TB and HIV

Second last post for MICR3350!

Tuberculosis (TB)

TB has been around for a while (there are 5000-year-old mummies that have evidence of TB infection), but it wasn't always called TB. It used to be called phthisis pulmonalis or consumption, and may have been transmitted between animals and humans. The causative agent, M. tuberculosis, was first identified by Robert Koch, who was awarded the Nobel Prize in Physiology or Medicine for his discovery.

Presentation

M. tuberculosis is an aerobic, non-motile, rod-shaped bacterium. It has a unique cell wall structure, which makes it resistant to most typical stains, such as the Gram stain. The main defining feature of the M. tuberculosis cell wall is the presence of mycolic acids, which resist drying, acids, alcohol and lytic enzymes. M. tuberculosis cell walls also have a unique component called lipoarabinomannan (LAM), which has been investigated as a possible diagnostic sign.

The most common form of tuberculosis is pulmonary tuberculosis. Pulmonary TB is characterised by chronic cough, haemoptysis (coughing up blood), fever, night sweats, loss of appetite and weight loss. It can be diagnosed by the presence of "Ghon foci" in a lung X-ray, as well as granulomatous lesions and caseous necrosis (especially in active infection). Pulmonary TB can persist for months. Extra-pulmonary TB, which is more common in patients who are also HIV+, affects all organs and may cause meningitis and lymph node disease. "Potts Disease" is TB that affects the spine.

TB can be transmitted via respiratory droplet nuclei, which is why most infections are in the lungs. TB can grow within macrophages to evade the immune system, and from there it can spread via the blood to various organs of the body. Around 10% of infections will become symptomatic, but the remaining ~90% remain latent. It is estimated that around 1/3 of the world's population have latent TB. Only people with active TB can transmit the disease, and it is estimated that every active case results in around 10-15 transmissions per year.

Diagnosis

Specimens used for TB diagnosis include sputum and biopsy. Tests done include microscopy and culture, though culture of mycobacteria can take a long time. Therefore, molecular tests such as PCR and special blood tests such as the Quantiferon TB-Gold blood test (which detects cell-mediated immune response) are increasingly being used.

Treatment

Treatment of tuberculosis requires prolonged therapy (6 months or more). The first phase, the induction phase, lasts around 2 months. In this phase, patients are given rifampicin, isoniazid, pyrazinamide and sometimes ethambutol (if the organism is not sensitive to rifampicin and isoniazid). This cocktail of drugs results in a cure rate of over 90%. In the consolidation phase, which lasts for around 4 months, patients are given rifampicin and isoniazid. The consolidation phase may continue for over a year if patients present with meningitis.

Drug resistance

Unfotunately, TB is gaining resistance to many treatments. MDR-TB (multi-drug resistant TB) is resistant to at least rifampicin and isoniazid. XDR-TB (extensively drug resistant TB) is resistant to rifampicin, isoniazid, fluoroquinolones and at least one anti-TB injectable drug. Finally, XXDR-TB is totally drug resistant.

Human Immunodeficiency Virus (HIV)

HIV is a lentivirus of the retroviridae (retrovirus) family. As such, it is an RNA virus that uses reverse transcriptase to convert its genome into DNA and integrate into the host genome.

The two types of HIV are HIV-1 and HIV-2. HIV-1 is the most common cause, and is very similar to a chimpanzee retrovirus called SIVcpz. HIV-2 is much less common as it is less transmissible and less severe, and is largely confined to West Africa. It is similar to a virus in Sooty Mangabey monkeys called SIVsm. The most common forms of HIV transmission are sexual intercourse, intra-uterine, childbirth and sharing needles. Breastfeeding may also pose a risk, but there is still some controversy surrounding this.

As I have stated in other posts, HIV infects many cells, but particularly CD4+ cells, such as T-helper cells. CD4 falls by around 40-80 cells/μL per year, leading to impaired cell-mediated immunity and a higher risk of opportunistic infections. Opportunistic infections mainly appear when CD4+ cell count falls beneath 200 cells/μL, which normally happens around 6-10 years after diagnosis.

HIV is diagnosed primarily through detection of HIV antibodies or HIV p24 antigen via ELISA. These tests are then confirmed by a Western blot assay which has high specificity. The Western Blot used for HIV detects antibodies to all three major HIV gene products: gag, pol and env. Treatment response can be monitored by looking at CD4 count and at HIV RNA PCR. The goal for HIV RNA PCR is for an "undetectable viral load," or less than 40 copies/mL.

There are a range of treatments for HIV. These include NRTIs, NNRTIs, protease inhibitors, integrase inhibitors and entry inhibitors. However, I will not go into these drugs in further detail in this post.

TB and HIV

There is a profound interaction between TB and HIV. Over 25% of TB deaths are in patients who are HIV+, and around 80% of TB infections are co-infected with HIV. TB patients who are HIV+ have a 10% chance of TB reactivation every year, which is very different to HIV- patients who have a less than 5% risk of reactivation in their lifetime. HIV+ patients also have an increased risk of drug-resistant TB. Nevertheless, treatment for TB is the same in HIV+ and HIV- patients.