Treating active tuberculosis

Generally, the standard first-line tuberculosis regimen is the same whether someone is HIV-positive or not, but there are important considerations when treating TB and HIV co-infection.

There are two phases to tuberculosis treatment, an intense initial phase, during which more drugs are given to clear the infection, and a longer continuation phase to be certain the infection is gone.

In most settings, for adults with previously untreated tuberculosis, the initial phase consists of two months of daily isoniazid at 4 to 6mg/kg, with 8 to 12mg/kg rifampicin, 20 to 30mg/kg pyrazinamide, and 15 to 20mg/kg ethambutol.

In order to make certain that people take all their medication correctly, a health care worker usually observes dosing during this phase. This is called directly observed therapy, short-course (DOTS). This is particularly important, as people tend to feel better as the disease comes under control. It is vital to complete the full course of treatment to avoid relapse and drug resistance.

After two months, if new smear results are negative, the patient is no longer deemed infectious and can be switched to a less intensive continuation phase. Different continuation phases are used to take into account local and individual drug susceptibility patterns, drug availability, and the level of monitoring that can be provided to assist in adherence. Although it has been thought that patients with drug-susceptible TB are generally non-infectious after two weeks of treatment, at least one recent study has found that many patients remain smear- and culture-positive for longer, and that many remain culture-positive for weeks after becoming smear-negative.¹

There are two leading continuation phase regimens:

• Four months of isoniazid and rifampicin. This regimen has been shown to be superior but can only be given with support for adherence, such as directly observed therapy (DOT) to prevent the development of resistance to rifampicin.² This regimen is usually used in the United Kingdom and the United States.

• Six months of isoniazid and ethambutol, which can be given to patients with monthly follow-up

Some national guidelines recommend a five-month continuation phase with three drugs for some patients. Additionally, TB treatment programmes in different countries differ on whether medication is most effectively administered (re efficacy and adherence) once a day, three days a week, or five days a week.

There are also differing approaches to how treatment should be given. In many resource-limited settings, TB programmes provide at least the first two months of TB treatment as directly observed therapy (DOTS) in order to minimise the risk of treatment default during this critical phase. Directly observed TB therapy may also be used in industrialised countries with groups that have a higher likelihood of TB treatment failure, such as injecting drug users and the homeless.

People with tuberculosis are often given 25 to 50mg pyridoxine (vitamin B-6) daily to reduce isoniazid side-effects. Cotrimoxazole (Septrin / Bactrim) use has also been shown to decrease morbidity and mortality in HIV-infected patients.

Two other standard drugs are used, but less frequently than in the past. Thioacetazone can cause severe life-threatening skin reactions in HIV-positive patients. Streptomycin, used as a first-line treatment, can cause toxicity and high resistance rates and is inconveniently dosed by injection.

A US study conducted between 1990 and 2001 suggests that a treatment duration of six months may not be long enough for HIV-positive people, particularly in those not using antiretroviral therapy. Relapse was seen in 7% of  HIV-positive patients, as compared to 1% of HIV-negative patients, who completed a full course of treatment.³ 

According to a 2009 meta-analysis that included 57 randomised, controlled trials that enrolled more than 20,000 people treated for TB since 1965, treatment with rifampicin for the first two months only resulted in significantly higher rates of failure, relapse, and acquired drug resistance as compared to regimens that used rifampicin for at least six months. An intermittent (thrice weekly) dosing schedule for rifampicin was associated with an increased risk of acquired drug resistance, but not of relapse or treatment failure.⁴

Another systemic literature review dealt with the issue of how best to manage previously treated individuals who had relapsed after treatment or failed to respond to treatment, or those with isoniazid-resistant infection, excluding cases of multidrug-resistant TB (MDR-TB). Nearly 10 to 20% of patients receiving TB treatment in low and middle-income countries require retreatment and this need should be taken into account when planning any DOTS strategy.

Researchers were unable to find any randomised trials comparing the currently recommended WHO retreatment regimen against other approaches. In non-comparative (cohort) studies, failure rates were generally low if participants were infected with strains that were sensitive to all antibiotics in the regimen. When participants were infected with a strain of Mycobacterium tuberculosis resistant to one or more drugs, failure rates ranged from 9% to 45%.

This meta-analysis found lower relapse, failure, and acquired drug resistance rates to be associated with longer duration of rifampicin treatment, daily therapy early in treatment, inclusion of the drug streptomycin, and regimens that included a greater number of drugs to which the patient's TB infection was sensitive.

This led to the conclusion that increased access to drug sensitivity testing and a redesigned re-treatment regimen, based on the assumption that in the future all patients will have received a six-month course of rifampicin, are needed. Cases of monoresistance in TB patients remain around five times more common than MDR-TB; effective strategies for managing isoniazid resistance are one way to reduce the incidence of MDR-TB.⁵