A Textbook of Clinical Pharmacology and Therapeutics

354 HIVANDAIDS

Drug interactions

These are numerous and clinically important; the following
list is not comprehensive:

1. probenecidinhibits 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.ganciclovirand 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

Tenofoviris the first nucleotide (as distinct from nucleoside)
reverse transcriptase inhibitor (NERTI) and is used in combina-
tion 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. Tenofoviris 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.

Tenofoviris also active against hepatitis B virus (HBV).

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, t1/2is 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 t1/2of

toxicity is rare. as a buffered capsule. 24–40 h. Didanosine decreases

Gastro-intestinal upsets Plasma t1/2is 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). Tmaxis 2 h; t1/2of 3–4 h. In vitro data show

plasmat1/2is 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; t1/2of Intracellular triphosphate has

3-thiacytidine) gastro-intestinal upsets, 3–6 h. Renal excretion t1/2of 12 h. Synergy in vitro with

hair loss, myelosuppression, (unchanged), requires dose ZDV against HIV. Co-

neuropathy reduction in renal impairment trimoxazole reduces

clearance by 40%

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.