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Drug resistant TB in India – Transmission, diagnosis, treatment

Drug resistant TB in India

Drug resistant TB has frequently been encountered in India and its presence has been known virtually from the time anti TB drugs were introduced for the treatment of TB. If a person has drug resistant TB it means that their illness will not respond to at least one of the main TB drugs. The prevalence of multi drug resistant MDR TB has though been believed to be at a low level in most regions of the country. Various studies have found MDR TB levels of about 3% in new cases and around 12-17% in retreatment cases. However even if there is such a small percentage of cases it still translates in India into large absolute numbers.

The transmission of drug resistant TB in India

Traditionally the view in India has been that drug resistant TB is not easily transmissible. So it is believed that most drug resistant TB in India arises from the failure of people to take their drugs properly, rather than from them becoming infected with an MDR TB strain. So a high quality DOTS program, which includes supervising people taking their drugs should prevent the emergence of resistance.

TB patients wait for their treatment at a DOTS centre in India. Several have drug resistant TB. © Maureen Scarpelli

TB patients wait for their treatment at a DOTS centre in India. Several have drug resistant TB. © Maureen Scarpelli

DOTS-Plus refers to a DOTS service with additional elements for drug resistant TB, and DOTS-Plus guidelines were published by the RNTCP in 2010. However, they acknowledged that ongoing transmission of drug resistant TB strains is also a significant source of new drug resistant cases. So timely identification of people with MDR TB cases and their treatment with appropriate drugs is essential to stop transmission. This is quite apart from the humanitarian aspects of providing appropriate treatment for people with drug resistant TB.

Despite this the DOTS-Plus guidelines emphasized that the basic DOTS programme without the MDR components must continue to be the priority for TB control in India. This meant that in every DOTS implementing unit of the country, DOTS should be prioritised above DOTS-Plus.

DOTS-Plus for the management of drug resistant TB in India had been launched in 2007. There was then very limited progress between 2007 and 2009. But by 2009 it was planned that by the end of 2011 that drug resistant TB services would be available across India. The DOTS-Plus services (now referred to as the “Programmatic Management of Drug Resistant TB” ) had been expanded across the whole country by 2012 and the service was available in all districts by 2013. By 2013 it had though been decided to decentralise the DOTS Plus services. The services were to be totally integrated into the main RNTCP services at local level.

Diagnosis of drug resistant TB in India

There are various groups of people that are presumed to have drug resistant TB (DRTB). This is until such time as drug susceptibility testing shows that they have drug susceptible TB. These include all re-treatment cases at diagnosis, any smear positive person during follow up, contacts of confirmed DRTB cases, and HIV associated TB cases at diagnosis. There is more about the treatment of drug susceptible TB in India.

For the diagnosis of XDR TB, drug susceptibility testing for second-line drugs is offered to patients on an MDR TB regimen if they are culture positive at 6 months, or if culture reversion (culture going back to positive) occurs during MDR TB treatment, after culture conversion to negative.

In 2013 a total of 181,021 drug resistant TB suspects were tested and 20,763 MDR TB patients were provided with treatment.

Historical treatment for patients with drug resistant TB

Before 2010 all patients receiving treatment through the governments RNTCP program, were placed in one of three categories, Cat I, Cat II, or Cat III. This was according to whether they had received treatment before, whether they were seriously ill and whether they were sputum positive. However all categories received different combinations of up to four of the main first line anti TB drugs (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol).

Streptomycin was added for those who had received TB treatment before and who had relapsed. The addition of Streptomycin to an existing failing combination went against one of the fundamental aspects of TB drug treatment. This is that one single new drug shouldn’t be added to a failing regime. The fact that this was done meant that effectively no treatment was provided for those with drug resistant TB.

There had started to be some criticism of this approach and in particular the lack of second line TB drugs and appropriate regimes for people who had failed their first treatment. These were the people most likely to already have drug resistant TB.1Bhargava, A “The Revised National Tuberculosis Control Programme in India: Time for revision of treatment regimens and rapid upscaling of DOTS-plus initiative”, Medicine and Society www.ncbi.nlm.nih.gov/pubmed/19267041

In 2010, with the launch of the DOTS-Plus Guidelines (in future known as the Programmatic Management of Drug Resistant TB) TB treatment for drug resistant TB started to be properly provided. Treatment categories I & II became the treatment regimes for new and previously treated patients respectively. Category III was phased out, and two new categories were introduced. These were Category IV for patients requiring treatment for MDR TB, and category V for patients requiring treatment for XDR TB.

Treatment of multi drug resistant TB in India

In 2014 India achieved complete geographical coverage for diagnostic and treatment services for multi-drug resistant TB. In 2013, 248,000 cases of TB were tested for drug resistance and 35,400 were found to have either MDR or rifampicin resistant TB. However, only 20,700 received treatment. Yet these cases, about a third of the estimated number, cost over 40% of the annual RNTCP budget.

Patients with TB caused by drug-resistant organisms (especially M/XDR or only R resistance or with O (Ofloxacin) or K (Kanamycin) resistance) must  be treated with specialised regimens containing second line anti TB drugs. They should be treated using mainly ambulatory care, rather than models of care based principally on hospitalisation. If required there can be a short initial period of hospitalisation.

The treatment of drug resistant TB (DR-TB) is much more complicated than standard TB. Firstly, baseline resistance to crucial drugs (fluoroquinolone or injectables) can compromise the effectiveness of the regimen for MDR TB. Secondly, drug intolerance more frequently leads to discontinuation than in first-line anti TB treatment. Thirdly, a poor response to treatment should prompt an examination for programmatic, clinical and microbiologic reasons for poor treatment response, including non-adherence and additional drug resistance.

Treatment for MDR TB (or R resistance)

The regimen chosen for MDR-TB may be a standard one and/or based on microbiologically confirmed drug susceptibility patterns. At least four drugs (second line) to which the organisms are known or presumed to be susceptible should be used. The Programmatic Management of Drug Resistant TB sets out the integrated algorithm that in general should be used for the treatment of DR-TB (i.e. MDR TB, XDR TB, second line drug resistance, and poor treatment response).

In general the regimen should comprise 6 drugs Pyrazinamide, Ethambutol, a later generation Fluoroquinolone (such as high dose Levofloxacin) and a parenteral agent (such as Kanamycin or Amikacin), Ethionamide (or Prothionamide), and either Cycloserine or PAS (P-aminosalicyclic acid), if Cycloserine cannot be used. This regimen should be used during six to nine months of the intensive phase. Four drugs usually Levoflaxacin, Ethionamide, Ethambutol and Cycloserine, should be used during the 18 months of the continuation phase.

Consideration should be given to treatment extending for at least 18 months beyond the last evidence of mycobacteria in a culture from a patient. This means that the total duration of treatment should be at least 24 months up to a maximum of 27 months in patients newly diagnosed with MDR-TB (i.e. not previously treated for MDR-TB). The total duration of treatment can be modified according to the patient’s response to therapy.

If Ofloxacin or Kanamycin resistance is detected either at the initiation of MDR-TB treatment, or early during the intensive phase of treatment, then the treatment regimen can be suitable modified.

The drugs are supplied to patients in 1 month of supplies at a time. They are in “patient wise” boxes of different weight bands. These are similar to those provided to patients who have drug susceptible TB, but because the patient needs to take so many drugs only one months supply of drugs is provided at any one time.

The drug bedaquiline is soon to be available for some TB patients in India who have drug resistant TB. Six hundred doses are going to be obtained under the Conditional Access programme from Johnson & Johnson, and another 2,000 doses will be obtained from USAID. The drug is apparently going to be provided under strict supervision at six government hospitals across the country. It is important that people realise that bedaquiline should not be used on it’s own, and it must only be used in combination with other drugs.2Mascarenhas,A “The roll out of a TB curing miracle drug – Bedaquiline” http://indianexpress.com/article/

Major Sources for Drug Resistant TB in India

Draft 2015 report on Indian Revised National TB Control Programme from Joint Monitoring Mission www.tbonline.info/media/uploads/documents/jmmdraft2015.pdf

Revised National Tuberculosis Control Programme Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India www.tbcindia.nic.in

Revised National Tuberculosis Control Programme National Strategic Plan 2012-2017

Standards for TB Care in India www.tbcindia.nic.in

TB India 2015 Revised National TB Control Programme Annual Status Report, New Delhi, 2015 www.tbcindia.nic.in

References

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1. Bhargava, A “The Revised National Tuberculosis Control Programme in India: Time for revision of treatment regimens and rapid upscaling of DOTS-plus initiative”, Medicine and Society www.ncbi.nlm.nih.gov/pubmed/19267041
2. Mascarenhas,A “The roll out of a TB curing miracle drug – Bedaquiline” http://indianexpress.com/article/