Diseases of The Immune System - HIV/AIDS I

Question 1

What is HIV?

Answer 1

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes Acquired Immunodeficiency Syndrome (AIDS), a disease condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections (O.Is) and cancers to thrive.

Question 2

Fill the years for these:
- AIDS was first discovered as a clinical entity in ____
- HIV was identified as the causative agent in ____
- The first HIV in Lagos was discovered in ____

Answer 2

• 1981
• 1983
• 1986

Question 3

Discuss the stages in the HIV replication cycle.

Answer 3

1. Entry: The target for HIV is CD4 T lymphocytes. However, other cells such as macrophages, monocytes, and glial cells of the brain are also attacked by the virus. Following transmission, the virus binds to specific cellular receptors, CD4 and host cell co-receptors. Upon binding, the viral envelope undergoes conformational changes allowing the virion and the cellular membrane to fuse.
2. Reverse transcription: After fusion, the viral core particle is released into the cytoplasm of host cell, where reverse transcription takes place via the reverse transcriptase enzyme, which converts the viral ssRNA genome into a dsDNA.
3. Integration: The integration of the viral DNA into the host cell DNA occurs via the viral encoded integrase enzyme. The integrated DNA is called the provirus and may be latent in certain cell types or dependent on host viral life cycle.
4. Transcription: The integrated viral DNA is transcribed either as a whole to form a new viral RNA genome or selectively transcribed to form mRNA from the various viral genes that make up the viral genome.
5. Translation: The HIV mRNA is translated to corresponding large molecular weight viral proteins. These
   proteins undergo post-translational modifications by cleavage into smaller molecular weight proteins using the viral protease enzyme.
6. Assembly and Budding: All necessary viral structural proteins and viral RNA are produced for assembly into virions, and they bud from the surface of the infected cell.

Question 4

Discuss the pathophysiology of HIV/AIDS

Answer 4

• After infection there’s a rapid burst of viral replication peaking at 2-4 weeks, with 109 or more infected cells.
• This peak comes with a transient dip in the number of peripheral CD4 cells
• Due to host immune responses and target cell depletion, the number of infectious virions declines to a quasi steady state. This reflects the interplay between host immunity and pathogenicity of the virus.
• Seroconversion (antibody production occurs between 2-12 weeks after infection.
• Eventually, CD4 cell count steadily declines with increasing HIV RNA concentration.
• Once CD4 count is <200 cells per mm^3, the individual becomes susceptible to opportunistic infections such as Pneumocystis jiroveci
• Median time to clinical disease (opportunistic infection) is 8-10 years in HIV-1.

Question 4

Mention 4 modes of HIV transmission.

Answer 4

1. Unprotected sex
2. Mother-to-child transmission
   - in utero
   - intrapartum
   - breastfeeding
3. Contaminated blood and blood products transfusion and organ donations
4. Contaminated needles and blades

Question 5

The standard usually recommended for HIV diagnosis consists of three parts. They are _____.

Answer 5

Pre-test counselling, HIV testing and Post-test counselling.

Question 6

What are the categories of HIV tests?

Answer 6

1. Nucleic acid test (NAT): Uses blood drawn from vein to detect virus and can determine viral load. Can detect HIV within 10-33 days post-exposure. It is however expensive, so it is not used routinely.
2. Antigen/Antibody Test: Detects both antibodies and antigens from blood which can be obtained from the veins (within 18-45 days) or from finger prick (within 18-90 days). Infection with HIV produces p24 antigen even before the antibodies are developed. This is recommended test for HIV in the lab e.g. ELISA test.
3. Antibody Tests: detects antibodies only in patient’s blood sample or oral fluid. Most rapid tests and the only currently approved HIV self-test belong to this group. Detection is between 23-90 days from finger prick

Question 7

__________ is the gold standard confirmatory test for HIV.

Answer 7

Western blot

Question 8

The standard serologic test consists of a screening _______ followed by ________

Answer 8

Enzyme-linked Immunosorbent Assay (ELISA) followed by a confirmatory Western blot (WB)

Question 9

Mention the classes of drugs used to treat HIV.

Answer 9

1. Fusion inhibitors
2. Entry inhibitors/ CCR5 antagonists
3. NRTIs and NtRTIs
4. NNRTIs
5. Integrase inhibitors
6. Protease inhibitors
7. Capsid inhibitors
8. Post-attachment inhibitors

Question 10

________ is the first class of ARV medication to target HIV replication cycle extracellularly.

Answer 10

Fusion inhibitors.

Question 11

Naming a drug belonging to this class, discuss Fusion Inhibitors under mechanism of action and adverse effects.

Answer 11

Example: Enfuvirtide (T20)

MOA: Fusion inhibitors act extracellularly to prevent the fusion of HIV to the CD4 or other target cell. Enfuvirtide blocks the second step in the fusion pathway by binding to
the HR1 region of glycoprotein 41 (gp41). This prevents HR1 and HR2 from folding properly, thus preventing the conformational change of gp41 required to complete fusion.

The use of fusion inhibitors has been limited because of the inconvenient administration (subcutaneous injection), and adverse effect profile which include:
i. Injection site reactions; erythema, cysts, and nodules at injection sites
ii. Neutropenia
iii. Possible increased frequency of pneumonia.

Question 12

Naming a drug belonging to this class, discuss Entry Inhibitors/ CCR5 Antagonist under mechanism of action and adverse effects.

Answer 12

Example: Maraviroc

MOA: CCR5 antagonists block the CCR5 co-receptor on the surface of certain immune cells, such as CD4 cells, preventing HIV from entering the cell.

Adverse Effects:
i. Elevations in liver function tests
ii. Hepatitis
iii. Upper respiratory tract infection
iv. Muscle and joint pain
v. Headache
vi. Nausea, diarrhoea and fatigue
vii. Cough
viii. Headache

Question 13

Discuss the mechanism of action of nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs).

Answer 13

NRTIs and NtRTIs are analogues for naturally occurring deoxy nucleotides needed to synthesise viral DNA and they compete with the natural deoxy nucleotides for incorporation into the growing viral DNA chain.
When incorporated into the growing viral DNA chain, NNRTIs and NtRTIs cause chain termination.
Unfortunately, they also compete as substrates for host DNA synthesis and cause chain termination. This is responsible for their side effects.

Question 14

Mention 6 examples of NRTIs and NtRTIs.

Answer 14

NRTIs
1. Zidovudine (ZDV, AZT): First US government-approved drug.
Used to treat and prevent HIV/AIDS
Side effects include:
i. Headache
ii. Nausea
iii. Anaemia and Neutropenia
iv. Metabolic complications such as lactic acidosis and lipoatrophy
Haemoglobin monitoring is
recommended before and during treatment with AZT, especially in areas with malaria prevalence where anaemia is common.

2. Lamivudine (3FC): Proven safety, low toxicity, non-teratogenicity
   - Also effective against Hepatitis B
   Adverse effects include headache, nausea and vomiting.
3. Abacavir (ABC): Of all the NRTIs, it has the least effect on mitochondrial DNA depletion, which is associated with lactic acidosis, lipoatrophy and peripheral neuropathy.
   - Can substitute for Zidovudine and d4T
   - Available in pediatric formulation
   Adverse effects include: Hypersensitivity, nausea, vomiting, fever and malaise.
4. Emtricitabine (EFC): An equivalent alternative to Lamivudine, as they are structurally related
   - Just like lamivudine, it is also effective against Hepatitis B.

NtRTIs
5. Tenofovir Disoproxil Fumarate (TF, TDF):
- Dose should be decreased in patients with renal insufficiency.
Adverse effects include:
i. Low bone marrow density
ii. Renal toxicity
iii. Flatulence
iv. Nausea and vomiting

6. Tenofovir Alafenamide (TAF)
   - Used for patients with Hepatitis B co-infection.
   - Used for PrEP.

Question 15

Discuss the mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Answer 15

The NNRTIs act by binding non-competitively to the reverse transcriptase enzyme. The binding causes conformational change in the enzyme that affects the catalytic activity of the enzyme and reduces its ability to bind nucleotides, blocking the HIV-1 replication.

Question 16

Mention 5 drugs that belong to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) class.

Answer 16

1. Nevirapine (NVP)
2. Efavirenz (EFZ)
3. Etravirine (ETR)
4. Rilpivirine (RPV)
5. Doravirine (DOR)

NEERD

Question 17

About Nevirapine. Answer with True or False

i. NVP adverse effect is more frequent in women than in men
ii. It is more likely to be seen in antiretroviral-naïve women with higher CD4 cell counts (above 250 cells/mm3).
iii. NVP is associated with a higher incidence of rash than EFV.
iv. Rash is life-threatening and Stevens-Johnson syndrome may occur.
v. NVP is safe for patients taking hepatoxic drugs.
vi. In the case of severe hepatic or skin reactions, NVP should be paused, to be resumed when symptoms disipate.
vii. Careful monitoring is needed during the first 12 weeks of therapy.
viii. Concurrent use of NVP with other drugs (e.g. co-trimoxazole) that can also cause rash is allowed.
ix. NVP is preferred NNRTI for women if there is potential for pregnancy or during the first
trimester.
x. NVP is administered 3 times daily.

Answer 17

i. True
ii. True (Use with caution in women with CD4 counts between 250 and 350 cells/mm3)
iii. True
iv. True
v. False ( potentially life-threatening risk of hepatotoxicity makes it less suitable for patients who are using hepatotoxic medications)
vi. False. (It should be discontinued permanently)
vii. True
viii. False
ix. True
x. False (Twice daily)

Question 18

About Efavirenz. Answer True or False.

i. EFV is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects
ii. EFV is primarily associated with toxicities related to the central nervous system (CNS), teratogenicity and rash
iii. Rash is severe and requires the discontinuation of therapy.
iv. The CNS symptoms typically abate after 2-4 weeks in the majority of patients
v. EFV is safe when there is potential for pregnancy and during the first trimester of
pregnancy.
vi. Patients with a history of psychiatric illnesses may use EFV
vii. EFV is the drug of choice in individuals with TB/HIV co-infection who are receiving rifampicin-based therapy.
viii. EFV is taken twice daily.
ix. It is often used in combination with emtricitabine and tenofovir

Answer 18

i. True
ii. True
iii. False (Rash is generally mild, self- resolving and usually does not require the discontinuation of therapy)
iv. True
v. False ( EFV should be avoided when there is potential for pregnancy and during the first trimester of pregnancy)
vi. False ( EFV should be avoided in patients with history of severe psychiatric illness)
vii. True
viii. False (It is taken once daily)
ix. True

Question 19

About Etravirine (ETR). Answer True or False.

i. Patients who are resistant to other NNRTIs may not use Etravirine.
ii. Elevation of LFTs is an adverse effect of ETR
iii. Etravirine therapy is affected by type of food taken
iv. Etravirine recommended dose is 200mg twice daily before meal.
v. Tablet must be taken whole and not chewed

Answer 19

i. False (Unlike other agents in the class, resistance to other NNRTIs does not confer resistance to etravirine)
ii. True
iii. False
iv. False ( Twice daily after meal)
v. True

Question 20

About Rilpivirine. Answer True or False.

i. RVP has higher potency and longer half-life compared with older NNRTIs
ii. It has a higher side-effect profile compared with older NNRTIs
iii. Adverse events include insomnia, depression, elevations in liver function tests and in serum creatinine.

Answer 20

i. True
ii. False (It has a reduced side-effect profile)
iii. True

Question 21

About Doravirine. Answer True or False

i. It is available alone and in combination with 3TC and TDF
ii. It is used in patients who are virally suppressed with no previous history of treatment failure and substitutions associated with resistance to DOR.
iii. It is used in the treatment of HIV-1 in ART naïve adult patients.

Answer 21

i. True
ii. True
iii. True

Question 22

Providing a suitable example of a drug belonging to this class, highlight the mechanism of action and adverse effects of Integrase Inhibitors/Integrase Strand Transfer Inhibitors (INSTI)

Answer 22

Example: Raltegravir

MOA: Integrase strand transfer inhibitors (INSTIs) block integrase, an HIV enzyme, which integrates HIV DNA into the DNA of the host CD4 cell. This prevents HIV from replicating.

Adverse Effects:
i. Nausea
ii. Diarrhoea and flatulence
iii. Headache and dizziness
iv. Rash and pruritus
v. Muscle pain and fatigue
vi. Abnormal dreams
vii. Elevations in LFTs
viii. Elevation in amylase

Question 23

Mention 3 INSTIs

Answer 23

1. Raltegravir
2. Elvitragravir
3. Dolutgravir

Question 24

WHO has recommended ____ as the preferred first line and second line drug in combination with other ARV in the treatment of HIV in all populations.

Answer 24

Doltugravir (DTG)