Microbiology pharm – HIV drugs

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HY points about each drug followed by a quiz at the end

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Simplified mechanism of HIV entry into CD4 T cell

1. HIV virion produces Gp160 envelope protein via the env gene.
2. Gp160 is cleaved into Gp120 and Gp41 (correct, the numbers don’t add up).
3. Gp120 is expressed outwardly from the HIV virion cell membrane; it connects to Gp41, which is transmembrane.
4. Gp120 binds to CD4 receptor on CD4+ T cells.
5. This binding enables the cell membranes of the HIV virion and T cell to fuse.
6. After binding to CD4, Gp120 then binds to the T cell co-receptor CCR5 or CXCR4. Without this co-binding, the T cell may sometimes shed the HIV virion particle. Hence this co-binding is a crucial step.
7. Once Gp120 is bound to both CD4 and either CCR5 or CXCR4 on the T cell, Gp41 on the HIV virion is released from its metastable location and inserts itself into the CD4+ T cell membrane.

Entry/fusion inhibitors

Maraviroc

MOA of maraviroc?

• Binds to and inhibits CCR5 on the CD4 + T cell.
• This prevents binding of Gp120 and therefore HIV entry/fusion.

Enfuviritide

MOA of enfuviritide?

• Binds to and inhibits Gp41 on the HIV virion.
• This prevents Gp41 from binding to the T cell membrane and therefore HIV entry.

Integrase inhibitors

• Inhibit HIV integrase enzyme.
• Integrase enables the HIV DNA (after it’s been produced from RNA via HIV reverse transcriptase) to be incorporated into the DNA of the host cell genome.

Raltegravir

• Can cause ↑ creatine kinase (CK).

Nucleoside reverse-transcriptase inhibitors (NRTIs)

• Nucleoside = nitrogenous base (A, C, G, T) + a sugar (ribose if RNA; deoxy-ribose if DNA).
• Nucleotide = nucleoside + phosphate group(s).
• NRTIs competitively prevent nucleotides from being added to the growing HIV DNA strand during reverse transcription (RNA –> DNA).
• The NRTI inserts itself into the growing DNA strand but lacks a 3′ OH, so the DNA chain terminates.
• NRTIs require phosphorylation for activation.

Side-effects common to most NRTIs?

• Bone marrow suppression (↓ WBCs, RBCs, platelets; ↑ MCV).
• Lactic acidosis.

Abacavir

• Causes hypersensitivity reaction in patients who are HLA-B5701 positive.
• Sounds really fucking weird, yes. But this is asked for some magical reason.
• 42M + recently diagnosed with HIV + is to be started on abacavir; what to do first? –> answer = HLA-B5701 testing.
• 42M + HIV + is positive for HLA-5701; which drug can patient not receive? –> answer = abacavir.

Didanosine

• Can cause pancreatitis.

Emtricitabine

• Safe during pregnancy.
• Patients who are pregnant and taking efavirenz (will discuss this below; an NNRTI not safe during pregnancy) can be switched off of evavirenz and onto emtricitabine.

Zidovudine

• Classically the HIV drug given intrapartum to pregnant women.
• Given to neonates for six weeks, starting within 12 hours of birth if mother is HIV + in order to prevent vertical transmission (on 2CK NBME).

Lamivudine, Stavudine

• Just be aware of their names as additional NRTIs, but nothing special about these you need to know for USMLE.

Tenofovir

• The only nucleoTide reverse-transcriptase inhibitor you need to know for HIV.
• The other NRTIs are all nucleoSides.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

• “Never Ever Deliver Nucleosides” –> Nevirapine, Efavirenz, Delaviridine.
• Non-competitively inhibit reverse-transcriptase (i.e., do not cause DNA chain termination via incorporating competitively).
• Do not require phosphorylation for activation (in contrast to NRTIs).

Side-effects common to the NNRTIs?

• Rash.
• Hepatotoxicity.

Efavirenz

• Can cause wild/vivid dreams.
• Not safe during pregnancy. Switch to emtricitabine.
• Varenicline (smoking cessation agent) is the other agent known to cause wild dreams for USMLE.

Protease inhibitors

• All end in -navir.
• HIV-produced proteins must be cleaved into functionally smaller proteins via protease (pol gene); protease inhibitors prevent these cleavages.

Side-effects common to the HIV protease inhibitors?

• Hyperglycemia (insulin resistance + type II diabetes).
• Lipodystrophy (fat redistribution with Cushing syndrome-like presentation).

What is a notable point about HIV patients who also need treatment for TB?

• Rifampin used for TB is a P-450 inducer and will decrease serum concentrations of protease inhibitors. Rifapentine is used instead of rifampin in these patients.

Indinavir

• Can cause thrombocytopenia.

Ritonavir

• P-450 inhibitor. Can “boost” serum levels of other HIV drugs taken as part of HAART therapy by decreasing rate of metabolism.

Highly active anti-retroviral therapy (HAART)

• Three drugs: Two NRTIs plus either an NNRTI or a protease inhibitor.
• For some reason, a HY question USMLE asks is if someone with HIV should be on a two- or three-drug regimen, and the answer is always three-drug.
• HAART should be commenced as soon as someone is diagnosed with HIV, regardless of CD4 count. In other words, the wrong answer is commencing HAART only after CD4 count drops to a certain level. The correct answer is, yes, commence HAART right away.
• Pregnant women should be on HAART, yes. This is the most important way to prevent vertical transmission to the fetus during delivery.
• 32F + pregnant; Q asks how to best prevent vertical transmission –> correct answer = HAART therapy.

—

1. How do HIV Gp160, Gp120, Gp41, CCR5, and CXCR4 work?

(Important to know mechanism for Step1 + to understand the drugs)

1) HIV virion produces Gp160 envelope protein via the env gene.

2) Gp160 is cleaved into Gp120 and Gp41 (correct, the numbers don’t add up).

3) Gp120 is expressed outwardly from the HIV virion cell membrane; it connects to Gp41, which is transmembrane.

4) Gp120 binds to CD4 receptor on CD4+ T cells.

5) This binding enables the cell membranes of the HIV virion and T cell to fuse.

6) After binding to CD4, Gp120 then binds to the T cell co-receptor CCR5 or CXCR4. Without this co-binding, the T cell may sometimes shed the HIV virion particle. Hence this co-binding is a crucial step.

7) Once Gp120 is bound to both CD4 and either CCR5 or CXCR4 on the T cell, Gp41 on the HIV virion is released from its metastable location and inserts itself into the CD4+ T cell membrane.

2. Which gene produces Gp160?

HIV virion produces Gp160 envelope protein via the env gene.

3. What is HIV Gp160 cleaved into?

Gp160 is cleaved into Gp120 and Gp41 (correct, the numbers don’t add up).

4. Gp120 vs Gp41; which extends outward from the cell vs is transmembrane?

Gp120 is expressed outwardly from the HIV virion cell membrane; it connects to Gp41, which is transmembrane.

5. What does HIV Gp120 bind to on the CD4+ T cell?

Gp120 binds to CD4 receptor on CD4+ T cells.

This binding enables the cell membranes of the HIV virion and T cell to fuse.

After binding to CD4, Gp120 then binds to the T cell co-receptor CCR5 or CXCR4. Without this co-binding, the T cell may sometimes shed the HIV virion particle. Hence this co-binding is a crucial step.

Once Gp120 is bound to both CD4 and either CCR5 or CXCR4 on the T cell, Gp41 on the HIV virion is released from its metastable location and inserts itself into the CD4+ T cell membrane.

6. MOA of maraviroc?

Binds to and inhibits CCR5 on the CD4 + T cell.

This prevents binding of Gp120 and therefore HIV entry/fusion.

7. MOA of enfuviritide?

Binds to and inhibits Gp41 on the HIV virion.

This prevents Gp41 from binding to the T cell membrane and therefore HIV entry.

8. a) MOA of raltegravir?

b) Main side-effect?

a)

Inhibit HIV integrase enzyme.

Integrase enables the HIV DNA (after it’s been produced from RNA via HIV reverse transcriptase) to be incorporated into the DNA of the host cell genome.

b)

Can cause ↑ creatine kinase (CK).

9. a) What’s the difference between a nucleoside and nucleotide?

b) How does an HIV NRTI work vs NNRTI?

a)

Nucleoside = nitrogenous base (A, C, G, T) + a sugar (ribose if RNA; deoxy-ribose if DNA).

Nucleotide = nucleoside + phosphate group(s).

b)

NRTIs competitively prevent nucleotides from being added to the growing HIV DNA strand during reverse transcription (RNA –> DNA).

The NRTI inserts itself into the growing DNA strand but lacks a 3′ OH, so the DNA chain terminates.

NNRTIs non-competitively inhibit reverse-transcriptase (i.e., do not cause DNA chain termination via incorporating competitively).

NRTIs require phosphorylation for activation; NNRTIs do not require phosphorylation for activation.

10. Side-effects common to most NRTIs?

Bone marrow suppression (↓ WBCs, RBCs, platelets; ↑ MCV).

Lactic acidosis.

11. a) MOA of abacavir?

b) Notable side-effect?

a) NRTI.

b)

Causes hypersensitivity reaction in patients who are HLA-B5701 positive.

Sounds really fucking weird, yes. But this is asked for some magical reason.

42M + recently diagnosed with HIV + is to be started on abacavir; what to do first? –> answer = HLA-B5701 testing.

42M + HIV + is positive for HLA-5701; which drug can patient not receive? –> answer = abacavir.

12. 42M + recently diagnosed with HIV + is to be started on abacavir; what to do first?

HLA-B5701 testing.

—

Abacavir causes hypersensitivity reaction in patients who are HLA-B5701 positive.

Sounds really fucking weird, yes. But this is asked for some magical reason.

13. 42M + HIV + is positive for HLA-5701; which drug can patient not receive?

Abacavir.

Causes hypersensitivity reaction in patients who are HLA-B5701 positive.

Sounds really fucking weird, yes. But this is asked for some magical reason.42M + HIV + is positive for HLA-5701; which drug can patient not receive?

14. a) MOA of didanosine?

b) Notable side-effect?

a) NRTI

b) Pancreatitis

15. Which HIV drug notably can cause pancreatitis?

Didanosine

16. a) MOA of emtricitabine?

b) Any notable point for USMLE?

a) NRTI.

b)

Safe during pregnancy.

Patients who are pregnant and taking efavirenz (will discuss this below; an NNRTI not safe during pregnancy) can be switched off of evavirenz and onto emtricitabine.

17. a) MOA of zidovudine?

b) Any notable points?

a) NRTI.

b)

Classically the HIV drug given intrapartum to pregnant women.

Given to neonates for six weeks, starting within 12 hours of birth if mother is HIV + in order to prevent vertical transmission (on 2CK NBME).

18. MOA of lamivudine?

NRTI

19. MOA of stavudine?

NRTI

20. MOA of tenofovir?

The only nucleoTide reverse-transcriptase inhibitor you need to know for HIV.

The others NRTIs are all nucleoSides.

—–

Nucleoside = nitrogenous base (A, C, G, T) + a sugar (ribose if RNA; deoxy-ribose if DNA).

Nucleotide = nucleoside + phosphate group(s).

NRTIs competitively prevent nucleotides from being added to the growing HIV DNA strand during reverse transcription (RNA –> DNA).

The NRTI inserts itself into the growing DNA strand but lacks a 3′ OH, so the DNA chain terminates.

NRTIs require phosphorylation for activation.

21. Name three non-nucleoside reverse transcriptase inhibitors (NNRTIs).

“Never Ever Deliver Nucleosides” –> Nevirapine, Efavirenz, Delaviridine.

Non-competitively inhibit reverse-transcriptase (i.e., do not cause DNA chain termination via incorporating competitively).

Do not require phosphorylation for activation (in contrast to NRTIs).

22. Side-effects common to the NNRTIs?

Rash.

Hepatotoxicity.

23. a) MOA of efavirenz?

b) Any notable points?

a) NNRTI

b)

Can cause wild/vivid dreams.

Not safe during pregnancy. Switch to emtricitabine.

Varenicline (smoking cessation agent) is the other agent known to cause wild dreams for USMLE.

24. Which HIV drug is known to cause wild/vivid dreams?

Efavirenz.

—–

Can cause wild/vivid dreams.

Not safe during pregnancy. Switch to emtricitabine.

Varenicline (smoking cessation agent) is the other agent known to cause wild dreams for USMLE.

25. Name two HY HIV protease inhibitors.

Indinavir, Ritonavir.

They all end in -navir.

26. Side-effects common to the HIV protease inhibitors?

Hyperglycemia (insulin resistance + type II diabetes).

Lipodystrophy (fat redistribution with Cushing syndrome-like presentation).

27. What is a notable point about HIV patients who also need treatment for TB?

Rifampin used for TB is a P-450 inducer and will decrease serum concentrations of protease inhibitors.

Rifapentine is used instead of rifampin in these patients.

28. a) MOA of indinavir?

b) Notable side-effects?

a) Protease inhibitor

b)

Indinavir notably causes thrombocytopenia.

HY side-effects common to the protease inhibitors in general:

Hyperglycemia (insulin resistance + type II diabetes).

Lipodystrophy (fat redistribution with Cushing syndrome-like presentation).

29. a) MOA of ritonavir?

b) Any notable point?

c) Side-effects?

a) Protease inhibitor

b) P-450 inhibitor. Can “boost” serum levels of other HIV drugs taken as part of HAART therapy by decreasing rate of metabolism.

c) Common to the protease inhibitors in general:

Hyperglycemia (insulin resistance + type II diabetes).

Lipodystrophy (fat redistribution with Cushing syndrome-like presentation).

30. What is HAART therapy? And is it two or three drugs?

Highly active anti-retroviral therapy

Three drugs: Two NRTIs plus either an NNRTI or a protease inhibitor.

For some reason, a HY question USMLE asks is if someone with HIV should be on a two- or three-drug regimen, and the answer is always three-drug.

31. Comment on HAART therapy during pregnancy.

HAART should be commenced as soon as someone is diagnosed with HIV, regardless of CD4 count. In other words, the wrong answer is commencing HAART only after CD4 count drops to a certain level. The correct answer is, yes, commence HAART right away.

Pregnant women should be on HAART, yes. This is the most important way to prevent vertical transmission to the fetus during delivery.

32F + pregnant; Q asks how to best prevent vertical transmission –> correct answer = HAART therapy.

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