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  HIV DART 2008
Rio Grande, Puerto Rico
December 9-12, 2008
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Siliciano Proposes Novel Gauge of Antiretroviral Activity
  HIV DART 2008, December 9-12, 2008, Rio Grande, Puerto Rico
Mark Mascolini
A new way to rate antiretroviral activity ranks darunavir as the strongest current antiretroviral. Tied for second place are saquinavir and indinavir [1,2].
What's wrong with this picture? Nothing, according to Robert Siliciano of Johns Hopkins University. The first scientist to show that current antiretroviral combinations cannot eradicate the virus, Siliciano seems set to shake up the HIV field again with a new yardstick--instantaneous inhibitory potential (IIP)--to gauge activity of antiretrovirals.
Everyone would agree that darunavir, the highest-ranking drug in Siliciano's scheme, is a powerhouse antiretroviral. But saquinavir and indinavir? And the surprises don't end there. Integrase inhibitors like raltegravir are no stronger than nucleosides, according to IIP analysis. Nonnucleosides (NNRTIs) do a little better.
Siliciano spelled out the details at HIV DART 2008 [1] and in a recent Nature Medicine report [2]. He argued that standard dose-response methods, like 50% inhibitory concentration (IC50) or inhibitory quotient (drug concentration/IC50), have a severe limit: They're linear, while potent antiretroviral combinations have an exponential (logarithmic) impact in limiting viral replication. As a result, Siliciano proposed, you need a logarithmic scale to measure antiretroviral activity.
The new tool depends on a single-round infectivity assay in which primary CD4 lymphoblasts are transfected with a plasmid carrying the HIV provirus minus env and an X4 env expression vector. Measuring viral release from the cells yields IIP, a dose-response curve for antiretrovirals. IIP equals the number of logs (factors of 10) by which a clinically relevant antiretroviral concentration reduces a single round of infectivity.
All current nucleosides, as well was tenofovir, yield a dose response slope approximating 1, as did raltegravir, elvitegravir, and three experimental integrase inhibitors. The six NNRTIs studied had slopes in the neighborhood of 2 log (100-fold), as did the fusion inhibitors enfuvirtide and T1249. Slopes ranged from 2 to 3 log (100- to 1000-fold) for amprenavir, atazanavir, lopinavir, nelfinavir, and tipranavir. Indinavir and saquinavir had about a 4-log effect (10,000-fold), while darunavir had close to a 5-log impact (100,000-fold) in stopping a single round of replication. The Hopkins team has not completed evaluation of CCR5 antagonists such as maraviroc and vicriviroc, but Siliciano expects their IIP to approximate 1.
At maximum concentrations of the drugs studied, IIPs ranged all the way up to 10-log (10 billion-fold) for darunavir, indinavir, and saquinavir, while the other PIs had values ranging from about 3- to 7-fold, NNRTIs from 3- to 6-fold, NRTIs from 1- to 4-fold, and integrase inhibitors from about 2- to 3-fold. IIP explains why standard first-line regimens including a PI or an NNRTI do so well, Siliciano proposed, but it does not explain why saquinavir and indinavir nearly equaled darunavir but fell from favor, or why viral load dropped faster with raltegravir than with efavirenz in a trial that enrolled previously untreated people [3]. The problem with saquinavir and indinavir, Siliciano explained, is that both have short half-lives. As a result their IIP slope decays rapidly after the last dose.
To explain the faster response to raltegravir than efavirenz [3], Siliciano noted that rapid decay of circulating virus reflects turnover of cells that can produce virus during treatment. More rapid decay would be expected with raltegravir, he reasoned, since blocking viral integration leaves a smaller and "older" population of infected cells. As for the prolonged effect of raltegravir plus tenofovir/emtricitabine in this trial (up to 96 weeks at last report), Siliciano maintained that once a regimen suppresses active replication, it doesn't matter whether you have 10-log inhibition or 2-log inhibition: virus won't rebound as long as a person keeps taking the drugs.
On the basis of these results, Siliciano concluded that the best way to pick an antiretroviral regimen is to figure out how much inhibition a person needs to control HIV quickly, then to pick drugs that yield that level of inhibition without causing toxicity. He stressed that IIP is hardly the only factor that should be considered in choosing a regimen or in figuring why it works--or doesn't. And HIV DART attendees eagerly underlined that point. Other variables not directly addressed by IIP, they suggested, include activity against resistant virus, genetic barrier to resistance, compartment penetration, and protein binding by antiretrovirals.
1. Shen L, Peterson S, Sedaghat AR, et al. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. HIV DART 2008. December 9-12, 2008. Rio Grande, Puerto Rico. Abstract 07.
2. Shen L, Peterson S, Sedaghat AR, et al. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med. 2008;14:762-766.
3. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125-133.