FURTHER READING AND WEB MATERIAL
Dybul M, Fauci AS, Bartlett JG et al. Panel on Clinical Practices for
Treatment of HIV. Guidelines for using antiretroviral agents
among HIV-infected adults and adolescents. Annals of Internal
Medicine2002; 137 : 381–433.
Gazzard B; BHIVA Writing Committee. British HIV Association
(BHIVA) guidelines for the treatment of HIV-infected adults with
antiretroviral therapy. HIV Medicine2005; 6 (Suppl 2): 1–61.
Lalezari JP, Henry K, O’Hearn M et al. Enfuvirtide, an HIV-1 fusion
inhibitor, for drug-resistant HIV infection in North and South
America.New England Journal of Medicine2003; 348 : 2175–85.
Martin AM, Nolan D, Gaudieri S et al. Pharmacogenetics of antiretro-
viral therapy: genetic variation of response and toxicity.
Pharmacogenomics2004; 5 : 643–55.
Mofenson LM, Oleske J, Serchuck L et al. Treating opportunistic infec-
tions among HIV-exposed and infected children recommendations
from CDC, the National Institutes of Health, and the Infectious
Diseases Society of America. Clinical Infectious Diseases2005; 40
(Suppl 1): S1–84.
Schols D. HIV co-receptor inhibitors as novel class of anti-HIV drugs.
Antiviral Research2006; 71 : 216–26.
Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, patho-
genesis, prevention, and treatment. Lancet2006; 368 : 489–504.
Recommended websites: http://www.bhiva.org, http://www.hopkins-aids.edu,
http://www.aidsinfo.nih.gov360 HIVANDAIDS
Case history
A 69-year-old man has had a blood transfusion 12 years ago
following surgery for a perforated gastric ulcer. He now com-
plains of a history of fatigue for 18 months and recent weight
loss of 5 lb. After thorough clinical assessment and investiga-
tion, 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 reg-
imen, 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 cap-
sules 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 nucle-
oside analogue reverse transcriptase inhibitors (ZDV and
3-TC) and ‘boosted protease’ inhibitor regimen. The explana-
tion 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 concentra-
tions at a lower lopinavir dose. In addition, lopinavir poten-
tially 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 prima-
rily due to mutual inhibition of metabolism by the gastro-
intestinal 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 bioavail-
ability of lopinavir from the lopinavir/low-dose ritonavir com-
bination shows less variability between individuals, than does
the same dose of lopinavir given without ritonavir.360 HIVANDAIDS