WK 5- Tuberculosis and HIV

Question 1

What causes tissue destruction in TB

Answer 1

results from “excessive” cellular immune response (macrophage-derived proteases)→ degrade collagens, elastin, proteoglycans, fibronectin, laminin

Question 2

How can immunosuppression cause reactivation of TB

Answer 2

Primary infection is usually by inhalation of micro-droplets containing M. tuberculosis→ when inhaled will move to the lungs and be engulfed by pulmonary macrophages→ resistant to macrophage killing so will create a granuloma→ this is what allows for latency (shields off infection) → granulomas can sit in lungs for decades, and when you are exposed to immunosuppressive factors the granulomas can change structure into necrotic granuloma→ granuloma breaks down and releases the MTB

Question 3

What are the symptoms of TB

Answer 3

weight loss, fatigue, night sweats, cachexia, chest pain, fever, cough with sputum/blood stained sputum

Question 4

What are the 4 drugs used for the initial HRZE TB regimen

Answer 4

• Isoniazid (INH)
• Rifampin (RIF)
• Pyrazinamide (PZA)
• Ethambutol (EMB)

Question 5

How often are the HRZE drugs given for

Answer 5

• all four drugs are given for an extended period of time→ multiple agents are given daily for 2 months
• continue to give isoniazid and rifampin for another 4 months to ensure TB is cleared

Question 6

What drug of the 4 produces peripheral neurotoxicity and what medication is given along with HRZE to reduce this

Answer 6

Isoniazid-> give vitamin B6 to reduce toxicity

Question 7

What are the specific adverse reactions of Ethambutol (EMB)

Answer 7

Eye damage causes blurred/changed vision, including colour vision

Question 8

What drugs cause hepatitis as a side effect (what symptoms appear as a result)

Answer 8

• Isoniazid (INH)
• Rifampin (RIF)
• Pyrazinamide (PZA)
• -> cause abdo pain, dark urine, fatigue, lack of appetite, nausea, vomiting, jaundice

Question 9

What specific drug causes peripheral neuropathy as a side effect

Answer 9

Isoniazid (INH)

Question 10

What 2 side effects are specific to only Pyrazinamide (PZA)

Answer 10

Stomach upset (vomiting, abdo pain) and increased uric acid (gout, joint aches)

Question 11

What is Multi-drug resistant TB

Answer 11

-strains of TB are resistant to at least isoniazid and rifampin, the two most potent TB drugs.

Question 12

What is XDR= extensively drug resistant tuberculosis

Answer 12

rare type of MDR TB that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). Because XDR TB is resistant to the most potent TB drugs, patients are left with treatment options that are much less effective.

Question 13

What can contribute to/cause drug resistant TB

Answer 13

can occur when these drugs are misused or mismanaged. Examples include when patients do not complete their full course of treatment; when health-care providers prescribe the wrong treatment, the wrong dose, or length of time for taking the drugs; when the supply of drugs is not always available; or when the drugs are of poor quality.

Question 14

How can MDR/XDR be prevented

Answer 14

take all medications as prescribed and for the prescribed time, don’t miss doses, quickly diagnosing cases, avoid contact with known MDR or XDR patients.

Question 15

Who is the BCG vaccine not recommended for and why

Answer 15

not recommended for infants due to it being a live vaccine→ increased risk of complications
-not shown to be affective

Question 16

What is the interaction between HIV and TB

Answer 16

ability for co-infection due to diminished immune system, co-infection makes tx more complicated due to resistance and multiple drug use (isoniazide prevention therapy)

Question 17

What are the 3 pillars of the global TB strategy and what do they involve

Answer 17

→ Integrated, patient-centred TB care and prevention: involves preventative treatment for high risk pt, treatment for all infected people including MDR, early diagnosis, systematic screening of contacts and at risk
→ Bold policies and supportive systems: political commitment with adequate resources for TB care and prevention, engagement of communities, social protection, poverty alleviation
→ Intensified research and innovation: research to optimise implementation and impact and promote innovations, discovery, development and rapid uptake of new tools

Question 18

What is PMTCT and how can it apply to HIV transmission

Answer 18

-prevention of mother to child transmission
→ can be prevented by giving the mother ART- if viral load is too high, mothers are advised not to breastfeed
-primary prevention of HIV is a key component of preventing HIV transmission→ prevent the mother getting HIV through regular screening, safe sex practice, not sharing needles etc

Question 19

What are the 3 methods by which HIV can be transmitted from mother to child

Answer 19

1. Pregnancy - The chance of HIV being passed from mother-to-child is 15% to 45%
   without treatment. With treatment, the risk falls below 5%.
2. Labor & Delivery – medically assisted delivery can help prevent vertical transmission during labour and delivery
3. Breastfeeding – HIV +ve pregnant/ breastfeeding women should be treated with TDF, 3TC or FTC, EFV

Question 20

What are the 5 classes of drugs used to treat HIV

Answer 20

• nucleoside/tide reverse transcriptase inhibitors
• non-nucleoside reverse transcriptase inhibitors
• HIV-protease inhibitors
• integrase inhibitors
• entry / fusion inhibitors

Question 21

What is selective toxicity

Answer 21

-effective antimicrobial therapy relies on targeting pathogen-specific processes that do not occur in the host (ie. Targeting bacterial cell wall)

Question 22

Why is treatment for viral infections delayed slightly

Answer 22

most available antiviral drugs are effective only while the virus is replicating→ treatment is often delayed until the infection is well established

Question 23

How do nucleotide reverse transcriptase inhibitors (NRTI) work

Answer 23

-once inside cell, is phosphorylated by host cell enzymes to 5’-trisphosphate derivatives and will act as a false substrate→ competes with the natural deoxynucleotides, and will get made into a non-functional nucleoside that will then get taken up into the DNA chain→ don’t have 3-hydroxyl group, meaning next nucleotide group cannot bind, resulting in chain termination

Question 24

What are the adverse effects of NRTI’s

Answer 24

DNA polymerase (makes DNA from RNA) is also inhibited→ cells naturally use this enzyme but at a lower affinity→ toxic to mitochondrial DNA polymerase gamma→ cells are not able to repair self as well→ can cause redistribution of fat (lipoatrophy) and lactic acidosis

Question 25

How do Non-nucleoside reverse transcriptase inhibitors (NNRTI) work

Answer 25

• bind to and cause conformational change in enzyme (reverse transcriptase) catalytic site and prevent it to act on its substrate→ stops the ability to convert viral RNA to DNA→ reduces viral DNA synthesis
• don’t require intracellular phosphorylation for activity

Question 26

How do HIV-protease inhibitors work

Answer 26

in HIV, mRNA transcribed from the provirus is translated into two biochemically inert polyproteins, which are then converted into active proteins by virus-specific protease
-these proteins are essential for HIV maturation and replication→ HIV protease inhibitors block this protease and results in the formation of immature viral particles and prevent immature virions from becoming mature, infectious viruses

Question 27

How do integrase inhibitors work

Answer 27

chromosomal integration only occurs in the viral cell→ after reverse transcriptase, a pre-integration complex is formed and can remain dormant (doesn’t occur in normal cells)→ integrase inhibitors prevent insertion of processed viral DNA into host DNA

Question 28

How do entry inhibitors (chemokine antagonists work)

Answer 28

-inhibits the chemokine receptor 5 (CCR5) on surface of immune cells→ HIV binds to the CD4 receptors, but is unable to bind to the CCR5 co-receptors, preventing fusion of the virus envelope with the cell membrane

Question 29

How do fusion inhibitors work

Answer 29

• viral envelope expresses glycoprotein gp41 which is involved in fusion with CD4+ receptors on the host immune cells
• enfuvirtide binds to gp41 and prevents initiation of fusion of the virus envelope with the cell membrane→ prevents HIV from gaining entry to the host immune cell

Question 30

What is HAART

Answer 30

• typical HAART 3 or 4 drug combination would involves two NRTIs plus either a NNRTI or one or two protease inhibitors–> multiple drugs lowers chance of resistance occurring
• need to take drugs daily to ensure that virus is unable to replicate-> requires life long compliance

Question 31

What are the adverse effects of HAART

Answer 31

• Lipodystrophy→ noticeable, so can produce a stigma→ with NRTIs and HIV-PIs
• peripheral lipoatrophy
• central fat accumulation
• insulin resistance, dyslipidaemia
• Hyperglycaemia- with HIV-PIs
• CV disease risk
• Lactic acidaemia- with NRTIs
• Hepatotoxicity
• Bone loss, rash

Question 32

What are some treatment issues facing HAART

Answer 32

• consider factors affecting long term adherence to therapy
• strategies to improve adherence→ eg pill containers, alarms, detailed information
• address psychiatric / social issues
• identify HIV-related illnesses that will require treatment
• identify co-existing medical conditions and treatments that may influence the choice of therapy
• drug interactions -many CYP450 effects
• resistance testing

Question 33

What does ritonavir inhibit and why does this create an issue with treatment

Answer 33

potent inhibitor of cytochrome P450 enzymes and has the potential to interact with many drugs

Question 34

What do Nevirapine and efavirenz induce

Answer 34

Induce CYP450 causing rapid metabolisation of other drugs, reducing their conc and activity

Question 35

What HRZE drug interacts with PPI’s and why does this create an issue

Answer 35

Atazanavir-> solubility decreases as the pH increases-> meaning it becomes less effective