Once
adherence preparation has been completed, it is important to get someone on an
effective regimen as quickly as possible. But knowledge of what regimen to use
— or even who to treat — is limited by lab capacity.
HATIP
164 described how most countries do not yet have access to rapid drug
sensitivity testing, and as a site visit to Khayelitsha demonstrated, even when the new tests are being rolled out, it takes a while to
use them to their full potential in the clinic (at present rapid DST is only
being conducted on cultures). In other words, it can take at least one month to
confirm drug-resistant TB in suspected cases, and the process takes longer when
rapid drug susceptibility testing is only performed after documented treatment
failures.
In the
meantime, clinical decisions need to be made about how to treat people at risk
of resistance — keeping in mind that people with HIV in particular, may not survive
long on ineffective first-line treatment. In some cases, empiric treatment for
drug-resistant TB may be warranted — but there are few clinical data, and
opinions vary widely on the subject.
In Lesotho (and in the Field Guide), the
following protocol is recommended for empiric treatment.
Whenever anyone is categorised as being at
medium or high risk of DR-TB (based upon their treatment and contact history),
two sputums are sent out for culture and DST.
The initial treatment while waiting for the DST
results depends upon catagorisation by risk of resistance. Migrants and health
workers with TB are categorised as being at risk for DR-TB but are placed upon
a first-line regimen until DST results come back indicating the need for second
line treatment.
Previously treated patients who have defaulted
or relapsed are placed upon what was once called the ‘category II regimen’ or
now, the retreatment regimen (a slightly prolonged and beefed up version of the
standard regimen with streptomycin thrown in). WHO wants to move away from the
retreatment regimen as rapid DST becomes more widely available, because it is
not effective against drug-resistant TB and it is unnecessary for drug-susceptible
TB.
People with active TB who are household
contacts of a person with M/XDR-TB are placed upon the same second-line TB
treatment that their contact is taking. For anyone with a history of treatment
with second-line drugs, a specialist is consulted to help construct an
individualised regimen (avoiding previously used drugs if possible). Probable
treatment failures, including anyone who is smear-positive in the fifth month
of the first-line or re-treatment regimen, or people with HIV who worsen on treatment,
start with a standardised second-line treatment regimen. But, the Field Guide
notes: “there are many reasons for clinical worsening in HIV-positive patients
besides treatment failure. Consult specialist for advice."
Dr Hind Satti insisted that, in Lesotho at
least, “We find
empiric treatment of MDR-TB suspects is very helpful in decreasing early
mortality of these patients and this is why we worked out the protocol for medium
and high-risk patients.”
In other settings, though, clinicians are likely to
wait for more laboratory or clinical confirmation of failure on first-line
treatment. During a visit to the Ubuntu clinic in Khayelitsha, we learnt that
if a household contact of a person with M/XDR-TB develops active disease, the
care team doesn’t immediately put the person on the same treatment as the index
case, because they have found that in most of the cases, the person will have
drug-susceptible TB (which is really ubiquitous in this setting). However, they
will send out for a rapid DST and switch treatment if necessary based upon
those results. And according to Dr Simiso Sokhela, a clinical officer at the site, they still commonly use the retreatment regimen.
“The few cases that have
had empiric TB treatment, it will be discussed and started on by
specialists. We can’t do it on a clinic basis. We have to refer to somebody else to make the
decision to start on empiric MDR-TB treatment.
But the best that we can do is the retreatment regimen, which is just adding one drug to a failing regimen,” she said.
“We do have to be careful about starting patients on empiric
treatment for failure,” Dr Helen Cox said. “Because in Dr Graeme Meintjes and
Dominique Pepper’s study on deterioration on TB treatment, drug-resistant TB
is only a small fraction of that. There are all of these other reasons for
failure.”
Indeed, in the study by Pepper et al in people with
HIV and TB on dual treatment, only 10% of the clinical deterioration that
occurred was due to drug-resistant TB, while 72% was due to other illness, most
commonly other AIDS-defining events. TB Immune Reconstitution Inflammatory
Syndrome was a greater cause of illness than MDR-TB (18%). 4
Dr Graeme Meintjes of GF Jooste Hospital explained
his view on the matter to HATIP.
“Regarding the decision to start empiric MDR
treatment in a patient suspected of having MDR TB before lab confirmation, there
is no clinical data on this that I am aware of. My view is that this should
only be done in exceptional circumstances given the toxicities, duration, cost
and poorer efficacy of MDR-TB treatment. The latter consideration is important
because starting a patient with susceptible TB on MDR treatment is doing them a
major disservice. My approach is to only consider MDR-TB treatment empirically
in the following circumstance:
•
The patient is hospitalised
•
The original diagnosis of TB is proven by smear or
culture
•
Other causes for deterioration have been excluded
•
The patient is deteriorating with features of TB
despite adherence to TB treatment
•
If this patient had MDR-TB and I don’t start MDR-TB
treatment they are likely to die within the next 2-3 weeks (respiratory
distress, severe wasting syndrome, neuroTB, etc)
•
That several clinical specimens have been sent for
culture and DST
•
Then start 3 MDR-TB drugs in addition to Rifafour while awaiting the DST result
•
Follow up clinical and lab results closely”
Only a minority of patients who deteriorate have MDR. This is relevant
to the decision.”
The starting second-line regimen can vary from place to place — in Nepal
for instance, the standardised regimen has been selected upon the basis of
resistance surveillance studies of the population — and according to the recent
paper by Malla et al, this was simpler for supply logistics and for providing
standardised training to health personnel.5
In other settings, programmes use a broad standardised regimen with the goal of
having several active drugs, which might be modified based on treatment or
contact history, and then modified again on the basis of DST results once they
become available.
WHO’s recent TB Treatment Guidelines lists five groups of drugs to treat
M/XDR-TB:
Group 1: First line oral agents: pyrazinamide (Z), ethambutol (E),
rifabutin (Rfb)
Group 2: Injectable agents: kanamycin (KM), amikacin (AM), capreomycin
(CM), streptomycin (S)
Group 3: Fluoroquinolones: levofloxacin (Lfx), moxifloxacin (Mfx),
oflaxacin (Ofx)
Group 4: Oral bacteriostatic second-line agents: para-aminosalicylic
acid (PAS), cycloserine (Cs), terizidone (Trd), ethionamide (Eto), protionamide
(Pto)
Group 5: Agents with unclear role in treatment of drug-resistant TB:
clofazimine (Cfz), linezolid (Lzd), amoxicillin/clavulanate (Amx/Clv),
thioacetazone (Thz), imipenem/cilastatin (Ipm/Clv), high-dose isoniazid (high
dose H), clarithromycin (Clr).
The TB Treatment Guidelines state that treatment regimens should consist
of at least four drugs with either certain, or almost certain, effectiveness,
including whatever first-line drugs to which the individual may still be
susceptible to. If the effectiveness of a certain drug is not clear (and for
some drugs, this may be because DST results are less reliable), the drug may be
used, but it should not be depended upon as one of the four drugs. Group 5
drugs are generally reserved for XDR-TB regimens (and to some extent, are only
used because it is difficult to come up with any other options). More detailed
information on each drug, including adverse effects, contraindications,
monitoring, and dosing based on weight bands is available in the annexes of the
Treatment of Tuberculosis Guidelines (4th Edition).
Treatment is generally given in an intense phase (with more drugs) for
at least six months (Nepal treats intensely for eight months) followed by a
less intense phase of 12-18 months (usually without the injectable drugs).