Treatment Action Campaign (TAC) News: 22 August, 2000 ----------------------------------------------------- TAC news is divided into 2 sections, an "In Brief" section, which contains headlines and "BRIEF" descriptions of events, and an "In Depth" section which contains full versions of some of the events mentioned in the "In Brief" section. We have added the email addresses of the delegates to the TAC/MSF conference in Durban to our mailing list (at their request). Welcome to our new subscribers! This newsletter is published, on average, once every 9 days. Regards, Nathan Geffen on behalf of the Treatment Action Campaign ----------------------------- http://www.tac.org.za mailto:info@tac.org.za In Brief -------- Mother-To-Child-Transmission Prevention (MTCTP) ----------------------------------------------- * BRIEF: TAC is preparing legal action against the Minister of Health. The government failed to meet the 18 August deadline to announce the phased implementation of an MTCTP programme. * Mark Heywood, deputy-chairperson of TAC, published an article in the Sowetan explaining why the government should implement an MTCTP programme. This is definitely worth reading. (see In Depth) * BRIEF: TAC recently sent a letter to the Minister of Health explaining our vision of the MTCTP programme. At this time, the newsletter editor does not have the final copy. It will be reproduced next week. * We reproduce a Mail & Guardian report on MTCTP (reprinted for fair use). (see In Depth) * BRIEF: On Saturday, TAC held a march consisting of approximately 100 people in Khayalitsha, Cape Town to protest against the government's intransience on MTCTP. * BRIEF: TAC has demanded that the Western Cape government role out an MTCTP programme to the entire province, on the basis of the success of the Khayalitsha pilot project and the SAINT trials. Fluconazole Campaign -------------------- * Pfizer and TAC have exchanged letters since June 20. These are reprinted below. (see In Depth) * BRIEF: TAC is preparing to take Pfizer to court because it is abusing its fluconazole patent. Fluconazole costs the South African Government approximately R28 per 200mg pill. High-quality generic equivalents are available for less than R2 per 200mg pill from various generic manufacturers around the world. Fluconazole is used to treat patients with systemic thrush and cryptococcal meningitis, two commonly occurring opportunistic infections in people with HIV. Many South Africans die because they do not have access to this simple medication. * BRIEF: TAC is preparing its defiance campaign to import generic medication. General ------- * Cotrimoxazole, a prophylactic against PCP in HIV+ children, is not sufficiently available in public hospitals. (reprinted for fair use from Health- E) (See In Depth) * TAC issues a short statement on cotrimoxazole. (See In Depth) BRIEF: On Friday, SAA admitted in front of the constitutional court that they unfairly discriminated against a propective employee because of his HIV status. * We have reproduced (for fair use) an important article published in Nature on the world-wide TB epidemic and prospects for developing new treatments to combat multi-drug resistant TB. (see In Depth) * Timber industry hit hard by HIV (Business Report on Sunday article reprinted for fair use -- see In Depth section) * BRIEF: The TAC website has been revamped and updated. There are some minor glitches under Netscape which we are addressing. Please visit the site at www.tac.org.za. The Frequently Asked Questions page is still being worked on. You can contribute by sending questions to info@tac.org.za. Previous newsletters are available on the website. --------------------------------- In Depth -------- Something missing in the debate about mother to child transmission By Mark Heywood Head: AIDS Law Project and Vice Chairperson: Treatment Action Campaign Since July 12th this year the South African government has known that a single 200 mg pill, given to a woman who has HIV and is about to go into labour, and another 6 mg pill, given to her child immediately after birth, can reduce the risk that she faces of transmitting HIV to her infant during delivery -- and for a few months after -- by nearly 50%. This drug is known as Nevirapine (NVP). Since April the government has had in its possession a report that explains that the cost of this intervention, which could save at least 14 000 lives every year, would come to less than 0.3% of the national health budget. Put another way, it would cost the equivalent of R1.99 in the taxes of every person in South Africa. How many people, even poor people, would refuse R2 to prevent an HIV infection and save a life? These drugs are being used in the private health sector. They can be used by privileged people, including Ministers and MPs, who have HIV or AIDS. They are recommended for use by the World Health Organisation (WHO) and the Joint United Nations Programme on AIDS (UNAIDS). But despite this knowledge the Minister of Health has warned that: "Nevirapine currently should not be used outside approved research environments." The Minister has rebutted Nelson Mandela's call for "large-scale action to prevent mother to child transmission" and instead offered only to "expand the research sites on Nevirapine to all the provinces so that we can improve our understanding of the operational challenges that would attend any introduction of anti-retrovirals to prevent MTCT in the public health system." Something seems to be rotten in the brain of the Civitas Building, the head quarters of the Department of Health. Instead of acting urgently on these possibilities, the government seeks out obstacles. Instead of planning in accordance with the government's politically and constitutionally vested duties to promote the health of all women and children, the government seems to abide to a hidden agenda. Why? If we look at the big picture, if we put on the cynical eye-glass of Presidential spokesperson Parks Maklakhana, saving 14 000 lives, in the context of nearly one million births every year – is small change. If we think hard enough we can almost hear the silent thoughts of our Ministers: "When the government is faced by so many other challenges and difficulties in the realm of health care are 14 000 lives worth the effort?" But the Government does not have a choice -- it has a duty. According to South Africa's Constitution, decisions of the government cannot be influenced by privately held suspicions or individual and controversial objections to the public use of anti-retroviral drugs. The government's actions must be rational. In the context of mother to child transmission they must be dictated by "the best interests of the child", people's rights to equality, dignity and to make decisions concerning reproduction. And, in the words of the Constitution, these duties "must be performed diligently and without delay." In a democracy such as South Africa's, the pressure of the electorate and our rights to freedom of expression are a vital duty that we must exercise to remind government of its priorities and duties. At times like these, we need organizations like the National Association of People Living with HIV/AIDS (NAPWA) to stand up and shout. Engage in civil disobedience; occupy government offices. Let the voices of poor and marginalized people, whose decision-making powers the government has falsely appropriated under the rubric of poverty, be heard. Unfortunately, the apparent complexity of this debate, has meant that those most affected have stayed silent. Some of the most important things have not been said. In the meantime, let me try to fill this gap. I am not a woman. I cannot get pregnant. I do not have HIV. But I believe that I can help to provide a voice to a large number of people whose feelings, fear ands needs seem to have been absent from the government's thinking and decision- making. I have lost two children. More importantly, my wife has. I have watched two pregnancies take place over nine months. I have seen the bond that grows between a mother-to-be and her unborn child. I have felt the bond that develops as a father. Late in pregnancy, this bond becomes physical. For the father it is expressed in the little kicks and movements that dent the mother's stomach. For a mother the kicks are an expression of the imminence of life – a life that she has created and nurtured. I have also learnt the meaning of loss. Two of my children died shortly before or after birth. So I can remember their faces. I also know the look of a mother when she is told that her child is dead – the harrowing cry of "give me back my baby, it's not true" as it echoes through a maternity ward that is suddenly emptied of life and promise . And years of pain that follow it. Perhaps, we escaped lightly. Unlike many thousands of parents in South Africa we did not have to live with the torment of birth and life and then years of knowledge of inevitable, looming loss. But I have seen other people and friends who have to live with this. The death of a child of two, or three or four, must be one of the most terrible pains of all. Each year now, 70 000 infants are born with HIV. Each day, many babies and children die of AIDS. Why are these mothers and fathers so silent in this debate? It is a tragedy that our government now allows this to happen hundreds of times a day. Perhaps if our MPs and Ministers were stripped of their medical aid schemes – the privileged access that the votes of poor people has given them to first world health care -- and once again made dependant on public health services, there would be more of a sense of urgency and understanding. Perhaps, if MPs were mandated to spend time in paediatric wards, or sit besides over-burdened and under-paid nurses, who have to act as grief counselors, theoretical arguments about "resistance" would give way to day-to-day reality. Finally, perhaps the government would see the recent breakthroughs in medicine as an opportunity rather than a threat. Preventing mother to child HIV transmission has benefits that extend far beyond the life saved and grief prevented. An intervention like this could be used by the government to launch a campaign to encourage much more wide-spread voluntary HIV testing, beginning with pregnant women, but soon extending to fathers. It would create an immediate necessity to train more health workers as counselors and to place them at ante-natal wards. It could also be used as a reason to rapidly improve access and quality of primary health care. In short this intervention could be used to change the tone and methods of HIV/AIDS prevention in SA. It could assist prevention, but offer the hope of care. It could restore faith in the government's commitment to HIV prevention, and rebuild a shattered partnership. Comrade Manto, now is the time. --------------------------- State dithers over R1,99 AIDS drug BELINDA BERESFORD, Johannesburg | Friday (reprinted for fair use from the Mail & Guardian) THE government has been sitting on a report it commissioned that vigorously endorses the use of antiretroviral drugs in stopping the transmission of HIV between mothers and children. The study, commissioned by the Department of Health and delivered four months ago, suggests that using antiretroviral drugs to curtail mother-to-child transmission (MTCT) of the virus could not only save almost 14 000 lives a year, but could also save South Africa as much as R270-million a year. Written by a European Union-sponsored consultant in the directorate for health financing and economics, the report says the estimated costs of a Nevirapine programme work out at approximately R1,99 a person for the whole population. The report, leaked to the Mail & Guardian this week, estimates that "a nationwide Nevirapine MTCT programme could save almost 14 000 babies a year at the cost of R6 284 a life saved". A similar programme using AZT could save more than 12 000 babies' lives a year, for just over R10 000 a life. The consultant's investigation comes amid mounting controversy about the government's slowness in providing antiretroviral drugs to pregnant women with HIV. An NGO, the Treatment Action Campaign, is poised to take legal action against the government for its failure to do so. The government has justified its hesitation to fund the drugs with a variety of reasons, ranging from possible toxicity to cost. The Department of Health's Dr Nono Simelela said the department knew the drugs were cost effective but that the government had to consider a whole range of issues in preventing MTCT, such as breast feeding. She said there had not yet been enough information on Nevirapine to carry much weight, but said that policy on MTCT would be a Cabinet decision - and not that of the department alone. The author of the report, Martin Hensher, suggests Nevirapine intervention would be less cost effective than traditional public health measures such as child immunisation, but would be "very substantially more cost effective than many medical and surgical treatments offered as common interventions in the South African public sector". The M&G reported last month that a study conducted by a health economist at the University of Cape Town had found that the government could save R800-million a year - and more than 800 childrens' lives each month - if it made antiretroviral drugs and milk formula available to all HIV-positive women who were pregnant. --------------------------- TAC LETTER TO PFIZER, JUNE 20 William C. Steere CEO Pfizer 235 East 42nd Street New York, NY 10017 20 June 2000 Dear Mr. Steere IMMEDIATE PRICE REDUCTION FOR FLUCONAZOLE The Treatment Action Campaign (TAC) has learnt from sources inside your company that Pfizer has limited its offer of free fluconazole for cryptococcal meningitis for people with HIV/AIDS who cannot afford the drug to two and a half years. This limitation coincides with the expiry of your patent. In addition, you have excluded other countries from this donation and you refuse to negotiate a significant price reduction. As you are aware, the South African government can import fluconazole for less than R2.00 per 200mg capsule. TAC supported by the trade unions, religious bodies and civil society organisations demand that you lower your price to less than R4.00 per 200mg capsule and provide an appropriate equivalent for infants and children with HIV/AIDS. TAC accepted your donation in good faith and as an indication that you are willing to negotiate a price reduction. We also indicated that our Minister of Health should accept your donation. We have been misled. Pfizer leaves us no option but to take public action against your company and to mobilise international public opinion against profiteering. Every day's delay in a significant price reduction costs lives. Finally, we request that you lower your price to less than R4.00 per 200mg capsule before 29th June 2000 or that you issue a voluntary licence to allow the importation of the generic equivalent of Diflucan--fluconazole. Yours faithfully Zackie Achmat (TAC Chairperson) Promise Mthembu (TAC Executive) cc Dr. Manto Tshabalala-Msimang, Minister of Health; Dr. George Flouty, Medical Director, Public Health Programs, Pfizer; Barry Smith, CEO, Pfizer South Africa; Lodewijk J.R. de Vink, CEO, Warner-Lambert; Gordon Knapp CEO, Warner-Lambert South Africa --- PFIZER RESPONSE TO TAC LETTER OF JUNE 20 July 10, 2000 Zackie Achmat and Promise Mthembu HIV & AIDS Treatment Action Campaign PO Box 33014 Braamfontein 2017, Johannesburg South Africa Dear Mr. Achmat and Ms. Mthembu, I am writing in response to your letter of June 20 to Pfizer Chairman and CEO William Steere. As you know, our primary goal is to set up and administer, in close co-operation with the South African government, a program that will bring Diflucan to those in need in South Africa as soon as possible. The tragic proportions of HIV/AIDS require the close co-operation of political leaders, the medical, patient and activist communities and private industry. Let me assure you that, for its part, Pfizer is fully committed to the Diflucan Partnership Program, and that we have communicated openly with the South African government on the key provisions. Specifically, we will: ¨ Provide Diflucan at no charge, through qualified health workers, to HIV/AIDS patients with cryptococcal meningitis who cannot afford treatment. As you know, cryptococcal meningitis is a life-threatening opportunistic infection affecting approximately eight percent of patients infected with HIV and is frequently the AIDS-defining condition. Over 100,000 patients in South Africa stand to benefit from this program through improved quality of life and increased survival. We believe that giving the medicine to patients at no charge is the most effective and immediate way of making a significant positive impact on the lives of these patients. ¨ Ensure that patients are enrolled in the program receive treatment for as long as they need it. We respect the need for sustainability of treatment. ¨ Evaluate the success of the program after two years. Together with the South African government, we want to assess the impact of the program, make whatever modifications may be necessary on behalf of patient welfare, and share our key learnings with the international medical community. Careful planning and evaluation are crucial for a program of this size and complexity, and the success of the program, as measured in real-life human terms of survival and improved quality of life, can only be evaluated over time. Peter Piot also reinforced this in his quote from The Wall Street Journal: "This is the help we've been asking for for years. But if this support … is going to have an impact, it must be done very carefully. This is by no means a simple problem and money and drugs are not going to solve it." – The Wall Street Journal, July 10. But again, let me emphasize that we are committed to the success of the program and we intend to be long-term partners with the South African government. ¨ Explore how to best replicate the program in other countries. We are working with South Africa because there is an existing health infrastructure in place, but we have already initiated contact with the government of Kenya. We believe that additional programs must fit within the normal clinical practice and regulations of the country involved and have the full support of the Minister of Health. This partnership can make a meaningful contribution to relieving the suffering of many thousands of AIDS patients throughout South Africa. Pfizer is committed to working closely with the South African government to make it a success. Yours truly Dr Jack Watters c.c.: Dr Manto Tshabalala-Msimang, Minister of Health Dr Konji Sebati, Pfizer, South Africa --------------------------- Cheap drug could reduce mortality in HIV infected infants by Anso Thom 15-08-2000 (reprinted for fair use from Health-E News, www.health-e.org.za) A cheap prophylaxis drug, trimethoprim-sulphamethoxazole (TMP-SMX) cotrimoxazole, has shown to prevent the unnecessary death of many HIV infected infants who succumb to a deadly strain of pneumonia, according to University of Cape Town (UCT) researchers. Pneumocystis carinii pneumonia (PCP), one of the major causes of hospitalisation and death in HIV-infected patients in developed countries before the introduction of anti-retroviral therapy, is also prevalent in Africa. Cotrimoxazole is part of the Essential Drug List, which means it should be available at all state hospitals. PCP was previously considered rare on this continent, but researchers have since established that a significant number of HIV-infected children are admitted to hospitals with PCP, where they often die. A study by Dr Heather Zar and colleagues of the Department of Paediatrics and Child Health at UCT, found PCP in 10 percent of 151 HIV-infected children hospitalised with pneumonia in Cape Town's Red Cross Children's Hospital. Moreover PCP was the AIDS-defining infection in 20 percent of those diagnosed as HIV positive at the time of hospital admission. "It is important to note that PCP, which is associated with a high mortality, is a preventable infection. One solution would be for those who are seeing these kids in a primary health care setting to test children early for HIV infection so we can identify children with HIV early and start preventative therapy for this pneumonia," Zar said. She said the prophylaxis drug, cotrimoxazole should be administered to HIV- infected newborns from as young as six weeks. A week's worth of cotrimoxazole for use in an infant as a prophylaxis is estimated to cost the state less that R1 per week. But this does not automatically mean health care workers can prescribe the drug for use as a prophylaxis. Provinces are left to formulate their own policies on how drugs should be administered. The national guidelines only indicated that cotrimoxazole could be prescribed as a prophylaxis for adult patients in the event of a previous PCP infection, or when the CD4 count drops below 200 or when there are signs of advanced immune deficiency. No mention is made of infants. PCP is accompanied by coughing, high fever and difficulty in breathing. The infants, who are usually about six months old, have a fifty- percent chance of survival with death occurring within days. Zar said post-mortem studies have found that PCP occurred in 31 percent of HIV- positive children younger than 15 months in Cote d'Ivoire and 16 percent of HIV- infected Zimbabwean children who died at home. Two South African studies of children dying in intensive care units reported that PCP was common in the subset of patients that had postmortem lung biopsies, namely in 7 of 27 cases and 5 of 12 cases in Durban and Johannesburg respectively. "This is a devastating pneumonia for children," said Zar, who recently received an international research award in the United States for her work in diagnosing tuberculosis in children. ------------------ TAC Statement on Cotrimoxazole Deaths from PCP, "a fatal pneumonia" associated with AIDS, are a public scandal and human rights violation because they can be treated for a few rands every month. Dr. Heather Zar's important study on children and PCP at Red Cross Children's Hospital confirms what treatment activists have always said. The gross neglect of children's health by government undermines the claim that it prioritises the lives of children--particularly in poor communities. Apart from preventing suffering in children and adults, it is cheaper to prevent illnesses such as TB and PCP in people with HIV/AIDS than to treat them. Government has promised several major HIV interventions in its 'new plan'--two crucial interventions include voluntary counselling and testing and the treatment of opportunistic infections. But, provincial Health Departments have not shown a serious inclination to treat opportunistic infections despite promises and guidelines. Therefore, they cannot expect people to volunteer for testing without treatment. TAC demands that all provinces provide PCP prophylaxis for children and adults as a matter of urgency. -------------- 17 August 2000 Nature 406, 670 - 672 (2000) © Macmillan Publishers Ltd. (reprinted for fair use) New fronts in an old war DECLAN BUTLER Declan Butler is Nature's European correspondent. There has been no new treatment for tuberculosis for three decades. But there is now the potential for a radical resurgence of drug development, says Declan Butler, if the political and industrial climate stays fair. LIBA TAYLOR/PANOS PICTURES Kill or cure? More than one in three people in the developing world is infected with TB and unless new drugs are found to fight the disease, many will die. Next time you are in a busy street, glance around. If you live in North America or Western Europe, one in ten of those walking past you is probably infected with Mycobacterium tuberculosis — the bacterium that causes TB. And with infection rates in developing countries and Eastern Europe soaring, the global average is close to one in three. Thankfully, the virulence of M. tuberculosis does not match its prevalence: less than a tenth of those infected will develop the full-blown disease. In the rest, the bacterium seems to lie dormant. But the number of cases where this latent TB becomes activated is increasing, mainly because the rise in HIV infection is weakening the immune systems of those also carrying M. tuberculosis. At the same time, many strains of the bacterium are developing resistance to the drugs used to treat the disease. Together, these trends have led the World Health Organization (WHO) to declare a global health emergency (see 'The rise and rise of tuberculosis', opposite). Figure 1 The rise and rise of tuberculosis Full legend High resolution image and legend (57k) "We need new drugs," concludes the draft of a scientific blueprint being prepared by the Global Alliance for TB Drug Development, a consortium of scientists, donor agencies and pharmaceutical companies set up earlier this year to provide a new impetus for the field1. The document will be released in the autumn. Rick O'Brien. The good news is that recent scientific developments, including the sequencing of the M. tuberculosis genome2, mean there is a chance of making significant progress. "This is the most exciting time for TB drug development in over two decades," says Rick O'Brien, chief of research in the Division of TB Elimination at the Centers for Disease Control and Prevention in Atlanta, Georgia, and rapporteur for the alliance's scientific blueprint. "At long last technical advances and increasing interest in the global TB problem are coming together." Traditional treatment TB is usually treated with a cocktail of four drugs — ethambutol, isoniazid, pyrazinamide and rifampicin. These drugs are ineffective against latent TB, but work well when M. tuberculosis is actively dividing. Two months of treatment can reduce infection in sick patients to the point where they can no longer transmit the disease. But in the face of this pharmaceutical assault, the remaining bacteria slow their cell division and enter a persistent state that resembles latent infection. It can take another six months of treatment to kill these remaining bacteria. For this reason, the WHO devised a scheme called DOTS, or Directly Observed Treatment, Short-course. In DOTS, doctors actively diagnose TB cases and subsequently ensure that patients swallow each and every pill — which may also include the broad-spectrum antibiotic streptomycin — over six to eight months. But DOTS requires trained medical staff, infrastructure and money that lie beyond the resources of many developing countries. In practice, a quarter of TB cases are not diagnosed before they become infectious, and many people given the treatment do not stay the course. The Global Alliance for TB Drug Development says its priority is to develop a drug that will speed up elimination of the slow-growing bacteria that initially survive the drug cocktail. Ideally, the alliance wants to reduce the total time needed for treatment to two months or less, says Ariel Pablos-Mendez, associate director for health equity at the Rockefeller Foundation in New York. This would be a revolution in TB control, he adds. Persistent problem Given the similarities between the persistent bacteria and those involved in latent infections, such a drug might also prove effective in eradicating M. tuberculosis from asymptomatic TB-positive people. Many researchers agree that studying slow-growing M. tuberculosis is a top priority. "If you could find a drug that would kill these persistent organisms that would be an enormous step forward," says Denis Mitchison, now retired, but continuing to carry out research at St George's Hospital in London, where he worked on the clinical development of today's TB drugs. Alternatively, it might be possible to force the bacteria to start dividing rapidly again, so that other drugs could do their work. "We could prevent latency, or even stimulate persistent or dormant bacilli to grow and be better able to kill them," says William Bishai of Johns Hopkins University in Baltimore, Maryland. New families of drugs that can target dividing M. tuberculosis are also urgently needed to sidestep growing bacterial resistance to isoniazid and rifampicin. Multiple-drug-resistant TB accounts for around 2% of all cases worldwide, and this figure is increasing. The proportion of cases that are multidrug resistant has reached 14.1% in Estonia, and more than 25% in Russia's prisons. The problem confronting drug developers is that decades of neglect in TB research — partly fostered by the misconception that existing drugs had beaten the disease — have left severe gaps in our knowledge of the biology of M. tuberculosis. "We know singularly little about pathogenesis," says Mitchison. Bright prospects But morale among TB researchers is improving. There is a raft of new scientific opportunities and M. tuberculosis has a host of unique features that, in principle, should make it a relatively easy target for drugs. In addition, there is renewed political and public interest worldwide in funding TB research. For example, at last month's summit in Okinawa, Japan, the G8 economic powers pledged to halve the number of TB deaths and the prevalence of disease by 2010. Much of the impetus for research has come from the availability of the M. tuberculosis genome. Functions have been identified for almost half of the bacterium's genes2, and genomic approaches are now being applied to drug discovery. At the Affymax Research Institute, a biotech company in Santa Clara, California, Mike Wilson is using microarrays of the bacterium's 4,000 known genes to investigate the effects of TB drugs on gene expression3. By adding 'complementary' DNA, which is made from the bacterium's messenger RNA and binds to the corresponding genes on the microarray, he can see which genes are active before and during treatment. SCOTT CAMAZINE/SPL Shadow of death: TB lesion in the lung. Wilson is now working with Clifton Barry's group at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, to speed up screening of candidate drugs by profiling gene expression patterns specific to particular biochemical pathways — starting with the production of M. tuberculosis's characteristic waxy cell wall. "These are complex structures that require many biosynthetic steps, so we might expect to find a variety of potentially useful targets if we could identify the set of genes responsible," says Wilson. Initially, they are concentrating on finding new families of drugs that have similar effects on gene expression to isoniazid, which is known to disrupt cell-wall formation. But latent TB remains a mystery. 'Latent' is a clinical definition, meaning simply that the bacteria are present but there is no active disease. Biologists do not know whether the bacteria are lying dormant or are actively replicating but held in check by the immune system. "I prefer the term 'persistent and chronic TB infection'," says David Russell of Cornell University in Ithaca, New York. "The terms dormancy and latency imbue the bacterium with properties that have not really been demonstrated." Cell in-mates ALFRED PASIEKA/SPL The enemy within: Mycobacterium tuberculosis. One hypothesis is that the bacteria hide inside immune cells known as macrophages. These are large cells that ingest foreign microorganisms and cellular debris in diseased tissues. Unlike other bacteria, M. tuberculosis can survive inside these cells, where it initially grows and divides. Over time, the immune system walls off infected macrophages into structures called granulomas, and the bacteria slow down their division. There they can lie for many years before suddenly resuming their rapid multiplication and bursting out of the granuloma to cause active disease. Inside a granuloma, M. tuberculosis has to adapt to declining levels of oxygen. To investigate this, Lawrence Wayne of the Long Beach Veterans Affairs Medical Center in California has devised an experimental model in which oxygen levels in M. tuberculosis cultures are gradually reduced so that the bacteria survive but do not divide4. Other researchers are studying infected mice which develop a chronic infection similar to latent human TB. But mouse granulomas are different from those seen in humans — they do not form structures that can eventually rupture into a bronchus, allowing virulent bacteria to be coughed out. Guinea pigs5 and rabbits6 provide better models, but it is more difficult to obtain large inbred populations and, unlike mice, these animals can spread the disease to humans. As a result, they can only be studied in expensive isolation facilities. Drugs on target Although all of the models have shortcomings, they have helped to identify many new drug targets for persistent and chronic forms of M. tuberculosis over the past year or so. Among the most exciting is the discovery, announced in this issue of Nature7 by a team led by Russell, that an enzyme called isocitrate lyase seems to be crucial to the survival of M. tuberculosis in granulomas. This enzyme allows the bacteria to get energy and build carbohydrates from fatty acids in the absence of oxygen. Russell and his colleagues, who this month also reported the crystalline structure of isocitrate lyase8, are now working to develop inhibitors of the enzyme. The UK-based drug company Glaxo Wellcome is also taking an interest. "We have already begun to look for inhibitors of the isocitrate lyase enzyme in our library of compounds, using the structure of the protein to guide the search," says Ken Duncan, manager of Glaxo Wellcome's Action TB programme. Another clue to the genes involved in persistent infection came earlier this year from Stanley Falkow's laboratory at Stanford University in California. Falkow and his colleagues studied M. marinum, which causes latent TB in frogs and is the closest relative of M. tuberculosis. They identified gene promoters that were only switched on when the bacteria were encapsulated in frog granulomas. Two of these were from genes in the PE-PGRS family, and when the researchers examined the sequence of the genomic region containing these genes they found a third family member9. PE-PGRS genes code for unusual proteins that are rich in the amino acid glycine but have unknown function. They are unique to the genus Mycobacterium and account for more than 10% of the coding regions of its genome2. Falkow and his colleagues created strains of M. marinum in which each of the three genes was knocked out individually. Two of these knockout strains could not divide in macrophages, and one showed greatly reduced persistence in frog granulomas. The group now intends to knock out all three genes in unison to see whether this will reduce the bacterium's persistence further. The researchers hope that similar genes in M. tuberculosis will play the same role in human TB, and therefore make useful drug targets. "We know that these genes have a role in virulence," says Lalita Ramakrishnan, a member of the team. Hot on the heels of Falkow's paper came the news, from a group led by Kendall Stover at PathoGenesis, a company in Seattle, that molecules called nitroimidazopyrans seem to kill M. tuberculosis, including persistent, slow-dividing bacteria10. This discovery stemmed from observations that related molecules called bicyclic nitroimidazofurans, originally developed to improve the effectiveness of cancer radiotherapy, were active against M. tuberculosis. Those drugs were too mutagenic to use against TB, however. Survival strategies Meanwhile, researchers led by Jean Pieters at the Basel Institute for Immunology in Switzerland have been looking at how M. tuberculosis bacteria living inside macrophages avoid attack by lysosomes — cell structures containing enzymes that break down bacteria and debris ingested by the macrophages. Last year, they discovered that a macrophage protein called tryptophane aspartate-containing coat protein, or TACO, seems to play a key role11. When the bacteria are ingested by a macrophage they end up surrounded by a host-cell membrane, forming a structure called a phagosome. The researchers found that TACO surrounds these phagosomes, preventing transport of the bacteria to the lysosomes. Pieters wanted to discover how to release TACO from the phagosomes. After testing several chemicals, he found that digitonin, a solubilizing agent, completely released the protein12. It occurred to Pieters and his colleague John Gatfield that digitonin also binds to cholesterol. "As we knew TACO was responsible for mycobacterial survival within phagosomes, we reasoned that if we get rid of the cholesterol, TACO cannot be recruited to the phagosome and the mycobacteria will be transferred to lysosomes and killed," says Pieters. When the researchers tested this idea in cultures of macrophages, they found that reducing cholesterol had a second, even more dramatic effect. "To our surprise we found that the bacteria were no longer taken up by the macrophages," says Pieters. "Cholesterol thus has dual roles: getting the bacteria to be taken up, and then conferring protection from lysosomes." It would not be feasible to reduce cholesterol levels as a therapy for persistent TB. But Pieters believes it might be possible to identify cholesterol-binding sites on M. tuberculosis, block them with drugs and so prevent the bacteria entering macrophages. He and his colleagues are now planning to look at mutant bacteria that cannot get into macrophages to work out which genes are involved. TB researchers are optimistic that continued research will generate many more potential drug targets. But the route from a target to a drug is long and expensive, and the big unknown is whether drug companies will invest the multimillions of dollars needed for drug development. Realizing this, the Global Alliance for TB Drug Development is preparing a report on 'pharmaco-economics' alongside its scientific blueprint. This will assess in detail the size of the TB drug market, current investment and gaps in corporate research and development. It plans to use this report as the basis for a business plan for a joint drug-discovery programme between the public and private sectors. The alliance's stated goal is to register one new drug for chronic and persistent TB by 2007, and a second by 2012. With the difference between success and failure being measured in millions of human lives, the stakes could not be much higher. References 1. Butler, D. Nature 403, 692 (2000). 2. Coles, S. T. et al. Nature 393, 537-544 (1998). 3. Wilson, M. et al. Proc. Natl Acad. Sci. USA 96, 12833-12838 (1999). 4. Wayne, L. G. & Haynes, L. G. Infect. Immun. 64, 2062-2069 (1996). 5. O'Grady, F. & Riley, R. L. Adv. Tuberc. Res. 12, 150-190 (1963). 6. Dannenberg, A. M. in Tuberculosis: Pathogenesis, Protection and Control (ed. Bloom, B. R.) 149-156 (American Society for Microbiology, Washington DC, 1994). 7. McKinney, J. D. et al. Nature 406, 735-738 (2000). 8. Sharma, V. et al. Nature Struct. Biol. 7, 663-668 (2000). 9. Ramakrishnan, L., Federspiel, N. A. & Falkow, S. Science 288, 1436-1439 (2000). 10. Stover, C. K. et al. Nature 405, 962-966 (2000). 11. Ferrari, G., Naito, N. H., Langen, J. & Pieters, J. Cell 97, 435-447 (1999). 12. Gatfield, J. & Pieters, J. Science 288, 1647-1651 (2000). 13. Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M. C. J. Am. Med. Assoc. 282, 677-686 (1999). ---------------------------- Business Report on Sunday 19/8/00 (reprinted for fair use) Timber industry hard hit by Aids Margie Inggs August 19 2000 Durban - The HIV infection rate in the labour intensive timber industry was believed to be about 15 percent, compared with 11,5 percent in the general workforce, Stephen Kramer, Metropolitan Life's manager of Aids research, said this week. This could double to 30 percent by 2010, he said. The findings were based on the Metropolitan-Doyle model, which provides reliable estimates of the progression of HIV/Aids in South Africa. In KwaZulu-Natal and the Eastern Cape, where nearly half of the 25 415 strong workforce is concentrated, HIV-positive figures are believed to be 16,3 percent and 14,7 percent respectively. "On a national level, at least 490 forestry workers, or 2 percent of the workforce, have probably already died of Aids-related conditions. We estimate that this will soar to 5 600, or 22 percent of the workforce, by 2010. "This means that, within the next 10 years, 20 percent of current workers will have to be replaced to maintain the workforce at current levels," Kramer said. He said, however, that the figures were lower than expected, owing largely to the age profile of workers. "Mainly in their late thirties and early forties, the workers fall outside the most vulnerable 20 to 30 bracket. The other factor in the industry's favour is its high proportion of male workers." Jaap Steenkamp, general manager of Forestry Services & Facilitators, said emerging forestry contractors and small furniture manufacturers were expected to have their hands full trying to cope with the effects of the pandemic on their workforce. "While the impact of HIV/Aids on the timber industry has not yet been formally quantified, contractors have admitted that they are beginning to feel the effects," he said. "Our greatest concern is the impact on skilled forestry personnel, which is expected to increase significantly in the short term. "Training is already labouring under financial constraints, but the means will have to be found to intensify training programmes and establish realistic strategies," Steenkamp said. He predicted the semi-skilled workforce, representing about 80 percent of forestry workers, would also be severely affected, because this level probably had the highest exposure to HIV/Aids. "We expect the epidemic to exacerbate labour shortages and increase costs," he said. Steenkamp said the industry was well aware of the problem and had staffed its clinics with suitably qualified people. "Aids councillors are also contracted from non-governmental organisations like Sanca. Awareness campaigns focusing on the use of posters, other literature and the availability of free condoms are part of daily life and all personnel are exposed to it. "There is, however, an urgent need for more accurate information to address the problem effectively. A research study will be undertaken within the next two years to quantify the problem and develop specific strategies to enable contracting businesses and corporate growers to deal with it in an holistic, appropriate and focused way," Steenkamp said. Numerous initiatives have been launched by the government and business, the latest boost for prevention being the R500 million earmarked in the national budget to finance an integrated response to the pandemic. A further incentive is the relief from tax on donations to Aids organisations. "However, employers will probably have to continue shouldering at least part of the responsibility for prevention programmes," Steenkamp said.