Clinical Pharmacology and Therapeutics

360 HIV AND AIDS
Case history
A 69-year-old man has had a blood transfusion 12 years ago
following surgery for a perforated gastric ulcer. He now complains
of a history of fatigue for 18 months and recent weight
loss of 5 lb. After thorough clinical assessment and investigation,
he was found to be HIV-1-positive. His HIV-1 RNA was
150 000 copies/mL and his CD4 count was 200 cells/μL on two
occasions. He was started on ZDV (300 mg twice a day) and
lamivudine (150 mg twice a day) given as the combination
tablet ‘Combivir’ one tablet twice a day, and lopinavir
200 mg/ritonavir 50 mg capsules; one capsule twice a day.
Two months later, he does not feel significantly better and
despite his HIV isolate being sensitive to all agents in the regimen,
his plasma HIV RNA is 110 000 copies/mL. He was
adamant that he was taking his medication correctly and was
tolerating it well and this was confirmed by his wife. His
physician increased his lopinavir/ritonavir combination capsules
to two capsules twice a day, When reviewed four weeks
later, he had put on weight and felt less tired, and his plasma
HIV RNA was 45 000 copies/mL.
Question
What is the underlying pharmacological principle of the
benefit of combining lopinavir with low-dose ritonavir?
Answer
This patient with late-stage HIV-1 infection was started on a
‘triple’ combination therapy regimen consisting of two nucleoside
analogue reverse transcriptase inhibitors (ZDV and
3-TC) and ‘boosted protease’ inhibitor regimen. The explanation
for the therapeutic benefit of the lopinavir/low-dose
ritonavir combination is that ritonavir causes the systemic
lopinavir exposure (AUC) to be increased by between 10- and
15-fold, yielding more effective anti-HIV lopinavir concentrations
at a lower lopinavir dose. In addition, lopinavir potentially
increases the AUC of ritonavir, although the extent and
clinical relevance of this interaction is less important as the
IC 50 of HIV-1 for lopinavir is ten times lower than that for
ritonavir, thus most of the anti-HIV effect of the lopinavir/
ritonavir combination is due to the lopinavir. These effects on
the oral bioavailability of lopinavir and ‘first-pass’ metabolism
of each of these protease inhibitors are thought to be primarily
due to mutual inhibition of metabolism by the gastrointestinal
and hepatic CYP3A isoenzyme. Data also show that
lopinavir is a P-glycoprotein substrate and that inhibition of
the gastro-intestinal P-glycoprotein drug efflux transporter
by ritonavir increases the bioavailability of lopinavir in this
complex drug–drug interaction. Additionally, the bioavailability
of lopinavir from the lopinavir/low-dose ritonavir combination
shows less variability between individuals, than does
the same dose of lopinavir given without ritonavir.
FURTHER READING AND WEB MATERIAL
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Lalezari JP, Henry K, O’Hearn M et al. Enfuvirtide, an HIV-1 fusion
inhibitor, for drug-resistant HIV infection in North and South
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Mofenson LM, Oleske J, Serchuck L et al. Treating opportunistic infections
among HIV-exposed and infected children recommendations
from CDC, the National Institutes of Health, and the Infectious
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Schols D. HIV co-receptor inhibitors as novel class of anti-HIV drugs.
Antiviral Research 2006; 71: 216–26.
Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis,
prevention, and treatment. Lancet 2006; 368: 489–504.
Recommended websites: www.bhiva.org, www.hopkins-aids.edu,
www.aidsinfo.nih.gov