Hi Elizabeth .
Welcome to the forum.

It seems her doctor prescribed a regime a bit longer than the norm and also added Riba. (Possibly being GT 3 and chirrotic) to add some extra insurance.
Also being still <10 Det.at week 12 that added insurance could make the difference as Mar mentioned.

I myself was added Riba and did extra time for the added insurance and was glad I did.

She most likely will be UND. @ 16 and hopefully the next 8 wks. after that will pass by quickly for her.

Doctor when you say:

“We know that about 22% of patient will detected at 4 weeks, and also that these people form 44% (our data) or 50% (US VA data) of the treatment failures
Being still detected at 12 weeks is, therefore, a worry.

I had read some recent research awhile ago and actually I had seen here that you also had copied it for perusal where the conclusion now states;

“Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at [end of treatment] do not preclude treatment success,” the study authors concluded.

https://fixhepc.com/forum/viral-load-and-svr/785-hcv-viral-load-and-speed-of-decline-do-not-predict-cure.html

Also I had read this not long ago:

Conclusion:

Presence of DNQ results at EOT does not predict HCV relapse, independently to the sensitivity of the test used.

In less than half of DNQ samples, HCV-RNA detection is confirmed by the US test with LLQ of 4UI/ml.

Frequency of DNQ samples decreases during and after treatment, suggesting to reflect treatment efficacy and not aspecific RNA carry over in PCR

http://livertree.easl.eu/easl/2017/international.liver.congress/168237/ubaldo.visco.comandini.virological.and.clinical.significance.of.detectable.html?f=m3t4035

Am I possibly missing what the latest data seems to be saying?

Thx

S

Hello Songbird,

I’m not talking about EOT results. I’m talking about on treatment kinetic decay, or more specifically rate of kinetic decay.

If you have a look here https://fixhepc.com/component/k2/itemlist/tag/International%20Liver%20Congress%202016.html you will see my original presentation to EASL in 2016. It contains 2 graphs about the kinetic decay of the viral load. The first is a comparator to SOF+PEG+RIBA to SOF+LDV and SOF+DCV. The

At the time I had some unique data, namely the kinetic decay for SOF+DCV in patients with both GT1 and GT3 as well as SOF+LDV for GT1. The upshot is that SOF+DCV produces a slightly faster kinetic decay than SOF+LDV in GT1 patients, and that, for SOF+DCV the GT3 kinetic decay is considerably slower than GT1.

The significance of the rate of kinetic decay is that logically we need to get to ~0-100 total virions left to get cure. This is the infective dose and also way too small to measure as you have 1000 5ml tubes of blood in you so even if the virus was completely blood born, and the cure remainder was <100 viruses only 1 in 10 blood tubes would have a single virus in it.

Anyway, it follows that if you are going down slower you need to treat for longer to have the same overtreatment insurance buffer.

Hello Songbird,

This study was published in 2015 and the conclusions came from pooled data from small clinical trials.

Here’s a much larger VA study 4,365 patients all taking Harvoni that followed this and was published April 2016.

https://www.researchgate.net/publication/301671429_Real_World_Effectiveness_of_LedipasvirSofosbuvir_in_4365_Treatment-Naive_Genotype_1_Hepatitis_C_Infected_Patients

pp408

Significantly lower SVR rates were observed in those receiving LDV/SOF who had a 4-week on-treatment detectable HCV RNA <15 IU/mL compared to those who were undetectable by week 4.

pp410

Four-week on-treatment HCV RNA was an independent predictor of SVR when included as a variable in the models (Supporting Table S2). Having a detectable HCV RNA <15 IU/mL was associated with reduced odds of SVR compared to undetectable in the full model (OR 0.40, 95% CI 0.29-0.56, P<0.001)and in the model limited to those who completed 12weeks of treatment (OR 0.38, 95% CI 0.25-0.58, P<0.001).

pp413

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 and LDV/SOF+RBV, respectively, who had a detectable 4‐week HCV RNA ≥15 IU/mL compared to those with undetectable 4‐week HCV RNA. In patients who completed 12‐week courses of LDV/SOV there remained a significant 6.4% reduction in SVR rates between those with detectable 4‐week HCV RNA ≥15 IU/mL and those with undetectable 4‐week HCV. For those who completed 12 weeks of LDV/SOF+RBV the difference in SVR rates was no longer statistically significant. In multivariable analysis, having a HCV RNA ≥15 IU/mL after 4 weeks of treatment was associated with a 60% reduced odds of achieving SVR for the cohort and a 62% reduced odds of achieving SVR for those who completed 12 weeks of treatment. The VA guidance recommends obtaining 4‐week HCV RNA testing, thus providing a large sample size to evaluate this variable which has not generally been assessed in prior LDV/SOF studies. The clinical implications of this finding on treatment decisions, such as potentially adding RBV or extending treatment duration based on 4‐week on‐treatment HCV RNA, warrant further study.

Call it an inconvenient truth if you like, but a truth it is. I have 3460 patients at last count and initial slow responders used to feature disproportionately in the retreatment group. They feature less now because I extend or modify their treatment.

You may find this interesting in terms of digging into the science of what needs to be done to get to cure:

https://www.bhiva.org/file/lOvBacnRQiHzM/ValeriaCento.pdf

You may also note that this is an early study based on small numbers and concludes in a 1/2 and 1/2 way saying

• In contrast with IFN-containing regimens, a Rapid Viral Response after 4 weeks of INF-free treatment seems not to correlate with SVR12 (proven wrong by VA)
• Cirrhotic patients have a slower HCV-RNA kinetics, and in this population response-guided therapy can still have a role in determining the optimal duration of treatment. (right)

Hello Songbird,

You can’t really compare Maviret to Sofosbuvir based regimens and say what is true for the most potent NS3/4A and NS5A agents ever invented is applies to NS5A/NS5B combinations.

HCV represents a heterogeneous quasispecies – the population in any patient exhibits a great deal of variability. It stands to reason some is easy to kill (call them ordinary infantry), some is harder to kill (call them special forces with body armour) and some is harder again to kill (call them tankers).

Rapid viral suppression represents two distinct things. First we are looking at the decline of the easy to kill population (and this is relatively irrelevant) but secondly, and perhaps more importantly, it represents the window period where there are viable replicons and a drug-driven selective pressure on resistance. In the context of drugs being present, we are selecting for the resistant forms to replicate, and one more mutation could be enough to overcome the EC50 of the drugs we are using.

We do know from HIV that continuing to use drugs where the patient has a viral load leads to the development of resistance.

We are lucky that the drugs work as well as they do.

To me, the issue with fibrosis is that the lower blood supply of fibrotic tissue leads to lower tissue concentrations and thus the potential for the drugs to be present at < EC50. The same goes for BMI - we have certainly seen Daclatasvir toxicity in < 50kg patients and treatment failure more common in > 150kg patients. This is a problem with the one size dose fits all model currently in use. Gilead’s research in children adjusts the dose down based on bodyweight (makes perfect sense) but there is no dose adjustment UP for larger people. There is dose adjustment up for many other drugs – antibiotics, anaesthetics, …