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CATIE-News: Bite-sized HIV/AIDS news bulletinsCaution urged when switching regimensIn many high- and middle-income countries, doctors treating HIV-positive people have a choice of more than 20 drugs in six classes from which to choose when formulating a regimen. Factors that can influence the decision to choose particular medicines include the following:
The combination of two protease inhibitors—one protease inhibitor with another protease inhibitor called ritonavir (Norvir)—results in a potent combination that is often used as part of triple therapy for HIV. One combination in particular, lopinavir + ritonavir, is co-formulated into a fixed-dose tablet and sold under the brand name Kaletra. Regimens containing lopinavir-ritonavir have been widely used in the past decade. This combination of protease inhibitors has a good track record of being effective and generally safe. As a result of the widespread use of lopinavir-ritonavir, in the last four years pharmaceutical companies making new anti-HIV drugs have performed trials comparing the new drug against lopinavir-ritonavir or efavirenz (Sustiva and in Atripla), another commonly used drug. Raltegravir (Isentress) is a relatively new anti-HIV drug that works by interfering with an enzyme called integrase. This enzyme is needed by HIV-infected cells to make more viruses. When raltegravir is used as part of combination therapy in clinical trials, it rapidly reduces HIV levels in the blood, both in people using anti-HIV therapy for the first time as well as in treatment-experienced people. Raltegravir seems to be relatively safe when used in clinical trials. Because raltegravir is new, safe and effective, there is interest in using it as a substitute for established anti-HIV drugs. Merck and Company, Inc., the developer of raltegravir (known as Merck Sharp & Dohme, or MSD, outside of North America) has conducted two clinical trials in which some users of lopinavir-ritonavir-based regimens had this combination replaced with raltegravir. The studies were prematurely halted because of unexpectedly higher rates of virologic failure among some raltegravir users. The possible reasons for this unexpected finding and the implications for decision-making about switching therapies are discussed later in this report. Study detailsResearchers in Australia, the European Union, North and South America, South Africa and Thailand recruited HIV-positive adults for two identical clinical trials called Switchmrk 1 and 2. All participants had been taking a lopinavir-ritonavir-based combination and for three months prior to entering Starkmrk had their viral load below 50 copies in the blood. Volunteers were randomly assigned to either continue to take their lopinavir-ritonavir-based regimens or to replace their lopinavir-ritonavir regimens with raltegravir. Participants kept taking the other medicines in their regimens, usually two nukes (nucleoside analogues). To reduce bias when interpreting the results, the study was designed so that neither participants nor researchers knew who received which drug until the end of the trial. The study was designed to show that raltegravir was roughly equivalent (the technical statistical term is “non-inferior”) to lopinavir-ritonavir when both drugs were used as part of combination HIV therapy. The average profile of participants at the start of the study was as follows:
Results—LipidsAfter 12 weeks, statistically significant reductions in some lipid levels occurred as follows: Total cholesterol
Non-HDL cholesterolNon-HDL cholesterol is calculated by subtracting the amount of good cholesterol (HDL-c) from the total cholesterol.
TriglyceridesLevels of this fatty substance often rise when ritonavir is used. However, the significance of increased triglycerides arising from the use of ritonavir is not clear.
Other changes to lipid levels, such as those involving bad cholesterol (LDL) and good cholesterol (HDL), were small and not statistically significant. Results—Changes in CD4+ countsAfter 24 weeks, there was no significant difference in CD4+ counts between the two study regimens; changes were very small. Results—Changes in HIVResearchers were surprised to find out that the proportion of people taking raltegravir whose regimens had failed (16%) was greater than the proportion of people taking lopinavir-ritonavir (9%) who also developed virologic failure. Another way to examine the overall virologic success of the regimens is to assess what proportion of participants had achieved a viral load below the 50-copy mark by the 24th week of the study:
Because of these differences in virologic outcomes, by the rules of the trial, raltegravir did not meet the standard of being roughly equivalent to lopinavir-ritonavir. Focus on virologic failure—raltegravirA total of 49 participants developed virologic failure during the study, as follows:
Among the 32 raltegravir user who had virologic failure, 27 people (82%) reported that the lopinavir-ritonavir-containing regimen was not their first anti-HIV regimen. What’s more, in 18 of these 27 people, 67% had a history of virologic failure. Only 11 of these 18 participants had blood samples from which HIV could be successfully analysed after the study ended. In eight of these 11 people, technicians found that HIV was resistant to raltegravir. Focus on virologic failure—lopinavir-ritonavirAmong the 17 people who had virologic failure, eight reported that their lopinavir-ritonavir-based regimen was not their first anti-HIV regimen. What’s more, four of these eight people (50%) had a history of virologic failure. What if things had been done differently?Although this was not part of the trial design, because of the unexpected results they encountered, researchers later analysed the data to try to determine the effectiveness of the study’s regimens in people who did not have a history of virologic failure. Here’s what they found:
This finding suggests the possibility that raltegravir might have worked very well if it had been reserved for people whose regimens had not previously failed. Side effectsThe proportion of participants who developed side effects due to their medications was as follows:
Side effects—DropoutsA small number of participants left the study because of adverse effects. Their distribution was as follows:
Making sense of the virologic resultsRaltegravir had powerful anti-HIV activity in previous clinical trials, with both treatment-experienced people and people who were using anti-HIV medicines for the first time. In trials with treatment-experienced people, raltegravir is particularly effective when used with two or more active agents. Protease inhibitors, particularly when taken with a low-dose of ritonavir, present a difficult barrier for HIV to overcome. Major or critical mutations in HIV that confer resistance to ritonavir-boosted protease inhibitors do not usually develop rapidly when these drugs are used as part of combination therapy for the initial treatment of HIV infection. However, raltegravir, like efavirenz (Sustiva and in Atripla), might lose its effectiveness if HIV manages to develop just one major mutation to raltegravir. In Switchmrk 1 and 2, testing volunteers’ blood samples for HIV that might be resistant to the study medications was not done because potential participants were required to have a fully suppressed viral load in their blood. Such a very low viral load makes it very difficult to conduct resistance testing. And because raltegravir was expected to have a high rate of success, detailed records of participants’ treatment history were not kept. What may have happened in Switchmrk 1 and 2 is that some participants, particularly those who had a prior episode of treatment failure, had likely developed HIV that had some degree of resistance to some of the medications they were taking when they entered the study. Thus, when these people with pre-existing drug resistance mutations were given raltegravir, it was equivalent to taking raltegravir with either no additional agents or only partially active agents. This allowed HIV to overcome raltegravir’s antiviral activity. What to do?Commenting on the results of Switchmrk 1 and 2 in the journal Lancet, Dr. Michael Kilby from the Medical University of South Carolina, made this statement: “…whenever possible, to assure sustained dependable activity, even our most promising antiretroviral agents should be used in combination with two or more active drugs.” The researchers involved in the Switchmrk trials made this recommendation to physicians: “In practice, clinicians need to gather all available background information, including past resistance tests and treatment outcomes, when contemplating the potential risks and benefits of modifying a suppressive antiretroviral regimen.” Look for SpiralSpanish researchers have conducted a study called Spiral, which was also designed to assess the impact of switching from lopinavir-ritonavir to raltegravir in virologically stable participants. The interim results from Spiral should become available later in 2010, perhaps at the annual Conference on Retroviruses and Opportunistic Infections (CROI). —Sean R. Hosein REFERENCES:
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Created on: 01/28/2010 |
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Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner who is knowledgeable about HIV-related illness and the treatments in question. MORE | |