STANDARD 8.

All patients (including those with HIV infection) who have not been treated
previously should receive an internationally accepted fi rst-line treatment regimen
using drugs of known bioavailability. The initial phase should consist of two
months of isoniazid, rifampicin, pyrazinamide and ethambutol.(Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have
extensive pulmonary tuberculosis or severe forms of extrapulmonary disease, and who are known to be HIV negative.) The preferred
continuation phase consists of isoniazid and rifampicin given for four months.

Isoniazid and ethambutol given for six months is an alternative continuation
phase regimen that may be used when adherence cannot be assessed but is
associated with a higher rate of failure and relapse, especially in patients with
HIV infection.

The doses of antituberculosis drugs used should conform to international
recommendations. Fixed-dose combinations of two
(isoniazid and rifampicin), three (isoniazid, rifampicin, and pyrazinamide)
and four (isoniazid, rifampicin, pyrazinamide, and
ethambutol) drugs are highly recommended, especially when
medication ingestion is not observed.

Rationale and Evidence Summary

A large number of well-designed clinical trials have provided the evidence
base for this Standard and several sets of treatment recommendations
based on these studies have been written in the past
few years.24,25,69 These are referenced and data will not be reviewed
in this document. All these data indicate that a rifampicin-containing
regimen is the backbone of antituberculosis chemotherapy and is highly
effective in treating tuberculosis caused by drug-susceptible M. tuberculosis.
It is also clear from these studies that the minimum duration of treatment for smear
and/or culture-positive tuberculosis is six months. For the six-month treatment duration to
be maximally effective, the regimen must include pyrazinamide during the initial two-month
phase, and rifampicin must be included throughout the full six months. There are several
variations in the frequency of drug administration that have been shown to produce acceptable
results.24,25,69

Two systematic reviews of regimens of less than six months have found that shorter durations
of treatment have an unacceptably high rate of relapse.70,71 Thus, the current international
standard for smear or culture-positive tuberculosis is a regimen administered for a
minimum duration of six months.24,69

Although the six-month regimen is the preferred option, an alternative continuation phase
regimen, consisting of isoniazid and ethambutol given for six months, making the total
duration of treatment eight months, may also be used. It should be recognized, however,
that this regimen, presumably because of the shorter duration of rifampicin administration,
is associated with a higher rate of failure and relapse, especially in patients with HIV
infection.72–74 Nevertheless, the eight-month regimen may be used when adherence to
treatment throughout the continuation phase cannot be assessed.24 The rationale for this
approach is that if the patient is nonadherent, the emergence of resistance to rifampicin
will be minimized. A retrospective review of the outcomes of treatment of tuberculosis in
patients with HIV infection shows that tuberculosis relapse is minimized by the use of a
regimen containing rifampicin throughout a six-month course.72 Thus, the six-month regimen
containing rifampicin throughout the entire course is preferable in patients with HIV
infection to minimize the risk of relapse; however, the patient’s HIV stage, the need for and
availability of antiretroviral drugs, and the quality of treatment supervision/support must be
considered in choosing an appropriate continuation phase of therapy.

Intermittent administration of antituberculosis drugs enables supervision to be provided
more effi ciently and economically with no reduction in effi cacy. The evidence on effectiveness
of intermittent regimens was reviewed recently.75,76 These reviews, based on several
trials,77–82 suggest that antituberculosis treatment may be given intermittently three times a
week throughout the full course of therapy or twice weekly in the continuation phase without
apparent loss of effectiveness. However, WHO and The Union do not recommend the
use of twice-weekly intermittent regimens because of the potentially greater consequences
of missing one of the two doses.24,25,83 A simplifi ed version of the current WHO recommendations
for treating persons who have not been treated previously is shown in Table 2.²⁴

TABLE 2: Recommended treatment for persons not treated previously²⁴

1. Streptomycin may be substituted for ethambutol.
2. Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum
   smears, do not have extensive pulmonary tuberculosis or severe forms of extra-pulmonary disease, and
   who are known to be HIV negative.
3. Associated with higher rate of treatment failure and relapse; should generally not be used in patients with
   HIV infection.
   

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The evidence base for currently recommended antituberculosis drug dosages derives
from human clinical trials, animal models, and pharmacokinetic and toxicity studies. The
evidence on drug dosages and safety and the biological basis for dosage recommendations
have been extensively reviewed in publications by WHO,24 The Union,25 ATS, CDC,
the Infectious Diseases Society of America (IDSA),69 and others.83,84 The recommended
doses for daily and thrice-weekly administration are shown in Table 3.

TABLE 3: Doses of first-line antituberculosis drugs in adults and children

* The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15mg/kg), because
the pharmacokinetics are different. (Peak serum ethambutol concentrations are lower in children than in adults
receiving the same mg/kg dose.)

Treatment of tuberculosis in special clinical situations, such as the presence of liver disease,
renal disease, pregnancy, and HIV infection, may require modifi cation of the standard
regimen or alterations in dosage or frequency of drug administration. For guidance
in these situations, see WHO and ATS/CDC/IDSA treatment guidelines.24,69
Although there is no evidence that fi xed-dose combinations (FDCs) are superior to individual
drugs, expert opinion suggests that they may minimize inadvertent monotherapy
and may decrease the frequency of acquired drug resistance and medication errors.24,69
FDCs also reduce the number of tablets to be consumed and may thereby increase patient
adherence to recommended treatment regimens.85,86