HIV therapy

Left part is for HIV, right part is for other virus. Pasted image 20240114163028.png

Class	Example(s)	Mechanism of action
NRTI	Tenofovir, emtricitabine, lamivudine, abacavir, zidovudine	Inhibits HIV DNA synthesis from RNA template by terminating DNA chain elongation NRTI: Competitive nucleoside/nucleotide RT inhibitor
NNRTI (-vir-)	Efavirenz, nevirapine	NNRTI: Allosteric RT inhibitor
PI (-navir)	Atazanavir, darunavir, indinavir, ritonavir	Inhibits HIV polyprotein cleavage
Integrase inhibitor (-gravir)	Dolutegravir, raltegravir	Inhibits HIV DNA integration into host genome
Fusion inhibitor	Enfuvirtide	Inhibits HIV fusion with target cell membrane by binding to HIV gp41
CCR5 antagonist	Maraviroc	Inhibits HIV entry by blocking the HIV gp120 allosteric interaction with CCR5 (tropism testing required)

NRTIs (Nucleoside reverse transcriptase inhibitors)

Medications in class
- Abacavir (ABC)
- Didanosine (ddI)
- Emtricitabine (FTC)
- Lamivudine (3TC)
- Stavudine (d4T)
- Tenofovir (nucleotide analog, also called nucleotide reverse-transcriptase inhibitor; NtRTI)
  - Tenofovir disoproxil (TDF)
  - Tenofovir alafenamide (TAF)
- Zidovudine (ZDV, formerly AZT)
Mechanism of action
- NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3' to 5' phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
- Activation requires intracellular phosphorylation, into their active triphosphate form like natural nucleotides
  - thus, NRTI efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Adverse effects
- Abacavir hypersensitivity reaction
  - Potentially life-threatening systemic reaction consisting of fever, rash, constitutional symptoms, vomiting, diarrhea, and, occasionally, respiratory distress
  - Avoid abacavir in HLA-B*5701-positive patients.
- Pancreatitis: didanosine, stavudine
- HIV-associated lipodystrophy (Cushing syndrome-like appearance): abnormal distribution of fat
  - Can caused by NRTI or PI
  - Loss of subcutaneous fatty tissue (lipoatrophy) in the face, extremities, and buttocks
  - Probable accumulation of fat in liver, muscles, abdomen, breasts, neck (double chin), and upper back (enlarged dorsocervical fat pad)
  - Metabolic changes: impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL)

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Mnemonic

Zidovudine -> get rid of hemoglobin -> anemia

NNRTIs

Mechanism of action
- Noncompetitive inhibitors of viral reverse transcriptase that bind to the reverse transcriptase at a different location than NRTIs
- NNRTIs do not require intracellular phosphorylation for activation because they are direct inhibitors.

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Protease inhibitors

Mechanism of action: inhibition of viral HIV-1 protease (encoded by pol gene) → inability to cleave viral polyproteins into functional units → generation of impaired viral proteins → production of immature (noninfectious) virions

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