Clinical Pharmacology and Therapeutics

354 HIV AND AIDS
Drug interactions
These are numerous and clinically important; the following
list is not comprehensive:
1. probenecid inhibits the glucuronidation and renal
excretion of ZDV;
2. ZDV glucuronidation is reduced by atovaquone;
3. rifamycins increase ZDV metabolism;
4. ZDV and antituberculous chemotherapy cause a high
incidence of anaemia;
5. ganciclovir and ZDV combined therapy produces
profound bone marrow suppression;
6. ZDV/ddI or ZDV/3-TC combinations (but not
ZDV/D4T) are synergistic.
Table 46.2 shows the properties of other NRTIs used in HIV
therapy.
NUCLEOTIDE REVERSE TRANSCRIPTASE
INHIBITOR
Tenofovir is the first nucleotide (as distinct from nucleoside)
reverse transcriptase inhibitor (NERTI) and is used in combination
with NRTIs. It is a derivative of adenosine monophosphate,
but lacks the ribose ring. It is phosphorylated sequentially to the
diphosphate and then the triphosphate which is a competitive
inhibitor of HIV reverse transcriptase. It is adequately absorbed
orally and administered once a day (half life 14–17 hours). It is
renally eliminated. Tenofovir is well tolerated with few adverse
effects (mainly flatulence). Occasional cases of renal failure and
Fanconi syndrome have been reported, so it should be used with
caution in patients with pre-existing renal dysfunction.
Although it is not a CYP450 inhibitor or inducer, it increases the
AUC of didanosine and reduces the AUC of atazanavir.
Ritonavir and atazanavir increase the AUC of tenofovir.
Tenofovir is also active against hepatitis B virus (HBV).
Key points
Anti-HIV drugs – nucleoside analogue reverse transcriptase
inhibitors – ZDV
• Used in combinations to increase anti-HIV efficacy and
reduce resistance.
• Zidovudine is phosphorylated intracellularly to ZDV-TP,
which inhibits viral reverse transcriptase.
• Good oral absorption, penetration of CSF, hepatic
metabolism and short half-life.
• Adverse effects include bone marrow suppression and
myopathy in the long term.
• Used in HIV-positive pregnant women, in whom it
reduces transmission to the fetus/neonate by
approximately 60%.
• Combination NRTI therapy, e.g. ZDV/3-TC form the
‘backbone components’ of HAART.
• Resistance develops slowly to NRTIs.
• Genotyping of the HIV mutations for drug resistance
may guide drug choice.
Table 46.2: Properties of other anti-HIV NRTIs
Anti-HIV nucleoside Side effects Pharmacokinetics Additional comments
analogue
Emtricitabine (FTC) – a One of the least toxic NRTIs. Well absorbed. Food – no FTC-TP long intracellular
cytosine analogue, Skin pigmentation, hepatitis, effect on AUC, t 1/2 is 8–10 h. half-life
chemically related to pancreatitis Renal excretion
lamivudine
Didanosine (ddI; Peripheral neuropathy, Acid-labile absorption Intracellular triphosphate
dideoxyinosine) pancreatitis, bone-marrow affected by pH – given anabolite ddA-TP has a t 1/2 of
toxicity is rare. as a buffered capsule. 24–40 h. Didanosine decreases
Gastro-intestinal upsets Plasma t 1/2 is 0.5–1.5 h. absorption of drugs requiring
and hyperuricaemia Renal excretion (50%) and acid pH (e.g. keto- or
hepatic metabolism
itraconazole)
Stavudine (d4T; Peripheral neuropathy Well absorbed (86% Intracellular triphosphate has
didehydro-thymidine) bioavailability). T max is 2 h; t 1/2 of 3–4 h. In vitro data show
plasma t 1/2 is 1 h, rapidly
antagonism with ZDV
cleared by renal (50%) and against HIV
non-renal routes
Lamivudine (3-TC; 2-deoxy- Well tolerated. Uncommon Well absorbed; t 1/2 of Intracellular triphosphate has
3-thiacytidine) gastro-intestinal upsets, 3–6 h. Renal excretion t 1/2 of 12 h. Synergy in vitro with
hair loss, myelosuppression, (unchanged), requires dose ZDV against HIV. Coneuropathy
reduction in renal impairment trimoxazole reduces
clearance by 40%