A 35 year old former intravenous drug user who is now a successful investment banker has been found to be HCV RNA positive. He last injected drugs 10 years ago after a 3 year period of needle sharing. He is sent to see you for advice on treatment for his viral hepatitis. A liver biopsy reveals periportal inflammation, some piecemeal necrosis and early fibrosis. He drinks 30 units of alcohol per week. He wants to know if he should have treatment and if so, does combination therapy of interferon with ribavirin really offer much more chance of viral clearance than interferon alone or just waiting to see what happens.

You formulate the question, “In 35 year old man who is HCV RNA positive does treatment with interferon + ribavirin, compared to interferon alone, or no treatment, offer a significant chance of viral clearance.” Fortunately, you have brought your notebook computer with you which has the latest version of Best Evidence on it. You search Best Evidence using the term ” hepatitis c” and “randomised controlled trial” find an abstract and commentary on an article by Poynard et al which looks promising.Lancet 1998;352:1426-32.

You tell the patient that you will obtain this article from your office and will return to him with the evidence.

Read the article and decide:

• Is the evidence from this randomised trial valid?
• If valid, is this evidence important?
• If valid and important, can you apply this evidence in caring for your patient?

Completed Therapy Worksheet for Evidence-Based Gastroenterology and Hepatology

Citation

Poynard T, Marcellin P, Lee SS, et al. Interferon a 2b and ribavirin increased the loss of HCV RNA in chronic hepatitis C.
Lancet 1998;352:1426-32.

Are the results of this single preventive or therapeutic trial valid?

Was the assignment of patients to treatments randomised?

And was the randomisation list concealed?

Yes

Were all patients who entered the trial accounted for at its conclusion?

And were they analysed in the groups to which they were randomised?

Yes

Were patients and clinicians kept “blind” to which treatment was being received?

Yes, the trial was placebo controlled.

Aside from the experimental treatment, were the groups treated equally?

Yes

Were the groups similar at the start of the trial?

Yes

Are the valid results of this randomised trial important?

Sample Calculations

Virological presence at 6 months post treatment		Relative Risk ReductionRRR	Absolute Risk ReductionARR	Number Needed to TreatNNT
Interferon aloneControl Event RateCER	Interferon + ribavirinExperimental Event RateEER	(CER – EER)/CER	CER – EER	1/ARR
$$80.7%$$	$$57.4%$$	$$(80.7% – 57.4%)/80.7%= 28.8%$$	$$80.7% – 57.4%= 23.3%$$	$$1/23.3%= 4.3 text{pts}$$

$$95% text{Confidence Interval (CI) on an} mathit{NNT}\
= 1 / (text{limits on the} mathit{CI}~text{of its} mathit{ARR})\
= pm1.96 sqrt{frac{mathit{CER}times(1-mathit{CER})}{text{# of control pts.}}
+ frac{mathit{EER}times(1-mathit{EER})}{text{# of exper. pts.}}}\
= 7.4%
$$

Your calculations

		Relative Risk ReductionRRR	Absolute Risk ReductionARR	Number Needed to TreatNNT
CER	EER	(CER – EER)/CER	CER – EER	1/ARR
.81	.57	.29	.24	4

Can you apply this valid, important evidence about a treatment in caring for your patient?

Do these results apply to your patient?

Is your patient so different from those in the overview that its results can’t help you?

1. No, this patient is similar.

How great would the potential benefit of therapy actually be for your individual patient?

1. Method I:$$mathit{f}\\
   text{Risk of the outcome in your patient, relative to patients in the trial (expressed as a decimal)}: 1\\
   mathit{NNT}/mathit{F}\\
   = 4/1\\
   = 4 (mathit{NNT} ~ text{for patients like yours})$$

2. Method II:$$1 / (mathit{PEER}times{RRR})\\text{Your patient’s expected event rate if they received the control treatment:} mathit{PEER}: \_\_\_\_\_\_ \\
   1 / (mathit{PEER}timesmathit{RRR}) \\
   = 1/\_\_\_\_\_\_\_\_ \\
   = \_\_\_\_\_\_\_ (mathit{NNT}~text{for patients like yours})
   $$

Are your patient’s values and preferences satisfied by the regimen and its consequences?

Do your patient and you have a clear assessment of their values and preferences?

Needs to be assessed in each patient

Are they met by this regimen and its consequences?

Needs to be assessed in each patient

Additional Notes

–

Chronic hepatitis C – Interferon + Ribavirin increases virological clearance of HCV

Clinical Bottom Line

Interferon + Ribavirin “combination therapy” is significantly more effective than interferon alone or no treatment in clearing HCV.

Citation

Poynard T, Marcellin P, Lee SS, et al. Interferon a2b and ribavirin increased the loss of HCV RNA in chronic hepatitis C.Lancet 1998;352:1426-32.

Clinical Question

In a patient with nonulcer dyspepsia and helicobacter pylori infection, will helicobacter eradication therapy result in a reduction in symptoms of dyspepsia?

Search Terms

“HCV” and “RCT” in Best Evidence

The Study

• Double-blinded randomised controlled trial with intention-to-treat.
• Patients >18 years, compensated CHC, naïve to IFN and Ribavirin, Hb>12 (F) 13(M). Exclusions decompensated liver disease or other serious illness.
• Control group (N = 281; 281 analysed): interferon a2b plus placebo
• Experimental group (N = 281; 281 analysed): virological status at 24 weeks after the end of treatment.

The Evidence

Outcome	CER	EER	RRR	ARR	NNT
$$Viral clearance$$	$$0.81$$	$$0.57$$	$$29$$	$$0.23$$	$$4$$
$$95% text{Condidence Intervals}$$				$$0.16 ~text{to} ~0.31$$	$$3 ~text{to} ~ 6$$

Comments

• Poynard’s trial results are very similar to those published by McHutchinson based on US data.
• The results should be compared with background rates of clearance of HCV in established CHC of ~1%
• Drop out rate was low with 80% of patients completing the study