RNTCP DOTS Plus Programme:
The emergence of resistance to drugs used to treat tuberculosis (TB), and particularly multidrug-resistant TB (MDR-TB), has become a significant public health problem in a number of countries and an obstacle to effective TB control. In India, the available information from the several drug resistance surveillance studies conducted in the past suggest that although the rate of MDR-TB is relatively low in India, this translates into a large absolute number of cases.Specific measures are being taken within the Revised National Tuberculosis Control Programme (RNTCP) to address MDR-TB problem through appropriate management of patients and strategies to prevent the propagation and dissemination of MDR-TB. Traditionally, DOTS-Plus refers to DOTS programmes that add components for MDR-TB diagnosis,
management and treatment.
It is well known that resistance levels are higher in areas with a poorly performing DOTS programmes. Use of inadequate regimens and inappropriate directly observed treatment (DOT) leads to increase in drug resistance levels in the community. It has been acknowledged that good treatment is a pre-requisite to the prevention of emergence of resistance. RNTCP recognizes that implementation of a good quality DOTS programme is the first priority for TB control in the country. Prevention of emergence of MDR-TB in the community is more imperative rather than its treatment. Provision of DOTS-Plus for management of MDR-TB, is a supplementary service under the expanded framework of the DOTS package. Therefore in every DOTS implementing unit of the country, DOTS would be prioritised above DOTS-Plus with the view that DOTS reduces the emergence of MDR-TB, and therefore the need for DOTS Plus over time.
The first WHO endorsed DOTS-Plus programmes began in 2000. At that time, the Green Light Committee
(GLC) was established to promote access to high quality second-line drugs for appropriate use in TB control programmes. DOTS-Plus pilot projects have demonstrated the feasibility and effectiveness of MDR-TB
Treatment in less affluent countries. In 2002, the Global Fund to fight AIDS, TB, and Malaria (GFATM) started financing TB control programmes, including MDR-TB, thus greatly reducing the economic barrier to MDR TB control. Since then, DOTS-Plus projects have multiplied rapidly. By the end of 2007, 67 projects in 52 countries approved by the GLC, with a cumulative total of over 30,000 MDR-TB patients, had been launched worldwide, many of them with financial support from the GFATM. Based on data and experience from these projects, practices and further scientific evidence have emerged regarding services for MDR-TB.
Drug resistant tuberculosis has frequently been encountered in India and its presence has been known virtually from the time anti-tuberculosis drugs were introduced for the treatment of TB. There have been a number of reports on drug resistance in India in the past, but most studies used non-standardized methodologies and biased or small samples, usually from tertiary level care facilities. The prevalence of multi-drug resistant TB (MDR-TB), defined as resistance to isoniazid and rifampicin with or without resistance to other drugs, is found to be at a low level in most of the regions. Data from studies conducted by TRC and NTI, have found MDR-TB levels of less than 1% to 3% in new cases and around 12% in re-treatment cases.
RNTCP has recently undertaken two community based state level drug resistance surveillance (DRS) studies in Gujarat and Maharashtra. These surveys have been conducted as per a common generic protocol based on internationally accepted methodology and have estimated the prevalence of MDR-TB to be about 3% in new cases and 12-17% in re-treatment case.
A major limiting factor in making the treatment of MDR TB (Category IV under RNTCP) is the lack of quality assured culture and DST laboratory facilities since diagnosis of MDR-TB is purely a laboratory based diagnosis. For RNTCP to provide diagnostic and treatment services to MDRTB
Patients the programme is in the process of establishing, in a phased manner, a network of quality assured culture and DST laboratory facilities. RNTCP aims to have atleast one such laboratory, known as the Intermediate Reference Laboratory (IRL), for culture and DST in each large state by 2009-10. The State level laboratory could be in a STDC, a Medical college or a State public health laboratory. Besides the IRLs the programme is also involving the existing Medical College and Private sector Laboratories to support the diagnostic and follow up services. Any laboratory that wishes to be included in the network will need to undergo an assessment and accreditation process under RNTCP.
In Maharashtra the two STDC (Nagpur and Pune) are proposed to be the IRL (accredited culture and DST facility. STDC Nagpur is already accredited and the facility at STDC Pune is being upgraded. The medical college laboratory in JJ hospital Mumbai is also being upgraded to support DOTS Plus activity in Mumbai. Involvement of existing private and NGO sectors in Mumbai is also under consideration for laboratory support. The DOTS Plus services were launched in Nagpur division in early 2008 and later expanded to Akola division in December 2008. a phase wise expansion to other parts of the state is planned between 2009 to 2011.
Causes of drug-resistant tuberculosis
Drug-resistant TB has microbial, clinical, and programmatic causes. From a microbiological perspective, the resistance is caused by a genetic mutation that makes a drug ineffective against the mutant bacilli. An inadequate or poorly administered treatment regimen allows drug-resistant mutants to become the dominant strain in a patient infected with TB. The table below summarizes common causes of inadequate treatment.
However it should be stressed that MDR-TB is a man-made phenomenon – poor treatment, poor drugs and poor adherence lead to the development of MDR-TB.
Causes of inadequate treatment:
The RNTCP views the treatment of MDR-TB patients as a “standard of care” issue. Recognizing that the treatment of MDR-TB cases is very complex, the treatment follows the internationally recommended
DOTS-Plus guidelines and is done in designated RNTCP DOTS-Plus sites. These sites are established in a limited number of highly specialized centres which have ready access to an RNTCP accredited culture and DST laboratory, with qualified staff available to manage patients using standardized second-line drug regimens given under daily DOT and standardized follow-up protocols, have systems in place for an initial short period of in-patient care to stabilize the patient on the second-line drug regimen followed by ambulatory DOT and with a logistics system and standardized information system in place. Till date 2 DOTS Plus sites are established in the state 1st at GMC Nagpur and 2nd at GMC Akola for the respective divisions.
The DOTS-Plus framework for the management of multidrug-resistant TB
The framework is organized around the same five components of the DOTS strategy, as the underlying principles are the same.
FIVE COMPONENTS OF DOTS-PLUS
Case finding strategy
At present, RNTCP does not have sufficient quality assured laboratory capacity to do culture and DST in all patients. Hence the programme is using a strategy that enrolls patients with a very high risk of MDR-TB into
RNTCP DOTS-Plus activities and treatment with the RNTCP Category IV regimen. Patients who are defined
as an “MDR-TB suspect” should be identified and investigated further for MDR-TB: MDR-TB Suspect can be any of the following:
• Any TB patient who fails an RNTCP Category I or III treatment regimen
• Any RNTCP Category II patient who is sputum smear positive at the end of the fourth month of
treatment or later.
MDR TB Case: A patient is confirmed to have multi-drug resistant TB only by an RNTCP quality assured culture and DST laboratory. Such patients are classified according to the following definition:
• Confirmed MDR-TB case: An MDR-TB suspect who is sputum culture positive and whose TB is due to Mycobacterium tuberculosis that are resistant in-vitro to at least Isoniazid and Rifampicin (the culture and DST result being from an RNTCP accredited laboratory).
Culture and DST results and further action
Deciding on treatment
The DOTS-Plus site committee reviews the patient details, including previous history, DST result and concurrent illnesses, and makes a decision in relation to treatment under RNTCP with a Category IV regimen. If the Committee decides on treatment with Category IV patient is initially admitted at the DOTS-Plus site, counseled in regards to their treatment, their treatment card is opened and treatment initiated. If the patient is able to tolerate the Cat IV drugs he/she can be discharged 1 week post-treatment initiation. In case a patient refuses for hospitalization all efforts are made to convince him/her. However, if despite all efforts the patient is still unwilling for hospitalization, treatment is not denied and alternative local arrangements are made for pre-treatment evaluation and initiation of treatment.
RNTCP Category IV regimen: RNTCP is using a Standardised Treatment Regimen ( Cat IV) for the treatment of MDR-TB cases under the programme. Cat IV regimen comprises of 6 drugs (kanamycin, ofloxacin, ethionamide, pyrazinamide, ethambutol and cycloserine) during 6-9 months of the Intensive Phase and 4 drugs (ofloxacin, ethionamide, ethambutol and cycloserine) during the 18 months of the Continuation Phase. p-aminosalicylic acid (PAS) is included in the regimen as a substitute drug if any bactericidal drug (K, Ofl, Z and Eto) or 2 bacteriostatic (E and Cs) drugs are not tolerated. All drugs are to be given in a single daily dosage under directly observed treatment (DOT) by a DOT Provider. The treatment is given in two phases, the Intensive phase (IP) and the Continuation phase (CP). IP is given for at least six months. After 6 months of treatment, the patient is reviewed and treatment changed to CP if the 4th month culture result is negative. The IP can be extended upto a maximum of 3 months after which the patient is initiated on the CP irrespective of the culture result. The recommended duration for CP is 18 months.