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Quantifying ARTs & Combination Effectiveness by R Silciano et al
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A quantitative basis for antiretroviral therapy for HIV-1 infection by R Siliciano et al - (02/23/12)
"This approach provides a quantitative basis for HAART. HAART controls viral replication because of steep, upwardly inflected dose-response curves for some drugs and synergies reflecting the independent action for other drugs. Despite the extremely high IIPave of some regimens, HAART is not curative because of stable reservoirs of nonreplicating virus39,40. Our results demarcate a minimum threshold level of antiviral activity (IIPave = 5-8 logs) necessary for successful treatment. Above this range, additional inhibitory potential is not necessarily beneficial, particularly if it involves the use of poorly tolerated drugs. Evaluating new regimens in relation to this threshold may reduce the need for costly clinical trials for regimens lacking sufficient IIPave. This approach also permits a comprehensive search for regimens with suprathreshold antiviral activity, maximum tolerability and minimum cost. Simpler two- or three-drug regimens with adequate IIPave but lower cost and toxicity may be important for extending therapy in resource-limited settings. Finally, this approach may allow more rational selection of salvage regimens."
"Grouping curves by drug class and normalizing by IC50 revealed that all protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have steep, upwardly inflected curves, with maximum slopes >3 and >2, respectively (Fig. 1e and Supplementary Table 1) .......For the protease inhibitors ATV, darunavir (DRV) and lopinavir (LPV) and the NNRTI efavirenz (EFV), curves inflect upward at concentrations below the minimum plasma concentration (Cmin), giving extraordinarily high IIP at clinical concentrations, consistent with clinical trial results10,11 ..........Overall, the results explain the established clinical value of NNRTIs and protease inhibitors10,11. Treatment guidelines have until recently recommended that all initial HAART regimens include an NNRTI or protease inhibitor10,11. Steep, upwardly inflected curves allow these drugs to achieve extremely high IIPave. We previously estimated that 1 · 106 infection events occur per viral generation in the average untreated patient, suggesting that IIPave > 6 would be required to immediately halt replication23. Only NNRTIs and protease inhibitors approach this level. The protease inhibitor DRV has the highest IIPave. Of note, protease inhibitors are the only class for which monotherapy has been successful24-26. .........Some drugs with low IIPave such as RAL and the chemokine receptor antagonist maraviroc (MVC) are effective in combination therapy27,28. We hypothesized that these drugs might have favorable or synergistic interactions in combinations that compensate for low intrinsic IIPave. .......Drugs binding to the same site, such as the hydrophobic NNRTI pocket31, should follow Loewe additivity. This is illustrated by the NNRTI-NNRTI combination etravirine (ETR)-nevirapine (NVP) ........These results suggest that a minimum of 5-8 logs of inhibition are required for successful HAART .......Three of the other regimens currently recommended for initial treatment had IIPave1+2+3 >8, primarily owing to the IIP of the base drug (EFV, ATV/r, DRV/r) . Above IIPave1+2+3 = 7, there was little correlation with outcome (correlation coefficient = 0.125, P = 0.29) because above this level, replication is essentially halted, and outcome depends mainly on adherence."
Which Anti-HIV Drug Combinations Work Best and Why?
ScienceDaily (Feb. 19, 2012) - Using a mathematical formula that carefully measures the degree to which HIV infection of immune system cells is stalled by antiretroviral therapy, AIDS experts at Johns Hopkins have calculated precisely how well dozens of such anti-HIV drugs work, alone or in any of 857 likely combinations, in suppressing the virus. Results of the team's latest research reveal how some combinations work better than others at impeding viral replication, and keeping the disease in check.
"Our study results should help researchers and clinicians develop simpler treatments, using either existing or new drugs, for people who are just starting therapy or people who have already tried and developed resistance to another combination," says senior study investigator and infectious disease specialist Robert Siliciano, M.D., Ph.D.
Siliciano, a professor at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator, and colleagues constructed the measurement tool, called the instantaneous inhibitory potential, or IIP, in the laboratory several years ago by analyzing the shape of drug dose-response curves in human immune system cells infected with HIV. They found that the curves' steepness reflects the extent to which small increases in the amount of drugs can further suppress attempts by the virus to bounce back, reproduce and spread.
Researchers say their latest study findings, to be published in the journal Nature Medicine online Feb. 19, along with other recent studies, provide valuable information to physicians about the potential strength of different combination drug therapies, and can help in streamlining and tailoring so-called highly active antiretroviral therapy, or HAART, to as few possible drugs as needed. Several hundred thousand of the more than 1 million Americans living with HIV disease are currently using HAART to fight the disease.
Among the latest study's key findings was that the most potent drug combos included the drugs efavirenz (a non-nucleoside reverse transcriptase inhibitor) and darunavir (a protease inhibitor.) According to the Hopkins team's calculations, the drug mix suppressed viral replication by more than a trillion times, enough to prevent infection of every single lymphocyte, or immune system cell, of which there are a trillion in the body.
The least-powerful drug was found to be one of the oldest anti-HIV medications, d4T, or stavudine (a nucleoside analogue reverse transcriptase inhibitor), which had the power to suppress viral replication by less than 10 times if used on its own (although, Siliciano points out, it works much better when taken in combination with other drugs.)
Siliciano says the most widely used combination, a single pill known as Atripla, consisting of tenofovir disoproxil fumarate (a nucleotide analogue reverse transcriptase inhibitor), emtricitabine (a nucleoside analogue reverse transcriptase inhibitor), and efavirenz, was able to reduce viral replication to as few as one in a billion.
Siliciano points out, however, that any drug combination which suppresses viral replication to the degree that out of every 100,000 lymphocytes exposed to the drugs, only one lymphocyte is likely to be infected (for five tenfold reductions) -- is sufficient to keep the disease in check, so long as people take their medication as prescribed.
"This means that overall access to anti-HIV medications could also improve as we develop simpler combinations of fewer drugs to achieve near total suppression," says Siliciano. Less than 7 million of the 34 million people worldwide infected with HIV are taking antiretroviral therapy, he notes.
The Johns Hopkins team based its new calculations on five years of analyzing just how antiretroviral drugs hinder key steps in HIV's life cycle, preventing it from replicating and infecting other immune system cells.
Scientists have for decades focused on multiple drugs targeting different enzymes that are key to the viral life cycle, thinking that multiple barriers along the chain could best halt replication.
Although the strategy worked, scientists had, until now, no theory to explain why some drug combinations worked well and others did not. Indeed, they point out, one of the newest classes of anti-HIV medications, so-called integrase inhibitors, did not work well as single drug treatments in laboratory experiments, but were highly effective in people when combined with other drugs.
Siliciano says that as a result of the Hopkins team's latest research and another of their recent findings, published in Science Translational Medicine in July, experts can finally demonstrate how different drug combinations disrupt and halt viral replication.
Researchers found that the steepest curves occurred when the drug targeted a stage in HIV's life cycle, in which many copies of viral enzymes, were needed. Citing protease inhibitors as an example, Siliciano says several copies of protease enzyme are needed to cleave the virus into hundreds of working parts before HIV can infect a new immune system cell. He goes on to say that "a level of inter-enzyme cooperation" is happening, specific to each stage of HIV replication.
"Our research shows that drugs like protease inhibitors really work like an on-off switch," says Siliciano. "Above a certain concentration, these drugs completely turn off viral replication. When you have only one copy of a viral enzyme needed in any key part of HIV's life cycle, a little more drug won't give you a lot more suppression; but, when you have more than one copy of enzyme needed for viral replication, then the dose-response curve for the drug will be a lot steeper, and a little more drug will completely shut off viral replication, which is what we want.
"It's gratifying to finally have a consistent metric for evaluating HAART medications that offers reliable information on how well they work in stopping HIV replication, and which also gives us a baseline target for suppression at less than one in 100,000 immune cells becoming infected in the presence of any drug combination," he adds.
The Johns Hopkins inhibition index was first developed to compare the level of viral inhibition from different drugs in different classes and to show how they could be graded.
Having measured the different potencies of many drugs, Siliciano conducted his next set of lab experiments to focus on the explanation behind different strengths of viral inhibition. The scientists measured the changes in the dose-response curves, plotting the results on graphs and comparing the sloping curves for each drug or combination of drugs.
Funding for this study, conducted solely at Johns Hopkins, was provided by the Howard Hughes Medical Institute and the National Institute of Allergy and Infectious Diseases, a member of the National Institutes of Health (NIH).
Besides Siliciano, other Hopkins researchers who took part in this study were lead investigator Benjamin Jilek, Ph.D.; Melissa Zarr, B.Sc.; Maame Sampah, B.Sc.; Alireza Rabi, B.Sc.; Cynthia Bullen, B.Sc.; Jun Lai, B.Sc.; and Lin Shen, M.D., Ph.D.
Currently, there are more than 34 million people in the world living with HIV, including an estimated 1,178,000 in the United States.
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