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.
Traditionally, the view in India has been that drug resistant TB is not easily transmissible. So it was believed that most drug resistant TB in India arose from the failure of people to take their anti TB 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.
This belief was based largely on animal studies. It had then been found that drug resistant bacilli were not less infectious. In fact people who had contact with previously untreated patients had a similar risk of infection regardless of whether the bacilli were drug susceptible or drug resistant.1Grover, G & Takkar, J, “Recent advances in multi drug resistant tuberculosis and RNTCP”, 2008 Oct, 33(4): 219-223, Indian Journal of Community Medicine,
All patients receiving treatment through the governments RNTCP program used to be 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).
By 2006 the DOTS programme had reached over 600 districts across India. But there were some problems. Delays in diagnosing patients and prescribing medications continued the cycle of disease transmission. There were also difficulties in ensuring that patients adhered to their regimens. Some people also believed that:
Giving this one size fits all regimen to patients only amplified the drug resistance Dr Zarir Udwadia
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 people with drug resistant TB in India.
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.2Bhargava, 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
There’s a high incidence of TB and drug resistant TB in India because of years of policy failure. The government initially ignored the drug resistant TB patients, pretending they didn’t exist, allowing the numbers to proliferate.3Ubaid, M “The challenges of treating drug-resistant TB in India”, 18 Jul, 2017, https://www.aljazeera.com/indepth/features/2017/05/challenges-treating-drug-resistant-tb-india-170523133035639.html
DOTS-Plus refers to a DOTS service with additional elements for drug resistant TB.
In 2007 DOTS-Plus was launched for the management of drug resistant TB. By 2012 the DOTS-Plus service (now referred to as the “Programmatic Management of Drug Resistant TB” ) had been expanded across the whole country and by 2013 the service was available in all districts. By this time 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.
In addition, treatment categories I & II became the treatment regimes for new and previously treated patients. 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.
In 2014 India achieved complete geographical coverage for diagnostic and treatment services for multi-drug resistant TB.
Treatment of multi drug resistant TB in India
Category IV regimen
Patients with TB caused by drug-resistant organisms (especially M/XDR or only R resistance or with O (Ofloxacin) or K (Kanamycin) resistance) should 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, existing resistance to crucial drugs (fluoroquinolone or injectables) can limit the effectiveness of the multi drug resistant TB regimen. Secondly as described in the treatment of drug resistant TB, the difficulty that patients have in coping with the pills and injections, can lead to significant numbers of patients not completing their course of treatment.
Diagnosis of drug resistant TB in India
There are various groups of people that are presumed to have drug resistant TB (DR-TB). This is until such time as drug susceptibility testing (DST) 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 DR-TB cases,
- and HIV associated TB cases at diagnosis.
There is more about the treatment of drug susceptible TB in India.
If patients on an MDR TB regimen are culture positive at six months, or if culture reversion (culture going back to positive) occurs during MDR TB treatment, after culture conversion to negative, then DST for second line drugs should be offered. This is to find out if the patient has XDR TB.
Treatment for MDR TB (or R resistance) without additional 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 RNTCP Technical & Operational Guidelines for TB Control in India 2016 sets out the detailed information about the drugs 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).
The regimen should usually 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 “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 three months supply of drugs is provided at any one time. With drug susceptible TB the patient receives the whole course at the beginning.
The cost of MDR-TB treatment
For MDR-TB, treatment can cost almost $2,000 for one year. Additionally patients have to get sputum cultures regularly during the time of their treatment, which can add another $800 to the bill annually. This can be the cost when patients get their drugs from the private sector. The drugs are completely free when a patient gets them from the government RNTCP programme.
Bedaquiline is becoming available for some TB patients in India who have drug resistant TB. Six hundred doses are being obtained under the “Compassionate Access programme” from Johnson & Johnson, and another 2,000 doses will be obtained from USAID. The drug is going to be provided under strict supervision at six government hospitals across the country.
However, by November 2017 it had become apparent that this number of doses was completely inadequate as there were apparently nearly 100,000 TB patients in the country asking for the drug. Doctors were calling for India to purchase the drug instead.4Venkatesan, N “India’s dependency on charitable program for MDR TB drugs not helping, doctors say” Nov 17 2017 //economictimes.indiatimes.com
“It is laughable that given the crisis at hand in India, we are talking about a mere 600 doses of drugs. It is too little, the access has to improve. Lalit Anande, Chief Medical Officer, Sewri hospital
Subsequently the charitable endeavour was extended again in 2017, when the health ministry said it would extend the access programme across 156 sites. However, it is not absolutely clear that all these patients really do need bedaquiline. For most drug resistant TB patients it should be possible to follow the WHO recommendations and devise a regimen which has at least five effective TB medicines, without using bedaquiline. See the Treatment of drug resistant TB for more information. So does this mean that there are 100,000 patients in India, with such extensive drug resistance that this is the only way that they can be treated?
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.5Mascarenhas,A “The roll out of a TB curing miracle drug - Bedaquiline”
The new drug delamanid is also beginning to become available in India. The maker of the drug Otsuka has granted a licence for the drug to be supplied to India to treat patients with MDR TB. At least 400 patients in India will have access to delamanid as part of the Indian’s government’s Conditional Access Programme.