The largely unnoticed collision of the global epidemics of HIV and tuberculosis (TB) has exploded to create a deadly co-epidemic that is rapidly spreading in sub-Saharan Africa. However, health systems cannot adequately diagnose, treat, or contain the co-epidemic due to unanswered scientific and medical questions, according to a report issued today by The Forum for Collaborative HIV Research and amplified by experts from leading global health organizations.
Approximately one-third of the world's 40 million people with HIV/AIDS are co-infected with TB, and the mortality rate for HIV-TB co-infection is five-fold higher than that for tuberculosis alone. This situation is made yet more urgent by the surging rates of multi-drug resistant TB in some areas with high HIV prevalence, according to the report.
"Now the eye of the storm is in sub-Saharan Africa, where half of new TB cases are HIV co-infected, and where drug-resistant TB is silently spreading," said Veronica Miller, coauthor of the report and director of The Forum for Collaborative HIV Research, a global independent public-private partnership comprised of researchers, patient advocates, and government and industry representatives. "Unlike bird flu, the global threat of HIV/TB is not hypothetical. It is here now. But the science and coordination needed to stop it are utterly insufficient."
First detected 23 years ago, HIV-TB now affects nearly one-third of the 40 million people infected with HIV. Without proper treatment, 90 percent of people living with HIV die within months of contracting TB.
The rapid spread of HIV-TB is due to the geography and biology of co-infection. One-third of the global population--approximately two billion people--are infected with TB. But in the vast majority of those infected, the disease is latent, walled off by the body's immune system. Only one-in-ten people infected with TB develop active disease in their lifetime. HIV changes this equation. Of those whose immune systems have been weakened by HIV, 10 percent will develop active TB each year.
"In today's world, a new TB infection occurs every second. When one considers that much of this transmission occurs in areas with high HIV prevalence, the imminent danger of a global co-epidemic is clear," said Diane Havlir, Chair of the WHO TB/HIV Working Group.
According to the report, the HIV epidemic has completely destabilized TB control in regions with high rates of HIV. For example, in one community of 13,000 people outside of Cape Town, South Africa, the TB patient caseload increased six-fold between 1996 and 2004, from 30 to 180 per year. Rates of TB in this community are over 150-fold higher than the national rates in many high-income countries.
"There has been a staggering increase in TB in this community, and this has been replicated right across southern Africa," said Stephen Lawn, a medical researcher at the University of Cape Town in South Africa.
The co-epidemic represents a setback to global control of tuberculosis, which would otherwise be in global decline.
HIV and Multi-drug Resistant TB
Earlier this year, the U.S. Centers for Disease Control and Prevention mounted a massive effort to stop the international travels of one man suspected of carrying XDR-TB. Yet, according to the report, rates of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are increasing dramatically and are often associated with HIV co-infection. (MDR-TB is resistant to the top two TB drugs, and XDR-TB is resistant to the vast majority of first- and second-line drugs.)
The report cites an outbreak of HIV/XDR-TB in Tugela Ferry, South Africa, where the number of cases has increased five-fold in the last two years. All of the 53 people originally diagnosed with XDR-TB in this outbreak were co-infected with HIV. They suffered an extremely high mortality rate of 98 percent, and survived only an average of 16 days from the time of diagnosis. Since then, over 450 cases of MDR-TB have been reported in Tugela Ferry, of which 55 percent are XDR-TB cases, most co-infected with HIV. The mortality rate for XDR-TB has dropped slightly but is still high at approximately 85 percent, and even mortality rates among MDR-TB cases in this setting remain alarmingly high, approaching 70 percent.
Tugela Ferry is not alone. Global estimates of multi-drug resistant TB are skyrocketing. As of October 2007, XDR-TB had been confirmed in 41 countries, up from 17 countries in March 2006. There are now an estimated 400,000 individuals infected with MDR-TB and 26,000 infected with XDR-TB. But these numbers underestimate the problem, since there is no data from many high HIV prevalence areas.
"The mortality rate from extensively drug-resistant TB in combination with HIV is staggering, with more than 80 percent of patients dying rapidly," said Richard Chaisson, Director of CREATE. "Despite the urgency and severity of the problem, we have neither the drug testing nor the surveillance tools in place to know the full extent of XDR-TB and HIV across large areas of Africa."
According to the report, South Africa is the only country in sub-Saharan Africa with the laboratory capacity to diagnose XDR-TB. In addition, the report calls for the use of outbreak investigative methods to map out hotspots of HIV and drug-resistant TB.
Key Medical and Scientific Challenges
Co-infection with HIV-TB presents serious medical and scientific challenges, among them difficulties in diagnosis, infection control, and managing co-toxicities between drugs previously used to independently treat the two diseases. All of these problems are heightened in children. In addition, most treatment programs remain targeted at either HIV or TB, and clinics for each are often miles apart.
"We need integrated HIV-TB services using primary health care to reach the broad population," Havlir said. "This means we need not only basic and clinical research into HIV-TB, but also research now to determine the best models for care delivery."
The report details several of the most urgent problems in need of accelerated research:
Diagnosis of HIV-TB
In many clinics, HIV can be reliably diagnosed in as little as 15 minutes using a simple test. In contrast, the standard diagnostic test for TB, invented 120 years ago, fails to detect between 40 percent to 80 percent of TB cases in those with HIV-TB. While a more advanced sputum culture test exists, a lack of laboratory facilities means the test is unavailable for the overwhelming majority of patients in Africa. Even when it is available, results typically take many weeks to obtain. During that time, people with active TB, including MDR- and XDR-TB, may unknowingly spread their infection.
Detection of TB is further complicated by atypical symptoms in people who are co-infected. In co-infection, TB is less likely to cause typical lung disease and more likely to cause "disseminated TB," affecting almost any organ of the body. This makes standard chest x-rays much less useful for diagnosis.
TB in HIV-Infected Children
Almost one-quarter of HIV-infected children develop TB every year and drug-resistant TB among children is increasing, according to the report. Many unanswered questions remain in the diagnosis and treatment of pediatric HIV-TB co-infection, and there is a lack of pediatric drug formulations for both TB and HIV drugs. Despite all this, very few clinical trials of childhood TB have been conducted to optimize diagnosis or treatment outcomes.
"Nearly every infant with HIV suffers from pneumonia. TB also causes acute pneumonia, but with our current tools it is hard to know what is and is not caused by TB," said Mark Cotton, a pediatrician and HIV researcher at Stellenbosch University in South Africa. "Children should be included in trials to evaluate new anti-TB drugs."
A further cause for concern is the use of the Bacille Calmette-Guérin (BCG) vaccine in children, the report says. The vaccine provides some protection against disseminated TB in children. Therefore, based on WHO recommendations, BCG is given once at birth in most developing countries. But recent studies have found high rates of BCG disease and related deaths in HIV-infected infants who have received the vaccine, and WHO has issued an advisory note regarding the use of BCG in HIV-infected children.
"One study found a 75 percent mortality rate in children with BCG disease, and 70 percent of those children were HIV-infected. Clearly, this is a problem in need of immediate attention," Cotton said.
A medicine that appears to prevent active disease in HIV/TB co-infected patients, thus aiding infection control, is practically unused for this purpose, says the report. The medicine, Isoniazid, is a front-line drug used to treat TB. But concerns about Isoniazid Preventive Therapy (IPT) are such that Botswana is the only country in sub-Saharan Africa to use IPT nationally. These concerns include the potential for IPT-related drug resistance, the short duration of IPT efficacy, and the difficulties in ruling out active TB in co-infected people.
"Research that definitively addresses these concerns is needed now, in order to make this tool available or come up with alternatives to control the spread of infection," Lawn said.
What Is Needed
According to the report, key multilateral, government, scientific and donor organizations are beginning to strengthen their commitments to fighting HIV-TB, but much more remains to be done. The report summarizes the role and commitments of the leading global health organizations that participated in the roundtable discussion.
"Urgent action on the part of funding agencies, researchers, policy makers, drug companies and communities is needed to face the challenge posed by the dual epidemic of HIV-TB," Miller said. "The fact that all these organizations have begun to jointly tackle the challenge of HIV-TB shows that the walls between the two diseases are finally coming down. We must scale those walls, or the HIV-TB co-epidemic will continue to overwhelm us."
The report outlines key research questions and other measures needed to stem the HIV-TB co-epidemic. These include:
- Research to develop safe rapid diagnostic tests to detect both drug-susceptible and drug-resistant TB, for use in HIV-infected adults and children at the point of care.
- Development of screening tools to identify potential cases of MDR/XDR-TB.
- Equipping laboratories to be able to diagnose MDR and XDR-TB.
- Use of outbreak investigative methods to rapidly map out hotspots of HIV and drug- resistant TB, rather than relying upon standard surveillance methods.
- Research addressing practical questions, such as ventilation, that can facilitate implementation of infection control procedures in health care facilities
- Research into diagnostic tools to exclude active TB before initiation of Isoniazid Preventive Therapy (IPT) in HIV-infected patients, in order to avoid under treating active TB, which could lead to drug resistance.
- Authoritative studies to determine the risk of IPT causing isoniazid resistance.
- Research to better understand TB and HIV drug interactions in adults and children and to optimize treatment in both groups.
- Studies on the virological, immunological, and microbiological outcomes of HIV- TB co-infection in children.
- Evaluation of BCG vaccination in HIV-infected children.
- Research to provide evidence-based models for HIV-TB programs at local, district, and national levels, in rural areas and cities, to demonstrate ways in which HIV and TB programs can positively interact and deliver services.
- Resources, advocacy, and community mobilization to push for implementation and to prioritize the HIV/TB research agenda.
The new report, titled "HIV-TB Co-Infection: Meeting the Challenge," is based on a symposium and roundtable discussion held in Sydney, Australia, during the International Aids Society (IAS) conference in July 2007. Along with the Forum for Collaborative HIV Research, many of the world's leading global health organizations co-sponsored these events, including the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) in France, the Bill & Melinda Gates Foundation, CREATE (Consortium to Respond Effectively to the AIDS-TB Epidemic), the European and Developing Countries Clinical Trials Partnership (EDCTP), the International AIDS Society, Tibotec, the U.S. National Institutes of Health, and the World Health Organization's (WHO) TB/HIV Working Group of the Stop TB Partnership.
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