Is hole in DOTS policy playing a role in the evolution of an XDR-TB strain?

In 2001 – the year South Africa implemented the WHO’s DOTS strategy to combat TB – multidrug-resistant strains of TB (MDR-TB) had already been circulating for at least seven years in the South African province most affected by a recent outbreak of extensively drug-resistant TB (XDR-TB). The authors of a study, published in the December 1^st edition of Clinical Infectious Dieases, which examines the evolution of the KwaZulu-Natal XDR strain suggest the strategy – to treat all diagnosed individuals with a fixed combination of drugs without drug susceptibility testing – may have, in part, led to the rapid evolution of XDR-TB.

MDR and XDR-TB

Multidrug-resistant strains of TB (MDR-TB) – resistant to at least two first-line anti-TB drugs, including isoniazid and rifampicin – can emerge in several ways. A person may develop drug resistance as a result of poor adherence to treatment. A strategy known as DOTS (Directly Observed Treatment, Short-course) – where an individual diagnosed with active infectious pulmonary TB (as detected by smear microscopy), takes a standardised combination of anti-TB chemotherapy during supervised treatment – was developed as a means to improve adherence. This strategy was implemented in South Africa in 2001.

However, an individual may also acquire a strain of TB that already has some resistance to drugs used in its treatment. In the absence of drug susceptibility testing (DST), however, the anti-TB chemotherapy provided may well be suboptimal, leading to the development of further resistance.

A recent pharmacokinetic (PK) study also suggests that suboptimal anti-TB drug levels are more likely to be seen in HIV-positive individuals with CD4 counts below 200 cells/mm³ making it more likely that people with advanced HIV disease experience treatment failure (and, therefore, acquire further drug resistance).

In all cases, further drug treatment can increase the level of resistance, leading to treatment failure and to the emergence of extensively drug-resistant TB (XDR-TB) , which is TB that is resistant to at least three of the six classes of drugs that can be used in second-line treatment.

Both MDR-TB and XDR-TB can also be transmitted from person to person, and anyone who acquires either has a poorer prognosis than someone infected with drug-sensitive TB.

Evolution of the KwaZulu-Natal XDR strain

Investigators from the Department of Medical Microbiology at the Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa sought to describe the evolution of a particular MDR-TB strain in KwaZulu-Natal province, where a devastating outbreak of XDR-TB was first reported in 2006.

This XDR-TB strain – which is resistant to isoniazid, rifampicin, kanamycin, and the fluoroquinolones – is known as ‘the KwaZulu-Natal strain’, or F15/LAM4/KZN.

The investigators examined genetic variations in the F15/LAM4/KZN strains that had been collected for a variety of studies performed between 1994 and 2002 and stored at one of two of KwaZulu-Natal's TB laboratories.

Out of a total of 966 M. tuberculosis strains collected during this period, 109 (11%) were F15/LAM4/KZN. Although the proportion varied each year (from 2% in 1994 to 31% in 1997 and 2000), higher proportions were seen when only drug-resistant isolates were included.

They found that, in total, F15/LAM4/KZN was the strain with the highest proportion of multidrug-resistant genotypes (75/109; 69%) whereas only 4% of all other strains (34/857) were found to be MDR-TB. (p < 0.001).

No genotyping was performed in 2003 and 2004, due to budget restraints, but in 2005, a group of 102 MDR-TB isolates from one district in KwaZulu-Natal was analysed, and 60 (59%) of these isolates were found to be F15/LAM4/KZN strains.

When they examined the chronological evolution of resistance in the F15/LAM4/KZN strain, they found that MDR-TB already existed in 1994 (resistance to isoniazid/rifampicin) and triple-first-line drug resistance was also seen (isoniazid/rifampicin/streptomycin) in the same year. In 1995, isoniazid/rifampicin/ethambutol resistance was first seen.

MDR-TB with resistance to second-line drugs began to emerge in 1997 (resistance to isoniazid/rifampicin/ethionamide), followed by capreomycin in 1998, kanamycin in 1999, and fluoroquinolones in 2000.

The first F15/LAM4/KZN strain found to be XDR-TB was seen in one patient in 2001. No information was available between 2002-4, but by 2005 a cluster of XDR F15/LAM4/KZN strains were already found in Tugela Ferry, the epicentre of the XDR-TB outbreak.

Man-made evolution?

“One can only speculate about the reasons for this development,” write the investigators. However, they point out that the XDR-TB strain seen in 2001 and those seen in 2005 were resistant to different second-line drugs, and therefore cannot have only been transmitted from person-to-person but must have also evolved through exposure to suboptimal drug regimens.

An accompanying editorial suggests that Darwin’s theory of evolution provides a template to help us understand how the scaling-up of DOTS – which focused on supervised adherence to a fixed combination of anti-TB drugs without drug susceptibility testing, and which is at the heart not only of South Africa’s TB policy but WHO’s global Stop TB Strategy – resulted in the emergence of XDR-TB.

The investigators note that the DOTS “policy ignores the observations of spreading MDR strains such as the F15/LAM4/KZN strain. This means that, in the absence of susceptibility testing, a growing proportion of patients started receiving a [first-line] regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol while infected with an MDR strain...Therefore, in the absence of susceptibility test results at the commencement of treatment, patients have been treated unintentionally with 1 or 2 active drugs only. This not only resulted in treatment failures, but also in further selection of drug-resistant strains.”

They add that, “it is obvious that, when the directly observed therapy–plus strategy was implemented in 2001, a proportion of patients again started receiving regimens that contained too few effective drugs. This has likely contributed to the development of XDR-TB in different parts of the province, as indicated by its development into a family of strains and the difference in susceptibility between the 2001 XDR isolate and the isolates from Tugela Ferry.”

They also suggest that since “the South African TB-control program uses streptomycin as a fifth drug in its re-treatment regimen” and since “it is that arm out of which the XDR strain developed...it is tempting to postulate that the addition of streptomycin to the standard 4-drug regimen for patients who required re-treatment has assisted in the selection and spread of organisms from the isoniazid-rifamycin-streptomycin–resistant variant.”

The investigators suggest other contributory factors, including fitness of the F15/LAM4/KZN strain, which led to more effective person-to-person transmission of MDR-TB alongside “an expanding epidemic of HIV infection. As a result, the number of immunocompromised individuals—and, with that, the number of those with increased susceptibility to M. tuberculosis—increased. As a result, the pool of patients in whom the F15/LAM4/KZN strain could spread increased as well.”

They conclude that “empirical treatment, as applied in TB-control programs, needs to be supported by drug-resistance surveillance programs.”

In an accompanying editorial, Michael Iseman of the University of Colorado School of Medicine, in Denver points out that the scaling-up of WHO’s DOTS programmes have “made [anti-TB] therapy available to many additional patients...and have doubtlessly had a substantial, positive impact.”

However, he notes that “supervised administration of all or the great majority of doses of anti-TB medications during the six-month standard regimen” is a rarity outside of the United States “owing to inadequate resources and/or skepticism about the need for use of such a model.”

Consequently, he argues, “an unwanted by-product of the expanded treatment program was the generation of new cases of drug-resistant TB...if we never had treated TB, there would be no drug resistance.”

“Given the widened use of the fluoroquinolones and other second-line medications, including the injectable agents,” he adds, “the appearance of XDR-TB was inevitable. Clinicians who treated patients with presumed MDR-TB did not have access to in vitro susceptibility test data to guide their regimen selections, and despite the admonition that such cases be given highest priority for DOTS, true supervision was understandably rare.”

“In roughly 55 years,” he concludes, “we have squandered our precious legacy of chemotherapy for these XDR-TB cases.”

Later this week the TB world will meet in Cape Town, South Africa to consider the global challenge of multi-drug resistant TB. Coverage of the 38th World Lung Health conference will appear at aidsmap.com from Friday November 8^th. The lack of drug susceptibility testing, and remedies for this problem, will be the focus of one major report.