Progress in TB and TB/HIV Treatment
Tuberculosis, a severe (and sometimes fatal), communicable respiratory infection characterized by chronic cough, fever, appetite loss, and weight loss, is an urgent health risk in many areas around the world. Despite effective existing treatments, tuberculosis remains an extremely dangerous disease in terms of global health, as 1.4 million people died from the disease in 2011 (Hafner et al). It is most dangerous in low-income regions where treatment is not always available, and is especially prevalent in sub-Saharan Africa, Western Europe, China, India, Pakistan, and Russia (Flor de Lima et al, Hafner et al). Immigrants also pose a health threat because they can carry TB (including drug-resistant strains) across borders and often do not seek treatment because of their citizenship status.
As with many other infections, drug-resistant strains of tuberculosis have developed amidst the many different treatment options available. The most commonly accepted way to handle drug resistant tuberculosis is to diagnose it early via a tuberculin skin test and take preventative measures to ensure the disease doesn’t spread. New drugs are currently being developed with the goal of shortening treatment regimens with multidrug therapies, but funding issues have slowed production of more effective tuberculosis treatments. New treatments appear promising and have the potential to greatly alter current approaches to TB management.
Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis, and as such it has commonly been treated with antibiotics. The first step in treatment is to diagnose exactly which type of TB infection the patient has: latent infection, drug sensitive pulmonary infection, or drug resistant pulmonary infection. Latent infection (where the bacterium is present but there are no symptoms yet) can be diagnosed rather easily using either the tuberculin skin test (where TB proteins are injected under the skin and the patient’s reaction is measured) or an interferon-gamma release assay (where a patient’s blood sample is mixed with TB proteins and the sample is monitored for interferon-gamma release) (Hafner et al). For latent infection, isoniazid is the antibiotic of choice, with the standard regimen consisting of 9 months of oral isoniazid treatment. Rifapentine, a longer-half-life form of the older TB drug rifampicin (Elamin et al), is also effective at handling latent infection. However, evolution of drug resistance over time prevents these antibiotics from becoming a standard “cure” for the disease. Drug resistant TB infection is much harder to treat and requires a “cocktail” of different antibiotics in order to find a weakness in the pathogen. Treatment of multidrug resistant disease often takes up to 20 or 30 months (Hafner et al).
To combat these different kinds of TB infection, a number of new treatments are being developed. Some of these approaches feature existing antibiotics (or variations of older ones) being used in different combinations. For example, an effective new combination for latent TB infection, consisting of isoniazid and rifapentine, was put into regular use in 2013. This treatment took approximately 12 weeks to complete, as opposed to the 9 months generally required for isoniazid treatment alone (Parekh et al). In addition, drugs that have originally been used to treat other diseases are now being adapted for TB treatment. Because the pathogen has not encountered them before, it has had no chance to develop resistance. For example, clofazimine, a drug originally used to treat leprosy, is now being used to disrupt cellular respiration in M. tuberculosis (although its precise mode of operation is unknown) (Elamin et al).
Other treatments consist of entirely new medications and/or approaches, which are being developed because strains of M. tuberculosis have developed resistance to traditional treatments. Some new antibiotics are far along in testing and are on the verge of “filling the drug pipeline” in the consumer market (Elamin et al). For example, bedaquilline and nitroimidazoles could be highly effective at treating TB because the bacterium hasn’t had time to adapt to them yet. These antibiotics attack the disease by inhibiting the proton-movement step in the production of ATP, the cells’ main energy source (although each drug operates in a slightly different manner). While these antibiotics have been shown to shorten treatment times, their side effects are still unclear. Benzothiazinones have also shown promise. These drugs act to inhibit enzymes that maintain the bacterial cell wall, and can be safely combined with many other TB drugs without adverse effects. All three antibiotics have shown so much promise in early bactericidal studies (which study drugs’ ability to kill bacteria soon after treatment begins) that they are likely to reach the market in the near future (Abubakar et al).
Another new approach to TB treatment involves inhibition of cellular communication pathways within the bacteria. This new type of therapy targets serine/threonine protein kinases (which play a major role in M. tuberculosis cell signaling) using a nucleotide deletion agent called pknE. The agent disrupts the cell-cell communication of the pathogen, reducing phosphorylation of MAPK inhibitors (components that act in cell signaling) and inhibiting cell survival. In the lab, macrophages infected with pknE were limited in their ability to transcribe DNA to RNA, and so their protein function (and hence the disease’s spread) was inhibited (Hanna et al). Knowledge of enzyme function and biosynthesis pathways (methods by which chemicals are metabolized and energy is produced) is being employed to develop new drugs, and many new treatments are on the verge of market approval.
In individuals infected with Human Immunodeficiency Virus (HIV), TB treatment is more complicated and requires even more careful handling of drug combinations. Because their immune systems are severely compromised, HIV-infected individuals are much more likely to contract serious diseases like TB, which are able to wreak havoc in the body since there is little immune support. Additionally, the chances of TB recurrence after treatment is higher in HIV coinfected individuals. TB, more than other diseases, is especially troublesome when combined with HIV for two reasons. First, TB infection leads to a higher rate of replication among HIV viruses (although the reason for this is still unclear), which further suppresses the immune system and allows the TB bacteria to reproduce even more (Hafner et al). Second, coinfected patients display the same symptoms as TB-only infected patients, and chest x-rays show no discernible differences between the two conditions (Cohn et al). Therefore, it can be easy to overlook HIV and simply treat for TB. Since tuberculosis is caused by a bacterium and HIV is caused by a retrovirus (virus that uses RNA rather than DNA as genetic material), treating both at once can be problematic because antibiotics have no effect on HIV, and drug-drug interactions between antibiotics and antivirals can be dangerous.
Several different methods can be used to treat TB/HIV coinfection, but researchers have found one action in particular that is vital to controlling coinfection: early use of anti-retroviral therapy (ART) to manage the spread of the HIV retrovirus. As Cohn and Gray point out, ART is necessary in order to inhibit HIV immune suppression. Abubakar et al agree, citing the “Results from three trials addressing the question when to start antiretroviral (ART) treatment in patients coinfected with TB and HIV,” which showed that starting ART early in the course of TB coinfection “increased AIDS-free survival whereas deferral of ART to the start of the continuation phase” decreased it. Treatment for the TB portion of the coinfection is essentially the same, featuring isoniazid, rifapentine, and other antibiotics. However, the complication lies in adjusting types and amounts of these antibiotics so as to avoid potentially dangerous drug-drug interactions. Another possible regimen for TB and HIV includes pknE, the cell signaling disruptor being researched in TB treatment. The pknE method impacts TB/HIV coinfection by limiting inflammation and thus diminishing strain on the immune system, which allows for shorter treatment times (Hanna et al). Research trials of these coinfection approaches have shown greater survival rates and shorter treatment times in patients, and so progress in the field appears promising.
Overall, despite the many complications relating to TB and TB/HIV coinfection, the variety of different treatments in development are showing signs that they will be able to significantly shorten treatment regimens and more effectively manage the diseases. Trials of the new medications have been carefully run and controlled, and have provided objective data to support claims of shorter treatment times and higher survival rates. While research in the field has shown promise, several questions remain regarding treatment of TB and TB/HIV in the developing regions (such as sub-Saharan Africa) where they are most prevalent. First, how will the drugs be transported and stored there? Contamination of antibiotics and anti-retrovirals can alter their modes of action and render them ineffective. Second, how will the drugs be distributed? The cost of running trials and producing new treatments is high, and a method of distributing them to low-income regions in large quantities without losing money needs to be established. Third, how long can these drugs (or variants of them) be relied on before M. tuberculosis adapts to them? Inherent variation in the bacterial population will allow bacteria that resist the drugs to survive and reproduce, eventually leading to a population of M. tuberculosis that is highly resistant to them. If we are able to answer these questions, we will have a way to diminish the number of global deaths due to TB and TB/HIV by a significant amount.
Abubakar, I., Nunn, A., Phillips, P. (2013). Treatment of Pulmonary Tuberculosis. Current Opinion in Pulmonary Medicine, 19, 273-279. Web.
Cohn, D., Gray, J. (2013). Tuberculosis and HIV Coinfection. Seminars in Respiratory and Critical Care Medicine. Web.
Elamin, A., Singh, M., Stehr, M. (2014). Filling the Pipeline – New Drugs for an Old Disease. Current Topics in Medicinal Chemistry, 14, 110-129. Web.
Flor de Lima, B., Tavares, M. (2013). Risk Factors for Extensively Drug-Resistant Tuberculosis: A Review. The Clinical Respiratory Journal, 8, 11-23. Web.
Hafner, R., Raviglione, M., Fordham von Reyn, C., Zumla, A. (2013). Tuberculosis. New England Journal of Medicine. Web.
Hanna, L., Narayanan, S., Parandhaman, D. (2014). PknE, a Serine/Threonine Protein Kinase of Mycobacterium tuberculosis Initiates Survival Crosstalk That Also Impacts HIV Coinfection. U.S. National Library of Medicine, NIH. Web.
Parekh, M., Schluger, N. (2013). Treatment of Latent Tuberculosis Infection. Therapeutic Advances in Respiratory Disease. Web.