New insights into an old foe: TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

WHITE PLAGUE. KING’S EVIL. WASTING disease. Phthisis. Consumption. Tuberculosis (TB) is an old disease with many names and guises. But it wasn’t until last year that scientists discovered how old this ancient scourge really is. Egyptian mummies, skeletal remains, and genetic analysis had all suggested that TB had been around for at least a few thousand years. But in a block of rock mined from a quarry in Western Turkey, anthropologists discovered the fossil of a young male dating back some 500,000 years and infected, unexpectedly, with tuberculosis. They announced in December 2007 that the young man had lesions on the inside of his skull, the imprint of brain membranes that the disease has been ravaging humans for much longer than anyone had ever suspected.

An estimated 2 billion people — nearly one-third of the world’s population — are thought to harbor Mycobacterium tuberculosis (M. tb), the bacterium that causes TB. It grows slowly, lurking in the lungs for years, and outwits the body’s immune system, in part by waiting for the host’s defenses to weaken. In most people, that opportunity never arises, and they show no symptoms of the disease. But once M. tb takes hold, it literally consumes the body from within, eating through lung tissues and the blood vessels that run through it. Every time someone with a full-blown infection speaks, sings, coughs, or sneezes, the bacteria expelled linger in the air for hours, ready to invade the next victim.

This is why TB has so often been a disease of the poor, because it is at its most deadly in overcrowded, unsanitary conditions. In 2006, TB infected 9.2 million people worldwide, claiming the lives of 1.5 million people, most in the developing world. In some parts of South Africa, as many as 70 percent of those with TB are also infected with HIV, because TB is opportunistic.

Worst case: HIV + TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

When HIV joins forces with TB, the results can be horrific. The neck bulges with lumps as big as an orange, filled with pus-like fluid teeming with the germs that cause TB. Occasionally, these bacteria travel through the blood and lymph vessels, forming lesions in the liver, spleen, and beyond. In chest X-rays, it looks as if the lung were studded with small nodules the size of millet seeds.

This gruesome scenario is rarely seen when TB is the sole affliction. But as HIV ravages the immune system, TB quickly and effortlessly spreads through the body. HIV’s compounding effect on TB has long been known, but recently scientists have discovered that this pernicious partnership works both ways. TB, in turn, eases the path of HIV, dismantling the system that keeps the virus under control in the lungs, allowing it to mutate and multiply.

“If you have HIV and TB, then TB 
will kill you much more rapidly,” notes Michael Weiden, M.D., associate professor of medicine and environmental medicine. In fact, TB is the leading cause of death among people who are HIV-positive, accounting for one-third of AIDS deaths worldwide.

Hope grows for new TB test

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

To confirm that you have TB, the doctor will ask you to cough up at least a teaspoonful of phlegm, or sputum. You’ll have to come back to the hospital twice more to provide samples, and technicians will painstakingly culture the slow-growing bacteria from the sputum.
 A few weeks after that third visit — by which point you may have exposed others — the doctor should be able to tell you whether you have TB.

This crude sputum diagnostic test is 100 years old. “The situation is fairly horrendous,” says Dr. Suman Laal, Ph.D., associate professor of pathology and mircrobiology.

There are a
few expensive alternatives: fluorescent microscopy, automated culture systems, and tests for the bacterial DNA. But 90 percent of the disease is concentrated in the poorest parts of the world, where these options are not feasible.

Clinically, TB symptoms can be difficult to distinguish from those of
 other bacterial or fungal infections, pneumonia, or certain tumors. Diagnosis with X-rays is subjective and all but useless 
in people who are HIV-positive, and
 a commonly used skin test gives false positives in anyone who has been immunized with the BCG vaccine or 
has been infected with the TB bug’s bacterial cousins.

The ideal test for TB would be fast, cheap, and would deliver a simple Yes or No answer — much like a dipstick pregnancy test. But developing a test like that has proved challenging.

Held to ransom

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(This Opinion column ran on Nature’s news site on March 26, 2007. You can download a pdf of the original post.)

A pharma giant’s decision to withhold new drugs from Thailand will only hurt patients, says Apoorva Mandavilli.

Is there ever a good enough reason to deny life-saving medicines to an entire country’s citizens? I say no. But it seems pharmaceutical giant Abbott begs to differ.

The Chicago-based company decided on 14 March not to introduce in Thailand any of its seven new drugs — including an antibiotic, an important AIDS drug called Kaletra and medicines to treat blood clots, kidney disease and high blood pressure. Without this crucial registration, the drugs cannot be imported to or sold in that country.

It seems to me that Abbott is, in effect, holding millions of Thais’ lives hostage to force their government to respect its patents. This is good business?

The price of drugs varies from place to place.

The price of drugs varies from place to place.

What’s shocking to me is that the company is making no bones about the fact that its decision is retaliation against Thailand’s decision in January to issue ‘compulsary licenses’ allowing some locals to import or make cheap copies of Abbott’s new version of Kaletra. “This matter is about intellectual property and the integrity of the patent system,” Abbott spokeswoman Melissa Brotz said in a statement.

Lofty words, but I’m reminded more of a schoolyard fight.

Petition aims to maintain cheap drugs

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(This article appeared on Nature’s news site on January 15, 2007.)

Court case in India threatens to derail generic medicines.

Free for all? Patent laws can make or break generic drug production.

The international humanitarian group Doctors Without Borders (Médecins Sans Frontières, or MSF) is ramping up their fight against the Swiss drug giant Novartis, urging the company to drop a lawsuit that could make it much more difficult for Indian companies to produce cheap, generic drugs.

With the case expected to come up for hearing on 29 January, MSF is pumping up efforts to collect signatures on a petition against the suit. Already they have tens of thousands of names, but are aiming to get many more. A win for the pharmaceutical company, they say, would deprive the world’s poorest people of affordable medicines.

Indian companies are known for making low-cost copies of expensive medicines, particularly AIDS drugs. More than half of the antiretroviral drugs used in developing countries, and about 80% of those provided by MSF, are made by Indian companies. “India is the pharmacy for the developing world,” says Ellen ‘t Hoen, director of policy advocacy for MSF’s Campaign for Access to Essential Medicines. “We largely depend on India.”

Business: Reinventing an industry

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(I reported this article when I was in India in 2006. Typically, I did not manage to get an interview with Kiran Mazumdar-Shaw till my uncle pulled some strings. Nature has less power in India than nepotism. Also, I’m proud of the fact that, along with an article I wrote about a famous Indian advocacy group, I managed to get photos of two Bollywood stars into Nature. You can download a pdf of this article.)

Two years after a radical change that brought India’s patent laws into line with international trading rules, the country’s drug makers are taking a new direction.

Star turn: Actor Shah Rukh Khan (left) helps Biocon’s Kiran Mazumdar-Shaw launch BIOMAb-EGFR.

Kiran Mazumdar-Shaw is India’s uncrowned queen of biotechnology. She started her company, Biocon, in a garage in 1978 with just Rs10,000 (US$225) in working capital and has built it into the country’s largest biotech company, with 1,800 employees and revenues last year of $180 million.

Said to be the richest woman in India, Mazumdar-Shaw was in the spotlight last September when her Bangalore-based company launched the first new drug to be developed, tested and taken through approval by an Indian company. The drug, BIOMAb-EGFR, is a monoclonal antibody for treating head and neck cancers.

This could be the harbinger of a brighter and more innovative future for India’s drug industry, which until recently relied on sup- plying cheap ‘generic’ copies of drugs — many of which were still under patent elsewhere.

That all changed in January 2005, when India brought itself into compliance with the Trade-Related Aspects of Intellectual Property Rights (TRIPS) — international rules that forbid the copying of patented drugs.

The transition has gone smoothly. “Companies are playing by the rules,” says Frederick Abbott, a professor of international law at Florida State University who knows the Indian drug industry well.

Make anything, anywhere

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(I wrote this article for Nature in August 2006. I spent a day at the FabLab outside Johannesburg, South Africa, amazed in particular at the unusual projects that housewives dreamed up. I was also convinced I would never make it out of Johannesburg alive, but that’s a story for another day. You can download a pdf of this article.)

Can everyone use technology creatively? Engineers at the Massachusetts Institute of Technology think so and have launched ‘Fab Labs’ around the world to prove it.

Valentina Kwofie, electronics pioneer

Neil Gershenfeld has been teaching a class called “How to make (almost) anything” to some of the brightest young adults in the United States for years. But it took an eight-year-old girl in a small village in Ghana to show that anyone, any- where, really can make just about anything.

One evening in June 2004 — the day after Gershenfeld had left Ghana having taught a week-long version of his class in the village — little Valentina Kwofie began cobbling together a circuit board.

Hours passed. Several times Kwofie’s par- ents stopped by the lab Gershenfeld had set up, imploring, “Valentina, let’s go home, let’s have dinner, let’s go to bed.” It was the first time any- one in the village, Takoradi, had made a circuit board: people crowded around, watching her nimble fingers manoeuvre parts half the size of a grain of rice. Finally, long past her bedtime, she crafted a board that worked.

Gershenfeld, director of the Center for Bits and Atoms at the Massachusetts Institute of Technology (MIT), hadn’t known what to expect when he put the fabrication laboratory, or ‘Fab Lab’, technology that he worked with at MIT into the context of rural Africa. What he got was inspiration. “This eight-year-old girl in Ghana was making microcontroller circuit boards for the love of it, for the joy of discovery,” he recalls. “That ordinary people can do it and want to do it was very surprising.”

The Fab Lab in which Kwofie made her circuit has been followed by others around the world, each equipped with the same key machines. Today, there are ten Fab Labs — above the Arctic Circle in Norway, in Costa Rica, India and South Africa — and within the next year, fifteen others are planned, of which five will be in Africa.

Together, these labs are showing that giving people the ability to make things for themselves can be the fastest way to solve their problems, particularly in communities with little access to education or technology.

DDT returns

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I wrote this article for Nature Medicine in July 2006. This was a big scoop. The news flew mostly under the radar, with the big announcement due that September. But I had heard rumblings of it at conferences, and was able to get fantastic access to (and quotes from) Arata Kochi, then head of the WHO’s malaria program. You can download a pdf of this article.)

The most infamous pesticide in history is also the most effective weapon against malaria. Ready or not, DDT is on its way back to Africa. Apoorva Mandavilli reports.

It’s possibly the most reviled chemical on the planet. Every adult anywhere in the world could list its supposed evils. And it’s been the subject of a long and bitter battle that defies traditional divisions of liberal and conservative.

But here it is, poised for a comeback.

After decades of being marginalized as a dangerous pesticide, DDT—short for dichloro-diphenyl-trichloro ethane—is set to be reintroduced into countries that have tried, and failed, to win the fight against malaria.

Big impact: Small amounts of DDT sprayed on walls can help control malaria.
Afp photo Alexander Joe
Natalia Soto / LN

On 2 May, the United States Agency for International Development (USAID), arguably the most powerful donor agency in the world, endorsed the indoor spraying of DDT for malaria control. The World Health Organization (WHO) is set to follow. In its new guidelines, a final version of which is expected to be released later this summer, the WHO is unequivocal in its recommendation of DDT for indoor residual spraying.

For the many African countries riddled with malaria, this is welcome news. “We in southern Africa feel extremely happy,” says John Govere, integrated vector control officer for the WHO’s Southern Africa Malaria Control Programme.

Malaria kills as many as 1 million people each year, about 90% of them in Africa. Someone dies of malaria every 30 seconds—and most of those are pregnant women and children under the age of five. Even the millions who survive can be reinfected, leaving them bedridden and decimating economies.

Little surprise then, that just days after USAID’s announcement, Tanzania said that it would lift its DDT ban. Others soon followed.

For these impoverished countries, the choice may seem clear: DDT is cheap and lasts longer than other pesticides, so it has to be sprayed less often. Most pesticides work by killing mosquitoes on contact, but DDT also repels them.

“DDT is the most effective chemical, the most effective insecticide in terms of malaria,” says Arata Kochi, director of the WHO’s Global Malaria Programme.

Silent spring
If DDT is that effective, why has it been so vilified? “You’ve heard of Rachel Carson? Well that’s your answer,” says Maureen Coetzee, chief of vector control research at South Africa’s National Institute for Communicable Diseases. “DDT was so abused in the ’50s and ’60s that it is still suffering from that abuse.”

In the 1940s, DDT was considered a miracle chemical. Airplanes sprayed thousands of tons of the pesticide, coating acres of crops, villages and cities with abandon.

By 1949, the US was malaria free. Between 1955 and 1969, the Global Malaria Eradication Campaign also relied heavily on DDT. In Europe, India, South America, Africa, wherever it was used widely, DDT cut malaria rates dramatically and saved millions of lives.

Then came Carson’s Silent Spring— credited with launching the environmental movement—which famously described DDT’s horrific effects on the food chain, and the stark silence left behind by dying birds. The book was so effective that to this day, any mention of DDT instantly evokes images of bald eagles and thinning eggshells.

DDT soon became a symbol of Western governments’ rash embrace of science. In the US and in Europe, environmental groups waged a successful campaign against the pesticide. Based largely on its effect on the environment—and on public opinion—the US Environmental Protection Agency in 1972 banned DDT. Norway and Sweden had begun the trend in 1970, and the UK signed on in 1986.

Environmental groups that still oppose DDT see its use in developing countries as a double standard. On the other hand, note champions of DDT, most of those groups are based in countries where malaria is only a distant memory.

“I think the whole push of the environmentalists like Rachel Carson and many others to eliminate all uses of DDT are, quite honestly, responsible for millions and millions and millions of human deaths,” says Don Roberts, professor of tropical public health at the Uniformed Services University of the Health Sciences in Maryland.

Money talks
In theory, any country is free to use DDT. The Stockholm Convention of 2001 sought a global ban on DDT, but many countries and scientists argued against the ban, citing its value in malaria control. The final treaty made an exemption for DDT’s use in public health, but called for countries to gradually phase out the pesticide.

Still, in places where malaria was still endemic, the treaty spelled disaster.

Most African nations are heavily dependent on foreign aid and can ill afford to cross a line drawn by donor agencies.

USAID never banned DDT outright, for instance, but nor did it fund DDT’s purchase—which amounts to the same thing. For that reason, the May announcement is widely seen as a change in policy even though the agency doesn’t position it as such.

The World Bank went one step further, making the ban of DDT a condition for loans. The WHO supported the use of bednets dipped in insecticide over indoor spraying, even though malaria rates continued to increase. DDT was “further ignored and intentionally or unintentionally suppressed,” by these agencies, says Kochi.

“People are very emotional about DDT, even within the WHO,” Kochi says, adding that much of the reaction to DDT was a response to political pressure. Since his arrival at the agency in late 2005, he has pushed for the return of indoor spraying not just to Africa, but wherever malaria continues to be a problem.

The WHO plans to field test its new guidelines for indoor residual spraying in Yemen, Sudan and two countries in south eastern Asia. “Quite often in this field, politics comes first and science second,” Kochi says. “We must take a position based on the science and the data.”

Disputed dangers

Watch out: In the 1940s, DDT was sprayed aerially for agriculture.
Associated Press

The WHO recommends 12 insecticides including DDT—which is an organochlorine—six pyrethroids, three organophosphates and two carbamates. In terms of toxicity to humans, DDT is considered safer than many of the others.

Because only small quantities are sprayed on the walls for malaria control, “unless you go and lick the wall, you’re not likely to ingest the insecticide,” notes Coetzee.

Over the years, however, based primarily on data from agricultural use, DDT has been linked to various illnesses—but those studies are rarely convincing and never consistent.

DDT was thought to cause liver and breast cancer and disrupt hormonal balance, for example, but the claims have since been debunked (Lancet356, 267–268; 2000; Nat. Med. 6, 729–731; 2000). Studies have found that in areas where DDT is sprayed for malaria control, mothers show traces of DDT in their blood and breast milk (Bull. World Health Organ. 68, 761–768; 1990). Some scientists say those levels might trigger premature births and a shorter time for breast-feeding (Lancet 366, 763–773; 2005), but the results are much disputed.

Most recently, researchers in California reported in July that babies of mothers exposed to DDT fare worse on mental tests and motor skills tests (Pediatrics 118, 233–241). But critics note that the study followed only 360 women and that because the mothers were born in Mexico—where DDT was used for agriculture till 1995—the researchers cannot link the exposure to malaria control.

But even critics of DDT agree that in countries ravaged by malaria, the benefits far outweigh the risks. “I’d rather have a child with three IQ points less than have a dead child,” says Brenda Eskenazi, lead researcher of the Mexico study.

Although DDT might be a short-term solution for malaria control, however, more research is needed before it can be regarded as entirely safe, Eskenazi and others caution.

For instance, when assessing DDT’s effect on malaria, global agencies should measure rates of total infant mortality, and not just malaria-related deaths, says Walter Rogan, an epidemiologist at the US National Institute on Environmental Health Sciences. That would help catch any adverse affects DDT may have on infant health, he says.

“I think that DDT is not entirely a benign compound,” Rogan says. “If you’re going to use it, you should consider the idea that it might do harm.”

Within walls
DDT’s use in malaria is far different from its application in agriculture. In contrast to indiscriminate aerial spraying several times a year, individuals spray a small amount—about two grams per square meter, a fraction of that used in agriculture—on the inside walls and eaves of houses, where mosquitoes rest.

Because DDT is not sprayed outdoors, there is little chance of it getting into the environment, notes Simon Kunene, chair of the malaria subcommittee for the Southern African Development Community (SADC).

But with thousands of tons of the cheap pesticide available, some of it will inevitably be diverted for agricultural use, experts warn.

“What concerns me a lot is that it’s going to be misused and end up in the environment,” says Mark Rowland, a malaria control expert at the London School of Hygiene and Tropical Medicine.

The WHO is considering a method that South Africa has developed over the years. Precise amounts of DDT are shipped from a central location to the area where they are needed, minimizing middlemen en route, and once spraying is complete, the containers are returned for checking.

But South Africa, with its relatively well-developed infrastructure, may be an exception, argues Rowland. From 1991 to 1998, Rowland led a malaria control program for Afghan refugees in Pakistan. That program employed a similar method, using packets of DDT that were closely supervised. Still, some packets were misused, Rowland says. “It’s very difficult to monitor every kilogram that gets distributed.”

Fine print
The best long-term prospect may be to develop safe and effective alternatives, several of which are being developed by public-private partnerships.

Meanwhile, the use of DDT, and of indoor spraying generally, is expected to rise sharply.

“People are now beginning to appreciate how effective indoor residual spraying can be,” says Richard Greene, director of the Office of Health, Infectious Disease and Nutrition in USAID’s Bureau for Global Health.

Unless done well, however, using DDT may be dangerous—and powerless against malaria.

For spraying to be effective, at least 80% of the affected area must be covered. Global agencies must first map the distribution and behavior of different kinds of mosquitoes and, most important, patterns of resistance to insecticides. “The last thing you want to do is select for resistance,” says Coetzee.

Convincing the local community to let people into their homes and spray their walls is another formidable challenge. At the height of the epidemic, people are generally terrified enough to do whatever it takes. But once the mosquitoes—and, as a bonus, the cockroaches—disappear, so does people’s tolerance.

Because DDT lasts longer than other pesticides—up to a year compared to six months with pyrethroids—it needs to be sprayed less often, making its use less challenging for governments.

“What can I say? It has worked for us,” says Kunene. “They’ll see the results. Give me one year or two years. There’ll be a big difference.”

Published online: 27 July 2006.

The coming epidemic

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(Reporting on this article was one of the most emotional experiences of my career. I met many, many sex workers, drug addicts, activists, truck drivers and housewives who had never heard the word AIDS before they were told they were dying from it. As someone born and raised in India, I found the many individual stories heartbreaking, and the denial of the officials deeply sad and scary. This article appeared in Nature in July 2005 as part of a special package on Indian science called Nature Outlook: India. A couple of years after the article appeared, the Indian government revised its numbers drastically downward. I’m deeply skeptical of its estimates, but haven’t yet been able to dig into the truth. You can download a pdf of this article.)

A staggering 5.1 million people are estimated to be HIV positive in India. Apoorva Mandavilli finds a country on the brink of a crisis.

Our son was born in June 1998. He was healthy but after eight months, he had diarrhoea and fever all the time. He was in the hospital many times. The sixth time, they diagnosed him with AIDS. That was when we found out that my wife and I have HIV. Our son died 12 July 2002. I also started to get sick. I didn’t take my medicines regularly; they didn’t tell me not to do that. Now my health has become worse. I haven’t worked in six months.We’ll be paupers. I don’t know what we’re going to do.

— Suresh, air-conditioning technician

Suresh is sitting in a small, dark room at an AIDS clinic in the southern Indian city of Chennai. This city is where the first cases of HIV in India were discovered in 1986 after a police sweep of sex workers. Nearly 20 years later, there are an estimated 5.1 million cases in India, a number second only to that in South Africa. The difference is that in India the epidemic has not yet peaked. According to the CIA, the number of cases in India could top 20 million by 2010.

AIDS care ignores children

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(This article was published on Nature’s news site on 13 July, 2004. I reported this from the XV International AIDS Conference in Bangkok.)

Companies fail to design drugs for kids.

Around 700,000 children were infected with HIV in
2003.

Bangkok – The global fight against AIDS is not addressing children, the very group that is hit hardest by the pandemic, says the medical charity Médecins Sans Frontières (MSF).

In recent years, there has been considerable progress in developing diagnostic tests and anti-AIDS drugs for adults. But doctors lack the simple tools needed to diagnose and treat children infected with the virus.

“Children are a discriminated minority, they are a marginalized community,” David Wilson, medical coordinator of MSF in Thailand told the XV International AIDS Conference in Bangkok.

In 2003, an estimated 700,000 children under the age of 15 were newly infected with HIV. Most of these live in sub-Saharan Africa.