Case for Geno 1 Tx Extension/Kaiser

[Califia]

This is a call for assistance.  A friend is going to be aggressively petitioning Kaiser Permanente for tx extension this week, and we want to make sure we have collected all the essential studies.  We have the Drusano and TeraVic in hand, for starters.   The treating doc attended the last AASLD conference,  but this doesn't guarantee anything.

Her stats:   Was on reduced dosage Peg-Intron for 6 months because of severe anemia; finally, in June, started full dosage.  Experienced EVR.  However, her 6-month PCR still shows detectable RNA.  (Viral count not in yet.)   Doctor promises to review after count is back, but in the meantime has rx'd just one additional shot.  Doesn't look good.

Given this situation, and Tony's, it would also be helpful for all Kaiser patients to share as much information as possible, as this HMO's treating guidelines strike me, at least, as two years behind the beat.

[BobK]

" Her stats: Was on reduced dosage Peg-Intron for 6 months because of severe anemia; finally, in June, started full dosage. Experienced EVR. However, her 6-month PCR still shows detectable RNA. (Viral count not in yet.) Doctor promises to review after count is back, but in the meantime has rx'd just one additional shot. Doesn't look good."

What was her start date for tx?  How long was she on full dose prior to dose reduction?  Was she treated with growth hormones (procrit ect)?  Was EVR after re-starting full dose or prior?  How long has she actually been taking the drugs?

Important questions whose answers will help focus the research.

regards,
BobK

[annainitaly]

scott,

I've read about your relapse. I'm so sorry about it. not so many words to add, just hope you'll get a smooth way through your tx next time and (most of all) I hope it will be the last time.

anna

[cuteus]

I copied the results of a very small study(9 patients) done in Israel. Why?
8 out of 9 achieved svr with extended tx. heck, I pay attention to that! to hell, the small sample part. like Scott said, anemia is not caused by the ifn, I was riba reduced not peg reduced. Kayser just sounds better and better.
check the hepatitisdoctor.com site for info on customizing tx.

[Califia]

" Her stats: Was on reduced dosage Peg-Intron for 6 months because of severe anemia; finally, in June, started full dosage. Experienced EVR. However, her 6-month PCR still shows detectable RNA. (Viral count not in yet.) Doctor promises to review after count is back, but in the meantime has rx'd just one additional shot. Doesn't look good."

What was her start date for tx? How long was she on full dose prior to dose reduction? Was she treated with growth hormones (procrit ect)? Was EVR after re-starting full dose or prior? How long has she actually been taking the drugs?
And I thought I was being clear. Uh oh.  

Don't know how many weeks she had a normal dose, mabe one or two; she became anemic almost immediately so riba was reduced, and then plunging platelets forced a cutback of interferon.   So the first block of time, from January to June of this year, she was on a suboptimal dose (while taking Procrit the whole time, trying to stabilize).  As far as I'm concerned, the REAL starting date is in middle of  June when improved blood values allowed her to take full dosages of  both interferon and ribavirin.  THIS time she experienced EVR, but this week's PCR (she calls it "six months" into treatment") still reads "detected."

She's a textbook flunkee when measured by standard criteria.  It's a miracle she made it through June; it speaks well for her doctor.   The question is, will he use his head and get creative, or arbitrarily decide that her viral load is still too high, the odds are against her, and drop her from tx?   The last time she measured a month ago the viral count was extremely low--nearly undetectable.  

I hope this helps to clarify--and thanks so much, BobK, for your input.

Scott--Interesting to see which road this HMO will take.   I myself am ready to blast them with both barrels if they misstep, brain fog be damned!

[Califia]

Sorry--real trouble cutting and pasting and right-handed trackball mouse scrolling.

Above message should start at paragraph 3.

CUTEUS:   Paste the Israeli study, please!

[Tony-z]

55th Annual Meeting of the American association for the Study of Liver Diseases
October 29-November 2, 2004
Boston, MA  Back  

  
  
  
  
Prolonged Pegasys+RBV Therapy to 72 Weeks May Improve SVR in Patients Who were HCV RNA+ after 4 weeks & slow responders


  
  Reported by Jules Levin

There were two studies presented at AASLD examining the potential benefits of extending treatment from 48 to 72 weeks with Pegasys plus ribavirin. One study found that patients with detectable HCV RNA after 4 weeks of therapy could benefit from extending therapy from 48 to 72 weeks. The second study found that in patients with 'slow viral response' (positive HCV RNA at week 12 with between 50 to 5,000 IU/mL, but negative HCV RNA ayt week 24) could reduce relapse rates and improve sustained response rates. Read details of both studies below.

"Longer Treatment Duration With Peginterferon alfa-2a (40KD) PEGASYS and Ribavirin (COPEGUS) in Naïve Patients with Chronic Hepatitis C and Detectable HCV RNA After 4 Weeks of therapy"

--The SVR rate was significantly higher in patients treated for a total of 72 vs 48 weeks, including those with genotype 1 and high baseline viral loads.

-Prolonged therapy reduced the relapse rate in this study

--there was not an increase in incidence or severity of adverse events, but there was an increase in the number of patients who voluntarily stopped treatment

Data from viral kinetic and pilot studies suggest that treatment for longer than 48 weeks may increase sustained virological response (SVR) rates in patients who do not have a rapid decrease in HCV RNA after the start of treatment. The TeraViC-4 study is focused on such patients. Those without a rapid virological response (nonRVR) at week 4 (ie patients with detectable serum HCV RNA, >50 IU/mL by PCR) to Pegasys plus Copegus were randomized to a total duration of 48 or 72 weeks of treatment. JM Sanchez-Tapias and the TeraVIC-4 Study group reported results from this study in an oral session at AASLD (October 2004). There was some criticism from researchers/doctors at the microphone after the presentation regarding the study design, but at these meetings there is frequently disagreement between researchers regarding the significance of study results.

Extended treatment beyond 48 weeks may also be potentially helpful for individuals with negative predictive factors such as HIV, previous nonresponders, cirrhotics, but this study did not specifically examine these questions.

Sanchez-Tapias provided this background. HCV kinetic analyses during antiviral therapy indicate that sustained virologic response: inversely correlates with the time of therapy necessary to clear serum HCV RNA; and directly correlates with the time on therapy after clearance of HCV RNA. Extension of treatment may increase the efficacy of therapy in patients who do not show virological response early during therapy.

On a personal note, I completed 18 months (72 weeks) therapy with peginterferon plus 800 mg ribavirin (I weigh 140 lbs) about two years ago. I did the extended 18 months therapy because there was data back then from a study suggesting that extended therapy might be helpful in achieving a sustained viral response and in preventing relapse. I felt and other key thought leaders also felt that people like myself with negative predictive factos might do better with 18 rather than 12 months therapy. My doctor, a leading researcher who also knew of this data and theory, agreed with me. I had previously been treated with standard IFN plus RBV but had no viral response, so I was a nonresponder. I have HIV, people with HIV have less SVR rates than HCV monoinfected, I had cirrhosis. So I had several important negative predictive factors. Within 5 weeks after starting pegIFN+RBV I had a complete viral response, my viral load was undetectable. It may have gone to undetectable sooner but my first test was at 5 weeks. It's two years since I completed 18 months therapy and I test my viral load every few months and it's still undetectable. I consider myself "cured". There is no way to be sure if the 18 months was more effective for me. Perhaps my outcome would've been the same with 12 months therapy. But in retrospect I'm glad I did the 18 months. If I hadn't I might have regretted it.

Back to the study. The aim of the study was to compare the efficacy and the safety of treatment with PEG-IFN alfa-2a (40KD) plus ribavirin administered during 48 or 72 weeks in patients who did not have a rapid virological response (RVR).

RVR was defined as undetectable serum HCV RNA at week 4 of therapy (COBAS AMPLICOR HCV Test v2.0, <50 IU/mL).

PATIENT STUDY POPULATION. Adults with chronic HCV; elevated ALT; HCV RNA >600 IUmL; liver biopsy proven; treatment-naïve; compensated liver disease; no contraindications for study drugs; no significant co-morbidity.

517 patients started the study. At week 4 a PCR HCV RNA was performed. 36% (n=184) of patients had negative HCV RNA and went on to treatment for 24 or 48 weeks depending on their genotype, 24 weeks for genotype 2/3 & 48 weeks for genotype 1.

326 (64%) patients had positive HCV RNA at week 4 and were randomized to 48 or 72 weeks of therapy with Pegasys and ribavirin 800 mg/day.

CHARACTERISTICS of the patients with positive HCV RNA at week 4: 65% men; 43 yrs old; 75 kg weight; 1.0 HCV RNA x 105 (IU/mL); 39-46% >800x 103 IU/mL. 94% genotype 1; ALT 2.5 x ULN.

RESULTS

The SVR rate was significantly higher in patients treated for a total of 72 vs 48 weeks, including those with genotype 1 and high baseline viral loads. As you can see patients with 72 weeks therapy had better sustained viral response rate (45% vs 32%), but also they had less relapses, presumably due to the longer treatment. (EOT=end of treatment response rate).

72 WEEKS THERAPY:
EOT 52%
SVR 45% (n=161)
ITT

48 WEEKS THERAPY:
EOT 61%
SVR 32%
ITT
P=0.014

RELAPSE RATE
The relapse rate was significantly less for patients taking 72 vs 48 weeks therapy (48% vs 13%, p=0.05).

SUSTAINED VIRAL RESPONSE IN GENOTYPE 1 PATIENTS
ITT

SVR was 28% for 48 weeks therapy vs 44% for 72 weeks (p<0.001).

ADVERSE EVENTS

The rates of commonly reported adverse events were the similar for patients whether they received 48 or 72 weeks therapy. Serious adverse events were 5% for 48 weeks & 8% for 72 weeks. There were no previously unreported AEs.

TREATMENT DISCONTINUATION

At week 24, disct was 12% in 72 week grp & 11% in the 48 week grp, the same. At week 48, disct was 18% in the 48 week grp 7 27% in the 72 week grp. And at week 72 the disct rate was 36%.

REASONS FOR DISCONTINUATION
adverse events: 10.3% in 48 wk grp, 13.0% in 72 wk grp
lab abnormalities: 0% in 48 wk grp, 1.2% in 72 wk grp
patient's own decision: 4.8% in 48 wk grp, 18.0% in 72 wk group
other reasons: 1.8% in 48 wk grp, 4.3% in 72 wk grp

SLOW VIRAL RESPONDERS MAY BENEFIT FROM 72 WEEKS THERAPY

"Reduction of Relative Relapse Rates by Prolongation of the Duration of Therapy with Peginterferon alfa-2a (Pegasys) plus Ribavirin up to 72 Weeks in Patients with HCV Genotype 1 Infection"

--Early viral responders (week 12 negative) achieved high SVR (75-80%) regardless of treatment duration (72 or 48 weeks)

--Slow viral responders (week 12 positive & week 24 negative) showed significantly improved SVR rates when treated for 72 weeks as a result of reduced relapse rates

--About 18% of the genotype 1 patients in this study were slow viral responders

--Authors said: our data do not support the concept of generally extending treatment duration to achieve higher SVR rates in patients with HCV genotype 1, BUT in the small significant sub-group of patients with slow viral response extension of treatment to 72 weeks may represent a strategy to improve sustained viral response rates in this difficult to treatment patient population

Thomas Berg presented these study findings at the AASLD meeting in the same oral session as the study above. The reasons for the relatively high virological relapse rates after antiviral combination therapy in patients with HCV genotype 1 are unknown. Slower turnover of hepatocytes infected with HCV type 1 could be a reason. A prolongation of the duration of the therapy could represent a strategy for reducing relapse rates in this difficult-to-treat patient group.

In a German multicentre study 453 treatment-naïve patients with histologically proven chronic HCV type 1-infection were treated with 180 µg peginterferon alfa-2a per week plus 800 mg ribavirin per day for either 48 weeks (n=231) or 72 weeks (n=222).

Patients had elevated ALT & compensated liver disease (Child Pugh A). Liver biopsy findings were consistent with chronic HCV. All patients had genotype 1 and HCV RNA >1000 IU/mL. 55% males; 97% Caucasian; 75 kg weight; 25.3-25.6 kg/m2 BMI; ALT 2.5 x ULN; HCV RNA 5,7 IU/mL; 7.4-9.0% had cirrhosis.

RESULTS

VIROLOGIC RESPONSE RATES
(ITT)

The intention to-treat analysis presented at AASLD 2003 didn't show a significant difference in the sustained virological response rate between the two treatment groups (52% vs 53% SVR; EOT 72% 48 wks, 67% 72 wks). In this study we examined the influence of the duration of therapy on the relative relapse rate in relation to viral kinetics.

RELAPSE RATES

Overall the relative relapse rate (related to the number of patients with negative HCV RNA at the end of therapy) was 23% (72/314). In patients treated for 48 or 72 weeks, the relapse rates were 26% (44/165) and 19% (28/149) (p=0.09), respectively.

SVR IN RELATION TO EARLY VIRAL RESPONSE

No significant difference was evident for sustained virological response in patients who were HCV RNA negative at week 4 or 12.

For patients with HCV RNA <50 IU/mL at week 4 there was no difference in SVR rates whether they were treated for 48 weeks (84%) or 72 weeks (77%). And also at week 12, patients with <50 IU/mL, 80% treated for 48 wks & 75% treated for 72 wks had SVR.

30% of patients with >50 IU/mL at week 12 receiving 72 weeks vs 18% receiving 48 weeks therapy had SVR, but this was not significant (p=0.08). For patients with detectable HCV RNA at week 4 SVR rates were similar (44% for 48 wks & 50% for 72 wks).

REFINED ANALYSIS OF THE STUDY; GOAL

Whether there is a difference in the relapse rates between type 1 infected patients treated either for 48 or 72 weeks in relation to the early viral response

Early viral response defined; HCV RNA >=2 log decline or undetectable at treatment week 12 by qualitative PCR (Roche Amplicor).

Slow viral response; HCV RNA <2 log decline or detectable at week 12 by qualitative PCR but becoming undetectable at week 24.

RELAPSE RATES in EARLY VIRAL RESPONDERS

In patients with >2 log decline in HCV RNA SVR was the same whether treated for 48 or 72 wks: 22% for 48 wks, 17% for 72 wks.

In patients with <50 IU/mL at week 12, SVR rate was also the same: 13% for 48 weeks, 12% for 72 wks.

BUT...

RELAPSE RATES IN SLOW VIRAL RESPONDERS

For patients with <2 log decline at week 12, 90% (9/10) had relapse with 48 wks therapy but only 57% relapse (4/7) with 72 weeks therapy (p=0.14). For patients with >50 IU/mL at week 12 34% with 72 weeks therapy had relapse vs 60% taking 48 weeks therapy (p=0.028).

RELAPSE RATES LOWER IF VIRAL LOAD WAS LOW AT WEEK 12

Patients with <50 IU/ml at week 12 had 13% (48 wks) & 12% (72 wks) relapse rates. BUT, for patients with 50-5,000 IU/mL (mean 1049) at week 12, the length of therapy mattered: 50% receiving 48 wks had relapse & 24% receiving 72 weeks had relapse (p=0.037). Patients with >5000 IU/mL at week 12 (mean 44,113) had similar relapse rates regardless of length of therapy (90% for 48 wks, 75% for 72 wks).


  
  



  

[Califia]

Thanks, guy.   Note that these are all European studies, first delivered at the European Assoc for the Study of the Liver held in Berlin last April.

I hope the obstacles roll from your path this week and that Kaiser comes through for you.   Onward!

[cuteus]

I finally found the darn study! (due to copywright stuff)and the fact that I can't link, take these directions; janis7hepc.com take a southbound turn to world news & research, click and scroll all the way to bottom to get 2003 articles, find it in May 2003. one out of nine dropped out, so 7 out of 8 achieved svr, all G1.

[Tony-z]

Most of my research is for non-Responders but I am looking.

What else can I do???????????

                TonyZ

http://janis7hepc.com/research_articles_2003.htm#extending

[Califia]

CUTEUS:   Good driving directions...now watch me make a few one-handed left turns!   (Better yet, avert your eyes.)   Muchas gracias, chica.

TONY:   Just being here to bounce ideas around is good.  I just found out that my friend was started out at a suboptimal riba dose (800 mcg), which makes no sense for someone weighing 135 lbs.  Why??????   This is the same doc who refused me a liver biopsy when I first entered the Kaiser system.   I'm grateful I followed my gut instincts and fired him back then.

There's a bit of a lull in action until her viral count is back...but I'm networking like crazy on her behalf in the meantime.   Ironically enough, she's an RN,  but is a pretty tired cookie after 11 months of anti-virals and is glad to have the assistance.   (Prayer is also good.  She's a woman of the cloth.)

to be cont'd....

[DoubleDose]

Two suggestions for your friend:

1.  She needs to increase the Peg-Intron dose as a first strategy, while keeping the ribavirin at full tilt (I am not sure what the max. recommended Riba dose is for 135 lbs.  It MAY indeed be closer to 800 mg. or maybe 1000 mg).  I believe that the Peg dosage level is what really gets one to undetected, and it needs to be adequate in order to get the job done.  The dose needed varies quite a bit, from patient to patient, so early ,and frequent viral load PCR's are really helpful in determining what adjustments might be helpful.  Most docs do not do this, and use very safe, approved protocols, which are often sub-optimal. They also do not do enough early PCR testing, to determine effectiveness of the regime.

2.  Since she was undetected for a period of time, but is now detected, lots will depend on the quantitative count for her current situation.  If it is very low, like 2000 IU or less, she might get undetected again with the current dose, or a slight bump upward...BUT the breakthrough of the virus is NOT a very good indicator.  If the interferon is working, the virus should keep decreasing as you go....so either she is on a sub-optimal dose OR she is somewhat of a non-responder.  Only renewed attempts, with creative dosing, will determing which she is.  I think there is lots of hope, since she apparantly did go undetected for awhile.  So the other strategy would be for her to discontinue tx, take a three to six month rest and recuperation, and start therapy again at 'full tilt'...higher Peg-Intron doses, full allowable ribavirin, growth factors as needed (Procrit, etc.) and to look for a good viral response pattern.  Ideally they might check PCR levels at 1 week, 4 weeks, 12 weeks, and further as necessary.  Getting the undetected before 24 weeks is pretty important, as well as getting the minimum of a 2-log drop by week 12.  She may need a more experienced, more aggressive doctor as well.  The right doc, and the right treatment protocol can make all the difference in the world.

Best of Luck!!!!   DD

[Califia]

We're all on the same page with this -- too bad the G.I. isn't.    BTW,  when I spoke of  her EVR once on full dosage,  this meant the requisite 2-log drop.  Sadly, she's never been undetected.   At any rate, thanks much for your input.   I really appreciate.

[DoubleDose]

Check out the thread above titled sexual transmission.  Post number three, by Sally say-so, is by my HCV doctor, Mark Sulkowsky.  It addresses Type 1's, and the need for creative treatment strategies, and asks whether 48 weeks is enough.  Also some good supporting documentation.  Sulkowski is at the top of the pack as far as knowledge and treatment experience.  His scientific foundation is the best, and he is a very insightful coach throughout tx.  He has seen it all, as far as HCV cases.

[Califia]

Extension!    Seems the viral load came back < 600 and > 7 virions, low enough to continue.    I am still suggesting that my friend continue tx under another doctor's care, however.  Her present situation is way too chaotic.  (Neither doctor nor patient seemed to recall that she had actually only been at full dosage for only 2 1/2 months.)

Keep excellent treatment records, everyone.  Elementary self-defense.

[DoubleDose]

Now is the time for your friend to hit it very fast, and very hard...at full dosages...both for Peg. and Riba.  A good doctor, with lots of HCV exp. can make all the difference in the world.  There are many drugs being used today, from antidepressants, to growth factors (Procrit, etc.), to sleeping aids, pain killers, anti-inflammatories, so that almost all tx patients should be able to stay at or very near full dosages THROUGHOUT tx, if not at even higher, tailored dosages, for slow responders.  

Good luck to your friend!

DD

[DoubleDose]

By the way, a PCR result of <600 would have been an 'undetected' result before the more recent, ultra-sensitive tests.  What her test results seem to show is that she is on a slightly sub-optimal tx regimen, which you already realized since dosages were reduced.

Ask the doc WHY she is not on PROCRIT, right NOW, to combat anemia, and to allow her to go fully undetected.  This is no academic game, and the doctor is doing her a grave disservice by not optomizing her therapy, and not using the tools available to get her undetected.  She is virtually RIGHT THERE, and probably just needs the bump back to full dosages, especially on the PEG, but also with the Ribavirin.  If she gets back to full dosing, and tolerates it, she should most probably go for a very extended period after the undetected result (48 weeks to 60 weeks), in order to assure full eradication.  This would of course also be at full dosages.  MAYBE very late into the final stages there may be some 'wiggle room' for dosage modifications, but now is the wrong time, and it is keeping her from being fully successful.

The opportunity is at hand, if she can get to a really good, highly experienced HCV doc, who can salvage her therapy.  She is SO close!!!!

DD

[Califia]

FYI,  she's been at full dosage for 2 1/2 months;  does take Procrit,  and has for months now.   (Still had trouble getting to acceptable Hg and hematocrit levels even with regular Procrit.)  The real problem was the neutropenia that presented way back in week two, and her allergic reaction to the prescribed Neupogen.   The doc wanted her to stop its use altogether (not an unreasonable assumption), but as my buddy is a nurse, she persisted w/  small  incremental increases on her own.  Got the white count high enough to start full dosage interferon.   (I'm sure she would want me to say don't try this at home. )

Regardless--this is a good opportunity for her to find another doc, and I'm lobbying hard for that outcome, even at the risk of being a bit obnoxious.   Hey, what are friends for?   I totally agree w/ your assessment  of her situation.  My gut feeling is that she needs to crank it up right now with an enhanced protocol and then extend to 72 weeks, with the weekly count starting in June,  which is when she started at full dose.   That's what she would like, too.