Direct-acting
antiviral (DAA) treatment is curing people of hepatitis C infection in clinics at
similar rates to those seen in clinical trials, and there don’t seem to be
major differences between drug regimens, according to results of a large
population study presented at the 2016 AASLD Liver Meeting in Boston this weekend.
Clinical trials
tend to show the best-case scenario for efficacy of new drugs. Patients in
clinical trials are carefully selected from populations who are already
attending clinics – by definition, a highly motivated group of patients.
Furthermore, patients recruited to clinical trials cost money to recruit and
monitor so they will be followed up carefully, and in many cases patients are
getting free treatment, maximising the incentive to stay in care. All these
factors tend to promote better outcomes in clinical trial populations than in
subsequent 'real world' clinic populations.
A review of the
Veterans Affairs Cohort – military veterans receiving care through US Veterans
Affairs’ (VA) clinics – finds that people receiving DAA treatment in those
hospitals are being cured of hepatitis C at similar rates to those seen in
clinical trials of the drug combinations in widespread use today. Clinical
trials that led to licensing of the DAA combinations recommended for treatment
reported sustained virologic response (SVR12) rates above 90% for genotype 1, around
75% for genotype 3, and somewhat lower for each genotype in cases where people
had cirrhosis or previous experience of unsuccessful treatment.
Glossary
- albumin
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
The study also
found that an 8-week regimen of sofosbuvir/ledipasvir (Harvoni) is just as effective as a 12-week regimen for those who
qualify to take it – genotype 1 patients without cirrhosis or previous
experience of treatment who have a viral load below 6 million IU/ml.
The study
population comprised 17,487 people with hepatitis C virus (HCV) infection who started therapy with DAA agents without interferon between January 2014 and June
2015 at 167 VA medical centres in the United States. Follow-up was to April
2016. The main study outcome was sustained virological response (SVR). This was
analysed according to HCV genotype and cirrhosis status.
The study
population was 97% male, 52% white, 29% black, 5% Hispanic, and had a high
prevalence of cirrhosis (30%) and decompensated cirrhosis (8.3%). Genotype 1
was the predominant form of hepatitis C infection (80%), with 12% having genotype 2, 7% with genotype 3 and 1% with genotype 4.
Regimens used by the
participants were:
- Sofosbuvir (SOF)/ribavirin: n =
2986
- Ledipasvir/sofosbuvir
(LDV/SOF): n = 11,327
- Paritaprevir/ritonavir/ombitasvir
and dasabuvir (PrOD): n = 3174.
The study measured
sustained virologic response rates 12 weeks after completion of treatment
(SVR12). If SVR12 data were missing, the SVR12 result was imputed from SVR4
measurements (5.7% of cases).
|
% treated
|
SVR 12%
|
Genotype 1
|
SOF/LDV
|
58%
|
92.%
|
SOF/LDV/riba
|
19%
|
92%
|
PrOD
|
6%
|
94.9%
|
PrOD/riba
|
17%
|
92.5%
|
Genotype 2
|
SOF/riba
|
100%
|
86.2%
|
Genotype 3
|
SOF/riba
|
57%
|
77.9%
|
SOF/LDV/riba
|
31%
|
87%
|
SOF/PEG/riba
|
11%
|
70.6%
|
Genotype 4
|
SOF/LED/riba
|
77%
|
87.6%
|
PrOD/riba
|
23%
|
96.4%
|
The study also
looked at the performance of DAAs in people with cirrhosis.
Whereas in people with genotype 1 infection there was little difference in
SVR12 between those with or without cirrhosis (90.6 vs 93.6%), virologic
response was considerably lower in people with cirrhosis with genotype 2 (77.3 vs
89.1%) and genotype 3 (65.7 vs 81.6%). Response was also lower in people with cirrhosis with genotype 4 (83.9 vs 91.5%), although less markedly so.
A similar pattern
was evident when treatment responses were compared in treatment-experienced and
previously untreated people. There was no difference in virological response
in people with genotype 1, but SVR rates in treatment-experienced people with
genotypes 2 or 3 were around 8% lower than in previously untreated people (80.2
vs 88% for genotype 2, and 77.5 vs 69.2% for genotype 3).
The study also
looked at treatment outcomes in 1975 people who qualified for an 8-week
course of sofosbuvir/ledipasvir – previously untreated people without cirrhosis
with viral load below 6 million IU/ml. 95.1% of these people achieved SVR12,
compared to 95.8% of those treated with sofosbuvir/ledipasvir for 12 weeks.
Independent
predictors of treatment failure included genotype 2 or 3 infection compared to
genotype 1 infection, and among those with genotype 2 or 3 infection, treatment
experience. Male sex, black or Hispanic ethnicity, diabetes, low platelet
count, low serum albumin and elevated bilirubin all independently predicted
failure to achieve SVR, as did cirrhosis.