HIV Antiviral Agents

Latent period – Time from point of infection to point of diagnosable infection

Detection of antibodies to virus – window period of 3 mos to 1 year; ELISA, EIA, and Western blotting; blood draw (1-3 wks), rapid (SUDS) available in 5-30 min, oral mucosa (OraSure), urine (less sensitive).

Detection of the virus – days to 2 wks; detection of RNA via PCR or branched chain DNA; detection of HIV viral protein (p24 usually done).

AIDS – 10^6 virus particles, <200>

Advanced HIV infection – 10^6 virus particles, <50>

HAART therapy – 2 RTIs and at least 1 PI or Efavirenz (NNRTI). Results of therapy are expected to show 1 log unit decrease at 8 weeks and no detectable virus at 4-6 months after initiation of treatment. Failed therapy should change at least 2 agents that are not likely to show cross-resistance with drugs given previously.

The goal of HIV antiviral therapy is to get the HIV viral load as low as possible and keep it there as long as possible. The majority of therapies affect the virus directly (RTIs and PIs), although some do affect the host by limiting virus activity in host.

Life cycle of HIV and key points for potential therapy –

1. Binding to host cell (experimental);

2. RT;

3. Integrase (no drugs);

4. Protease;

5. Immune system stimulators (experimental);

6. Host ribonucleotide reductase.

Nucleoside analogues (NRTIs) – Prodrugs. Must be formed into triphosphate nucleotide to be incorporated into DNA. Administered orally, with bid dosing. Competitive inhibitors to reverse transcriptase at the nucleotide binding site.

• Abacavir (ABC) – Good CSF penetration; life-threatening hypersensitivity.

• Didanosine (ddI) – Pancreatitis, peripheral neuropathy; ddI decreases the absorption of any drug that requires gastric acidity for absorption; synergistic effects with any drug that causes pancreatitis or peripheral neuropathy.

• Lamivudine (3TC) – Called Combuvir when combined with AZT; also used for treatment of hepatitis B; pancreatitis in pediatric patients.

• Stavudine (d4T) – DO NOT COMBINE WITH AZT; additive effect with any drug that causes peripheral neuropathy (ddI, ddC, INH).

• Zalcitabine (ddC) – TID dosing; peripheral neuropathy, pancreatitis, hepatitis (must monitor liver enzyme levels); additive effect with any drug that causes peripheral neuropathy.

• Zidovudine (AZT) – Good CNS penetration; bone marrow suppression (anemia, neutropenia), myopathu, macrocytosis, hepatitis; antagonistic to d4T; marrow suppression precludes concurrent use with ganciclovir or other marrow suppressants.

Non-nucleoside analogues (NNRTIs) – These agents DO NOT require activation. Orally administered with. Cross-resistance DOES NOT develop between NNRTIs and NRTIs. Cross resistance DOES occur within class. Noncompetitive inhibitor of RT. Most metabolized in liver and excreted by kidney.

• Delavirdine – Inhibits p450 enzymes; requires gastric acidity so caution with ddI.

• Nevirapine – Severe but transient rash on trunk, face, and mucous membranes; induces p450 enzymes; reduces indinavir levels.

• Efavirenz – Dizziness and “disconnected” feeling; induces p450; avoid clarithromycin.

Nucleotide analogues – Not FDA approved

• Adefovir – Obvious CNS penetration; severe nephrotoxicity and CNS effects; induces p450; reduces indinavir levels.

• Tenofovir

Protease inhibitors – Even in combination therapy resistance develops and it can be cross-resistance to compounds from within the same class.

• Amprenavir – Excreted in feces; rashes, diarrhea, nausea; inhibits p450; rifampin decreases amprenavir levels dramatically; efavirenz lowers levels 40%.

• Indinavir – Taken while fasting or with light, low-fat meal; biliary metabolism; dessication likely; kidney stones; lipodystrophy; inhibits p450; levels increased by delavirdine and nelfinavir; levels reduced by nevirapine and grapefruit juice; ddI reduces absorption

• Lopinavir

• Nelfinavir – Diarrhea; inhibits p450; biliary metabolism.

• Ritonavir – Biliary metabolism; GI intolerance, paresthesias, taste perversions; potent inhibition of p450; ddI decreases absorption; increases levels of AZT and saquinivir.

• Saquinavir – Fatal arrhythmias when used with cisapride; do not combine with indinovir; levels increased by grapefruit juice; levels increased by ritonavir.

Host’s ribonucleotide reductase

• Hydroxyurea – Inhibits cellular ribonucleotide reductase, inhibiting formation of deoxynucleotides. This leads to induction of cellular kinases causing increased phosphorylation of NRTIs. Metabolized in liver and excreted in lungs and urine. Use only if ddI is being used. Considered salvage therapy. Bone marrow suppression, GI intolerance, and increased risk of neuropathy. Contraindicated in renal failure.

Bad combinations – d4T+AZT, ddC+ddI, ddC+d4T (peripheral neuropathy); ddC+3TC (resistance); NNRTI combinations (lack of known synergy)

Pregnancy – Only drug shown to reduce risk of perinatal HIV transmission is AZT. Initiated at 14-24 weeks of gestation and continued to onset of labor. IV AZT during labor until delivery. AZT for newborn for first 6 weeks of life beginning 8-12 hrs after birth.

Post exposure prophylaxis – Initiate therapy within 72 hrs (1-2 hrs if possible). AZT+3TC+indinavir/ nelfinavir. Check HIV RNA levels at 14 days and discontinue if undetectable.

Category: Pharmacology Notes