When infection won’t quit
TB, AIDS, and malaria are finding new ways to resist treatment
Recent headlines paint an insidious trend in infectious disease. In San Francisco, 60 percent of new HIV infections are drug resistant. In Europe and the U.S., a deadly new form of tuberculosis — dubbed extremely drug resistant, or XXDR-TB — defies nearly all available antibiotics. And in parts of Asia, the newest treatment for malaria has lost its potency, portending a spike in malaria deaths worldwide.
Rising drug resistance has turned what public health officials call today’s Big Three infections — HIV/AIDS, tuberculosis, and malaria — even more fearsome. Together, these diseases kill millions every year, representing 10 percent of all deaths globally. Worse, the trio of epidemics is tragically interconnected, with TB, for example, the leading cause of death among individuals infected with HIV.
THE PRICE OF SUCCESS
“Drug resistance is the product of success: With treatment, we have drug resistance,” explains Eric Rubin, professor of immunology and infectious diseases at HSPH. So far, says Rubin, new drugs have helped doctors stave off the threat. A continuous stream of treatments for HIV has extended patients’ lives. More drugs for TB have entered the pharmaceutical pipeline than for any other bacterial infection. And novel anti-malarial compounds will soon enter clinical trials. “I’m optimistic about the ability to innovate. I think it will continue,” says Rubin. “But when poverty and poor access to health care occur together, resistance becomes a much bigger problem. Until brand-new drugs are widely available, a lot of people are going to die.”
HOW RESISTANCE EMERGES
Since the dawn of the antibiotic age, beginning with penicillin in the early 1940s, microorganisms have invariably figured out ways to defy or elude the newest addition to the medical armamentarium. And while the causes of resistance play out differently in HIV/AIDS (a virus), TB (a bacterium), and malaria (a parasite), the basic story line is the same.
Drug resistance occurs when infectious agents change in some way that reduces or eliminates the effectiveness of drugs or chemicals designed to cure or prevent infections. Sensitive organisms are killed, while resistant germs are left to grow and multiply. The more we use antimicrobials, the more resistance to these drugs emerges.
At HSPH, several of the world’s top researchers on drug resistance are grappling with the issue in today’s Big Three epidemics — leading a counter-resistance to one of public health’s most urgent problems.
Tuberculosis kills more adults worldwide than any other infection, claiming about 2 million lives annually, a figure that includes more than 450,000 people also infected with HIV. Each year also sees 10 million new cases of the infection.
In the public health lexicon, tuberculosis has acquired an alphabet of names denoting treatment failure. First, in the late 1980s, came multidrug-resistant tuberculosis — MDR-TB: resistant to the standard six-month treatment using first-line drugs (isoniazid and rifampicin). MDR-TB can take two years to treat with drugs that are more toxic and 100 times more expensive than first-choice drugs. More than 5 percent of cases worldwide are MDR-TB, with the highest rates (in some cases, more than 20 percent of cases) in countries of the former Soviet Union and China.
In 2006, after drugs to treat MDR-TB were mismanaged, extensively drug-resistant tuberculosis (XDR-TB) emerged. XDR-TB resists all the most effective drugs — that is, first-line antibiotics, plus any fluoroquinolone and any of the second-line anti-TB injectable drugs. It is especially common among drug-resistant cases in the former Soviet Union, where a weakened public health infrastructure meant that TB patients were no longer carefully treated and monitored. A World Health Organization survey published in 2008 found MDR-TB in 72 countries and XDR in 49, including the U.S.
A disease of poverty, TB no longer responds to established treatments — which themselves sicken patients.
First, new classes of medications that are better tolerated and that work over shorter periods. Just as urgently needed are new tools for rapid and accurate diagnosis of drug-resistant TB — tests that can be easily used by health workers, even in remote settings.
Today, the situation is grimmer — with cases of extremely drug-resistant tuberculosis, XXDR-TB, resistant to all first- and second-line anti-TB drugs. Though researchers have published just a handful of reports on the disease, the highly defiant bacterium may have been lurking for a long time. “For many years in Eastern Europe, they found unbelievable drug resistance — cases resistant to 20 different antibiotics,” says Rubin. And because tuberculosis is spread via droplets released in the air with a cough, healthy individuals can contract the fully drug-resistant strains of the infection just by breathing them in.
Though TB acquires its drug-resistant genetic mutations slowly, once such a mutation crops up, it sticks around. “When you hear about MDR-TB and XDR-TB, what you’re really hearing about are TB cases that have a whole pile of mutations,” says Rubin. “It’s not a single mutation that makes them MDR or XDR, but single mutations for every drug to which they’re resistant.”
Tuberculosis is a disease of poverty. Initially, resistance arose when patients did not or could not take their medications — which carry unpleasant side effects — for the required time. The more resistant the disease, the less effective and more toxic are the drugs used to beat it.
The emergence of MDR and XDR strains also reflects deeply-rooted problems in medical care. In poor locales, doctors can’t rapidly diagnose resistant strains of the bacterium, lacking the means to do sputum culturing and drug-susceptibility testing, all timely and expensive procedures that must be performed in competent labs. Without such technical support, physicians treat all patients with standardized drugs, which may lead to failure if the patients happen to carry strains impervious to the medicines. And drug supplies regularly run out.
“For TB, we have a double whammy,” says Rubin. “There’s disease out there [XXDR-TB] that we can barely treat right now. And the drug-resistant disease that we can treat requires very expensive therapy. Parts of the world just don’t have the resources for treatment.”
With HIV/AIDS, the pattern of drug resistance is precisely the opposite of that of TB: Affluent nations have borne the brunt of drug resistance since 1987, shortly after the anti-retroviral AZT was introduced, followed by an expanding array of state-of-the-art medicines. Ten years ago, 1 to 5 percent of HIV patients had drug-resistant strains of the virus. Today, 5 to 30 percent of new HIV/AIDS cases are drug resistant; in the U.S., the estimate is 15 percent.
In wealthy countries, more than 30 AIDS drugs have been approved, representing five classes that each work in different ways. Indeed, there are now more drugs licensed against HIV than against all other viral diseases combined. With far longer life expectancy, HIV infection is no longer the death sentence it once was.
Already a problem in developed nations, rising HIV drug resistance looms in hardest-hit sub-Saharan Africa.
DNA-based tests that can detect resistance mutations. Also, treatment with the right drug combinations followed by monitoring.
In developing countries, the story is different. They have relied on a narrow selection of older drugs. Yet while these nations should, theoretically, face less drug resistance-because there have been fewer drugs for the virus to resist — scientists haven’t actually measured the problem. “It hasn’t been studied nearly as much in Africa or Asia, even though the viruses of Africa or Asia, especially HIV-1C, are much more common in the world,” says Max Essex, Mary Woodard Lasker Professor of Health Sciences in the Department of Immunology and Infectious Diseases. According to the WHO, 56 percent of all infections globally are HIV-1C. But drugmakers and public health analysts have focused until now on resistance in HIV-1B, the strain that predominates in the U.S. and Europe, where the lucrative treatment market is based.
Because HIV both replicates and mutates rapidly, drug resistance has been a problem since treatments began rolling out. Even with the most effective antiretroviral drugs, some viruses survive — including the mutants that can resist anti-retrovirals. “Late in infection, every HIV-positive individual is actually infected with a gazillion different viruses at once,” says Eric Rubin. “Resistance arises very quickly in HIV because of the preexisting population of resistant bugs. And it arises in a single person.”
Not complying with a drug regimen fosters resistance. So does taking one drug at a time, as opposed to a combination of drugs that can keep viral levels down. This was true in the U.S. in the late 1980s and early 1990s, when treatments first hit the market, and is proving to be the case today in Africa, where local physicians may not have access to effective three-drug combinations.
In Africa, drug resistance also sprang up when mothers who were about to give birth received a single dose of nevirapine, an anti-HIV drug that reduces transmission of the infection to their offspring. Belatedly, researchers discovered that the medication triggers resistance to a key class of anti-HIV drugs known as NNRTIs, meaning that the mother couldn’t be treated with that group of drugs if she needed them later.
In sub-Saharan Africa, where the epidemic is concentrated, the specter of drug resistance looms large. Essex worries about the growing ranks of newly infected patients who have acquired infections resistant to the drugs known as reverse transcriptase inhibitors, such as AZT and tenofovir, which are largely the only drugs currently available.
“It’s particularly scary in Africa because the epidemic is so different there, with women representing 60 percent of those infected,” Essex says. “If a significant number of women become infected with drug-resistant variants of HIV-let’s say it’s 10 or 15 or 20 percent-those women will give birth to infants who are infected, because the drug regimens used to prevent transmission won’t work. Having infants or children infected is, in one sense, an even greater problem than adults, because you have to treat them for their entire lives.” Lifelong treatment with antiretrovirals could also leave patients more vulnerable to chronic conditions in adulthood, such as cardiovascular disease and stroke.
Malaria kills someone in the world every 30 seconds. Most of its victims are children living in Africa south of the Sahara. In 2009, the WHO announced that the emergence of parasites resistant to the newest anti-malarial drug — artemisinin — could undermine the success of global malaria control. Initially spotted along the Thailand-Cambodia border, it has since appeared as well in Vietnam and Myanmar.
The news didn’t surprise Dyann Wirth, chair of the Department of Immunology and Infectious Diseases and Richard Pearson Strong Professor of Infectious Diseases at HSPH. “For every new anti-malarial that’s been introduced, as with any microorganism, resistance has appeared,” she says. Along the Thailand-Cambodia border, the appearance of drug resistance may be partly attributable to patients taking too little medicine, substandard medicine, or counterfeit preparations with a tiny amount of the active drug; a 2010 WHO report found similarly poor-quality treatments in Africa. Once established, the drug-resistant strains spread via mosquitoes — the infection’s carrier in nature.
The malaria parasite has shown signs of resistance to the newest drug to combat the infection.
Determine if a patient is infected with a resistant strain and choose the right medications from the outset, instead of waiting for a drug to fail.
As Wirth and her colleagues at the Broad Institute have discovered, the genome of the most virulent malaria parasite —Plasmodium falciparum — is highly diverse. That genetic diversity plays a major role in both the emergence and spread of drug resistance. Mutations occur spontaneously. Some happen as a result of natural selection after exposure not only to modern malaria drugs, but also to the traditional medicines used to treat fevers, which may lead to cross-resistance with current drugs. Wirth also found genes that confer resistance to multiple drugs — not unlike the MDR genes in bacteria. “These are probably key players in the modulation of resistance,” she says. “They may allow parasites to survive in the presence of drugs, and perhaps permit other mutations to be selected.”
As Wirth sees it, the public health impact of drug resistance in malaria depends on how well a resistant organism spreads through human and mosquito populations. Indeed, most of the parasites unfazed by today’s drugs appear to have descended from common ancestors, suggesting that they have acquired an ability to survive in the complicated human-mosquito cycle of transmission. “If drug resistance is going to be a problem beyond an individual, then it has to spread,” she notes. “And to spread, it has to compete with all the other parasites out in the world. It has to compete for a place in the mosquito, and it has to compete for a place to get transmitted to the next person.”
In this population-level perspective, drug resistance tends to arise over long periods of time in places where humans and mosquitoes share the same terrain. If a drug-resistant mutation crops up and is capable of spreading, the parasite population suddenly shifts from being sensitive to being impervious to a drug.
At the moment, malaria is a treatable disease, Wirth says. “But artemisinin is the last drug we have in the armamentarium. If artemisinin resistance spreads, there will be the same situation as in the 1980s and 1990s. You’ll begin to see more serious malaria and more childhood deaths on the African continent.”
Compounding the problem is rising pesticide resistance in parasite-bearing mosquitoes. During the Global Malaria Eradication Program of the 1950s and 1960s, early success collapsed when mosquitoes became resistant to the solely used insecticide DDT. As a result, malaria resurged to previous or even higher levels. Today, that threat has returned with wide distribution of insecticide-treated bed nets and accelerated indoor spraying campaigns. Scientists fear that such measures may foster resistance to all four classes of insecticides used today, undermining any progress in human clinical treatment.
— Madeline Drexler is editor of the Review, and author of Emerging Epidemics: The Menace of New Infections (Penguin, 2010).
Tuberculosis image/SPL/Photo Researchers, Inc.
HIV image/Dr. Klaus Boller/Photo Researchers, Inc.
Malaria image/Eye of Science/Photo Researchers, Inc.