Biology Reference
In-Depth Information
Investigational regimens include combinations such as one to two protease
inhibitors plus NNRTI plus one to two NRTIs, and NRTI-sparing combina-
tions such as one protease inhibitor (plus low-dose ritonavir) plus one NNRTI.
With short-term clinical trials indicating comparable potency and e½cacy
of PI-, NNRTI-, and all-NRTI-containing regimens, the attention should be
rather focused on their di¨erences with regard to long-term outcome, toxicity,
constraints on future regimens, and the e¨ect on viral reservoirs in non-
lymphoid compartments. The answers to these questions and the ratio of the
advantages to disadvantages of these di¨erent treatment strategies will only
come from the results of well-controlled strategic clinical trials, such as ACTG
384, currently conducted by the Adult AIDS Clinical Trials Group (ACTG)
of the National Institutes of Allergy and Infectious Diseases ( NIAID) of the
National Institutes of Health ( NIH), and the European INITIO study. Both
of these large studies are aimed at investigating the e¨ectiveness not just of
single regimens, but rather of di¨erent therapeutic pathways, including a ®rst-,
second-, and eventually third-line regimen.
The choice of speci®c backbone NRTIs is based on convenience, resistance/
toxicity pro®le, and patient preference. Some widely used NRTI combinations
(not in preferred order) are zidovudine plus didanosine, zalcitabine, or lam-
ivudine; and stavudine plus didanosine or lamivudine. AZT and d4T should not
be administered together because of a negative interaction at the cellular level.
PI-containing regimens (two NRTIs plus one PI ) are very often used as ®rst
choice for initiating antiretroviral therapy, and there are su½cient data on the
long-term e¨ectiveness of these regimens. PI regimens have proven potency and
are e¨ective in patients at all levels of plasma viral load. However, there are
important disadvantages that limit their acceptability: a) the complexity of the
regimens makes adherence di½cult; b) cross-resistance between di¨erent PIs
may limit future use should initial therapy fail (and some clinicians may wish to
spare PI for second-line regimens); and c) there is growing concern over the
long-term toxicity of PIs, particularly the fat redistribution and the metabolic
abnormalities whose e¨ect on long-term cardiovascular morbidity and mortal-
ity remains uncertain.
Combinations of two PIs are increasingly being used instead of a single PI
because they have pharmacokinetic advantages (i.e., increase of drug plasma
levels and possibility to use a twice-a-day schedule of administration) and
therefore increase the PI regimen's potency while greatly improving adherence
to therapy. Addition of a low dose of ritonavir (100 or 200 mg twice a day) to
saquinavir, indinavir, or amprenavir improves the pharmacokinetic pro®le,
may reduce pill burden, lower the dose frequency, lower cost, and obviate the
need for administration of PIs on an empty stomach. A co-formulation of
lopinavir plus ritonavir, based on an extremely potent interaction, has been re-
cently introduced. The long-term bene®t and toxicity of dual PI combinations
remains to be fully characterized.
Combinations between NNRTIs and NRTIs have recently gained popular-
ity as ``PI-sparing'' regimens. There is convincing evidence from controlled
clinical trials that, in treatment-naive patients, NNRTI regimens o¨er a suit-
