nents in
are gi’-cn an opportunity to confidentially exclude their blood unit even after donation if circumstances prevented the donor’s forthright responses to the administered ques-
sion of infection by blood transfusion. These advances in the prevention of transfusion-transmitted NANBH will have little impact on sporadic (cam-
tions,
munity-acquired)
These conceptual changes have been supplemented by the introduction of specific assays for detection of antiHIV-l and anti-HTLV-1 and, in many areas, by surrogate assays(ALT, anti-HBc) for the detection of NANBH vi-
dent, except for decreasingthe pool of NANBH virus carriers. The prevention of sporadic NANBH will depend upon elucidation of the mechanisms of non-parented transmission of this agent. Studies are in progress to assess the &at&e rules of SeKual,maternu-fuetal and XCtor-borne transmission and appropriate prevention will
muscarriers. In lhe future, specifictests for anti-EKV wil! be universallyintroduced for donor screeningNo comprehensive study of NANBH incidence has been reported since these multiple intervention meaSures
NANBH which is transfusion-indepen-
depend upon the outcome of these studies. While the ultimate solution to the problem of NANBH
have been sequentially introduced. However, there is indirect evidence that NANBH incidence has markedly declined since 1986 as assessed by cases reported to state health departments and the CDC, by the general observation of those administering blood and by as yet incomplete
resides in prevention, fur the first time there is now B treatment option. As outlined in this symposium, initial studies with a-interferon are very encouraging, demonstrating that this drug can reduce hepatocellular inflammation and in some cases normalize serum ALT and re-
prospective studies where such cases have now become
verse the histological changes which accompany chronic hepatitis, A spectrum of responses to drug therapy have been noted, including treatment failures and partial and wmplete remissions. Relapses often mur when therapy is stopped, but it is clear that some NANBH patients
rare. Earlier praspective studies revealed transfusion-associated hepatitis incidences in the range of 7-12% prior to 1980(1). mark& ly varied incidences, depending on geographic location,
Studies Fran 1980-1985 have showi
with general levels between 5-10% (13,14). Although the lrue current incidence is unknown, it is my estimate that post-transfusion NANBH rates are now between 2-4% in the U.S. A. I would further project that the introduction of the specific assay for HCV will reduce these
treated with a-interferon sustain prolonged complete remission which far exceeds the spontaneousresolution rate.There are manyunresolvedissues,including the ap propriate indications for treatment, dosage, duration of therapy and optimal times to initiate therapy, but tha
BASIS FOR THE TREATMENT OF CIIRONIC NANBH are questicm which can be readily addressed in appropriate ctinical trials. Of particular importance is the need to determine if early therapy would be the key tu the prevmion
of cirrhosis
S25 ploration is the rde of orher antiviral agents. particularly those shown to be efficacious against RNA viruses, and
and perhapsI-KC,Also requiringex-
References 1 Dienstag JL. Non-A, non-B hepatitis. I. Recognition. epidemidogy. and clinical features. Gastrwntcrology 1933; 85: 439-62. 2 Alter HI. Chronic consequences of non-A. non-B hepatitis. In: &elf LB, Lewis JH, eds. Current Perspectives in Hepatology. New York: Plenum Publishing, 1989; 83-97. 3 Kiyawa K, Akaiane Y, Nagata A, et al. Hepwltular car& noma after non-A, non-B posttransfusion hepatitis. Am J Gxitroenrerol 1s; 79: 777-81. 4 Dimstag IL. Non-A, non-Blqxds. It. Experimental transmis*o, putative virus agents and markers aad prcvcatia. Gas_ cnterology 1m; 85: 743-60. 5 Bradley DW, McCaustland KA, Cook EH. Schabk CA, Ebert JW, Maynard JE. Posttransfusion non-A, non-8 lqatitis in chixparuecs: physidemical evidence she tubule-forming agent is a small, enveloped vines. Gastrocnterolugy 1935; 88: 773-9. 6 Cho4 Q-L, Kuo G, Weiner AJ, Qverby LR, Bmdky DW. lfoughton M. Is~htion of a cDNA ckm detived from a Mm% born mm-A. ~ton-5 viral hepatitis gnome. S&net IQE9; 224: 359-U. 7 Alter HJ, Prince AM Transfusion-tiated non-A, non-B hcp atitk an assessment of the causative agent ancl its clinical impact.
Transfus Mcd Rev 1988; 2: 288-93. 8 Kuo G. Chow Q-L, Alter HI, et a1. An assay fw dcculating antibodies 10 a major eiioIo@c virus of human non-A non-B hepatitis. Science 1989: 244: X2-4. 9 Alter HJ, Purcell PH. S!tih JW, et al. Detection of antibody to hepatitis C tin15 in prospectively followed transfusion receipients xith acute and chronic non-A, non-8 heparitis. N En@ d Med 198% 321: 1494-5#. 10 Alter HJ. Colemaa PJ, Altlwnder J, ef al. Irnpoti= of heterosexual activity in the 1mnsmission of hepatitis B and non-A, nonB hepatitis. JAMA 1989; 262: 1201-S. 11 Esteban JI. Esteban R, Viladorniu L. Hepatitis C virus antibodiesamongriskgroPpsinSpain.Lancetl~ii:294-6. 12~~An&HCVCIi~TriaIs:~oftbe%xecdiags, First lntern@n~I SvmpDsium Hcphtis c vuw, Rome,
Italy.
ScptcmbEr f445,1989.