Latvian study reports good responses to individualised, directly observed therapy in patients with multidrug resistant tuberculosis

A high proportion of patients with multidrug-resistant tuberculosis (MDRTB) can be successfully treated with individualised drug regimens administered by directly observed therapy (DOTS) programmes according to a study reported in the January 22^nd issue of The Lancet. The study, conducted in the Eastern European nation of Latvia, also demonstrated that it is possible for countries with somewhat limited resources to offer individualised therapy to manage MDRTB through their national TB programmes (NTPs).

Background

MDRTB is resistant to the two most important TB drugs (isoniazid and rifampicin) and, quite often, to other first and second line TB drugs. As a result, it is notoriously difficult to treat and frequently fatal. Although patients with pulmonary MDRTB are usually isolated as soon as they are identified, MDRTB is on the increase in many parts of the world, particularly in Eastern Europe.

One of the countries with the highest rates of MDRTB is Latvia. Multidrug resistance occasionally occurs in patients who have previously been treated for TB, but in Latvia (in1996), 54% of the TB cases among such patients were multidrug-resistant. MDRTB was also reported in 14% of the cases in patients who had never been treated for TB before — which meant that MDRTB was being transmitted. Latvia was in serious danger of an MDRTB epidemic.

For situations such as this, the World Health Organization had developed the DOTS-Plus strategy, which recommends one of two approaches to deal with resistance: 1) treat all patients with MDRTB with a standardised regimen derived from most common local pattern of resistance in the community or 2): treatment for each patient with MDRTB is individualised by using drug susceptibility testing on specimens from each patient to select the drugs in that patient’s treatment regimen. If a country can demonstrate that they have a well-functioning DOTS programme, WHO will help it in obtaining sometimes hard-to acquire second-line TB drugs.

Latvia’s NTP chose the individualised approach and began to put a DOTS-Plus programme in place in 1998. Diagnosis and treatment is provided through four specialised hospitals, while drug susceptibility testing was conducted at a centralised lab. By 2000, the country was able to offer full treatment to all its patients with MDRTB.

The study

To monitor how well the programme was working, researchers conducted a retrospective analysis of the records for all the patients with MDRTB who began treatment in the year 2000. The study also sought to identify factors associated with poor outcomes.

Patients with pulmonary TB were registered into the NTP; their demographic, diagnostic, and clinical data were entered into the programme’s database, and specimens were sent to the centralised lab for drug susceptibility testing.

Since susceptibility testing takes between 3 and 8 weeks, patients without prior TB were given standard TB treatment; and those previously treated for TB were treated with an individualised regimen based upon what they had previously taken. Once MDRTB was identified, the patient was hospitalised and treated as an inpatient with an individualised regimen based on the susceptibility tests until he or she became culture negative, after which point treatment was administered by direct observed therapy (with five to six visits a week) to ensure compliance.

The study involved 204 patients with MDRTB, 55 (27%) of whom had been newly diagnosed with MDRTB and 149 (73%) who had been earlier treated with first-line or second-line TB drugs.

Drug resistance was very common to the first line drugs: isoniazid and rifampicin (100%), streptomycin (94%), pyrazinamide (75%), and ethambutol (46%). More than a third of the patients were also resistant to kanamycin, one of the second line drugs.

Of the 178 adherent patients, 135 (76%) achieved cure or treatment completion. Overall, 135 (66%) patients were cured or completed therapy with a clinical response, 14 (7%) died, 26 (13%) defaulted their treatment, and treatment failed in 29 (14%).

But treatment wasn’t easy. The individualised regimens usually consisted of six drugs (range 3-8). 86% of patients had adverse effects associated with treatment, most commonly nausea, vomiting, and abdominal pain. And the time on treatment was long — a median of 18 months, with hospital stays of eight months required before cultures became negative and patients became less of a danger to the community.

The researchers also identified several critical predictors of poor outcome that could enable the programme to target MDRTB patients at greater risk for death or treatment failure. These included having previously received treatment for MDRTB (hazard ratio 5.7, 95% CI 1.9–16.6), using less than six drugs as treatment for 3 months or more (3.2, 1•1–9•6), resistance to ofloxacin (2.6, 1.2–5.4), and having body-mass index of less than 18.5 at start of treatment (2.3, 1.1–4.9). These patients “can be provided with enhanced clinical management to improve their outcomes.”

The success rate is encouraging in light of widespread drug resistance and the country’s limited resources. Furthermore, it is achieving the programme’s public health goals, the authors reported: “By implementing the DOTS and DOTS-Plus strategies, the Latvian national TB programme has been able to reduce the absolute annual number of MDRTB cases nationwide by 50%, from 332 in 1997, to 163 in 2003.”