E-DRUG: 4-drug fixed dose combinations for TB (2)
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With regard to the 4 drug fixed dose combinations for TB, I have become
convinced by the excellent work being done by staff at WHO, Bernard Fourie
in South Africa and Gordan Ellard in London of the correctness of this
approach. The advantages are very clear.
These include a simpler dosage schedule which will improve compliance. This
is not a matter of changing to once a day schedules. This is the same
whether for FDC's or single doses. It is the difference between 3 or 4 tabs
from a single bottle compared to 10 or 12 tablets from four different
bottles. It will make health worker DOTS supervision much easier!
It will prevent resistance; rifampicin or isoniazid is never alone in the
blood creating resistance. This is for me the major advantage that outweighs
any negatives. I am extremely alarmed at the reports I hear and read from
Russia and the Baltic states as well as from Peru where MDRTB is emerging.
Treating this condition is very difficult (2 years therapy with only 75%
cure rates at best at a cost at present of US$2-6,000 per year). In some
situations patients may be tempted to sell their rifampicin capsules to
individuals who want to treat or "prevent" STDs. This is a recipe for MDRTB.
There are other benefits such as simplifying drug storage and handling,
having only 1 expiry date (single products may have different expiry dates)
and having lower packing, storage and shipping costs
With regard to the CONS mentioned by Wilbert, cost is an issue but I think
it will be a short term issue. We only have to look at what happened with
the two drug Rifampicin Isoniazid combination. It started off more expensive
but within a few years the combination was cheaper than the single product
according to the MSH price indicator guide. At the moment there are a
limited number of suppliers but once the new WHO policy is implemented by
WHO, IUATLD and the World Bank as well as National TB programs, I feel sure
that a number of high quality producers will start producing driving the
price down. IDA will be one of these suppliers.
The quality issue is a real issue and it relates to the bio availability of
rifampicin and this is an issue for single product as well as combination
product. Testing of bioavailability is expensive but WHO have come up with
an abbreviated protocol which can be used and this is a cost that should be
borne by the producer. It is reasonable to demand from the company that they
document the bioavailability of their product. One related problem to this
is that small scale manufacturers who are producing the other oral TB drugs
(not rifampicin) may not be able to produce the combination product and they
are likely to resist it's introduction. But so long as there are a few good
quality producers in the market the price is likely to come down.
The allergy argument holds true for combination or single product systems.
The patient in the intensive phase takes four drugs whether these are in
combination or separately. If there is an allergic reaction the patient is
changed to different regimen which hopefully will not have the drug causing
the reaction. The rate of reaction is no higher with FDC's than with single
formulations nor should it be.
The tablet will be heavy but balanced against the other advantages I think
this is a minor problem.
WHO has produced a very good report on this issue and if E-Druggers or
TB-Netters are interested I would suggest that you ask Bjorn Blomberg
[blombergb@who.ch] for a copy of the report and a copy of the submission
being prepared for the Essential Drug List review committee which will be
meeting in November.
I would encourage E-Druggers and TB-Netters to get up to speed on this issue
as it is likely to be one of the most important issues faced in 2000. TB
kills over 3 million people a year, in many environments it is getting worse
and while DOTS has been great in improving cure rates, the danger of MDRTB
exploding lurks in the background unless we can ensure that no patient
receives monotherapy. For some countries TB drugs are the ones on which they
spend the most of their money. So there will be a lot of interest in this
topic from commercial interests.
Richard Laing
Associate Professor of International Health
Boston University School of Public Health
715 Albany St, T4W, Boston MA 02118 USA
Tel 617 414-1444 Fax 617 638-4476
E-mail richardl@bu.edu
[thanks, Richard, for the very detailed response. I hope the developing
countries are going to be convinced. So far in Southern Africa only South Africa
has introduced the 4-drug combination. Two countries are considering it,
the rest are (not yet?) interested.
There are 2 suppliers currently in South Africa. Let's hope their prices
will indeed go down in coming years.
One worry is that South Africa uses a 'light' version whereas WHO
recommends a 'heavy' 4-drug combination. The lack of consensus among the
TB specialists will probably mean that the prices will stay higher than
needed, as drug companies have to test quality of 2 different strengths.
Maybe African countries could start with harmonising weight bands? WB]
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