This page shows what was measured, who it was measured in, and what that does not settle.
What Ledipasvir does in the body
Long-standing hepatitis C infection, mainly genotype 1
Hepatitis C cannot copy itself out in the open. It first builds a private workshop out of folded cell membrane, and a viral protein called NS5A is the foreman that organises that workshop and packages finished genomes into new virus particles. Ledipasvir sticks to NS5A and stops it doing either job. Paired with sofosbuvir, which jams the copying machine itself, the virus loses both the workshop and the machine at once.
What happened in people
99% sustained virologic response at 12 weeks in 865 previously untreated genotype 1 patients in ION-1
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
That eight weeks equals twelve — the observed gap was one point, but noninferiority was declared against a twelve-point margin
Where it acts
Hepatocyte cytoplasm — the membranous web where NS5A assembles the viral replication complex
Kind of result
The kind of result is not recorded
Supervision
RNAWiki has not recorded a supervision or regulatory status for this substance.
What the registries record it as
The substance registry classes this as chemical.
FDA substance registry · 013TE6E4WV · read 2026-08-29
Where each sentence above came from
The recorded explanation is written in label language rather than for a beginner. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 96 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Sustained virologic response 12 weeks after end of therapy
✓ The study showed what it set out to show
Who was studied
ION-1 (NCT01701401)
How many people
865
Study design
Phase 3, randomised, open-label, four-arm
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
99% (95% CI 96 to 100) at 12 weeks without ribavirin; all four arms 97% to 99%
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Open-label with no placebo or active comparator arm. The trial compares four versions of the same regimen against each other, not against anything else.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral fixed-dose combination tablet with sofosbuvir, and oral pellets for children
Interval reported. 95% CI 96 to 100) at 12 weeks without ribavirin; all four arms 97% to 99%
Written into the record, not signed off as a reviewed claim.
Sustained virologic response at 12 weeks, 8-week against 12-week treatment in non-cirrhotic previously untreated patients
✓ The study showed what it set out to show
Who was studied
ION-3 (NCT01851330)
How many people
647
Study design
Phase 3, randomised, open-label noninferiority
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
94% at 8 weeks against 95% at 12 weeks; difference 1 percentage point (97.5% CI -4 to 6), noninferiority margin 12 percentage points
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. The prespecified noninferiority margin was 12 percentage points. A regimen curing 83% would have passed. The observed difference was 1 point, but the design licensed far more.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral fixed-dose combination tablet with sofosbuvir, and oral pellets for children
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 3 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Ledipasvir
What a person takes: Oral fixed-dose combination tablet with sofosbuvir, and oral pellets for children.
The measurement behind this step
One tablet daily, with or without food. Ledipasvir is not available separately, so every statement about it is a statement about the combination. Pellets exist for children from age 3.
Getting in
One tablet, taken once a day
Ledipasvir is never sold on its own. It comes fixed in a single tablet with sofosbuvir, so the two halves of the regimen cannot be taken apart or taken at different times.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Fixed-dose combination of 90 mg ledipasvir with 400 mg sofosbuvir. Ledipasvir solubility falls steeply as gastric pH rises, so acid-reducing agents lower exposure — an interaction written into the label and a real mechanism of treatment failure.
It reaches the liver cell, where the virus builds its workshop
Hepatitis C does not copy itself out in the open cytoplasm. It first pulls cell membrane into a folded compartment, and does its copying inside that.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
HCV remodels endoplasmic reticulum membrane into the membranous web. NS5A is a membrane-anchored phosphoprotein with no catalytic activity; it organises the replication complex, recruits host factors including PI4KIIIalpha and cyclophilin A, and later hands genomes to the core protein for packaging.
It clamps onto the scaffold protein at two points at once
The molecule is shaped like a dumbbell, with two identical grabbing ends held apart by a rigid bar. NS5A works as a pair, and the spacing of the two ends matches the gap between them.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Ledipasvir is a pseudo-symmetric bis-imidazole built on a gem-difluorofluorene spine, binding across the NS5A dimer interface in domain I. The bivalent geometry is why potency is picomolar: replicon EC50 is 0.031 nM against genotype 1a and 0.004 nM against genotype 1b.
The workshop stops being built and finished virus stops being packaged
With the foreman immobilised, the virus can neither maintain the compartment it copies itself in nor package the copies it has already made.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
NS5A inhibition blocks both replication complex formation and virion assembly, which is why NS5A inhibitors produce a faster first-phase viral load decline than either polymerase or protease inhibitors. Combined with sofosbuvir-mediated chain termination, the virus loses the replication compartment and the polymerase in the same dose.
For most people without cirrhosis, eight weeks is enough. Twelve is used when there is cirrhosis, or previous treatment that did not work.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
SVR12 was 94% at 8 weeks and 95% at 12 weeks in ION-3 in non-cirrhotic previously untreated patients, 99% at 12 weeks in ION-1, and 94% at 12 weeks in previously treated patients in ION-2. Almost all failures are post-treatment relapse rather than on-treatment breakthrough.
Failure means the virus altered the protein ledipasvir grabs. Those alterations stick around for years afterwards, and what that means for future treatment is not known.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Emergent NS5A substitutions Q30R, Y93H/N and L31M appeared in 55% of genotype 1a and 88% of genotype 1b failures, with 20-fold to >243-fold reduced susceptibility. S282T, the sofosbuvir escape route, appeared in none. Certain NS5A substitutions persist beyond one year; the label states the long-term clinical impact is unknown.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 6 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Adults and children aged 3 and over with genotype 1, 4, 5 or 6. It is never given alone and is not sold alone: ledipasvir exists only inside the fixed-dose combination with sofosbuvir.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Where the result stopped carrying
No useful activity against genotypes 2 and 3, which is why a pan-genotypic successor displaced it within two years of launch
Potency falls by four to five orders of magnitude against genotype 6 subtypes 6e, 6l, 6n, 6q, 6k and 6m, and against genotype 4b
Twenty-three per cent of trial patients started with an NS5A polymorphism at a resistance-associated position already present
The one fatal cardiac arrest in the sofosbuvir class amiodarone warning occurred on this combination
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Prescription only
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral fixed-dose combination tablet with sofosbuvir, and oral pellets for children
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
RNAWiki has not recorded a supervision or regulatory status for this substance.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
No register row and no identity class settled the question.
No source is stored against this line.
What is in the pack
One tablet daily, with or without food. Ledipasvir is not available separately, so every statement about it is a statement about the combination. Pellets exist for children from age 3.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Carries the class boxed warning for hepatitis B virus reactivation, including fulminant hepatitis, hepatic failure and death. Coadministration with amiodarone is not recommended: the single fatal cardiac arrest in the class warning occurred on this combination. Exposure falls when gastric pH rises, so acid-reducing agents are a labelled interaction. Commonest trial adverse events were fatigue, headache, insomnia and nausea; no patient in the 12-week arms of ION-1 or in any arm of ION-2 discontinued for an adverse event.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral fixed-dose combination tablet with sofosbuvir, and oral pellets for children
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Ledipasvir is not available separately, so every statement about it is a statement about the combination. Pellets exist for children from age 3.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
9 products list this as an active ingredient in the United States drug directory. 4 of them contain it and nothing else.
FDA National Drug Code directory · 61958-1801 · read 2026-08-29
They are sold as pellet, powder and tablet, film coated, taken oral.
FDA National Drug Code directory · 61958-1801 · read 2026-08-29
2 published labels name it as an active ingredient. None of them describes this substance alone, so no label text on this page can be attributed to it rather than to a combination.
US prescribing information · f4ec77e4-bae8-4db0-b3d5-bde09c5fa075 · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · f4ec77e4-bae8-4db0-b3d5-bde09c5fa075 · read 2026-08-29
Harvoni is oral at 3 DOSAGE FORMS AND STRENGTHS HARVONI is available as tablets or pellets for oral use., recorded as fda label in effect 2024-12-26 in the United States.
US prescribing information · f4ec77e4-bae8-4db0-b3d5-bde09c5fa075 · read 2026-08-30
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
RNAWiki could not confidently classify this substance, so no self-experiment plan is offered.
Questions worth asking
Which of the trials of Ledipasvir studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That eight weeks equals twelve — the observed gap was one point, but noninferiority was declared against a twelve-point margin
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the genotype 4, 5 and 6 indications are supported the way genotype 1 is; they rest on small clinical numbers plus an in vitro panel that is not uniform across the named subtypes
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That persistent NS5A resistance substitutions are clinically unimportant — the label states in as many words that their long-term impact is unknown
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That a 99% cure rate means the regimen has been shown to prevent deaths or liver cancers; ION-1, ION-2 and ION-3 all measured virus in blood
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Ledipasvir are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
ION-1: 99% cured in 865 previously untreated genotype 1 patients
In plain words
Almost everyone was cured, and adding ribavirin or doubling the treatment length changed nothing. Not one person in either twelve-week group stopped because of a side effect.
What was measured
Sustained virologic response 12 weeks after end of therapy
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
ION-1 randomised 865 previously untreated genotype 1 patients 1:1:1:1 to ledipasvir-sofosbuvir for 12 weeks, with ribavirin for 12 weeks, for 24 weeks, or with ribavirin for 24 weeks. Sixteen per cent had cirrhosis, 12% were black and 67% had genotype 1a. SVR12 was 99% (95% CI 96 to 100), 97% (94 to 99), 98% (95 to 99) and 99% (97 to 100) respectively. No patient in either 12-week group discontinued for an adverse event. Commonest events were fatigue, headache, insomnia and nausea.
Written into the record, not signed off as a reviewed claim
ION-2: 94% cured in patients whom interferon had already failed
In plain words
These were people for whom the previous generation of treatment had not worked, including some who had already failed a protease inhibitor as well. Twelve weeks cured 94% of them and twenty-four weeks cured 99%.
What was measured
Sustained virologic response at 12 weeks in previously treated genotype 1 infection
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
ION-2 randomised 440 genotype 1 patients who had not achieved SVR on peginterferon and ribavirin, with or without a protease inhibitor, to the same four arms. Twenty per cent had cirrhosis and 79% had genotype 1a. SVR12 was 94% (95% CI 87 to 97) at 12 weeks without ribavirin, 96% (91 to 99) at 12 weeks with it, and 99% (95 to 100) in both 24-week arms. No patient discontinued treatment for an adverse event.
Written into the record, not signed off as a reviewed claim
The eight-week regimen was declared noninferior against a twelve-point margin
In plain words
ION-3 shortened treatment from twelve weeks to eight. The trial was designed so that anything up to twelve percentage points fewer cures would still have counted as a success. The observed difference was one point, but the margin is what the design was willing to accept.
What was measured
That eight weeks is equivalent to twelve — supported by a one-point observed difference, but licensed by a noninferiority margin wide enough to have accepted a twelve-point loss
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
ION-3 randomised 647 previously untreated genotype 1 patients without cirrhosis to ledipasvir-sofosbuvir for 8 weeks, with ribavirin for 8 weeks, or without ribavirin for 12 weeks. SVR12 was 94% (95% CI 90 to 97), 93% (89 to 96) and 95% (92 to 98). The 12-week rate was 1 percentage point higher than the 8-week rate (97.5% CI -4 to 6) and the ribavirin arm 1 point lower (95% CI -6 to 4). Noninferiority was declared on a prespecified margin of 12 percentage points. Relapse, not breakthrough, accounted for almost all failures, and the label reports higher relapse after 8 weeks in patients with high baseline viral load.
Written into the record, not signed off as a reviewed claim
When the combination fails, it is always the NS5A half that broke
In plain words
Across the three registration trials, thirty-seven people relapsed. In almost all of them the virus had changed the target ledipasvir binds to. Not one of them had a virus resistant to sofosbuvir.
What was measured
Emergent NS5A resistance-associated substitutions and fold-change in susceptibility at virologic failure
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Pooled resistance analysis across ION-1, ION-2 and ION-3 covered 37 virologic failures, 35 of them relapses. Emergent NS5A resistance-associated substitutions appeared in 55% (16 of 29) of genotype 1a failures — commonly Q30R, Y93H or N, and L31M — and in 88% (7 of 8) of genotype 1b failures, commonly Y93H. Two or more NS5A substitutions were present in 38% (14 of 37). Phenotypically these isolates showed 20-fold to more than 243-fold reduced susceptibility to ledipasvir. The sofosbuvir resistance substitution S282T was not detected in any failure isolate from the phase 3 trials. In the SOLAR-1 and SOLAR-2 transplant and decompensated-disease trials the pattern was the same: NS5A substitutions in 82% of genotype 1a and 86% of genotype 1b failures.
Source
HARVONI United States prescribing information, Microbiology 12.4, pooled ION-1/ION-2/ION-3 resistance analysis (NDA 205834)
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
verified
Review state
Written into the record, not signed off as a reviewed claim
Genotype coverage is subtype-dependent and the label says so in numbers
In plain words
Ledipasvir is licensed for genotypes 1, 4, 5 and 6. Within genotype 6 there are subtypes against which it is roughly ten thousand times weaker than against genotype 1b, and one subtype of genotype 4 where the same is true.
What was measured
Replicon EC50 by HCV genotype and subtype
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Replicon EC50 values in the label run from 0.004 nM for genotype 1b and 0.031 nM for 1a, through a median 0.03 nM for genotype 5a and 0.002 to 0.16 nM across eleven genotype 4 subtypes, to a median 199.6 nM for genotype 4b (range 0.66 to 1,799 nM, N=3) and medians of 60.6 to 430.1 nM for genotype 6 subtypes 6e, 6l, 6n, 6q, 6k and 6m. Genotype 6a and 6h sit at 0.55 and 0.17 nM. The genotype 4, 5 and 6 indications rest on small clinical numbers plus this in vitro panel, and the panel is not uniform across the subtypes the indication names.
Source
HARVONI United States prescribing information, Microbiology 12.4, antiviral activity by genotype and subtype (NDA 205834)
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
Superseded by its own successor within two years
In plain words
Harvoni was launched in October 2014 as the answer to hepatitis C. In June 2016 the same company launched a combination that works against all six genotypes, and the genotype test that Harvoni required stopped being part of the pathway.
What was measured
That a 99% cure rate settles which regimen should be used — it does not, once a competitor reaches the same rate without needing to know the genotype first
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Ledipasvir has no useful activity against genotypes 2 and 3, which together account for a large share of infections outside North America and Western Europe, and its genotype 6 activity is subtype-dependent. Sofosbuvir/velpatasvir, approved under NDA 208341 in June 2016, replaced the NS5A component with one active across genotypes 1 to 6 and reported 99% SVR12 in 624 treated patients across genotypes 1, 2, 4, 5 and 6 in ASTRAL-1. The shift is not that ledipasvir was found wanting on its own terms — ION-1 has not been improved on — but that the clinical question changed from "which genotype is this" to "does it matter", and ledipasvir only has an answer to the first.
Written into the record, not signed off as a reviewed claim
A quarter of patients start with a resistance polymorphism already present
In plain words
Nearly one patient in four is already carrying virus with a change at one of the positions ledipasvir binds, before any treatment. Most are still cured. Nobody knows what happens to those changes in the long run.
What was measured
That resistance is not a practical concern with this class — true for cure rates in the trials, unestablished for what a persistent NS5A substitution means for a person who needs retreatment years later
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
In the pooled phase 3 analysis, 23% (370 of 1,589) of subjects had baseline NS5A polymorphisms at resistance-associated positions 24, 28, 30, 31, 58, 92 or 93, detected by population sequencing or by deep sequencing at a 15% frequency threshold. The label further records that certain NS5A inhibitor resistance-associated substitutions persist for more than a year after treatment failure, and states in as many words that the long-term clinical impact of that persistence is unknown. This is the structural asymmetry of the combination: sofosbuvir resistance is rare and self-limiting because S282T cripples the virus, while NS5A resistance is common at baseline and durable after failure.
Source
HARVONI United States prescribing information, Microbiology 12.4, baseline polymorphisms and persistence of resistance-associated substitutions (NDA 205834)
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
Where else this substance is registered
FDA substance identifier (UNII)
013TE6E4WV
CAS registry number
1256388-51-8
PubChem compound
67505836
ChEMBL
CHEMBL2374220
ChEBI
85089
WHO international nonproprietary name list entry
9796
RxNorm concept
1591922
EMA substance identifier
100000143385
DrugBank
DB09027
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Trial roles classified for highlighted evidence
No registered study is classified as testing this substance.
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No register row and no identity class settled the question.
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slug and display name present
What is missing or unclear◇Read from sources, not yet reviewed
How this medicine reached us
Kept near the foot of the page. A historical event moves up only when it changes something about this substance today.
What the approval register records
2 approved applications cover products containing this substance. The earliest was NDA205834, approved 20141010 to GILEAD SCIENCES INC.
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What is not here
7 questions this page could not answer
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What was measured, goal by goal — found nothing in the sources checked.
How close this is to real life — found nothing in the sources checked.
Felt, measured, or meaningful — found nothing in the sources checked.
How long anything takes — found nothing in the sources checked.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
What changed on this page — found nothing in the sources checked.
The record as stored
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
An NS5A inhibitor of extraordinary potency, active at four picomolar against genotype 1b in cell culture, which combined with sofosbuvir cured 99% of 865 previously untreated genotype 1 patients in ION-1 and 94% in eight weeks in ION-3 — and which has essentially no useful activity against genotypes 2 and 3, so a pan-genotypic replacement displaced it within two years.
Recorded evidence blocks (6)
Q1
93 registered trials of Ledipasvir — at which phases?
Registered studies posting no result
42 of 93
93 registered studies of Ledipasvir: 41 phase2, 19 phase3, 15 phase4, 12 na or unstated, 4 phase1, 3 na, 1 early phase1. CLINICALTRIALS_SNAPSHOT · 2026-09-01
118 with a PubMed record
Show the evidence
phase2
41
phase3
19
phase4
15
na or unstated
12
phase1
4
na
3
5 more recorded rows
early phase1
1
completed
77
unknown
8
terminated
7
withdrawn
1
recorded 2026-09-01 · last checked 2026-09-04
Q2
7 of Ledipasvir's trials stopped: accrual/recruitment, other?
NCT01193478, NCT01434498, NCT01353248, NCT01371578, NCT01356160 and NCT01435226, and 24 more
Completion dates
oldest 2011-12; newest 2022-11
Show the evidence
Trial
NCT01193478
2011-12
NCT01434498
2013-01
NCT01353248
2013-03
NCT01371578
2013-03
NCT01356160
2013-06
NCT01435226
2013-07
14 further recorded trials
NCT02470858
2015-12
NCT02480387
2016-01
NCT03005210
2016-12
NCT03063723
2016-12-01
NCT03188276
2017-05-01
NCT02768961
2017-05-10
NCT04039958
2017-05-28
NCT02333292
2017-06-30
NCT02705534
2017-10
NCT02405013
2017-11
NCT02591277
2017-11-01
NCT02771405
2018-01
NCT02482077
2018-03-15
NCT02576314
2018-03-15
Q5
At the median, Ledipasvir's trials enrolled 111 people — anything larger?
Median enrolment
111
Largest enrolment
50000
Registered trials counted
93
Q6
What do 9526 spontaneous reports say about Ledipasvir — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Ledipasvir appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 9526 reaction mentions were counted: fatigue 3374; headache 3281; hepatitis c 792; insomnia 629. FAERS via Open Targets · CHEMBL2374220 · 2026-06-24
Show the evidence
fatigue
3374
headache
3281
hepatitis c
792
insomnia
629
hepatocellular carcinoma
513
treatment failure
382
4 more recorded rows
ascites
222
genotype drug resistance test positive
159
hepatic cancer
95
hepatitis c virus test positive
79
recorded 2026-06-24 · last checked 2026-09-04
Where it is registeredIdentifiers, relations and other names
ChEMBL 37 — CC BY-SA 3.0 Unported · ClinicalTrials.gov — US Government work · Open Targets 26.06 — CC0 · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md
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✓ source coverage passed: 5 source rows
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