From: ((Steven B. Harris))
Subject: Re: Anti Viral and Antibiotic immunity
Date: 24 Apr 1995
Newsgroups: sci.life-extension

In <98401344wnr@longevb.demon.co.uk> John@longevb.demon.co.uk (John de
Rivaz) writes:

>Ribavirin has been recommended anecdotally as a quick way to get rid
>of colds and flu, and antibiotics are also used to get rid of bacterial
>complications thereof.

Ribavirin does not work on colds, and as it actually can be mildly
immunosuppressive (as well as horridly expensive) I don't recommend it
for that.  It does seem to work well on the flu, and the fact that it
isn't marketed for the flu in the US is as much a matter of politics as
science.  It's a wonderdrug for flu in animals, and (in most studies)
also works in people.  I'm reasonably sure this action is real.
Amantadine is also useful for influenza A (the kind most people had the
Winter before last).

                                            Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Subject: Hep C and Ribavirin (was: Collapse Of Orthodox Medicine)
Date: 03 Jun 1997
Newsgroups: misc.health.alternative,sci.med.diseases.hepatitis,sci.med,
	sci.med.nutrition

In <5mukr3$rkr3@hpcc883.corp.hp.com> pcook@a4455apc.esr.hp.com ()
writes:

>   I have a hunch there are quite a few people, especially in
>the hepatitis ng, who would find the information valuable.  Perhaps
>you could post it.



It's been posted before, but here it is again:


     RIBAVIRIN AND HEPATITIS C (May 1997)
       (c) 1997 Steven B. Harris, M.D.

The author is an internist and gerontologist, who, in the course
of advising patients about hepatitis C treatment, was recently
delighted to find a suggested role in the literature of treatment
for the obscure antiviral drug ribavirin.  While an undergraduate
chemistry student in the late 1970's, the author worked for one
of the inventors of ribavirin, R.K. Robins.  Among his projects
with Robins was synthesis of derivatives and analogues of that
drug, which had itself been newly synthesized a few years
previously.  The author has reviewed the literature on ribavirin,
once writing a book chapter on it [1], and has personally
medicated himself with the drug through several bouts of the flu
over the last two decades.  He holds no financial interest in it,
nor in its maker ICN pharmaceuticals.  But the still unapproved
drug continues to hold a place in his fancy.

This short informational outline may be reproduced not-for-profit
without permission, so long as the entire article is reproduced.
Feel free to copy it to other newsgroups and databases.
The abstracts at the end of the article are from the publicly
funded Medline database, and like other information from the
government may be reproduced separately for any purpose,
including profit, without asking permission of anyone.

[1] Harris, SB and Robins, RK  Ribavirin: structure and antiviral
activity relationships. in Ribavirin: A Broad Spectum Antiviral
Agent Roberts A. Smith and William Kirkpatrick (eds.), Academic
Press, San Francisco, 1980.


-----------------------------------------------------------

Facts About Ribavirin

Ribavirin is a nucleoside-like antiviral drug, which is broadly
similar in mechanism of action to the antiviral drug acyclovir.
Ribivirin was first synthesized in 1971 by a group headed by
chemist R.K. Robins, at ICN Pharmaceutical Corporation.
Subsequently the drug was shown to be active against a broad
range of both RNA and DNA viruses, working by means of selective
inhibition of viral replicase enzymes.  Ribavirin is a ribose
(rather than deoxyribose) nucleoside analog, and therefore is not
incorporated into DNA, as is AZT.

Ribavirin was developed first as an influenza drug, and shows
impressive reduction of mortality in mice in influenza models.
In human trials, however, results were mixed (some studies were
positive and some negative), and the FDA's eventual, and perhaps
somewhat capricious, failure to approve the drug in the U.S. for
influenza once caused ICN's stock to drop to such a precipitous
extent that the stockholders actually sued the company for false
representation.  ICN to this day maintains that the drug is
active for influenza, but that the negative clinical trials were
flawed.  The author, after reviewing the data, agrees with ICN.

Ribavirin is active against respiratory syncytial virus (RSV), a
common infection in children.  It is approved by the FDA for this
use in the U.S., but the approved preparation is a liquid
preparation for aerosol delivery.  Though some of the drug is
absorbed orally when used in this fashion, no oral preparation
has been approved in the U.S.   Use of the pediatric formulation
in adults for other purposes would be prohibitively expensive.

Ribavirin is available as an over-the-counter flu medication in
Mexico, where it is known as ribavirina, and by the tradename
Vilona (ICN).

In the early 1990's, ribavirin was shown to be active against the
recently characterized togavirus which causes hepatitis C (this
virus is somewhat similar to the virus which causes yellow
fever).  A number of tests of ribavirin showed that it was able
to suppress hepatitis C replication and viral load in humans with
chronic active disease, but that when the drug was discontinued,
even after long use, the virus rebounded.  Thus, ribavirin alone
is ineffective for chronic hepatitis C (as much as 80% of
hepatitis C infection becomes chronic).  Meanwhile, interferon
alpha had been tried against chronic hepatitis C, and it was
found that at six months cures were less than 10%, and even when
used at the longer treatment times of 12 to 18 months, were on
the order of 30 to 40% cure rate.  Interferon has unpleasant side
effects, and causes a feeling similar to having a mild flu, but
sustained.  When ribavirin was used in conjunction with
interferon for 6 months, however, cure rates of up to 50% have
been reported.   There are now many studies looking at this
combination, and without exception all have reported that the
combination of ribavirin and interferon is far more effective
than interferon alone in producing cures (2 to 3 times as potent
at generating cures, per month of therapy).  Generally, three
months of ribavirin therapy at a dose of about 1200 mg per day
has been used in studies, but longer periods of ribavirin are
tolerated with low incidence (< 10% of patients) of problems
significant enough to require that the drug be stopped.

Although ribavirin is not incorporated into DNA, it does inhibit
mammalian DNA synthesis in a dose-dependent manner (and in some
people more than others), and a major side effect of long term
ribavirin use is macrocytic anemia of the type seen with DNA
replication suppressant chemotherapies.  Ribavirin may also
causes a hemolytic anemia by mechanisms unknown.  Both of these
effects are usually not severe, and resolve when the drug is
discontinued or the dose reduced.  No drug related deaths have
been reported in the hepatitis C studies, but serial CBC
monitoring is essential when using ribavirin, much as with
Tegretol and other marrow-toxic drugs.   Ribavirin is a mutagen
and teratogen, and must not be used in women who may become
pregnant.  It should be used with the same precautions in women
as the drug Acutane.

Ribavirin will probably be officially approved eventually by the
FDA for treatment, in conjunction with interferon alpha, of
chronic hepatitis C.  Meanwhile it is available to U.S. citizens
only by importation from Mexico.  This is legal with a U.S.
physician's prescription.  Ribavirin is not a DEA controlled
substance.  Present U.S. equivalent cost of ribavirin is about
$40 for a box of 12 capsules of 400 mg (4 days' treatment at 400
mg three times a day). This cost varies with the peso exchange
rate, and with U.S. demand (which is rising due to hepatitis C
treatment demands).  At this rate of $10 per day, a 6 month
course of Mexican ribavirin for hepatitis C costs about $1800.
While this is less than the cost of the interferon alpha,
insurance plans will often not pay for ribavirin (it's worth
checking, though, as an occasional plans will pay for any drug a
doctor prescribes, even unapproved drugs.  Other plans will do so
on a pre-approval basis, which may succeed on the evidence now
available for ribavirin.  Combination therapy with ribavirin and
interferon for 6 months would be expected to be far more cost
effective than interferon for 12 months, something that may carry
some weight with insurance pre-approval committees).

With a prescription, ribavirin may be carried across the
Mexican/U.S. border by tourists, and the $300 dollar private use
drug importation limit for international border crossing is often
ignored in such cases, if the excess is not flagrant (one small
carrying bag of pharmaceuticals per tourist is expected at the
border in Tijuana).  One or two tourists should be able to carry
across 6 months supply of this drug, with ease.  Many Mexican
_pharmacias_ also have mail-order drug services, and use shipping
services which are rarely held up by customs.  Even when non-DEA
restricted pharmaceuticals are held up by shippers such as U.P.S.
(notorious sticklers for FDA rules), they can be freed with a
letter from a U.S. physician (readers who aren't my patients may
be thinking that *I* might be willing to write such a letter for
them.  Sorry, no can do.  Take this information, rather, to your
gastroenterologist.  Don't even bother to bug me-- that isn't the
way medical care works).


Good luck!


Steve Harris, M.D.
71450.1773@compuserve.com
sbharris@ix.netcom.com







          O
          ||
         /  \
     NH2      \ / N
              ||   \\
               N    /
                \ N
                  |
      HO__   O    |
         | /    \ |
           \___ /
           |   |
          HO   OH

          Ribivirin



------------------------------------------------------------


Abstracts:

Studies concluding that ribavirin plus interferon is better than
interferon alone:


A Meta-analysis

Schalm SW; Brouwer JT; Chemello L; Alberti A; Bellobuono A; Ideo G;
Schwartz R; Weiland O.
Interferon-ribavirin combination therapy for chronic hepatitis C.
Digestive Diseases and Sciences, 1996 Dec, 41(12 Suppl):131S-134S.
Abstract: Following preliminary reports of small studies that suggested
a clinically important enhanced benefit from combination therapy with
interferon-alpha (IFN) and ribavirin over IFN monotherapy in chronic
hepatitis C, a meta-analysis of data from these studies was performed
to estimate the efficacy and tolerability of combination therapy in
chronic hepatitis C. Records were obtained from 59 patients who had
received combination therapy with IFN 3 MU three times weekly and
ribavirin 1000-1200 mg daily for six months and were followed for six
months after stopping combination therapy. Outcome measures included
the percentage of patients showing ALT normalization and HCV-RNA
negativity six months after therapy (sustained response) and the
percentage of patients stopping therapy because of side effects.
Sustained response was observed in 21% of IFN nonresponders and in 60%
of patients who had relapsed after IFN. For naive patients, the
estimated sustained response rate was 52%; the observed response rate
was 46%. No serious adverse effects were noted; less than 10% of
patients discontinued study medication. This meta-analysis of
IFN-ribavirin combination therapy for chronic hepatitis C suggests that
combination therapy results in a two- to threefold greater efficacy
than IFN monotherapy, whereas side effects are similar to IFN
monotherapy, with the exception of ribavirin-induced anemia.
Interferon-ribavirin combination therapy might become the next step in
antiviral therapy for chronic hepatitis C.

Lai MY; Kao JH; Yang PM; Wang JT; Chen PJ; Chan KW; Chu JS; Chen DS.
Long-term efficacy of ribavirin plus interferon alfa in the treatment
of chronic hepatitis C.
Gastroenterology, 1996 Nov, 111(5):1307-12.
Abstract: BACKGROUND & AIMS: Sustained response to interferon treatment
for chronic hepatitis C is unsatisfactory. This study examined whether
combining interferon alfa with ribavirin induces a better sustained
efficacy than interferon alone in the treatment of chronic hepatitis C.
METHODS: Sixty noncirrhotic patients with chronic hepatitis C were
randomly assigned to three groups. Group 1 received 1200 mg oral
ribavirin daily plus 3 million units of recombinant interferon alfa 2a
thrice weekly for 24 weeks, group 2 received the same dose of
interferon alfa 2a alone for 24 weeks, and group 3 received no
treatment. The patients were then followed up for an additional 96
weeks. RESULTS: At the end of treatment, a complete response (normal
serum alanine aminotransferase level and undetectable serum hepatitis C
virus RNA) was achieved in 16 of the 21 patients in group 1 (76%), as
compared with 6 of 19 in group 2 (32%) and none in group 3. At
96 weeks after the end of treatment, patients in group 1 sustained a
higher complete response rate than patients in group 2 (43% vs. 6%).
Combined treatment with ribavirin and interferon alfa 2a for 24 weeks
is more effective than interferon alfa 2a alone for the treatment of
chronic hepatitis C. The biochemical and virological responses were
sustained in about one half of the treated patients for at least 2
years after cessation of the therapy.

 Schvarcz R; Yun ZB; Sonnerborg A; Weiland O.
Combined treatment with interferon alpha-2b and ribavirin for chronic
hepatitis C in patients with a previous non-response or non-sustained
response to interferon alone.
Journal of Medical Virology, 1995 May, 46(1):43-7.
Abstract: Ten patients with chronic hepatitis C, six of whom had not
responded and four of whom had responded in a non-sustained fashion to
interferon-alpha treatment alone, were given interferon alpha-2b and
ribavirin in combination during 24 weeks. Interferon alpha-2b was given
subcutaneously, at a dose of 3 MU thrice weekly, together with
ribavirin orally, at a dose of 1,000-1,200 mg/day. All four patients
with a prior non-sustained response to interferon alone had normal
alanine aminotransferase (ALT) levels at the end of treatment as well
as during follow-up (> or = 24 weeks post treatment). Furthermore, all
four lost serum HCV-RNA at the end of treatment and three continued to
be negative during follow-up. Among patients with a prior non-response
to interferon alone three of six had normal ALT levels at the end of
treatment and one at follow-up. Two of six became HCV-RNA negative at
cessation of treatment, one of whom was negative also at follow-up. All
former non-sustained responders and one of six non-responder patients
thus showed a sustained biochemical response with eradication of
HCV-RNA from serum in all cases but one. It is concluded that
combination therapy with interferon alpha-2b and ribavirin offers a
chance of sustained biochemical response with eradication of the
viremia in patients who have not shown a persistent response to
interferon-alpha alone.

Chemello L; Cavalletto L; Bernardinello E; Guido M; Pontisso P; Alberti
A.
The effect of interferon alfa and ribavirin combination therapy in
naive
patients with chronic hepatitis C.
Journal of Hepatology, 1995, 23 Suppl 2:8-12.
Abstract: BACKGROUND: Chronic hepatitis C may lead to cirrhosis and
hepatocellular carcinoma in a subset of patients. Because response
rates with interferon alfa therapy are unsatisfactory, new therapies
are needed. METHODS: We conducted a three-arm, randomized trial in 45
interferon-naive men (mean age 40.6 +/- 12 years) with chronic
hepatitis C to compare treatments: group A, ribavirin alone (15 mg/kg
daily for 6 months); group B, interferon alone (3 MU thrice weekly for
6 months); and group C, interferon plus ribavirin at the above doses.
Histologic outcomes of therapy were assessed by pretreatment and
post-treatment liver biopsies. RESULTS: In group A, alanine
aminotransferase levels normalized during therapy in 66% of those with
HCV-1b and 34% of those with HCV-2a, but all patients relapsed after
treatment ended. In group B, alanine aminotransferase levels normalized
during treatment in 66%, 75%, and 100% of patients infected with
HCV-1b, HCV-2a, and HCV-3, respectively; however, a sustained response
was noted in only 25% of those with HCV-3. In group C, a sustained
normalization of alanine aminotransferase with negative serum HCV RNA
was seen in 20% of those with HCV-1b, 40% of those with HCV-2a, and
75% of those with HCV-3 12 months after therapy. One year after therapy
ended, group C demonstrated a significant sustained response (47%) as
well as a significant reduction in piecemeal necrosis and portal
inflammation (p < 0.05). CONCLUSIONS: Combination therapy was
significantly superior to  ribavirin or interferon monotherapy in
producing a sustained response in interferon-naive patients with
chronic hepatitis C (p < 0.05). The results of our study suggest that
ribavirin potentiates the effect of interferon
therapy in chronic hepatitis C.

Schvarcz R; Ando Y; Sonnerborg A; Weiland O.
Combination treatment with interferon alfa-2b and ribavirin for chronic
hepatitis C in patients who have failed to achieve sustained response
to interferon alone: Swedish experience.
Journal of Hepatology, 1995, 23 Suppl 2:17-21.
Abstract: BACKGROUND: Only 10-20% of patients treated with interferon
alfa alone attain long-term benefits. More effective regimens are
needed. METHODS: Twenty Swedish patients with chronic hepatitis C virus
infection, ten with a prior non-response and ten with a non-sustained
response to interferon alfa treatment alone, were treated with
interferon alfa-2b and ribavirin in combination for 24 weeks, then
followed up for another 24 weeks. Patients received interferon alfa-2b
subcutaneously 3 MU thrice weekly and oral ribavirin 1000-1200 mg/day.
RESULTS: All ten patients with a prior non-sustained response to
interferon alone had a sustained biochemical response with normal
aminotransferase levels at follow-up; nine also had a sustained viral
response with a negative HCV-RNA test in serum. Among the ten patients
with a prior biochemical non-response to interferon alone, five had
normal aminotransferase levels at the end of therapy; four were
negative for HCV RNA in serum. At follow-up, three had normal
aminotransferase levels and a negative HCV-RNA test in serum. No major
adverse effect was seen, apart from fatigue and an expected fall in
hemoglobin levels from a mean of 155 g/l to 124 g/l at the end of
therapy. All patients completed the treatment schedule, but the
ribavirin dose was reduced in one patient because of a fall in
hemoglobin to 99 g/l. Interferon alfa-2b and ribavirin offers a chance
of sustained biochemical response and virus eradication in a subset of
patients who fail to achieve sustained response with interferon alfa
alone.

Bizollon T; Ducerf C; Trepo C.
New approaches to the treatment of hepatitis C virus infection after
liver transplantation using ribavirin.
Journal of Hepatology, 1995, 23 Suppl 2:22-5.
Abstract: BACKGROUND: Chronic liver failure resulting from hepatitis C
virus infection often necessitates orthotopic liver transplantation.
Recurrence of hepatitis C virus infection after transplantation is
inevitable, and the infection is usually severe. Interferon and
ribavirin have both been used to treat hepatitis C virus infection
after liver transplantation, but neither interferon nor ribavirin
monotherapy has demonstrated sustained biochemical or virologic
responses or histologic benefit in transplant recipients with recurrent
hepatitis C virus infection. The next logical approach to treatment was
combination therapy. METHODS: Fourteen patients with recurrent
hepatitis C virus infection were treated for 6 months with interferon
alfa-2b (3 MU thrice weekly) and oral ribavirin (1000 mg/day).
After 6 months, patients were maintained on ribavirin monotherapy until
the end of the study. Safety and tolerability were satisfactory, and no
patients experienced graft rejection during the study. RESULTS: Alanine
aminotransferase levels were normalized in all patients after 6 months
of therapy. Serum HCV RNA was negative in nine patients; the other five
demonstrated a 50% quantitative reduction of HCV RNA. After a mean
follow-up of 18 months, all but one patient maintained normal alanine
aminotransferase levels. Twelve out of 14 patients achieved a
histologic benefit. CONCLUSIONS: The biochemical and virologic
responses and the histologic benefit seen after combination therapy are
significantly better than those reported with either interferon or
ribavirin monotherapy. Combination therapy appears to be effective in
preventing the progression of HCV-related graft disease after liver
transplantation.

Braconier JH; Paulsen O; Engman K; Widell A.
Combined alpha-interferon and ribavirin treatment in chronic hepatitis
C: a pilot study.
Scandinavian Journal of Infectious Diseases, 1995, 27(4):325-9.
Abstract: 16 patients with chronic hepatitis C virus (HCV) infection
were treated with a combination of interferon-alpha and ribavirin for
24 weeks in an open study. One patient declined further treatment due
to depression after week 16 and did not complete further follow-up. A
moderate decline was observed in hemoglobin and an increase in
bilirubin level both reversible after discontinuing the treatment. 24
weeks after treatment cessation 9/15 (60%) evaluable patients had
complete clearance of HCV-RNA as measured with PCR. HCV genotype did
not seem to be correlated with response, but patients with sustained
response to treatment had a significantly reduced number of HCV RNA
copies/ml serum at treatment start compared with the other patients.
These findings support the promising results of this combination
therapy noted in other pilot studies.

Brillanti S; Garson J; Foli M; Whitby K; Deaville R; Masci C; Miglioli
M; Barbara L.
A pilot study of combination therapy with ribavirin plus interferon
alfa for interferon alfa-resistant chronic hepatitis C.
Gastroenterology, 1994 Sep, 107(3):812-7.
Abstract: BACKGROUND/AIMS: In chronic hepatitis C, interferon alfa
(IFN-alpha) therapy fails to achieve a sustained response in
approximately 75% of patients. Similarly, ribavirin induces only a
transient response. The aim of this study was to evaluate whether
ribavirin and IFN-alpha in combination could be effective in
IFN-alpha-resistant chronic hepatitis C.
METHODS: Twenty patients with chronic hepatitis C resistant to a
previous course of IFN-alpha were randomly assigned to receive either
ribavirin combined with IFN-alpha or IFN-alpha alone for 6 months.
RESULTS: Serum alanine aminotransferase levels decreased significantly
during therapy in both treatment groups, but after therapy, the levels
remained significantly decreased only in the combination therapy group.
Nine months after treatment, sustained normalization of
aminotransferase levels, associated with sustained loss of serum
hepatitis C virus RNA, was observed in 40% of the patients in the
combination therapy group but in none of the patients treated with
IFN-alpha alone (P < 0.05). The sustained response was accompanied by
reduced hepatic necroinflammatory activity on biopsy.CONCLUSIONS: These
findings suggest that ribavirin plus IFN-alpha combination therapy is
able to induce a sustained biochemical and virological response in a
significant proportion of patients with IFN-alpha-resistant chronic
hepatitis C.

Kakumu S; Yoshioka K; Wakita T; Ishikawa T; Takayanagi M; Higashi Y.
A pilot study of ribavirin and interferon beta for the treatment of
chronic hepatitis C.
Gastroenterology, 1993 Aug, 105(2):507-12.
Abstract: BACKGROUND: Chronic hepatitis C is a common and often
progressive liver disease for which interferon alfa therapy widely
spreads, but the beneficial response is frequently transient. Ribavirin
is a nucleoside analog with a broad spectrum of antiviral action, and
we investigated the efficacy of it in patients with chronic active
hepatitis C. METHODS: We conducted a pilot study of oral ribavirin in
patients with chronic active hepatitis C. Twenty-seven patients with
hepatitis C virus RNA were randomly assigned to receive either 0.8-1.0
g of ribavirin daily or 3 MU of interferon beta three times weekly or
combination of the two for 24 weeks.
RESULTS: Ribavirin was tolerated well, and all completed the treatment
schedule. Ribavirin decreased aminotransferase levels in all instances,
and the mean value at termination decreased to half of the baseline
level (P < 0.01), but the enzyme level increased after cessation of
therapy in most cases. Ribavirin suppressed amounts of hepatitis C
virus RNA in 4 of 9 patients, and 1 became negative during follow-up.
Interferon alone (P < 0.05) or with ribavirin (P < 0.01) significantly
decreased the viral population, resulting in sustained loss of viremia
with normal enzyme levels in 2 of 9 and 3 of 9 patients, respectively,
in each therapy during follow-up. CONCLUSIONS: These re sults indicate
that ribavirin has a beneficial effect in some patients with chronic
hepatitis C, although the antiviral effect is less than interferon
beta. Large-scale trials are needed to determine whether the
combination of interferon and ribavirin is of more benefit than
interferon alone.



RIBAVIRIN ALONE

Ribavirin alone can be used for long periods to suppress hepatitis C,
but without interferon is INEFFECTIVE at curing hepatitis C

Dusheiko G; Main J; Thomas H; Reichard O; Lee C; Dhillon A; Rassam S;
Fryden A; Reesink H; Bassend ine M; et al.
Ribavirin treatment for patients with chronic hepatitis C: results of a
placebo-controlled study.
Journal of Hepatology, 1996 Nov, 25(5):591-8.
Abstract: BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for
patients with chronic hepatitis C have reported efficacy in chronic
hepatitis C. We have evaluated the efficacy and safety of a 24-week
course of oral ribavirin in patients with chronic hepatitis C, compared
to placebo. METHODS: A total of 114 patients were randomised to
ribavirin or placebo. Ribavirin was administered in doses of 1000 or
1200 mg/day for 24 weeks. Efficacy was determined in the
intention-to-treat population: 76 received ribavirin and 38 placebo.
RESULTS: Ribavirin was significantly more effective than placebo in
reducing and normalising serum ALT
levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo
recipients had either normalisation of the ALT levels or a reduction
from
baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76
(29%) of ribavirin-treated patients vs 0/38 placebo recipients (p <
0.001).
Twenty-four weeks after stopping ribavirin, the majority of patients
had abnormal ALT levels. There was no difference between the treatment
groups in reduction or disappearance of HCV-RNA levels. HCV RNA
disappeared during treatment in 3% of ribavirin-treated patients and 3%
of placebo recipients. More ribavirin than placebo patients showed
improvement in total Knodell score (45% vs 31%), but these differences
were not statistically significant. Analysis of each component of a
histology activity index revealed no statistically significant
differences between treatment groups. Ribavirin patients had fewer
lymphoid aggregates than did placebo recipients at the post-treatment
assessment (p = 0.05). Ribavirin was associated with reversible
haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo-
and 32% (25/78) of ribavirin-treated patients, respectively (p <
0.001). CONCLUSIONS: These data indicate that ribavirin was no more
effective than placebo in reducing or eliminating HCV-RNA
levels, and was not significantly more effective than placebo in
improving hepatic histology after 6 months of treatment. The role of a
6-month treatment of chronic hepatitis C with ribavirin alone, without
a significant effect on HCV RNA, is therefore limited.

Other papers showing the same result:

Hoofnagle JH; Lau D; Conjeevaram H; Kleiner D; Di Bisceglie AM.
Prolonged therapy of chronic hepatitis C with ribavirin.
Journal of Viral Hepatitis, 1996 Sep, 3(5):247-52.

Cattral MS; Krajden M; Wanless IR; Rezig M; Cameron R; Greig PD;
Chung SW; Levy GA.
A pilot study of ribavirin therapy for recurrent hepatitis C virus
infection after liver transplantation.
Transplantation, 1996 May 27, 61(10):1483-8.

Di Bisceglie AM; Conjeevaram HS; Fried MW; Sallie R; Park Y; Yurdaydin
C; Swain M; Kleiner DE; Mahaney K; Hoofnagle JH.
Ribavirin as therapy for chronic hepatitis C. A randomized,
double-blind, placebo-controlled trial.
Annals of Internal Medicine, 1995 Dec 15, 123(12):897-903.
"Thus, ribavirin alone for periods as long as 12 months is unlikely to
be of value as therapy for chronic hepatitis C."

Koskinas J; Tibbs C; Saleh MG; Pereira LM; McFarlane IG; Williams R.
Effects of ribavirin on intrahepatic and extrahepatic expression of
hepatitis C virus in interferon nonresponsive patients.
Journal of Medical Virology, 1995 Jan, 45(1):29-34.

Gane EJ; Tibbs CJ; Ramage JK; Portmann BC; Williams R.
Ribavirin therapy for hepatitis C infection following liver
transplantation.

Tong MJ; Hwang SJ; Lefkowitz M; Lee SD; Co RL; Conrad A;
Schmid P; Lo KJ.
Correlation of serum HCV RNA and alanine aminotransferase levels in
chronic hepatitis C patients during treatment with ribavirin.
Journal of Gastroenterology and Hepatology, 1994 Nov-Dec, 9(6):587-91.

Camps J; Garcia N; Riezu-Boj JI; Civeira MP; Prieto J.
Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa
interferon.
Journal of Hepatology, 1993 Nov, 19(3):408-12.
"All patients with normalized aminotransferase values relapsed
after ribavirin was discontinued and aminotransferase activity returned
to pretreatment levels.  Before therapy serum hepatitis C virus RNA was
detected by polymerase chain reaction in 10 cases. None of them had
cleared viral RNA when tested following 3, 6 and 9 months of ribavirin
therapy. Side-effects were mild and reversible. In conclusion, about
half of the patients with chronic hepatitis C who are unresponsive to
alpha-interferon show a clear-cut biochemical response after 6-9 months
of ribavirin administration. However, ribavirin does not clear
circulating hepatitis C virus RNA and relapses occur after withdrawal."

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: Hepatitis C and HIV
Date: 24 Jul 1998 21:47:27 GMT

In <6pajsc$ejm@sjx-ixn6.ix.netcom.com> gmc0@ix.netcom.com (George M.
Carter) writes:

>Steve Harris wrote:
>>>  I don't know if it it's worth attempting to treat chronic heptitis C
>>>  in a person who also has HIV. I can find no study attempting to do it
>>>  with ribivirin and interferon, which is the standard protocol.
>
>I understand that AmFAR is supposedly conducting a study of IFN and
>Ribavirin in people who are co-infected.
>
>The combination is NOT the standard protocol.  This combination was
>approved ONLY for people who have done a course of IFN and for whom
>the IFN has failed.


    You're technically right.  It SHOULD be the standard protocol,
since 90-95% of people fail interferon alone, which is 6 months of hell
for a lot of money, for nothing.  After which the FDA expects you to go
through the idential 6 months of hell, for even more money, with
ribavin to get your 40-50% chance of cure.  I must say that even for
the FDA this is stupidity.  There are adequate papers on use of
interferon and ribavirin as primary, not salvage therapy.  It is known
to work just as well in either case, and there is little added toxicity
from the ribavirin (which can easily be monitored with blood tests).
The PROBLEM is that the people at the FDA are either morons, or else
(just as bad) those that have working brains haven't had them
stimulated properly by the prospect of having to feel like they are
coming down with a bad case of the flu for 6 months, for no good
reason.  It's the old information problem: to make risk vs benefits for
treatment of a disease, you have to be close enough to the disease to
see the suffering which the disease and the treatment cause.  Which you
cannot do from an airconditioned office in Washington.


>  It's a bit like approving AZT+3TC for those who
>have failed AZT or perhaps rifabutin+INH after people have failed
>isoniazid.

    Yes, it's a little like that.  But even dumber, since the
recommended primary therapy is so close to being ineffective, while at
the same time difficult and hard on the patient.  Six months of AZT at
400 mg a day doesn't put you in bed and unable to work.  I've seen six
months of interferon for hep C do just that, to patients.

>There is some speculation that there is a serious breach of monopoly
>laws by Schering-Plough in their "bundling" of their more toxic Intron
>A with ribavirin and that this may have been done in collusion with
>the FDA.  Activists are contemplating a demand for an investigation by
>the Department of Justice and/or the Federal Trade Commission for
>unfair practices against Schering.

    It surely WAS done in collusion with the FDA.  The FDA has been
punishing ICN forever, for trying to market ribavirin in capsules for
flu as soon as it had been approved as a inhalent for RSV.  The FDA
told them then they'd never see ICN sell ribavirin for anything else,
ever again.   And they kept their word.


>Ultimately, however, as a treatment for HCV, the combination sucks
>shit due to its intense toxicities of both drugs and uncertain
>benefit.

    I wouldn't got that far about the benefit.  It really does cure at
least 40% of those who make it through.  And those people, untreated,
have at least a 20% chance of the disease killing them.

    No argument that the treatment sucks.  But the combo treatment
doesn't suck much worse than interferon alone.  It's just a few more
blood tests.  My guess (which I can't prove) is that they're using
ribavirin in doses too large for a 6 month treatment period (they are
using the standard 1 week flu dose of 1200 mg a day), and that half as
much (200 tid) will do just as well.  It's the AZT story all over
again.


>Still, for people with a viral load more than 1-3 million, the
>combination may be of some benefit, at least for a while.  Several
>people I know have benefitted from the combo--but many others have
>seen any initial benefit lost as PCR suddenly goes "positive" again
>after 6 months or a year off therapy.

    Again, all the stats I know are for people not HIV infected.  For
these people, even followed out 2 years, they do NOT revert.  I believe
they ARE cured.  Hep C is not a retrovirus, and cure is certainly
possible in theory.

>But to compound matters, Schering simply BUYS the competition.  They
>bought ICN Pharmaceuticals (makers of ribavirin).

   Did they?  But the only reason they could do that was ICN crumby
stock value, in part due to the FDA's long vendetta against them, and
their failure to capitalize on ribavirin, their invention.

>Tbey are behaving badly in other ways with regard to competing IFN
>manufacturers.  While one study showed they all worked about the same,
>some appear to be less toxic than the variety of alpha IFN that
>Schering pushes.

   Wouldn't surprise me.


>To the extent patent laws protect an inventor for the proceeds of
>their invention for a limited period of time, there is a serious
>conflict when such patents limit one's ability to obtain the best and
>safest forms of treatment.  Sadly, efficacy and safety issues do not
>appear to be part of the considerations undertaken when a patent is
>given.

    That is why efficacy issues should not be part of the FDA's purvue.
Saftety studies are FAR cheaper, and efficacy studies can be left to
various sources while doctors and their patients are left to be able to
use the less toxic therapies on their own, while the full studies are
done.  It's a gamble, but gambles with low toxicity things are worth
running, on the basis of lesser quality data.  Our government has
never really understood that.

>(Another example: there is a conjugated ribavirin with lactosaminated
>lysine that may be safer than regular ribavirin.  But the laws of the
>corporate jungle tend to restrict access rather than foster the
>ephemeral "competition" that doesn't exist in the so-called "free"
>market.

    No, no.  We don't have anything close to a free market now.  Not
being able to market a product until you do exactly the efficacy study
the government says you have to, is not a free market.  It's not a free
market if the government makes you test new chemicals for toxicity
either (admitadly), but at least it's not as distorted as now.

                                       Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: Hepatitis C and HIV
Date: 29 Jul 1998 00:58:48 GMT

In <6pkst7$ev2@dfw-ixnews4.ix.netcom.com> gmc0@ix.netcom.com (George M.
Carter) writes:

>You've given me a lot of food for thought, but I still need more data.
>But even with these data, I still don't buy the word "cure."  They
>used to say that about IFN monotherapy (using 30-40% figures) and now
>it's down to 15% or less.  Still, if I opt for therapy, a) I won't
>waste my time non-responding or relapsing to IFN before combo therapy
>and b) I will avoid Schering's crap.

Fer sure.

>Thanks again, Steve.  And say, you skipped the Lancet study!
>
>		George M. Carter


Only `cause you said all the stuff came from that, and I wanted to show
you what else was out there.  The great unknown stuff that the FDA
ignored.  As you see, plenty enough to justify legalizing the combo
without the Lancet study.  It's criminal how long the FDA waited on
this.  Anybody with half a brain can look at the stuff above and see
that it's enough.  The numbers are small, but the differences are so
large as to be statistically and clinically significant.  And the
results were verified independently again and again and again.  They
are real.  What else do you look for in science?

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,sci.med.pharmacy
Subject: Re: Hepatitis C and HIV
Date: 29 Jul 1998 19:08:51 GMT

In <6pnjsi$rqn@sjx-ixn11.ix.netcom.com> gmc0@ix.netcom.com (George M.
Carter) writes:

>I agree re the FDA--and in fact requests have been put into the DoJ
>and FTC to examine the way that stupid approval was made and the
>subsequent "bundling" of the two drugs together by Schering as being
>anti-competitive and a direct threat to the lives of people with Hep
>C.
>
>		George M. Carter


   Yeah, but you KNOW the reason.  The reason is the FDA is still
trying to keep ribavirin capsules out of the hands of people who might
take a few days worth, for the flu.  My God, wouldn't the world come to
an end, then?

                                    Steve Harris, M.D.
                                    With plenty Mexican Vilona on hand