The advent of the four drug regimen recommended by the experts and the World Health Organisation (WHO) for the treatment of TB, had in recent times created a myth that new anti-TB drugs are not needed and better delivery of existing drugs would suffice to control this dreaded disease. The fact is that, with all present strategies, the battle against this organism, discovered a hundred years back, is far from being won.
The figures of active TB requiring treatment of some kind or the other are staggering. One third of the World's population (2 billion people) are infected, of which 16 million are active cases with an additional 8 million added every year. Mortality figures have reached 3 million per year, with one third of all AIDS patients eventually dying of TB. Of the new cases, 22% are from India, 21% from Sub-Saharan Africa, and another 21% from other Asian Countries.
Even though in a qualitative manner, the Directly Observed Short Course (DOTS) has been successful, the fact is that only half the patients are diagnosed for treatment in the first place. Half of the rest do not complete the full course of treatment, leading to emergence of Multi Drug Resistant (MDR) TB. Where monitoring is weak, compliance with treatment drops to as low as two months, against the six months stipulated.
The answer to these problems is the discovery of new drugs, which are effective with short duration of treatment, which will in addition ensure better compliance and reduce the incidence of adverse reactions to drugs. The new drugs should also be effective against latent infections of TB, defined as TB that has not manifested as a disease. The need for new drugs is even more acute, due to development of opportunistic TB in HIV positive patients.
Anti-TB drugs popularly used today are Rifampicin, Isoniazide, Pyrazinamide , Ethambutol, Thioacetazone, Rifabutine, Rifapentine and Sparfloxacin. Second line Anti-TB drugs for MDR TB are Ethionamide, Amikacin, Kanamycin, Capreomycin, Ciprofloxacin, Ofloxacin and Levofloxacin.. Currently the treatment of MDR TB is very unsatisfactory with the drugs available which require to be used for as long as 18 to 24 months, are expensive and have unacceptable side effects.
Even though BCG Vaccine has been around since the early 20th Century, its effectiveness is very limited. Both due to lack of commercial interest and technical problems, efforts at new Vaccine development has been meagre. Even if current efforts are strengthened, it will be another decade before they will be useful, during which time, total mortality from TB could reach figures as high as 50 million.
The problems of research on TB starts with the problem of growing the Mycobacterium tuberculosis (McTB), a highly pathogenic organism requiring sophisticated containment facilities at Biosafety level 3. Animal models available do not truly mimic the disease. In recent time there has been more success using the Aerosol mice model, where small quantities of McTB are delivered as a mist, similar to the natural infection process. Researchers are also identifying McTB proteins responsible for eliciting immune response in the hosts. The sequencing of the genome of McTB could provide new opportunities for development of new drugs, vaccines and diagnostics.
Market for Current Anti-TB Drugs
Current total market for Anti-TB drugs which includes both the Private and Public/Tender markets is around U.S.$ 450 million per year. By 2010, the market is expected to grow to $ 670 million. The International Donor Community is estimated to donate around $40 million per year out of the minimum of $120 million required only to meet the requirements of Public Health Programmes. Even for the planned expansion of the DOTS Programme an additional $ 50 million would be required.
Industry Interest In TB Drug Development
Primarily due to economic considerations, commercial interest in the discovery and development of new Anti-TB drugs suitable for shorter-term therapy, active against both Latent TB as well as MDR TB, is likely to be low, since any single drug for these indications is not likely to generate sales of over $ 200 million per year. Compare this with the any blockbuster drug, with annual sales ranging from $ 1 billion to $ 6 billion. The margins available from sale of Anti-TB drugs will be much lower, since the markets are in developing countries, where drug costs constitute a high proportion of health care budgets, which in any case are low.
Global Alliance for TB Drug Development
This not-for-profit Organisation, built through public-private partnership, has as its mandate, accelerated development of new Anti-TB drugs, and for this purpose outsources promising R&D projects in this area to public or private industry laboratories. In February 2002, the Alliance in-licensed a molecule from Chiron Corporation, PA 824, a molecule, which shows promise for treatment of MDR TB.
PA 824 is a novel Nitro Imidazole, which has shown activity against both Drug resistant and Drug sensitive strains of TB, with the potential of being able to reduce the duration of treatment. The rationale for this hope is that the molecule demonstrated bactericidal activity against replicating and static McTB organism. Unlike many other Nitro Imidazoles, PA 824 is non-mutagenic and is specific for Mycobacterium tuberculosis.
There have been reports of three other new molecules discovered in the Medical Research Council (MRC) of South Africa, which are being investigated through the joint efforts of Tuberculosis Research Centre in India and MRC.
In general there are four approaches being followed for the development of new agents. They are 1) new uses for existing drugs used even for other indications 2) new delivery systems of existing drugs 3) new derivatives of currently used drugs and 4) new classes of drugs.
Derivatives of Rifampicin. Fluoro Quinolone and Nitro Imidazole families are being tried out, so also many immune potentiators, such as Gamma Interferon, Interleukin 2 &12. Other strategies involve Adhesion molecules, genetic products from Mycobactera, suitably modified to ensure the organism's death. Phages may also deliver Anti-sense Nucleic Acids as inhibitors of Mycobacterial Gene expression.
All these developments, however are in very early stages and may take a decade or more before they become useful in therapy.
DOTS Programme
According to WHO-2002 Report, the number of countries implementing the DOTS Programme, increased by 14 in 2001, raising the total number to 148 Countries which together account for 55% of the World's population. Of the new smear-positive cases detected, 28% was from India and 19% from the Philippines. The target set for 2005 are 70% for case detection and 85% for treatment success. To reach these targets, DOTS should recruit 330,000 smear-positive cases every year, as against 130,000 currently being done. On the financial side, the 22 Heavy Burden Countries (HBCs), would require $ 1 billion per year for the period 2002-2005, as against $ 436 -470 million currently available or committed.
The major constraints for the success of DOTS in many Countries are lack of qualified staff and management skills, shortage of equipments and drugs and funds, and lack of collaboration between TB and AIDS control programmes.
The WHO-World Bank ' Stop TB Partnership' estimates funding requirements of $ 9 billion, of which the funding gap is currently $ 4.5 billion. Such investments, if and when available can cure 22 million TB patients and save 16 million lives by 2005.
Problems in TB Drug Development
The problems facing TB Drug development programmes have many components, including those of scientific, techno-commercial and financial nature. Except for PA 824, there are hardly any new molecules of a totally new chemical structure under development, nor are there any in the pipeline. In fact during the last three and a half decades, since the discovery of Rifamycins, no new chemical class of compounds has been discovered for TB treatment.
The challenge of MDR TB is real. Even in India over a 100 clinical isolates of MDR TB have been isolated, and many have been genotyped to understand the nature of MDR TB. It has been noted that a great deal of polymorphism exists in these strains with the patterns totally different from those isolated from Western cases. According to a Report, in China, India, Mozambique, Iran and Russia, multi drug resistant TB was seen in 3% of all cases of the disease detected. In 72 areas where 28% of the World's TB cases prevail, drug resistance was seen in 38 regions.
Even though much of new drug research is moving towards the use of Combinatorial Libraries and High Throughput Screening, TB research has so far made only very little use of these modern techniques. This is notwithstanding the fact that both the genetic codes of McTB and humans have been unraveled. Some advance has been made in the understanding of the putative functions of more than 70% of the genes in Mc TB, that has counterparts in other bacteria, through the use of computer-assisted database searching.
In 1998, Clifton Barry of the National Institute of Allergy & Infectious Diseases (NIAID) reported that Isoniazid affects the Protein KasA, which the bacterium needs to build its cell wall. The group also found that mutation of the KasA-coding gene conferred resistance to the drug. Such findings can lead to discovery of drug molecules as well development of primary tests which could give results in a few minutes, compared to existing screening methods which can take up to three weeks. As part of a comprehensive NIAID programme, which has a funding of $ 65 million per year, the Research Triangle Park is involved in research on understanding the basic biology, epidemiology, pathogenesis and diagnosis of Mycobacterium tuberculosis bacterium, as well as at discovering drugs and vaccines.
Conclusions
It is now well recognized that concerted global efforts are needed to control the disease, both through better use of available drugs, as well as through new and better drugs, which meet the specific needs. Newer Vaccines and diagnostic kits, which are cheaper, more user friendly and gives results faster are also required. The DOTS Programme needs not only additional financial inputs, but also more organizational support as well as better management skills.
The Global Alliance for New Drug Development has, as its laudable objective, support and management of new drug research. However even if the R&D based Pharmaceutical industry is not enthusiastic about investments in the area, due to poor commercial returns, they could provide their technical skills to ensure discovery and development of new drugs by undertaking contract research on behalf of the Global Alliance on commercial terms. Defining and implementing an integrated approach incorporating all available skills and resources, is essential for the success of efforts to control the spread of Tuberculosis.
-- The author is one of India's leading research scientists and an industry observer