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Zadaxin,
Lamivudine, Rebetron and Interferon. Zadaxin, Lamivudine, Rebetron e Interferon.
Bien es conocido por todos nosotros, el riesgo que TODO personal médico tiene de contraer hepatitis. Los productos son el denominado ZADAXIN de la casa SciClone Pharmaceuticals aprobado por la FDA en Mayo 1.998 el cual es efectivo en el tratamiento de la hepatitis B y C, químicamente se denomina thymosisn alfa 1.
EL REBETRON, una terapia combinada de ribavirin e interferon alfa2b recombinante para la hepatitis C, aprobado por la FDA en Junio 1.998.
El LAMIDUVINE, de la casa GLAXO WELLCOME, para la hepatitis B, nombre comercial EPIVIR. El
INTERFERÓN ALFA ha mostrado ser útil en el tratamiento de la hepatitis B, C, D y G
pero en combinación con el RIBAVIRIN, pareciera tener mayor efectividad.
También se esta utilizando la vacuna para hepatitis B, como inmunoterapia en la misma enfermedad. EEstas 25 REFERENCIAS nos aclaran algo este interesante tema de las hepatitis y sus tratamientos. RIBAVIRIN: (VIRAZOLE, TRIBAVIRIN)) AMPS 6 GRS (CANADÁ), REBETOL(R) Caps. THYMOSIN ALFA 1:
ZADAXIN: No encontré datos sobre presentación del producto en las bases de datos. Fue recientemente aprobado. REBETRON: Rebetron is a combination of Rebetol(R) (ribavirin, USP) Capsules and 1.) Engerix-B (SmithKline Beecham)
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DERMAGIC/EXPRESS(8)
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ZADAXIN, LAMIVUDINE,
REBETRON, INTERFERÓN
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REFERENCIA 1: thymosin alfa 1
Moshier JA; Mutchnick MG; Dosescu J; Holtz TK; Akkary S; Mahakala K; Merline JR;
BACKGROUND: Thymosin-alpha 1 is a biological response modifier that has been used
clinically, alone and in combination with interferon-alpha for the treatment of
chronic hepatitis B viral infection. Both immunomodulatory and immediate
intracellular mechanisms have been postulated to explain the effect of these two
agents on HBV-infected hepatocytes.
METHODS: In this study, hepatitis B transfected
HepG2 hepatoblastoma cells (HepG2-Nu2), derived from 2.2.15 cells, were used as an in
vitro model to determine the efficacy of thymosin-alpha 1 and interferon-alpha,
individually and combined, as proliferation inhibitors of HBV-infected cells. For
comparison, parental HepG2 cells and an SV40-transfected HepG2 cell line (HepG2P9T2)
were also evaluated.
RESULTS: In a clonogenic soft agar assay, thymosin-alpha 1
inhibited the anchorage-independent growth of the HepG2-Nu2 cells by 40% compared
with untreated controls, but did not inhibit parental HepG2 or HepG2P9T2 clonal
growth. The response was dose dependent over concentrations spanning three log units.
In comparison, 10000 units/ml of interferon-alpha inhibited parental HepG2, HepG2-N4Z
and HepG2P9T2 by 33%, 41% and 87%, respectively. The combination of thymosin-alpha 1
and interferon-alpha consistently inhibited HepG2-Nu2 clonal growth more effectively
than either treatment alone, reaching maximum inhibition levels of 51%.
CONCLUSIONS:
Thymosin-alpha 1 specifically inhibits the tumorigenic growth of HBV-transfected
HepG2 cells in contrast to the general inhibition displayed by interferon-alpha.
This panel of cell lines may be an important resource for dissecting the mechanism by
which thymosin, alone or in combination with other drugs, influences HBV-infected
hepatocytes and/or HBV-associated carcinoma.
BACKGROUND: Monotherapy for chronic hepatitis C using interferon (IFN) results in a
very small proportion of patients exhibiting a sustained response. Clinical trials
assessing the benefit of combination drug therapy may provide evidence of improved
treatment response over that seen with single drug treatment. AIM: To assess the
response in patients with chronic hepatitis C to one year of combination treatment:
thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU
thrice weekly.
PATIENTS AND METHODS: Fifteen patients with serum HCV RNA positive
chronic hepatitis C were studied. Eleven patients were treatment naive and four had
failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b.
All patients were given combination T alpha 1 and L-IFN therapy for one year with a
six month follow up period.
RESULTS: Six months after initiation of treatment seven
patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with
HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA.
CONCLUSIONS: The results of this open label trial suggest that there may be a
potential benefit to combining an immune modulator (T alpha 1) with an antiviral
(IFN) in the treatment of chronic hepatitis C. Verification of the observations in
this study require completion of a randomised controlled study.
3.) Emergence of an S gene mutant during thymosin alpha1 therapy in a patient with chronichepatitis B.
Abstract
The presence of a hepatitis B virus S gene mutant was investigated in a patient being treated with thymosin alpha1. He was seropositive for hepatitis B e antigen throughout therapy but was intermittently seronegative for hepatitis B surface antigen (HBsAg) by an RIA. Sequence analysis revealed an S gene mutant in HBsAg-seronegative serum with two consecutive amino acid substitutions: threonine115-to-isoleucine and threonine116-to-asparagine, whereas no amino acid substitution or deletion was found in the pre-S region. A site-directed mutagenesis experiment confirmed that these mutations were responsible for the failure to detect HBsAg. In summary, an S gene mutant was identified in an HBsAg-seronegative patient. The mutations were located outside the putative "a"
determinant. The emergence of an S gene mutant during thymosin alpha1 treatment suggests that enhanced host immunity against HBsAg may play a role in its antiviral activity.
4.) Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial.
Abstract
Thymosin alpha1 (Talpha) is an immune modifier that has been shown in a pilot study to be effective for chronic hepatitis B; this requires confirmation. Ninety-eight patients with clinicopathologically proven chronic hepatitis B were randomly allocated to 3 groups: 1) group A received a 26-week course of Talpha with a 1.6-mg subcutaneous injection two times a week (T6 group); 2) group B received the same regimen as group A, but Talpha therapy extended for 52 weeks (T12 group); and 3) group C served as a control group and was followed up for 18 months without specific treatment (T0 group). The three groups were comparable in clinicohistological features at entry. The complete virological response rate (clearance of serum hepatitis B virus [HBV] DNA and hepatitis B e antigen [HBeAg]) was higher in group A (40.6%) and group B (26.5%) than in group C (9.4%) (group A vs. group
C: P=.004; group B vs. group C: P=.068) when assessed 18 months after entry,
although complete response rates among these three groups were similar when first assessed at the end of therapy. There was a trend for complete virological response to increase or accumulate gradually after the end of Talpha therapy. None of the responders lost hepatitis B surface antigen. Blinded histological assessment showed a significant improvement in treated patients, particularly in lobular necroinflammation and scores excluding fibrosis. No significant side effects were observed. These results suggest that a 26-week course of Talpha therapy is effective and safe in patients with chronic hepatitis B.
5.) Lamivudine resistance in immunocompetent chronic hepatitis B. Incidence and patterns.
BACKGROUND: Lamivudine is a non-toxic, potent inhibitor of hepatitis B virus
replication. Recently, hepatitis B virus resistance to lamivudine has been described
in patients using immunosuppressive drugs after liver transplantation. METHODS: From
our cohort of 81 consecutive patients treated with lamivudine, we selected all
immunocompetent patients who received lamivudine monotherapy for a period over 26
weeks (n=14).
RESULTS: Lamivudine resistance with the characteristic mutation in the
YMDD motif was observed in four patients (actuarial cumulative incidence: 39%). Two
patterns of viral resistance were observed: incomplete response (n=2) and viral
breakthrough (n=2).
CONCLUSIONS: The observed high frequency of lamivudine
resistance may have implications for the concept of long-term virus-suppressive
therapy of chronic hepatitis B by lamivudine monotherapy.
The purpose of this study was to evaluate the effectiveness and safety of
lamivudine treatment in patients with advanced and end-stage liver disease caused by
hepatitis B. Nine cases of advanced or end-stage liver disease due to hepatitis B
infection were treated with lamivudine. Four received liver transplants while
receiving lamivudine. Moreover, each of these four has been maintained on lamivudine
therapy post-transplantation while receiving immunosuppression. No cases of HBV
reactivation have been seen. More importantly, the allograft liver tissue has been
HBc and HBs antigen negative as well as HBV-DNA negative by PCR. This report
suggests that: 1) lamivudine can be given safely to liver transplant candidates; 2)
lamivudine suppresses HBV replication, so much so that HBV-DNA becomes undetectable
in the serum; 3) despite powerful immunosuppression associated with transplantation,
HBV reactivation does not occur under lamivudine therapy; and 4) the observations
should cause transplant physicians, surgeons and third-party payers to reconsider
their positions relative to transplantation of individuals with HBV-associated
cirrhosis.
Nucleoside analogues can induce mitochondrial dysfunction leading to severe
clinical syndromes. Lamivudine, a new nucleoside analogue, is an active inhibitor of
hepatitis B viral replication without apparent clinical toxicity. To assess
subclinical mitochondrial toxicity, we studied the morphology and function of the
mitochondrial system in 15 patients treated with lamivudine. Morphology was
investigated by routine histological evaluation and electron-microscopic studies of
mitochondria in liver biopsy specimens.
Mitochondrial function was assessed by 2-
keto[1-14C] isocaproic acid decarboxylation (KICA breath test) and by measuring the
activity in liver biopsy specimens of the mitochondrial enzymes encoded by nuclear
and mitochondrial DNA (mt-DNA) (complex I and IV) as well as a mitochondrial and a
cytosolic enzyme both encoded by nuclear DNA only (complex II and lactic
dehydrogenase [LDH]).
All 15 patients underwent a liver biopsy before treatment and
a KICA breath test before and during treatment; 13 agreed to undergo a repeat liver
biopsy during lamivudine treatment. Liver tissue with no or minimal fibrotic changes
from 7 patients treated for 6 months with lamivudine was suitable for assessment of
the mitochondrial enzyme activity. We observed no signs of toxicity by routine
histological or electron-microscopic evaluation. KICA breath tests revealed no
differences in either peak exhalation or the area under the curve from 0 to 60
minutes between healthy controls (3.0% and 19.3%), untreated patients with chronic
hepatitis B (3.4% and 19.3%), and patients treated with lamivudine (3.1% and 20.6%).
The activities of the mt-DNA-encoded enzymes remained normal after lamivudine therapy.
Unexpectedly a significant decrease in the activity of nuclear-DNA-encoded enzymes in
patients with chronic hepatitis B in comparison with normal controls was found. The
mean activity of complex II dropped from 45.3 to 20.0 micromol x min(-1), that of
lactic dehydrogenase from 106 to 44 micromol x min(-1) (Wilcoxon rank sum; P < .05).
In conclusion, no subclinical signs of mitochondrial toxicity resulting from
lamivudine therapy for 6 months were observed.
The paired biopsies taken at entry and during treatment were scored by two
independent observers, using the components of the histology activity index (HAI) and
fibrosis (modified Knodell). The items scored were piecemeal necrosis, focal
necrosis, confluent necrosis, portal inflammation and fibrosis. Before treatment,
the biopsies yielded a mean HAI of 4.4 (+/- 0.8), which decreased to HAI 2.8 (+/-
0.5) during treatment. An analysis of the individual components of the
classification system showed a significant decrease in piecemeal necrosis from a pre-
treatment 1.4 (+/- 0.3) to 0.8 (+/- 0.1) during treatment (p = 0.02). Although a
trend was found for the other components, it was not statistically significant,
probably due to the number of pairs examined. In conclusion these results suggest
that prolonged suppression of viral replication by lamivudine can improve liver
histology. In contrast to previously published reports on alpha-interferon therapy,
this study indicates that the improvement in liver histology with lamivudine is
independent of HBe-seroconversion.
Almost 10 years after the first report of the effectiveness of interferon (IFN) for
chronic NANB hepatitis, the optimal treatment for chronic hepatitis C is still a
matter of debate. The issue of the relative importance of higher doses versus a
longer period of therapy remains unsettled, since the long-term response may be a
function of the total dose received. Controlled studies have shown that high doses
of IFN (5-6 MU t.i.w.), a long period of therapy (> 12 months) and the administration
of a large total dose are all associated with a higher cure rate. However, these
measures can cause more adverse effects and certainly cost more than the current
schedule of 3 MU t.i.w. for a period of 6 months. The standard schedule may be
appropriate for subjects with pre-treatment features predictive of a good response
(non-Ib genotype, low viraemia, absence of cirrhosis).
Alternative treatment
schedules or combination therapy with interferon/ribavirin should be considered in
subjects with normalized alanine aminotransferase (ALT) levels, but who are still
viremic after three months of therapy, as well as in relapsers and in non-responders.
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The effect of interferon in combination with ribavirin on the plus and minus
strands of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C (CHC) was
studied by means of nested RT-PCR. The results showed that in those who respond to
the combination of antiviral therapy, their increased serum ALT levels decreased to
normal range, but more than half (55.56%) of these patients relapsed 24 weeks after
cessation of the antiviral therapy. The positive rate of the plus strand HCV RNA in
serum (92.31%) decreased significantly to 38.46% (P < 0.005) and that of the minus
strands HCV RNA in peripheral blood mononuclear cells (PBMC, 76.92%) to 38.46% (P <
0.05) at the end of the treatment, but little effect on the plus strand HCV RNA in
PBMC in these patients was found. Relapse occurred in patients whose plus and minus
strands of HCV RNA in PBMC remained positive during treatment.
These data indicated
that absence of HCV RNA in serum do not mean complete clearance of HCV and can not
predict a sustained therapeutic response. For evaluating the antiviral effect and
prognosis it is essential to measure the plus and minus strands of HCV RNA in serum
and PBMC simultaneously. The results of the combined antiviral therapy were similar
to that of single interferon treatment; it seems that rib-a-virin do not enhance the
antiviral effect of interferon.
GB virus C/hepatitis G virus (GBV-C/HGV) is a newly described virus associated with
hepatitis in humans, and GBV-C/HGV coinfection is common in patients chronically
infected with hepatitis C virus (HCV). To determine the clinical impact of GBV-C/HGV
infection in such patients and the effect of interferon-alpha and ribavirin therapy
on serum GBV-C/HGV RNA levels, GBV-C/HGV RNA was detected and quantitated in serum
samples from 62 chronically infected HCV patients by a combination of a qualitative
nested reverse transcription-polymerase chain reaction and a newly developed
quantitative branched DNA assay: 10 patients were positive for serum GBV-C/HGV RNA.
There were no differences in the clinical, biochemical, and histologic features of
the patients with GBV-C/HGV-HCV coinfection compared with those with HCV infection
alone. Interferon-alpha treatment caused a marked but usually transient reduction in
serum GBV-C/HGV RNA, and ribavirin had, at most, a modest antiviral effect.
Interferon-alpha (IFN-alpha) induces sustained remission of chronic hepatitis C in
approximately 25% of patients. In patients who are non-responders to the first
course of therapy, retreatment with IFN-alpha is of limited efficacy. Ribavirin has
also been used to treat chronic hepatitis C, but it induces only a transient response.
In this study, we evaluated the efficacy of ribavirin and IFN-alpha combination
therapy for IFN-alpha resistant chronic hepatitis C. Twenty-four IFN-alpha non-
responders and 24 relapsers were randomized to receive either ribavirin (1000 mg per
day) together with IFN-alpha (3-6 million units (MU) thrice weekly) or the same dose
of IFN-alpha alone, for 6 months. Both at the end of treatment and 6 months later,
normal transaminase levels were more common in the patients receiving combination
therapy than in the group receiving IFN-alpha alone: 17 (70.8%) vs seven (29.2%)
patients (P = 0.009) and six (25%) vs one (4.2%) patient (P = 0.034), respectively.
At the end of treatment and 6 months later, serum HCV RNA was no longer detectable in
eight (33.3%) and five (20.8%) patients in the combination therapy group and in six
(25%) and one (4.2%) patient in the IFN-alpha therapy group, respectively. Three
patients (12.5%) were withdrawn prematurely from combination therapy because of side-
effects; ribavirin therapy was ceased or dosage reduced in six other patients (25%),
again because of side-effects.
In conclusion, this combination treatment was more
effective than retreatment with IFN-alpha, alone, in inducing sustained biochemical
remission of chronic hepatitis C that was resistant to a previous course of IFN-alpha.
The combination treatment, however, was frequently associated with significant side-
effects.
Administration has approved Schering-Plough Corp.’s Rebetron™, a
combination therapy for chronic hepatitis C in patients with compensated liver
disease who have relapsed following alpha interferon therapy
Rebetron is a combination of Rebetol(R) (ribavirin, USP) Capsules and
Intron(R) A (interferon alfa-2b, recombinant) Injection. Prior to Rebetron
combination therapy, the only drugs approved in the U.S. for treating hepatitis
C had been alpha interferons.
The FDA decision was based in part on clinical data from two pivotal
multicentre Phase III studies involving patients with hepatitis C who had
relapsed following alpha interferon therapy. Results of these studies showed
that Rebetron combination therapy resulted in a 10-fold increase in the number
of patients showing eradication of detectable [HCV-RNA (qPCR)-negative]
hepatitis C virus as compared to patients receiving Intron A alone.
A three million international units (MIU) three times a week and either
oral Rebetol 1,000-1,200 mg daily or a matched placebo for 24 weeks of
treatment. At six months post-treatment, 79 of 173 patients (45.7 percent) who
received the combination therapy had undetectable virus levels compared to
eight of 172 patients (4.7 percent) who received Intron A and placebo. Patient
tolerance of the combination therapy was good, with six percent of patients
treated with Rebetron discontinuing therapy due to adverse events versus three
These adverse events include depression, which may be severe, and rare cases
Of suicide ideation and suicidal attempt. Rebetron combination therapy is
associated with a significant risk of abnormal fetal development. Women of
childbearing potential should not begin therapy until a report of a negative
pregnancy test has been obtained.
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RESULTS. By the end of the treatment period, serum alanine aminotransferase values had become normal in 10 of 14 patients receiving 9 million units (71 percent), as compared with 4 of 14 treated with 3 million units (29 percent, P = 0.029) and 1 of 13 untreated controls (8 percent, P = 0.001). Seven patients treated with the higher dose of interferon (50 percent) had a complete response (normal levels of alanine aminotransferase and no detectable serum hepatitis delta virus (HDV) RNA), as compared with three of those who received the lower dose (21 percent, P = 0.118), and none of the controls (P = 0.004).
Treatment with 9 million units of interferon was associated with a marked improvement in the histologic findings (reduced periportal necrosis and portal and lobular inflammation), whereas in the untreated controls there was considerable histologic deterioration. In 5 of the 10 patients treated with 9 million units of interferon whose alanine aminotransferase values became normal, the biochemical responses persisted for up to 4 years (mean, 39 months), but the effects of treatment on viral replication were not sustained. In contrast, none of those who received 3 million units and none of the untreated controls had a sustained biochemical or virologic response.
CONCLUSIONS. In about half the patients with chronic hepatitis D treated with high doses of interferon alfa-2a (9 million units three times a week for 48 weeks), the serum alanine aminotransferase level becomes normal, HDV RNA becomes undetectable in serum, and there is histologic improvement. However, a relapse is common after treatment has been stopped.
Seventy-one anti-hepatitis A virus (HAV) negative volunteers were immunized against
hepatitis A. An inactivated hepatitis A vaccine (HAVRIX, SmithKline Beecham), derived
from tissue cell cultures, at single doses of 720 ELISA units was used following a
schedule of vaccinations at month 0.1 and 6. The vaccines were tested for the
presence of HAV antibodies 1 month after each vaccination and then after 2, 3, 4 and
5 years. The annual decrease of anti-HAV titres was 25%. Five years after
vaccination a protective antibody titre, varying between 20 and 5200 mIU ml-1, could
be demonstrated in all 47 retested volunteers with a geometric mean titre (GMT) of
442 mIU ml-1. Levels of anti-HAV-antibodies following active immunization were
significantly higher in female volunteers. This could be consistently demonstrated
throughout the observation period. Based on these data the antibody persistence was
calculated over time. GMTs at protective levels higher than 20 mIU ml-1 can be
expected to persist for at least 15 years.
Abstract
Hepatitis G virus (HGV), a positive sense RNA virus, is distantly related to hepatitis C
virus (HCV): its genetic organization and identity are consistent with the Flaviviridae family.
Coinfection with HGV occurs in 10% to 20% of HCV-infected subjects. These similarities
raise two theoretical questions. First, could HGV coinfection play any role in the response of
HCV to antiviral therapy and second, would this coinfected population have changes in
serum HGV-RNA induced by interferon. To address these questions, 98 patients with
documented chronic HCV underwent interferon therapy (3 million units three times a week)
for 6 months. Response to therapy was categorized using standard biochemical criteria.
Changes in HGV-RNA levels were evaluated before, during, and after interferon therapy by
a quantitative branched DNA amplification research-based assay. Eleven of 98 (11%)
patients with HCV infection had detectable serum HGV-RNA. There was no difference
between the groups (HGV+ vs. HGV-) when baseline alanine aminotransferase (ALT)
values, HCV-RNA levels, HCV genotype, histological severity, or other demographic
features were analyzed. Interferon response was similar in both groups and HGV was not
associated with outcome following therapy. Antiviral therapy appeared to induce a
reduction in HGV-RNA load in five of nine patients coinfected with HCV serially tested. In
two patients, the fall in serum HGV-RNA correlated with biochemical response, independent
of changes in HCV-RNA.
These observations indicate that a larger study of an HGV
population is required to more clearly define the relationship between HCV and HGV
coinfection and their response to antiviral therapy.
Abstract
BACKGROUND/AIMS: Pulmonary side effects of interferon-alpha therapy of chronic
hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with
interferon-alpha treatment of chronic hepatitis C have been described.
METHODS/CASES: We report on three patients who were treated with recombinant
interferon-alpha2a for chronic hepatitis C, two of them in combination with ribavirin. These
patients developed pulmonary sarcoidosis 12, 20 and 21 weeks, respectively, after beginning
interferon therapy, one patient with L¨ofgren's syndrome. In one patient sarcoidosis emerged
only after discontinuation of interferon therapy because of treatment failure. Clinical
symptoms of sarcoidosis in the three patients were suggestive of side effects of
interferon-alpha. Interferon therapy was discontinued and spontaneous remission was
observed in all three cases 5, 6, and 8 months, respectively, after the onset of symptoms.
CONCLUSION: The occurrence of sarcoidosis in association with interferon-alpha therapy
for chronic hepatitis C may have been underestimated so far. This could be due to the fact
that symptoms of sarcoidosis and common side effects of interferon are similar, and
sarcoidosis may occur after the end of interferon therapy. We hypothesize that
interferon-alpha as a potent stimulator for T-helper 1 (Th1) immune responses may trigger
the compartmentalized Th1 reaction that has been shown to take place in sarcoidosis.
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Abstract
BACKGROUND: Since a large fraction of patients affected by chronic hepatitis C do not
respond to alpha-interferon therapy, we planned a pilot study of intravenous beta-interferon
therapy in Italian patients non responsive to several courses of alpha-interferon.
METHODS: Ten Italian patients with chronic hepatitis C were treated intravenously with
beta-interferon to assess the biochemical and virological responses. Each patient received
intravenously 6 MU of beta-interferon daily for 7 days a week for a period of 2 months; in
responders, this treatment was followed by intramuscular beta-interferon administration 6
MU three times a week for an additional 8 weeks.
RESULTS: All the patients were infected
by the genotype 1b of hepatitis C virus and had a high serum concentration of HCV-RNA
(4.1 +/- 3.3 x 10(7) copies/ml). During intravenous therapy, 4 patients (40%) showed a
complete return to normal of alanino-aminotransferase and 3 cases became HCV-RNA
negative. During intramuscular beta-interferon administration, two patients breakthrough. At
the end of the follow-up (six months after the end of the treatment) two patients only showed
return to normal of alanino-aminotransferase, but one of them remained HCV-RNA positive.
CONCLUSIONS: These results indicate that even genotype 1b of hepatitis C virus can be
suppressed by intravenous beta-interferon therapy, as previously described in similar cases
in Japan. The rate of sustained biochemical and virologic response was, however, low,
suggesting that further studies are needed to define the best regimen to achieve eradication of
hepatitis C virus infection.
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Abstract
Chronic hepatitis B virus infection is endemic in Asian communities in the United States. The
purpose of the current study was to compare the antiviral efficacy of interferon-alpha2b in a
group of adult Asian patients chronically infected with hepatitis B with active replication
compared to a control group of Caucasian patients treated with the same regimen. Patients
with entry aminotransferase (ALT) levels greater than three times the upper limit of normal
received interferon-alpha2b, 5 million units, subcutaneously daily for 16 weeks.
Patients with
pretreatment ALT levels 1.5-3 times the upper limit of normal received prednisone for a total
of six weeks prior to interferon starting at 60 mg daily with reduction in dosage by 20 mg
every two weeks with a two-week period between finishing prednisone and starting
interferon-alpha2b. Eight (62%) of the 13 Asians and six (60%) of the 10 Caucasians
cleared HBeAg and HBV DNA from serum (NS). By the end of one year of follow-up after
therapy, four (67%) of six Caucasian responders but none of the Asian responders had
cleared hepatitis B surface antigen from serum (P < 0.05).
Loss of serum markers of active
replication appeared less durable in the Asian responders compared to the Caucasians with
reappearance of serum HBeAg in two (25%) of eight of the former but only one (17%) of
the latter group. Three other Asian patients subsequently redeveloped HBeAg in serum. It is
concluded that adult Asian-Americans have an identical initial response rate to antiviral
therapy with interferon-alpha2b; however, the response may be less durable and does not
usually lead to loss of HBsAg.
Abstract
Vaccine therapy is now used in various infectious diseases. The hepatitis B virus (HBV)
leads to chronic infection in around 5% of patients with a high risk of chronic active hepatitis
which may result in cirrhosis and hepatocellular carcinoma. The partial efficacy of antiviral
therapies (40% of sustained inhibition of HBV replication), their cost, their possible side
effects and the immune-mediated pathology of HBV infection explain the need of new
immune therapies in treating HBV infection.
Experimental and clinical evidences suggest the
usefulness of vaccine therapy in HBV chronic infection. In a pilot and opened study,
forty-six consecutive chronic HBsAg carriers with chronic hepatitis and detectable serum
HBV DNA were given 3 standard injections of the GenHevac B vaccine at one month
interval. Six months after the first injection, 12 patients (26.1%) had undetectable HBV DNA
while 8 others showed significant decrease (more than 50%) in HBV DNA titers.
Six of
these 12 responders received a standard course of alpha-Interferon (5 MU thrice weekly
subcutaneously for 4 months) and all six had still undetectable HBV replication at the end of
follow-up. Among the 34 non responders to vaccine, 20 were given alpha-interferon and 2
the monophosphate derivate of Vidarabine: 12 of these 22 patients stopped HBV replication
and in all 12, vaccine therapy had induced a significant decrease of HBV replication before
the antiviral treatment with a decrease of mean serum HBV DNA from 392 pg/ml before to
217 pg/ml after vaccine therapy.
In an ongoing controlled study, using the same vaccine
schedule, serum HBV DNA disappeared more frequently after 6 months, in patients who
were given a preS2/S vaccine (7/35) than in patients who received a S vaccine (1/21) or no
vaccine (1/32). In responders to vaccine, an induction of specific proliferative responses was
observed and this may contribute to the potential efficacy of anti-HBV vaccine therapy. No
side-effect or vaccine-induced escape-mutants occurred during the follow-up.
In summary,
serum HBV DNA disappeared in 28 of the 46 patients (60.9%) who were given vaccine
therapy, with (64.2%) or without (55.6%) Interferon. These results are not different at 6
months and at the end of follow-up from those of 43 HBsAg chronic carriers who were given
only an antiviral treatment. Active immune therapy against HBV appears efficient and less
expensive than antiviral therapies in stopping HBV replication. Such results need to be
confirmed by the completed results of our controlled, randomized trial which is now
conducted in our unit.
Abstract
BACKGROUND/AIMS: Alpha-interferon achieves seroconversion in about one third of
naive patients. Attempts to achieve seroconversion in patients who have previously failed
alpha-interferon have proved disappointing. Combination chemotherapy (alpha-interferon
with a nucleoside analogue) might provide a treatment alternative for these patients. We have
undertaken a phase 2 study in 20 patients who had previously failed at least one course of
alpha-interferon. The study was designed to assess the safety, tolerability and efficacy of the
combination.
Methods: All patients were treated for 16 weeks with alpha-interferon in
combination with 12 or 16 weeks of Lamivudine (3'TC). Patients were followed for 16
weeks post-treatment. Pharmacokinetic studies were performed to identify/exclude significant
pharmacokinetic drug interaction.
RESULTS: The combination was well tolerated, and
side-effects of the combination were indistinguishable from the recognised side-effects of
alpha-interferon. Pharmacokinetic studies performed on days 1 and 29 did not show any
significant interaction. All patients achieved HBV DNA clearance during treatment, but 19
relapsed at the end of treatment. HBeAg/anti-HBe seroconversion was observed for four
patients, but was sustained for a single patient (who also had sustained DNA clearance).
CONCLUSIONS: Combination therapy with alpha-interferon and lamivudine given for 16
weeks appears safe and is well tolerated. However, for this group of patients who had
previously failed interferon monotherapy, the efficacy of combination interferon/lamivudine
therapy appears disappointing, and other treatment strategies should be investigated.
Hepatitis E (HEV) is a faeco-orally transmitted hepatitis virus. It has many
features similar to hepatitis A but some differences, notably the high mortality
caused by HEV in pregnant women. A vaccine is being developed but at the moment only
a clean water supply will reduce the number of cases in areas where the virus is
endemic. (9 References)
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Thanks to progress in serologic techniques evidence was obtained in 1980 showing
that acute hepatitis epidemics observed in India were due to neither virus A nor
virus B. The presence of another virus was confirmed and its genome was cloned and
sequenced in 1991. Hepatitis virus E is a small RNA virus that differs from other
known human viruses. Man and probably a few animal species maintain dissemination by
the fecal route. Subjects not previously contaminated are susceptible and produce
protective antibodies. Contamination occurs by the fecal-oral route general from
water or tainted food.
Direct contamination is rare. Vertical transmission from
mother to fetus can also be observed. Outbreaks of the disease are characterized by
epidemic proportions, preferential involvement of adolescent and young adults, and
high incidence of fulminant cases especially in pregnant women. Outbreaks have been
observed in endemic settings in southern Asia, Africa, and Mexico where sporadic
cases are observed. Endemic areas are found in all developing countries. Hepatitis
E is not clinically different from other acute viral hepatitis. Asymptomatic forms
are common especially in children.
The course of the disease is usually benign with
little risk of development of chronic symptoms and cirrhosis. However hepatitis E is
associated with a high incidence of severe cases with a mortality of 1 to 2% from
icteric forms which occur in 15 to 20% of cases involving women contaminated during
the last three months of pregnancy. Diagnosis can be made using either synthetic
proteins or recombinant peptides. for the epitopes of the virus. Prevention depends
on protection of the water supply and proper sewage disposal. Successful active
immunization of monkeys holds promise for development of a vaccine. Due to its
magnitude and high mortality rate hepatitis E is a major health problem for numerous
regions around the world including Southeast Asia. (15 References) |
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Produced by Dr. José Lapenta R.
Dermatologist
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