South Africa has the world’s worst HIV/TB syndemic; now it’s trying to overhaul its response to both diseases.
Babu Sunkari shows the lungs of his young patient Sandile, who was infected with both HIV and M. tuberculosis.
CREDIT: MALCOLM LINTON
KWAZULU-NATAL PROVINCE, SOUTH AFRICA—On 4 April 2012, an 11-year-old boy named Sandile left his family in Ulundi and traveled 250 kilometers south to his new home at King George V, a hospital in Durban that specializes in the region’s most complicated tuberculosis (TB) cases. Like 69% of the other 224 patients at King George V, Sandile was co-infected with HIV, which in all likelihood he acquired from his mother. Records that came with him indicated that she had died, but they did not specify the cause.
Sandile had received a full 6-month course of treatment for TB in 2009. But HIV-infected people remain especially vulnerable toMycobacterium tuberculosis, and a few years later, he again developed an active case of the lung-damaging disease. The doctors here surmise that he didn’t receive his medication each day during his second bout, allowing drug-resistant strains of M. tuberculosis to flourish. With drug-resistant TB, his treatment at King George V would require 18 months of costlier, less effective, and more toxic “second-line” pills plus painful daily shots of medication for at least 1 year.
Multidrug-resistant (MDR) TB destroyed Sandile’s left lung and badly damaged his right one. In September, Sandile was healthy enough to play outside, but Babu Sunkari, the pediatrician in charge of the children’s ward, warned that Sandile had nearly died the month before: He had a severe respiratory attack and kidney failure, probably from a combination of TB drug side effects and an infection he picked up at the hospital, further compounded by his HIV infection.
Sandile urgently needed a lung transplant, Sunkari said, yet, like most South Africans without means—which is almost everyone infected with TB here—there was no transplant in the offing. “He doesn’t have a hope in hell of surviving,” Sunkari said.
Sunkari said he was seeing more and more of these sad cases. Sandile was one of 32 children on the pediatric ward at King George V last September who had MDR or the even more frightening extensively drug-resistant (XDR) TB. “This used to be the normal TB hospital, with one to two cases of MDR,” Sunkari said. “Now we’re not taking normal cases in the ward.”
Children like Sandile “mirror what is happening in the community,” says Nesri Padayatchi, who ran the TB program at King George V for 14 years until leaving to do clinical HIV/TB research at Durban’s Centre for the AIDS Programme of Research in South Africa (CAPRISA).
South Africa has the world’s worst convergence of HIV and TB. It has 5.7 million HIV-infected people, more than any country; the highest rate of TB per capita; and, after Russia, the second highest reported number of MDR TB cases. The big picture is that South Africa has less than 1% of the global population but more than 25% of people dually infected with these diseases—a particularly deadly combination. This alarming rise in coinfection has been dubbed the HIV/TB syndemic, because, for both biological and social reasons such as poverty, the two diseases have synergistic effects, with each making the other worse.
South Africa’s HIV/TB syndemic has its roots in a badly broken health system and years of neglect. For TB, a cure has existed for decades, but many sick people in South Africa remain undiagnosed, and those who receive treatment often fail to take their drugs as prescribed, which in turn gives rise to drug-resistant strains. “The reason we have so much MDR and XDR TB here is because implementation of our TB program has sucked,” Padayatchi says.
HIV infection cannot be cured, but drugs can effectively thwart disease for decades and also slow the spread of the virus. But from 1999 to 2008, as the AIDS epidemic exploded in the country, then–South African President Thabo Mbeki and his health minister—who for many years questioned whether HIV even caused the disease—dragged their feet when it came to both treatment and prevention.
Good news, bad news.
Bonnie Davis (top) says a new diagnostic, GeneXpert, saved the life of this MDR TB patient at Hlabisa Hospital. Davis’s colleague, Martin Tshipuk (bottom), says the wards are full because many patients don’t adhere to treatments.
CREDITS: MALCOLM LINTON (2)
Now, with President Jacob Zuma at the helm and a new health minister in place, South Africa has made a dramatic turnaround and is at the forefront of efforts to combat these married diseases. “We’re trying to integrate HIV/AIDS and TB, to regard them as two sides of the same coin,” says Minister of Health Aaron Motsoaledi, who Zuma appointed when he took office in 2009. And to that end, the government has allocated more of its own money and attracted substantial international support to find everyone who needs drugs for HIV and TB, better coordinate their treatment, improve prevention efforts, and ramp up research to figure out how the diseases interact.
But South Africa still has a long way to go, and progress often occurs more slowly than anyone would like.
HIV and TB’s disastrous marriage
In the mid-1990s, South Africa followed the lead of many other countries and introduced what’s known as DOTS—directly observed therapy, short course—to combat tuberculosis. DOTS used new drugs that led to cures more quickly, and as part of the program, observers watched people swallow their pills each day to make sure they took all of their doses. But just as TB rates began to decline, HIV infections skyrocketed, and by the turn of the century, the two diseases were climbing in parallel (see graph, p. 900).
Salim Abdool Karim, a clinical epidemiologist who heads CAPRISA, helped launch the DOTS program in Hlabisa, a rural municipality not far from Ulundi. At the time, he says, TB mainly afflicted elderly men. “In the mid ’90s, a couple of things hit us in a way that we just couldn’t grasp—overnight it caught up with us,” Karim says. Suddenly, the TB patients were predominantly young and female, a reflection of the fact that the AIDS virus was racing through that population. “All our previous efforts to improve TB control were overwhelmed,” he says.
Pre-HIV/AIDS, South Africa’s DOTS program—which certainly had operational challenges—made the headway that it did because intact immune systems help contain both illness and spread. M. tuberculosis infects one-third of the world’s population, but it remains latent in most, typically causing disease only when HIV or other factors compromise the immune system; 90% of people who have latent TB infections never develop active disease in their lifetime. But HIV drastically alters that equation. A person with a latent TB infection who then becomes infected with HIV has a 10% chance of developing an active case of TB each year. HIV and TB interact in a vicious cycle. HIV compromises the immune system, which allows M. tuberculosis to copy itself at higher rates. M. tuberculosis, in turn, triggers inflammatory responses and the secretion of transcription factors that directly activate HIV genes. More HIV means more immune destruction—and still more opportunities for M. tuberculosis to flourish. A compromised immune system has difficulty containing the infection to the lungs, which means the disease can travel around the body, damaging the brain, the spine, or joints. Diagnosing TB in HIV-infected people is also trickier, so they often do not receive treatment and spread the infection to others. Worldwide, TB is now the leading cause of death in HIV-infected people.
Joel Ernst, director of infectious diseases at New York University in New York City, says these two bugs likely aid and abet each other by several other mechanisms that scientists have yet to elucidate. “There is so much we don’t know about HIV/TB interactions,” says Ernst, co-author of “HIV and Tuberculosis: a Deadly Human Syndemic” in the April 2011 issue of Clinical Microbiology Reviews. “I can’t think of a better syndemic—or a worse one—than HIV/TB.”
The Mbeki administration fueled the syndemic with its pronounced skepticism about the link between HIV and AIDS and its reluctance to introduce antiretrovirals (ARVs). To the astonishment of the medical community inside and outside the country, Mbeki’s health minister, Manto Tshabalala-Msimang, went so far as to advocate treatments such as lemons, beetroot, and garlic instead of promoting ARV drugs. “It was very clear that our response to the HIV pandemic in the beginning was the wrong one,” says current Health Minister Motsoaledi (see Q&A, p. 902).
HIV prevalence in South Africa nearly doubled between 1998 and today, and many people needlessly died from AIDS. A study done by a team at the Harvard School of Public Health and published in the 1 December 2008 Journal of Acquired Immune Deficiency Syndromes calculated that 330,000 lives could have been saved between 2000 and 2005 had Mbeki’s administration launched a “feasible” ARV program. TB cases tripled during Mbeki’s time in office, and in 2010, nearly half a million South Africans developed active cases—only China and India had a higher incidence—and 60% of them had HIV.
Nesri Padayatchi says the rise in drug-resistant TB in kids reflects the exploding problem in adults.Early warning.
CREDIT: MALCOLM LINTON
A decade ago, South Africa, like many other countries, did little systematic testing for MDR TB—which is more difficult to diagnose than drug-susceptible TB. A 2004 World Health Organization (WHO) report cited only two provinces that had repeatedly surveyed their populations for MDR TB, and the trends suggested that cases were relatively stable. But then in 2006, news of the world’s first outbreak of XDR TB in KwaZulu-Natal—53 cases at the same hospital in Tugela Ferry—made clear that the mix of HIV and drug-resistant TB in South Africa had hit a flash point (Science, 15 February 2008, p. 894).
Patients with XDR TB don’t respond to the first-line drugs or several second-line treatments. Cases of XDR TB had been reported elsewhere before the Tugela Ferry outbreak occurred: Between 2000 and 2004, public health off icials had documented 347 sporadic cases worldwide. But no one had seen a cluster of cases, which indicated that an extremely difficult to treat strain of M. tuberculosis was likely spreading quickly from person to person. As researchers described at the 2006 International AIDS conference, of the 53 people who had XDR strains at Church of Scotland Hospital in Tugela Ferry, 52 died a median of 16 days after being diagnosed with TB. Although HIV status was not known for nine of the patients, everyone else was infected with the virus.
CREDIT: CHERYL BAXTER AND SALIM ABDOOL KARIM, CAPRISA
The Tugela Ferry outbreak set off alarm bells globally, sparking fears of a pandemic of XDR TB and intensifying attempts to find other cases. Last year, WHO said 84 countries had reported cases of similarly difficult to treat M. tuberculosis strains; it also estimated that of the world’s 650,000 or so cases of MDR TB, 9% were XDR TB.
Within South Africa, the Tugela Ferry outbreak led to extensive studies to determine why it happened and what relation it had to HIV. As it turns out, XDR TB had been bubbling beneath the surface in KwaZulu-Natal for several years, driven by a sharp increase in MDR TB cases that had gone unnoticed. A team led by epidemiologist Kristina Wallengren of the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) in Durban reviewed laboratory records for all TB patients who had their M. tuberculosis analyzed for drug resistance. In the October 2011 issue of Emerging Infectious Diseases, the team reported that between 2001 and 2007, MDR TB cases jumped from 216 to 2799, and XDR cases had a startling 45-fold increase from six to 270.
Several of the researchers who first described the Tugela Ferry outbreak published compelling evidence in the 1 January issue of The Journal of Infectious Diseases that most people became infected with XDR TB at the Church of Scotland Hospital. The researchers looked at 148 people—a larger group than the one originally described in the outbreak—who had XDR TB between January 2005 and December 2006. Genetic analyses of the M. tuberculosis isolates from the patients showed that all but 4% closely matched each other, and 82% of the people had overlapping hospital stays at Church of Scotland. Although 98% of the patients were HIV-infected, only 31% of them were receiving anti-HIV drugs. All had extremely low levels of CD4 white blood cells, leaving them vulnerable to TB.
The study concluded that the Tugela Ferry outbreak resulted from a combination of long hospital stays, poor infection control, delays in the diagnosis of TB drug resistance, and HIV infection. Although the feared pandemic never materialized, the Tugela Ferry outbreak will go down in history for prodding the world to realize that XDR TB had made more inroads across the globe than anyone had imagined. And in South Africa, it also sent a loud message to the country that the response to its HIV/TB syndemic needed a serious overhaul.
Extraordinary measures
On 1 December 2009, World AIDS Day, President Zuma announced sweeping reforms that aimed to prevent and treat infections with both HIV and M. tuberculosis more effectively. “We need extraordinary measures to reverse the trends we are seeing in the health profile of our people,” Zuma declared.
As Zuma spelled out, the health ministry would launch a “massive campaign” to test 15 million South Africans for HIV. ARVs, until then still restricted to people who had severely damaged immune systems, would become available to HIV-infected people with TB much earlier in the course of the disease. “TB and HIV/AIDS will now be treated under one roof,” he promised. Zuma also decided to make ARVs available to all HIV-infected, pregnant women and children under a year of age, regardless of their health status. Fifteen months later, on 24 March 2011—World TB Day—Motsoaledi unveiled a new, equally ambitious, two-pronged approach to diagnosing active cases of tuberculosis. First, the government would ramp up efforts to test the 407,000 families that had a relative with an active case of TB. The second prong called for a countrywide deployment of a new machine called GeneXpert, which promised to revolutionize the ability to find active TB cases.
The most common TB diagnostic is a sputum “smear” test for M. tuberculosis that relies on microscopy; it detects only 60% of active cases and that drops to as low as 35% in HIV-infected patients. Culturing the sputum samples gives the most accurate results, but these tests can take weeks. Drug-sensitivity tests require still more time and costs. GeneXpert, which uses PCR to amplify and detect specific M. tuberculosis sequences, in contrast provides a highly accurate diagnosis within 2 hours, and can also detect MDR TB. Although GeneXpert is more expensive than sputum smears or culturing, studies suggest that it will save money in the long run by reducing transmission.
A review article in the 8 December 2012 issue of The Lancet, “Health in South Africa: changes and challenges since 2009,” shows how these “radical policy changes” have already produced results. Co-authored by CAPRISA head Karim and several other leading South African researchers, the article notes that government funding for TB and HIV/AIDS nearly doubled between 2009–10 and 2010–11. The mass HIV-testing campaign still under way had reached 13 million South Africans by June 2011, up from 2 million. The country quickly developed the largest GeneXpert TB program in the world, performing nearly half a million tests by July 2012. Since April 2010, South Africa has doubled the number of people on ARVs to nearly 2 million, more than any other country. And nearly 400,000 HIV-infected people who have latent M. tuberculosis infections take isoniazid, a first-line TB drug that works as a preventive.
Tangible benefits have begun to surface, too. The proportion of deaths related to HIV/AIDS has dropped from 52.3% of the total in 2006 to 43.6% in 2011. (Death rates from TB, excluding HIV, have remained relatively constant.) As a study in this issue reports, life expectancy in KwaZulu-Natal went from 49.2 in 2003—the year before the government began providing ARVs—to 60.5 in 2011 (see p. 961). Only 2.7% of babies born to HIV-infected women in 2011 were infected after 6 weeks, down from a high of 20% to 30% a decade earlier. “Undeniably, much remains to be done,” the report concludes. “However, for the first time in two decades, this progress instills a basis for hope.”
The HIV/TB syndemic has walloped southern Africa.Hardest hit.
CREDIT: WORLD HEALTH ORGANIZATION,GLOBAL TUBERCULOSIS REPORT 2012
Several other recent developments illustrate how far South Africa has come in comparison to its neighbors. A study in this week’s issue of Science shows that widespread use of ARVs in KwaZulu-Natal reduced the spread of HIV in the community (see p. 966)—the first demonstration outside a clinical trial that treatment works as prevention in a sub-Saharan African setting. The country also has become a world leader in HIV/TB research, and now boasts its own world-class institute devoted to the study of these married diseases. With $40 million from the Howard Hughes Medical Institute, in October 2012 K-RITH opened a swank 4000-square-meter, 8-story building that features several high-tech biosafety spaces with negative air pressure that can handle dangerous pathogens, state-of-the-art DNA sequencing machines, and the fastest Internet connection available in the country. “We’re trying to put the technology where the problem is,” says K-RITH’s director, William Bishai, who maintains a lab at Johns Hopkins University in Baltimore, Maryland.
In the next 3 years, the government says in its National Strategic Plan for these diseases that it hopes to reduce new HIV and TB infections by 50%, which it will do by ensuring that everyone in the country receives an annual HIV test and an exam for TB symptoms. It also aims to increase ARV coverage to 80% and drive mother-to-child transmission below 2%. As the strategic plan notes, achieving these aspirations depends on substantial funding increases that will have to come mainly from government coffers. K-RITH’s Bishai also soon hopes to have a dozen leading HIV and TB researchers from around the world investigating how the two diseases interact. “It’s a black box,” says Bishai, whose own work focuses on the genetics of drug resistance. “And the fields have been siloed. There’s almost no co-authorship.”
CREDIT: MALCOLM LINTON
Despite these steps forward, Hlabisa Hospital, located atop rolling hills that abut one of several game parks in KwaZulu-Natal, reveals the staggering challenges that exist today. Martin Tshipuk, the doctor in charge of HIV/AIDS at the 275-bed hospital, in September 2012 led a tour of the crowded female adult ward, where some patients slept on mattresses on the floor. “Up to 80% are here for HIV, and all have complications of opportunistic infections,” Tshipuk says. “Almost all patients are coming in on ARVS, but they’re coming in very sick and the problem is adherence” to drug regimens.
Improved diagnostics and better use of existing drugs alone will not curb the HIV/TB syndemic. That will require even wider use of ARVs and existing antibiotics, as well as new treatments that cure drug-sensitive M. tuberculosis more quickly and have more power against resistant strains. (The United States just approved a new drug, bedaquiline, that combats MDR TB [Science, 11 January, p. 130].) Effective vaccines against both diseases, which remain elusive, would make huge inroads, too. But South Africa clearly has more tools—and more political will—to confront HIV/AIDS and TB than ever before.
Then again, meaningful change takes time, and it ran out for Sandile on 8 October. Despite specialty care at King George V, the tag-team drubbing from HIV and M. tuberculosis finally proved too much for the young boy’s body, leading to irreversible kidney damage and sepsis. During his entire 6 months of his hospitalization, he never had a visitor. One week passed before relatives arrived from rural KwaZulu-Natal to retrieve his body, which they took back to their village for a traditional funeral.