Prospects for new tuberculosis treatment in Africa - Wiley Online Library

Tropical Medicine and International Health volume 9 no 7 pp 827–832 july 2004

Prospects for new tuberculosis treatment in Africa A. Mwinga1 and P. Bernard Fourie2 1 University Teaching Hospital, Lusaka, Zambia 2 Lead Programme for Tuberculosis Research, Medical Research Council, Pretoria, South Africa

Summary

Health services in Africa are being overburdened by a continuous increase of cases of tuberculosis (TB), largely resulting from the large pool of infected individuals becoming co-infected with HIV. To help deal with the situation, TB treatment schedules need to be shorter and simpler, with minimal contact between the patient and the service provider required, if the problems of non-compliance and of ineffective service provision are to be overcome. Various drugs not marketed for use in the treatment of TB are currently under investigation for their potential roles in the simplification or shortening of treatment schedules. These mainly include the long-acting rifamycins and the fluoroquinolones. Furthermore, new drug development is focused on an understanding of the host–pathogen interaction leading to infection, latency and disease. Of these, latency is least understood. The use of molecular diversity and combinatorial chemistry, proteomics, and the use of the whole genome to discover drug targets are expected to produce new lead compounds for turning into drugs to treat active, latent and multi-drugresistant TB more effectively in the foreseeable future. keywords review, tuberculosis, treatment, drugs, Africa

Introduction HIV/AIDS, tuberculosis (TB) and other related infectious diseases are severely threatening sustained development in Africa, and in particular in those populations living in the sub-Sahara region. In April 2001, African Heads of State called a summit to focus on the development of strategies and resource mobilization for tackling these conditions in order to reverse the rate of infection on the African continent. This resulted in the Abuja Declaration issued at the close of the meeting (African Summit on HIV/AIDS, TB and other related infectious Diseases 2001). Tuberculosis in Africa has reached epidemic proportions, with an estimated 2 million new cases occurring annually, increasing at a rate of 10% each year, largely as a result of HIV co-infection (World Health Organisation 2001). Consequently, the numbers of TB cases in Africa are projected to double in the next decade because of the HIV epidemic and under-funding of effective strategies against TB. TB is the world’s leading killer among infectious diseases, with one person dying of it every 15 s across the globe. In Africa, it is responsible for 600 000 deaths each year, mainly occurring among the young and economically productive age group. The situation is compounded by the fact that on average, 30–40% of the TB cases in Africa are HIV positive, this figure reaching 70% in some countries. On a global level, 80% of the 8 million TB cases occurring annually are in only

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22 countries. Of the 10 countries with the highest incidence, nine are in Africa (Dye et al. 1999). Africa bears the additional burden of high levels of poverty and some of the lowest health indicators in the world. Natural calamities and man-made conflicts have worsened the situation in many countries, resulting in a large number of displaced persons. In addition, the AIDS epidemic has caused a reversal of the gains in development and has resulted in a decline in life expectancy in many countries (World Bank Group 1999). Status of TB drug treatment in Africa Given the growing burden of disease, health service delivery is under increasing pressure in Africa. In the context of TB, effective treatment and management of cases tend to suffer, not only because of additional direct expenditure on drugs, but also because of the long duration of treatment (6–8 months) required to cure patients. Patient adherence to the treatment regimen over such a long time is often deficient, and requires considerable investment in human resources and laboratory monitoring to ensure treatment success. Direct observation of drug taking is necessary, and the bacteriological status of sputum needs to be assessed regularly. Although the duration of treatment has been reduced to as short as 6 months where rifampicin is used throughout the course of treatment, this is still very long compared with the 827

Tropical Medicine and International Health

volume 9 no 7 pp 827–832 july 2004

A. Mwinga & P. B. Fourie TB treatment in Africa

treatment of most other bacterial infections. Many countries in Africa, however, tend to use the cheaper continuation phase combination of ethambutol and isoniazid after the first 2 months of rifampicin-based therapy, which lengthens the total treatment period to 8 months. Current first-line TB drugs have been available for the last 30 years. They are effective and provide the possibility of achieving cure rates of 95%. The 85% treatment success target set by the World Health Organization (WHO) for global TB control by 2005 should therefore be achievable. This goal has previously been reached in countries such as Tanzania and Malawi, which are often considered as model programmes. These countries received substantial support for their TB control efforts from organizations such as the International Union Against Tuberculosis and Lung Disease (IUATLD) and other co-operating partners. Indeed the treatment of TB using short course chemotherapy is recognized as one of the five most cost-effective health interventions (World Health Organization 2001). In the recent past, however, it has been less easy to maintain these high cure rates because of factors such as a decrease in the level of funding for TB control and the impact of HIV infection. It is an accepted fact that patient adherence is a major factor in determining the outcome of treatment. The role of non-adherence in the outcome of treatment has resulted in the promotion by WHO of the directly observed treatment strategy (DOTS, short course) strategy as a means of improving the outcome of treatment. The effectiveness of this strategy has been demonstrated by improved cure rates in countries that adopt the strategy widely. However less than one-third of TB patients live in areas where the 6–8-month course of treatment can be given effectively and only 15 of the 47 countries in the AFRO Region of WHO have consistently provided DOTS coverage of 90–100% (Murray 1994). The current situation is a paradox. TB in the 21st century is a global emergency despite the availability of effective drugs for the last 50 years or more, and the presence of well-elucidated and tried and tested control strategies. Although HIV infection is responsible for much of the increase in case rates in many countries, other factors such as poverty contribute to the rising burden of infection. Thus although the provision of TB treatment using the DOTS regimen can guarantee high cure rates, it is difficult to achieve in reality. The aim of treatment of TB is to reduce the length of infectiousness and hence break the cycle of transmission. Although the currently available drugs are effective, delay in diagnosis, interruption or non-availability of treatment and drug resistance lessen the likelihood of achieving a high cure rate. The resurgence of TB as a major public health problem in developing countries coupled with the reversal of the 828

downward trend of TB notifications in developed countries, mainly among the foreign-born and immigrant population, has galvanized the medical fraternity into action against TB. Other factors include the increase in the number and extent of drug resistance, particularly multidrug-resistant (MDR) cases. Development of new TB therapies was sadly neglected in the 1970s and 1980s. No new TB drugs were marketed after the discovery of rifampicin more than 30 years ago. This situation arose mainly from the perception at the time that TB was no longer a major public health problem in developed countries and that as the bulk of the market for TB drugs was in poor countries, it would be difficult for the drug companies to realize a sufficient return for their investment in new drugs for TB. However, with the declaration of TB as a global emergency by WHO in 1993 and the continued increase in TB cases worldwide, this situation has been reversed. There has been a marked increase in the level of investment in research and development for new drugs. The Global Alliance for TB Drug Development was launched in October 2000 in Bangkok Thailand with the major stakeholders being foundations such as the Bill and Melinda Gates Foundation and the Rockefeller Foundation, industry, non-governmental organizations and governments (Richards 2000). At the time of the official launch the investment in R&D for new drugs was expected to exceed US$ 150 million in 5 years. The expectation has been to have the first new drug registered by 2010 at a price affordable by developing countries. There have been other large investments pledged for the development of new drugs and vaccines for HIV/AIDS, TB and malaria such as the multi-billion fund for new drugs and vaccines for these three diseases set up by leaders of the Seven Industrialized Nations on 30 April, 2001 in Washington DC. Requirements and prospects for improved drug treatment for TB In the control of TB new drugs will have a greater impact if they can improve current treatment through facilitating patient and provider compliance. This would be possible with the availability of drugs that result in a shorter regimen and regimens that require less supervision. Other requirements would be the improved treatment of MDRTB and the provision of more effective regimens for the treatment of latent TB infection (O’Brien & Nunn 2001). This process can be achieved through the improvement or simplification of existing drug regimens and treatment strategies, or the development of new agents with specific anti-TB activity.





Existing drugs Not only is the length of anti-TB treatment a factor that impacts on the outcome of the medical management of patients, but also the complexity of the prescription which must take into account the number and dose of different antibiotics to combine in the regimen, the frequency of administration, and the fact that different categories of patients require different treatment options. It has been argued that incorrect prescription, drug selection by patients, and interruption of treatment are major contributing factors to treatment failure and the development of drug resistance (Blomberg et al. 2001). In an attempt to simplify and standardize treatment practices, the World Health Organization and the IUATLD have been promoting the use of fixed-dose combination (FDC) drugs of demonstrated quality for the treatment of TB as part of the DOTS strategy (Blomberg et al. 2001; Blomberg & Fourie 2003). Various drugs not currently used in the treatment of TB are currently under investigation for their potential roles in the simplification or shortening of treatment schedules. These mainly include the long-acting rifamycins and fluoroquinolones. The newer rifamycins, rifabutin and rifapentine, have shown promise as possible new drugs against Mycobacterium tuberculosis. Rifabutin, initially licensed in the US for M. avium complex (MAC) prophylaxis, has shown activity against M. tuberculosis and some rifampicinresistant strains. It also has less enzyme-inducing activity than rifampicin, an important attribute in the context of anti-retroviral treatment (protease inhibitors) in TB patients who are also HIV-positive. In a multinational randomized clinical trial the treatment success rate with rifabutin exceeded that of rifampicin (Gonzales-Montaner et al. 1994). A pilot study of rifabutin in HIV/TB patients conducted in Uganda showed no difference in clinical response or adverse reaction to rifabutin compared with rifampicin with a significantly better smear conversion rate at 2 months (Schwander et al. 1995). Rifapentine, a long-acting rifamycin, has treatment success and relapse rates similar to those of rifampicin, and has been registered in the USA for twice-weekly treatment of TB at a dose of 600 mg. However, there is a risk for rifampicin mono-resistance to arise in patients with advanced TB (Anonymous 2002) who are HIV-positive. This effect might be dose-related and has led to investigations of the tolerability of rifapentine administered at higher doses than normally used (900 and 1200 mg as opposed to 600 mg) (Bock et al. 2002). Nine hundred milligram given once per week (with isoniazid) has a good adverse effects profile and needs to be studied in efficacy trials, in particular in areas with a high prevalence of HIV


infection. Future plans with rifapentine include studies aiming to markedly reduce the contact with the health service to a single DOT event per week in the continuation phase of treatment (rifapentine 900 mg once per week supervised plus 300 mg isoniazid daily self-supervised). Another possibility is to pair rifapentine with a potent companion drug, both of which can then be given once per week under DOT. The fluoroquinolone, moxifloxacin (see also below), seems to be the best candidate for this purpose (Lounis et al. 2001). The fluoroquinolones that have shown activity against M. tuberculosis in both in vitro testing and in animal models include ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, moxifloxacin and gatifloxacin. These drugs are generally well tolerated, although clinical evaluation of the efficacy of the compounds has lagged behind because of the lack of information on clinical effects associated with long term use in humans. Nevertheless, there has recently been a growing interest in studying their potential role in the first-line treatment of TB (Gillespie & Kennedy 1998). Ofloxacin, ciprofloxacin and to some extent also levofloxacin, are exceptions, because they are already used extensively in the treatment of MDR-TB. Although there is currently limited evidence to support the use of fluoroquinolones as first-line drugs in TB, recent studies carried out by the Tuberculosis Research Centre in Chennai, India, indicate that there might be an important role for this class of drugs in TB treatment (Tuberculosis Research Centre 2002). Very promising results were obtained with several 4-month ofloxacin-containing regimens, showing 94–98% sputum smear conversion after 2 months and from 3 to 5% relapse rates after 48 months follow-up. In this trial, however, the ofloxacin-containing regimens were not compared with the widely used standard non-ofloxacin containing control regimen, using a combination of four drugs including rifampicin, isoniazid, pyrazinamide and ethambutol during the initial phase of treatment (2 months), and rifampicin and isoniazid in combination for a further 4 months. The expected relapse rate of such a regimen at 24 months after the end of chemotherapy is 3–5%. The two 8-methoxy-fluoroquinolones, moxifloxacin and gatifloxacin, both show anti-TB properties superior to ofloxacin in in vitro and in animal studies (Lounis et al. 2001; AlvirezFreites et al. 2002; Hu et al. 2003). Studies to determine the optimal dose and duration of administration of the drugs and to determine the presence of early bactericidal and sterilizing activity of these compounds are underway. Finally, the use of the immunomodulating agent SRL172 (M. vaccae) as adjunct therapy in TB treatment has been given much attention over the past 10 years. It raised great expectations for a simple, affordable, significant intervention in TB epidemics in high-burden countries. Many 829




studies have been conducted with this agent worldwide, most recently also in Africa and China, but it remains to be unequivocally shown that it leads to improved TB treatment outcomes (Fourie et al. 2002). New drugs The process of new drug development for TB has been facilitated by the availability of the complete genome sequence for M. tuberculosis that will enable a greater understanding of the host–pathogen interaction leading to infection, latency and disease. In addition the development of various molecular markers for infection and response to treatment are likely to have an important role in the development of new drugs for TB. Other new technologies that may be used in the R&D of new drugs include proteomics, the systematic analysis of proteins in a cell or pathogen; the use of molecular diversity and combinatorial chemistry; as well the use of the whole genome to discover drug targets. However, lead compounds based on the application of these technologies are only expected to be available several years from now. Existing molecules that show promise for development as anti-TB agents include members of the nitroimidazole, oxazolidinone and thiolactin classes. A series of nitroimidazopyrans, similar in structure to metronidazole, have been found to have bactericidal activity against M. tuberculosis for both replicating and static microaerophilic-adapted organisms, suggesting a possibility for the use of these compounds for the treatment of latent infection. The lead compound, PA-824, has shown activity in animal models against M. tuberculosis, including strains resistant to more than one drug. As this compound targets the cell wall of the mycobacteria, it is able to easily enter the cell and kill the bacteria (Stover et al. 2000). Oxazolidinones fall into a unique class of drugs which inhibit bacterial protein synthesis, and have shown both in vitro and in vivo activity against M. tuberculosis. Thiolactomycin, a unique thiolactin that specifically inhibits fatty acid and mycolic acid biosynthesis, has been shown to have potent antimycobacterial activity. More detailed summaries of these and other promising molecules or drug targets for TB drug development have recently been published by Roy et al. (2002) and Tomioka (2000). Novel drug delivery systems are also being investigated e.g. the use of inhaled aminoglycosides for patients with persistent smear-positive pulmonary TB (Sacks et al. 2001). The potential advantages of drug inhalation include optimal activity through enhanced absorption because of direct uptake and distribution of drug via the lung, and the possibility of lower dose and consequently fewer adverse effects. In addition, injectable drugs administered over long 830

periods create considerable discomfort to patients, and require particular attention to sterile practices in HIVprevalent situations. Breath activated, rechargeable, cheap devices utilizing dry-powder biologically inactive nanoparticle carriers (Edwards et al. 1997; Dunbar et al. 2002) might offer an alternative administration procedure for injectables, and for new compounds with good anti-TB activity and tissue distribution, but poor solubility. Traditional medicines In Africa, the role of the traditional healer using naturally occurring herbal remedies in the treatment of TB cannot be ignored as a large proportion of the population do consult them, often before consulting the formal health sector. These providers have made various claims on the efficacy of their drugs against TB and these claims warrant investigation. Issues of intellectual property rights and patenting should be discussed and clarified, though, in order to win the confidence of traditional healers. Operational aspects It is indisputable that new drugs at an affordable price are urgently needed in order to improve the armamentarium against TB and hence the probability of controlling the infection. However, new drugs alone are not the panacea for the global TB problem, important although this is. It has been said that a poorly functioning TB control programme is worse than having no programme at all. Equally important are increased awareness of the presenting symptoms and signs in a TB suspect, an effective system for the diagnosis of cases with a minimal delay, an efficient system for provision of an uninterrupted supply of effective drugs under supervision (DOTS) within the context of a health system that is responsive to the needs of the patients and that co-operates with community-based organizations. In addition, improved nutrition and other socio-economic conditions for the patients are important in the management of the patient with TB – it is difficult for the patient who does not have access to basic nutrition and a supply of clean water to take tablets every day. The use of fixed-dose drug combinations of proven bioavailability will ensure that the correct drug is taken at all times and will enhance the dispensing of the drug and lessen the number of tablets to be taken by the patient with improved compliance (Blomberg & Fourie 2003). Education of the general community will lead to an improvement in the recognition of symptoms and will hopefully lead to a decrease in the level of stigma associated with TB. Treatment of a latent infection with TB has relevance in areas with high prevalence rates of HIV. The synergy





between HIV and TB will ensure that there continues to be an increase in TB cases in Africa in the next decade. Therefore the implementation of this strategy in the context of provision of care for HIV-infected individuals should be considered. Research is also required into a greater understanding of the factors associated with latency and mechanisms to overcome this. In areas with high levels of drug resistance, in particular multi-drug resistance, the utility of the current recommendations for treatment need further investigation. Priorities for enhancing access to new treatment options The current level of investment in research and development for new drugs and vaccines against TB has raised optimism that there will be new drugs and vaccines for TB in the next decade. Large-scale clinical trials using the new drugs will have to be conducted, using the currently available drugs as the gold standard. Although the majority of the drugs will be developed in the north, phase II and III trials are likely to be carried out in developing countries that have high burdens of infection. Thus there is need to set up effective collaboration between the developed country institutions and scientists with host country institutions and scientists (host) based on equal collaboration. Thus, in the run-up to the availability of new drugs for phase II and III trials, the development of clinical trials capacity in Africa is vital. This should involve training local scientists in new laboratory techniques, training in clinical trials methodologies and monitoring, training in research ethics and setting up of well-equipped and functional laboratories that can participate in the clinical trials. As clinical trials are designed, the involvement of the developing country scientist from the inception of the study is vital to ensure local ownership, and to enhance the likelihood of transfer of such new technology to the communities that need it most. References African Summit on HIV/AIDS, Tuberculosis and other related infectious Diseases (2001) The Abuja Declaration on HIV/ AIDS, Tuberculosis and Other Related Infectious Diseases. Abuja, Federal Republic of Nigeria, 27 April 2001. Alvirez-Freites EJ, Carter JL & Cynamon MH (2002) In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 46, 1022–1025. Anonymous (2002) Acquired rifamycin resistance in persons with advanced disease being treated for active tuberculosis with


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Authors Alwyn Mwinga (current address), CDC Global Aids Programme, Lusaka, Zambia. Tel.: +260 1 250955; Fax: +260 1 251142; E-mail: [email protected] P. Bernard Fourie, Lead Programme for Tuberculosis Research, Medical Research Council, Pretoria, South Africa. Tel.: +27 12 3398547; Fax: +27 12 3237049; E-mail: [email protected] (corresponding author).

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