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TOPIC: Harvoni delivers only 91-92% SVR12 in VA study n=4365

Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21770

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Real World Effectiveness of Ledipasvir/Sofosbuvir in 4365 Treatment-Naïve Genotype 1 Hepatitis C Infected Patients

Abstract

Real-world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. The uptake of ledipasvir/sofosbuvir (LDV/SOF) regimens across health care settings has been rapid, but variations often occur in clinical practice. The aim of this study was to assess sustained virologic response (SVR) of LDV/SOF +/- ribavirin (RBV) in routine medical practice. This observational, intent-to-treat cohort was comprised of 4,365 genotype 1, treatment-naive, HCV-infected veterans treated with LDV/SOF +/- RBV. SVR rates were 91.3% (3,191/3,495) for LDV/SOF and 92.0% (527/573) for LDV/SOF+RBV (P = 0.65). African American race (odds ratio 0.70, 95% confidence interval 0.54-0.90, P =0.004) and FIB-4 >3.25 (odds ratio 0.56, 95% confidence interval 0.43-0.71, P < 0.001) were independently associated with decreased likelihood of SVR; age, sex, body mass index, decompensated liver disease, diabetes, genotype 1 subtype, and regimen did not predict SVR. In models limited to those who completed 12 weeks of treatment, African American race was no longer a significant predictor of SVR but FIB-4 >3.25 (odds ratio 0.35, 95% confidence interval 0.24-0.50, P < 0.001) remained. Among those without cirrhosis (defined by FIB-4 <= 3.25) and with baseline HCV RNA<6,000,000 IU/mL, SVR rates were 93.2% (1,020/1,094) for those who completed 8 weeks of therapy and 96.6% (875/906) for those who completed 12 weeks of therapy (P = 0.001). Conclusions: In this real-world cohort, SVR rates with LDV/SOF +/- RBV nearly matched the rates reported in clinical trials and were consistently high across all subgroups; those without cirrhosis but with HCV RNA<6,000,000 IU/mL were less likely to achieve SVR with 8 weeks compared to 12 weeks of therapy, although the numeric difference in SVR rates was small.

www.researchgate.net/publication/3016714..._C_Infected_Patients

Important take home:

In this analysis, 4-week viral kinetics predicted SVR with a greater effect in those who received LDV/SOF.Significant reductions of 10.5% and 7.1% in SVR rates were observed in patients receiving LDV/SOF andLDV/SOF1RBV, respectively, who had a detectable4-week HCV RNA <15 IU/mL compared to those with undetectable 4-week HCV RNA.
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YMMV
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21778

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Dr Freeman, thank you answering my question in what may be redundant.
The "important take home" on your final in the message below resulted in an approximately 3% point in favor of undetected vs 15iu/ML detected in patients after 4 weeks on Sof/Led?
Thank you.










?
Contracted HCV 1980's
Geno Type 1a
F3 ( doc says once treated I'll be F2 maybe F1)
Meds shipped 6/17/2016 arrived early 7/2016

Viral count - 3,471,080

4 week quantitative bloods: August 17, 2016. I have been diagnosed as <15 (told undetected)

8 week quantitative bloods: September 14th. I have been diagnosed as <15 (told undetected)

11 week PCR RNA Qualitative bloods: September 26th 2016 - Undetected

December 19th 2016: Cured!
Viral count: zero!!!
Last Edit: 1 year 8 months ago by Sven. Reason: Spelling iPad
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21783

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Hi Sven,

The "conventional wisdom" has been that on treatment monitoring is not really required and can't be used to guide therapy.

The observation that undetected at 4 weeks is better than <15 in predicting SVR (and better that >15 for that matter) does not really come as a surprise to me.

This VA study says a lot of things.

Gilead with ION said 97% SVR ie 3% failure in treatment naive patients on 12 week Harvoni. The VA study says it looks more like 9% so 3 times more failures.

Gilead with ION said 94% SVR ie 6% failure in treatment experienced patients on 12 weeks Harvoni. The VA study does not shed light on that but if we assume that the 3% holds the real SVR rate is probably 88%.

And it has the observation fast responders do better. With limited drugs this is academic but with options we may need to consider slow response == change drugs add drugs.

We have seen evidence that SVR is possible even in people <15 detected at EOT - Tina here is one example who was <15 detected EOT and is now SVR12, but undetected is clearly better.
YMMV
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21962

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When reading this study – and then isolating the results for patients without cirrhosis and a baseline VL of < 6,000,000 who received a full 12 weeks of LDV/SOF (Harvoni) – I find that the results look very good.

Table 4 shows an overall 12 week therapy SVR rate of 94.3% (1924/2040) with higher success rates in sub-groups depending on APRI and FIB-4 scoring.

The best number achieved was 96.6% (875/906) in patients with both a FIB-4 of ≤ 3.25 and a baseline VL < 6,000,000 IU/ml.

Looking over the health profiles of the study’s patient population – I wonder how the results would have been if the participants had received treatment earlier in their lives. With early diagnosis and treatment – the success rates might have been even better.

Will add that I found the cost/benefit discussion troubling. With the stratospheric price the Veteran’s Administration pays for HCV medicines here it seems both understandable and unacceptable at the same time.

J.
GT 1a (~1968)
Diagnosed Non A/B ’85 – HCV ‘89
Rebetron INF/RBV 17 months 2000 – Failure
Infergen INF/RBV 11 months 2002 – Failure
Viekira Pak + RBV 12 weeks 2015 – Failure
VL Und at +3 weeks > EOT – EOT+12 weeks 2,240k
Resistance Tests – NS5a Q30R
SMV/DCV/SOF + RBV 24 weeks 2016
VL Det <15 +2 and +4 weeks – Und +8 weeks > EOT
SVR4, SVR12 and SVR24 Undetected
Last Edit: 1 year 8 months ago by J. Eugene.
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21970

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You've pretty much hit the nail on the head.

Some subgroups do better than others. Drug companies tend to put as many patients with favourable characteristics into the trials as they can which is why the results out in the real world are never as good. I know of a mathematician whose job is to take Phase 2 data, identify the groups that will do well and then help set the exclusion criteria for Phase 3 to stack the deck as it were....

The good news is that it is over 90% in a really big group. The bad news is that it isn't 97%.

In Europe GECCO has been cataloguing the results of a variety or regiments and have 93% for Harvoni and 96% for Sofosbuvir + Daclatasvir. See fig 6 from CROI 2016 www.natap.org/2016/CROI/croi_190.htm
YMMV
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #21974

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Wow - Some very in depth reports there! Thank-you Dr F.

Am I right in seeing that Sofo/DAC has a tiny edge over Sofo/Led (ie 1%) for GT1s?
I tend to phase out with graphs a bit :blush:
GT1a Dec14 F2/8.7 VL 900000-2.5M
Jan16 Hepcivir-L MonkMed/Redemption
Baseline: VL 913575 Alt 76 Platelets low
Wk2 VL1157 Alt 23
DET Wk 8 VL 32 Alt19 'In the slow lane'
June16 Fibro 5.7 F0/1 LIF 1.5
Wk 11 VL<12 Alt 13 Det/Unq
Extending tx 12 wks Mylan Sofo/Dac MonkMed
Wk 14 VL <12 Det/Unq
Wk 16 VL UNDETECTED
Wk 22 + 4 Wks Sunprevir FixHepC
Wk 24 UNDETECTED Alt 13
Wk 12 post tx SVR12 Wk 26 SVR24
Thank-you Tim, Dr Debasis @ MonkMed & Dr Freeman @ Fix HepC
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #22004

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My GI Doctor stated if it was detected it would say detected, period. He unequivocally stated I was undetected since first 4 week testing to EOT.
Also he said, GI Doctor, the lowest a undetected Quan or Qual can go is <5-6 if you have the right testing equipment. He said, GI Doctor, it is impossible to test to zero in Quan or Qual and there is no testing available to tell you with 100% accuracy to zero.
So please chime in here and show me a testing web site that is governed for quality research to state that a HCV test can go to zero.
I plainly don't get the testing standards for HCV. It seems every doctor has their own testing protocol, very strange really.
Contracted HCV 1980's
Geno Type 1a
F3 ( doc says once treated I'll be F2 maybe F1)
Meds shipped 6/17/2016 arrived early 7/2016

Viral count - 3,471,080

4 week quantitative bloods: August 17, 2016. I have been diagnosed as <15 (told undetected)

8 week quantitative bloods: September 14th. I have been diagnosed as <15 (told undetected)

11 week PCR RNA Qualitative bloods: September 26th 2016 - Undetected

December 19th 2016: Cured!
Viral count: zero!!!
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Harvoni delivers only 91-92% SVR12 in VA study n=4365 1 year 8 months ago #22011

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Hi Sven,

Allowing for slight differences in the different brands of assay tests the actual testing is the same, the problem as you say is in the protocol of different labs and doctors in the way that results are reported and explained. I'll try to explain my understanding of these tests as best I can.

First you need to understand that most modern tests like you received can accurately read down to 15iu/mL or sometimes 12iu/mL. The key word is accurately. They can read below that level and as you doctor says they will often read down to around 5-6 but between 5-6 and 15 they aren't accurate. It is a bit like older car speedos which gave a good reading with 1mph divisions at 35mph but below 15mph there's no markings and the needle wavers around a lot.

There are two types of test result: Qualitative and Quantitative.

Usually the test assay and equipment used is basically the same. The differences are:

Qualitative: a blood sample is taken and processed. It is then examined to see whether they can see the virus. If they can see it then they report it as Detected, if not then Undetected. End of test and the report gives you one of those answers. So it is a quick and dirty Yes/No test with no attempt to work out how much virus is present.

Quantitative: a blood sample is taken and processed. It is then examined to see whether they can see the virus. If they can see it then they go further and measure it against their scale and if it is above 15iu/mL then they will give an accurate result of 27 or 153 or whatever it is. If it is below 15 they can't give you an accurate answer so they just say Detected <15 but the assumption is that it is probably somewhere between 5-6 and 15.

However, if when they check they can't see any virus then sometimes it is reported as Undetected the same as a qualitative test but sometimes with the accuracy level of <15iu/mL of the test included. This is because they don't accurately know where the lower level but they are confident that it must be less than 15. Some labs/doctors seem reluctant to put the Undetected result in writing and just report the <15 but then give a verbal undetected like your doctor appears to have.

The thing to keep in mind with these tests is that, as I think your doctor is trying to say, they can't determine no virus, only that the virus levels are so low that the test can't see it so it may or may not still be present which is what they mean by Undetected. If there is still virus then either our immune system will kill off the few remaining ones or it will start replicating again and eventually reach high enough levels to be detected and that is why we need to wait for a period of time such as SVR12 to see whether we are cured.

I hope that makes it a little clearer for you.

(I talk about 'seeing' the virus in these tests but really they are looking for viral RNA)
G3a since '78 - Dx '12 - F4 (2xHCC)
24wk Tx - PEG/Riba/Dac 2013 relapsed
24wk Tx - Generic Sof/Dac/Riba 2015/16 relapsed
16wk Tx - 12/01/17 -> 03/05/17 NS3/NS5a + Generic Sof
SVR7 - 22/06/17 UND
SRV12 - 27/07/17 UND
SVR24 - 26/10/17 UND
:cheer: :cheer: :cheer:
Last Edit: 1 year 8 months ago by Gaj.
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