BERLIN – This
has been a good decade in the fight against tuberculosis. We are likely to
achieve the United Nations Millennium Development Goal of cutting TB prevalence
and mortality in half by 2015, from 1990 levels. At least a dozen new vaccines
and drug candidates are in clinical trials, and the World Health Organization has
endorsed a new diagnostic test called the GeneXpert.
This progress is all the more important given the complacency that led to a
complete standstill in research and development for new TB interventions toward
the end of the twentieth century. The TB drugs currently in use were developed
between 1950 and 1970. Indeed, the Bacille Calmette–Guérin (BCG) vaccine is
almost 100 years old, while the most widely used diagnostic test, microscopic
detection of bacilli in sputum, was developed 130 years ago.No wonder that the efficacy of these tools has weakened. The current vaccine prevents severe TB in infants, but not the most prevalent pulmonary TB in all age groups. The microscopic test gives false results in nearly half of all cases.
We like to think of TB as a malady of the past. In fact, nine million people develop the active disease every year, and one in five will die. This places the tubercle bacillus second only to human immunodeficiency virus (HIV) on the list of top microbial killers.
One-third of the world’s population is infected with the causative agent, though only one in ten develops the active disease. The bad news is that infected individuals carry the agent with them for their entire lives. When one’s immune system weakens, the disease may erupt. With the emergence in the 1980’s of HIV, which compromises the immune system, TB reemerged, and is the number-one killer of HIV-infected individuals. Roughly 15 million people suffer from co-infection of HIV and Mycobacterium tuberculosis, the primary causative agent in most TB cases.
Moreover, the tubercle bacillus engages in trench warfare, gaining resistance to conventional antibiotics and canonical vaccination approaches, as well as delaying diagnosis and determination of drug sensitivity. Whereas pandemics appear suddenly, spread rapidly, and raise enormous fears of an impending threat, TB has been spreading slowly but consistently for tens of thousands of years, patiently waiting for new opportunities.
Treatment of TB requires a minimum of three drugs administered over at least six months. Compare this with antibiotic treatment of, say, a urogenital infection, which lasts a few weeks at most. As a result, compliance with TB drug treatment is particularly weak, paving the way for the emergence of multidrug-resistant (MDR) TB, which can no longer be treated by conventional therapeutic regimes. Some 50 million people are infected with tubercle bacilli that are MDR.
While treating MDR-TB remains possible, doing so is arduous, with a treatment time of roughly two years, using drugs that are neither as efficient nor as benign as canonical drugs – and at a cost that rises by a factor of 10-100. While this additional cost can be borne by health-care systems in the rich world, it is excessive for poor countries, implying no, or insufficient, treatment.
Moreover, in 85 countries, extensively drug-resistant (XDR) TB, which is virtually untreatable, has been diagnosed. Indeed, surgical resection of affected lungs has become the treatment of choice in many XDR-TB hotspots. Welcome back to the pre-antibiotic era!
So, the question is not whether we need novel drugs, vaccines, and diagnostics, but when they will become available. The new GeneXpert test diagnoses not only TB, but also, in the same step, MDR-TB, which means that it can rapidly direct adequate treatment and prevent infection of contacts – a true breakthrough. Unfortunately, the test is expensive and sophisticated, putting it out of reach for many poor countries.
A number of other drugs – some new and some repurposed – are currently in the last stage of clinical trials, and one new drug has been approved by US regulators for treatment of MDR-TB even before such trials have been completed. But the first potential vaccine to be tested for efficacy recently failed miserably. So, the good news of the last decade is just a glimmer of hope.
We still have a long way to go, and accelerated R&D to develop new drugs and vaccines can be achieved only with increased funding. Unfortunately, private-sector incentives for developing new TB interventions are too weak. New approaches, such as partnerships between public research institutions and private industry, are needed. While clinical trials of the most promising drugs and vaccines need to be pursued, we also need to go back to the drawing board and develop entirely new tactics.
Current annual funding for R&D devoted to TB is estimated to be $500 million. But more than $2 billion is needed annually. That amount may seem unrealistically high, but it is a negligible proportion of the estimated $160 billion spent on health-related R&D worldwide. More important, the economic burden of TB has been put as high as $20 billion annually – and even higher if the losses in human capital are included.
If we choose to continue suffering these losses, we might save some money in the short term. The wiser course, however, is to make the necessary investments today, thereby averting a much larger bill tomorrow.
Stefan H.E. Kaufmann is Professor of Immunology and Microbiology at the Charité University Clinics in Berlin and Founding Director of the Max Planck Institute of Infection Biology.
肺結核前線
柏林—這個十年是肺結核鬥爭大有進展的十年。我們也許可以達到2015年將肺結核感染率和死亡率在1990年水平的基礎上下降一半的聯合國千年發展目標。至少十幾種新疫苗和藥物候選已進入臨床試驗，世界衛生組織也支持一項被稱為GeneXpert的新診斷測試。
考慮到在20世紀末，自滿曾讓肺結核新干預療法的研發陷入完全停頓，這一進步尤其重要。目前使用的肺結核藥物是1950—1970年間開發出來的。事實上，Bacille Calmette–Guérin（BCG）疫苗問世已近百年，而使用最廣的診斷測試——用顯微鏡檢測痰中的細菌數量——更是擁有130年的歷史了。
毫不奇怪，這些工具的效力已有所減弱。目前的疫苗可以防止嬰兒患上嚴重肺結核，但對於所有年齡群體最常見的肺結核並無作用。顯微鏡觀測的出錯率也有近一半。
我們喜歡將肺結核視為過去的頑症。事實上，每年都有九百萬人發病，致死率高達五分之一。這意味著結核杆菌是僅次於艾滋病毒的第二號微生物殺手。
全世界三分之一的人都帶有肺結核病原體，但隻有十分之一會發病。壞消息是，病原體攜帶者會終生攜帶病原體。當他的免疫系統變弱時，肺結核就會爆發。隨著20世紀80年代出現了艾滋病毒（它會削弱免疫系統），肺結核也重回人間，並成為艾滋病毒攜帶者第一大致命病因。大約1500萬人同時感染艾滋病毒和結核分枝杆菌（肺結核的最常見病原體）。
此外，結核杆菌擅長陣地戰，對常規抗生素和接種方式具有抗藥性，對藥物敏感性的診斷和確認也具有拖延作用。通常流行病總是突然出現，快速傳播並造成大規模恐慌，而肺結核傳播緩慢，但會維持幾萬年，耐心地等待新機會。
治療肺結核至少需要三種藥物，服用至少六個月。與用抗生素治療（比如）泌尿系統感染相比，後者最多隻需幾周便可治愈。結果，肺結核藥物治療完成率極低，這為多重耐藥性（MDR）肺結核的出現創造了條件。MDR肺結核已不再能夠用常規治療方案治愈。大約5000萬人攜帶者MDR結核杆菌。
治療MDR肺結核仍是可能的，但費時費力，大約需持續兩年，使用的藥物也比常規藥物藥力更低、副作用更猛，所花費用也要高出十倍。儘管這一成本在發達國家可以納入醫保，但窮國就無力承擔了，這意味著這類肺結核得不到（有效）治療。
此外，有85個國家診斷出了超級耐藥性（XDR）肺結核（幾乎不可治愈）。事實上，手術切除受影響肺部已成為許多XDR肺結核高發地區的治療手段。歡迎回到前抗生素時代！
因此，問題不在於我們是否需要新藥、新疫苗和新診斷法，而是它們什麼時候能成為現實。新的GeneXpert測試不僅能診斷肺結核，還能同時診斷MDR肺結核，這意味著它能迅速引導充分治療並防止接觸感染——名副其實的突破。不幸的是，這一測試十分昂貴和複雜，不是一般窮國負擔得起的。
其他許多藥物——有些是新藥，有些是改良藥——已進入臨床試驗的最後階段，其中一種新藥已被美國監管者批准用於MDR肺結核治療，雖然其臨床試驗尚未完成。但第一種進入效力測試的潛在疫苗最終以慘敗收場。因此，過去十年的好消息也僅僅是一絲希望的曙光。
前路仍然漫長，加速新藥品和疫苗的研發離不開增加資金支持。不幸的是，開發新肺結核干預方法的私人部門激勵太弱了。必須依靠新的新方法，如公共研究機構和私人企業的合作。我們需要對大部分潛在高效藥品和疫苗進行臨床測試，也需要重新規劃藍圖，構想新的策略。
目前，每年用於肺結核研發的資金大約在5億美元。但年資金需求量高達20億美元。這個數字或許看起來高得不切實際，但和全球1600億美元的醫療相關研發資金相比並不多。更重要的是，肺結核帶來的經濟負擔高達每年200億美元——如果將人力資本損失也包括在內還會更高。
如果我們選擇繼續承受這些損失，那麼不如省點短期資金。但是，更明智的做法是在今天投入必要的投資，從而避免明天更大的損失。