Deadly duo

Joining forces to fight TB and HIV

An astonishing one-third of the world's population is infected with the bacterium that causes tuberculosis (TB),Mycobacterium tuberculosis. In most people it remains inactive or latent but in about 10% of people an active case of TB disease will develop within their lifetime. Simple antibiotics can prevent and treat most of these cases, yet 8-10 million people develop an active TB infection annually and two million die from it.

In recent decades the risk posed by TB and its consequences have been far greater due to the relentless spread of the HIV/AIDS pandemic. Stephen Lewis, the former United Nations Special Envoy for HIV/AIDS in Africa, has called the two diseases a "combination made in hell." HIV-infected individuals have a 20-fold greater risk of developing active disease, and TB is now the leading cause of death among HIV-infected people around the world. The TB bacterium and HIV are a deadly combination because both pathogens attack the immune system. "Both diseases suppress the immune system independently," says Jerald Sadoff, president and chief executive officer at the Aeras Global TB Vaccine Foundation, an organization developing improved TB vaccines. This compounds the damage to the body's defense system.

The relentless spread of the HIV epidemic is also making it impossible to continue to confront TB through traditional approaches. In response, the global health community is changing how it confronts these two diseases, incorporating more collaboration between historically separate TB and HIV/AIDS programs. A major goal of the World Health Organization's (WHO) new Stop TB Strategy, launched in 2005, is to decrease the burden of TB and HIV in populations affected by both diseases, and the plan is endorsed by a coalition of organizations involved in TB and HIV care. This new initiative combines the traditional approach to TB therapy, known as directly observed therapy short-course or DOTS where individuals are observed taking their medications, with a greater awareness of the interaction between HIV and TB.

The Stop TB policy recommends more thorough surveillance and prevention, both of HIV among TB patients and of TB in people living with HIV/AIDS. "TB prevention, diagnosis, and treatment services need to be core functions of HIV prevention, treatment, and care services, and vice versa," says Haileyesus Getahun, secretary of the TB/HIV working group at the WHO.

Identifying and treating TB

The majority of TB infections are acquired when an individual inhales bacteria shed via the coughing or sneezing of an individual with active TB infection. The bacteria then lodge deep in the lungs where they are kept in check by the immune system, resulting in a latent infection.

The transition from latent to active TB infection can happen on its own but is far more likely in individuals with compromised immune systems. HIV-infected individuals are particularly susceptible, making it one of the most common infections that occur in individuals with AIDS. During active infection the TB bacteria multiply and enter the bloodstream. They can also settle in internal organs, such as the kidneys and brain.

While HIV can be detected through a relatively simple antibody test, diagnosis of latent or active TB infection presents many challenges. Antibody tests for M. tuberculosis have proven useless and in many regions of the world the techniques used for diagnosing TB have remained relatively unchanged for the past hundred years.

The most common test for latent infection is a skin test where proteins from killed TB bacteria are injected just beneath the skin. A hypersensitivity reaction occurs in people with prior exposure to the bacterium, causing inflammation at the injection site. Though quick and easy, roughly 25% of those with active TB may have negative skin tests, meaning that people who need antibiotics to prevent the transition from latent to active TB will not receive them.

The test also does not work in newborns and infants due to their immature immune systems or in individuals with compromised immune systems, who may be unable to mount the necessary immune response. There is also the possibility of false-positive test results with the skin test, especially in people who were previously vaccinated against TB. The vaccine, known as bacille Calmette-Guerin or bCG, is used to immunize infants but its protection only lasts through childhood, which is why TB infection remains so common.

If latent TB is detected by the skin test, treatment with a single antibiotic (isoniazid) can dramatically reduce the chance of developing active TB. Diagnosis of active TB is done with a chest X-ray, but it must be confirmed by other methods. The gold standard is the smear test, which involves taking a sample of coughed-up sputum and smearing it onto a microscope slide and then examining it for the distinctive appearance of the M. tuberculosis bacterium.

Preventing the conversion from latent to active TB with isoniazid can reduce morbidity and improve survival, and the WHO recommends that all individuals with latent infection, including people living with HIV/AIDS, take isoniazid for six to nine months. But more recent studies indicate that nine months to a year is even more effective. In randomized controlled trials, isoniazid reduced the incidence of active TB by about 60% in HIV-infected patients with a positive skin test and 42% overall.

A more recent study investigated whether isoniazid, given to all individuals in a community regardless of their prior exposure to TB, could reduce the prevalence of the disease at the community level. Roughly 700 HIV-infected South African miners were given isoniazid preventive therapy for six months, reducing active TB infection by 38% overall, and by 46% in individuals not previously exposed to TB.

A similar effect was seen in a randomized clinical trial involving about 250 HIV-infected South African children. The group receiving isoniazid had a statistically significant lower incidence of TB than did the placebo group—5 cases compared to 13 in those who received placebo. The effect was so significant that the placebo arm was discontinued. Heather Zar, associate professor at the University of Cape Town, conducted this study and said it could have major public health implications. "This could be recommended routinely for HIV-infected children who do not have access to antiretrovirals and who live in high TB-prevalence areas," she says.

ARVs improve survival

Effective antiretroviral (ARV) therapy can dramatically improve the quality of life and survival time of HIV-infected individuals. The drugs' effective suppression of virus replication allows the immune system to rebound and keep HIV in check. Several studies have also demonstrated that ARVs can reduce the incidence of TB in HIV-infected people by greater than 80%. This effect is greatest among people with lower CD4+ T-cell counts and those who start ARVs early in the course of their HIV infection (see Primer, this issue).

A study presented at the International AIDS Conference in 2006 in Toronto showed that isoniazid plus ARVs may be the best way to prevent active TB disease in people co-infected with HIV and TB. The analysis of over 11,000 HIV-infected men and women in Rio de Janeiro found that isoniazid plus highly active antiretroviral therapy (HAART) is more effective than either therapy alone at preventing active TB disease—67% disease reduction among people treated with both drugs, while isoniazid or HAART alone reduced disease by 32% and 51% respectively.

The study is one of three ongoing projects by the Consortium to Respond Effectively to the AIDS/TB Epidemic, known as CREATE, led by Richard Chaisson of US-based Johns Hopkins University in Baltimore. Chaisson is also looking at the question of how long HIV-infected individuals should take isoniazid. "We are doing a clinical trial funded by the National Institutes of Health that is looking at giving preventive treatment for an indefinite period of time to see if that is more effective in settings where there is more TB transmission," says Chaisson.