Anti- HIV

Question 1

Outline Highly Active Antiretroviral Therapy (HAART)

Answer 1

When to start tx

• CD4 < 500
• Pt has AIDS defining illness
• High viral load
• Decrease transmission or if pregnant woman

Combination of 3 or more anti-retrovirals
- 2 nucleoside/nucleotide RTIs + either: a NNRTI, a P.I + Ritonavir booster, an integrase inhibitor

Question 2

Guidelines for use of antiretrovirals in pregnancies complicated by HIV

Answer 2

• Mother HIV +ve and meets HAART criteria - start on zidovudine + Lamivudine + another agent
• Mother HIV +ve but doesn’t meet HAART criteria - start tx by 2nd trimester
• After birth, if mother doesn’t meet HAART criteria then stop therapy
• For baby, if mother’s viral load at time of birth is <50, start on zidovudine, if mother’s viral load is >50 then start on 3 drug HAART therapy for 4 weeks

Question 3

Reverse Transciptase Inhibitors;
NRTIs - Examples, M.O.A, Adverse effects

NNRTIs - Examples, M.O.A, Adverse effects

Answer 3

NRTI (Nucleoside Reverse Transcriptase Inhibitors)

E.g. zidovudine, tenofovir, abacavir, Lamivudine

M.O.A - RT will create DNA from viral RNA using available nucleotide, however, when it selects an NRTI and this is incorporated into DNA, it will prevent the addition of further nucleotides, therefore inhibiting DNA synthesis

A.E’s - BM suppression and anaemia, mitochondrial toxicity leading to peripheral neuropathy and lactic acidosis

All are nucleosides, except for Tenofovir (nucleotide), which much be phosphorylated to their active form
Zidovudine can be used as general prophylaxis or during pregnancy to decrease the risk of foetal transmission

NNRTIs - Efavirenz, Delavirdine, Nevirapine

M.O.A - non-competitively bind to RT at a site other than NRTIs to prevent the conformational change of RT required to start transcription of RNA to DNA - don’t need to be phosphorylated to their active form

A.Es - Hepatotoxcity and rash (SJS), Efavirenz can cause vivid dreams, both Efavirenz and Delvirdine are contraindicated in pregnancy

Question 4

Protease Inhibitors

• Examples
• M.O.A
• Adverse effects

Answer 4

• All end in “navir” - atazanavir, indinavir
• M.O.A - inhibit viral protease, which cleaves viral polypeptides into mature, viable proteins and therefore prevents the formation of a mature virus
• Ritonavir can be given to boost P.Is by inhibiting CYP450

A.E’s - hyperlipidaemia, GI problems (diarrhoea), lipid redistribution

Question 5

Integrase Inhibitors

• Examples
• M.O.A
• Adverse effects

Answer 5

• Raltegravir
• M.O.A - inhibit viral integrase, which incorporates viral DNA into host cell genome
• A.E’s - hypercholesterolaemia

Question 6

Fusion and Entry Inhibitors (M.O.A)

• Enfuvirtide
• Maraviroc

Answer 6

Enfuvirtide (entry)
- inhibits gp41 preventing viral entry

Maraviroc (fusion)
- inhibits CCR5 on T cells and macrophages, preventing their interaction with gp120

Question 7

Co-Trimoxazole

• Indications
• Basis for its use
• MOA
• A.E’s

Answer 7

Co-Trimoxazole (trimethoprim + sulfamethoxazole)

Indicated for CD4 <200, toxoplasma gondii, pneumocystis jirovecci, UTIs, pneumonia

Basis - bacteria must make their own tetrahydrofolate for nucleotide and DNA synthesis. Pathway:

• PABA to dihydropteroic acid (by dihydropteroate synthase)
• Dihydropteroic acid to dihydrofolate
• Dihydrofolate to tetrahydrofolate (by dihydrofolate reductase)

Sulfonamides inhibit dihydropteroate synthase
S.E’s - hypersensitivity rash, nephrotoxicity, photosensitivity, kernicterus in children etc

Trimethoprim inhibits dihydrofolate reductase
S.E’s - BM suppression - megaloblastic anaemia, leukopenia, granulocytopenia