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Ziagen,Emtriva and Reyataz
Sep 10, 2008

Dear Dr. Frascino,

Any thoughts on the combination Ziagen, Emtriva and Reyataz. I have been on Truvada, Norvir and Reyataz for the last 8 months and am having some diarrhea from it. I had the Ziagen blood test and it came back negative so should be ok on that drug. I'm thinking of this combination because I suspect the Norvir is causing some of the diarrhea as well as the Viread in the Truvada. Have also discussed with my Dr. about staying on the Truvada, eliminating the Norvir but then increasing the Reyataz. Any thoughts on that also? What dose of Reyataz would you then recommend in this case? My doctor seems to be willing to work with me (trying a new combination) even though there may not be a clinical trial examining the combination so as to eliminate the side effects and keep me happy and on the drugs which are saving my life. Thank you for your much appreciated advice, Scott

Response from Dr. Frascino

Hello,

Your problem is a common one! Gastrointestinal problems are a frequent complaint among those of us on antiretrovirals, particularly Norvir! Over time, we have become better at managing this annoying side effect by using medications to control the symptoms, manipulating the dose or timing of the medication and, when necessary, switching to an alternative regimen. The decision to change a medication regimen needs to be based on many factors, including drug resistance profiles, drug-drug interactions, dosing convenience, number of pills, etc. You should work closely with a competent HIV specialist physician to evaluate your symptoms (not all diarrhea in HIVers is caused by their meds!) and to discuss dosage modification (this can be tricky) or a switch in therapy (which in turn may well have its own set of challenges, side effects and toxicities).

Regarding the options you propose:

1. I am not a fan of Ziagen. The blood test you had (HLA-B*5701 ) will decrease your chances of having severe abacavir-induced hypersensitivity. However, there are other problems associated with this drug, including an increased risk of cardiac complications (see below) and recent reports that it is not as potent as other agents in this class of drugs (see below).

2. Regarding unboosted Reyataz, I also would not recommend this and certainly not when concurrently using Truvada.

Talk to your HIV specialist. There may well be a way to minimize your diarrhea. Depending on your resistance profile, one possibility might be Isentress, Intellence and Norvir-boosted Prezista. By using a once-daily dosing of Prezista, you can decrease your Norvir to a single 100 mg dose per day. As always Scott, quality of life must be an integral component of all treatment equations. Working closely with a knowledgeable HIV specialist is key.

Good luck.

Dr. Bob

Position Statement by the D:A:D Steering Committee February 4, 2008 Regarding: Abstract entitled "Do Thymidine Analogues, Abacavir, Didanosine and Lamivudine Contribute to the Risk of Myocardial Infarction (MI)? (vis a vis: Recent Use of Abacavir and Didanosine, but not of Thymidine Analogues, Is Associated with Risk of Myocardial Infarction): the D:A:D Study" presented at Conference on Retroviruses and Opportunistic Infections (CROI), Boston, 2008 This abstract details new findings suggesting that current use of the antiretroviral drugs, abacavir and didanosine (ddI), may be linked to an increased risk of heart attacks (myocardial infarctions). This was shown in patients who used either of the two drugs. Abacavir use was associated with a 90% increased risk of getting a heart attack. The risk of a heart attack with use of ddI was increased by 49%. The data showed that the effect from abacavir and ddI on increased risk of a heart attack was observed only while patients were receiving the drug(s), but not in patients that previously had received them but had stopped them more than 6 months previously. This finding suggests that the drug effect is reversible upon cessation of the drug(s). There is no evidence to suggest that duration of exposure to either drug(s) increased the risk of a heart attack. Conversely, no increased risk of heart attacks was noted with the use of d4T (stavudine), AZT (zidovudine) and 3TC (lamivudine), three other drugs in the same drug class of nucleoside reverse transcriptase inhibitors (NRTIs). There were insufficient amount of data to assess the role of two other drugs in this class - tenofovir and emtricitabine. It is important to keep in mind that the associations described in this abstract are based on follow-up of a large number of patients over a long period of time. However, the findings are not based on a trial in which patients were randomized (assigned by chance) to receive one drug or another so it is impossible to definitively exclude the possibility that the findings are explained by bias. However, the authors extensively investigated this possibility and could not find any evidence for appreciable bias. These findings are derived from the year seven analyses of the (D:A:D) study (Data collection of Adverse effects of anti-HIV Drugs Study).1 This study was initiated in 1999, and includes 33,347 patients from around the world, of whom 517 developed a heart attack during 157,912 prospective observational person-years. Of the 517 patients with a heart attack, 192 were using abacavir and 124 were using ddI, as part of their anti-HIV drug regimen at the time when the heart attacks occurred. The effect of abacavir and ddI was most pronounced in absolute terms in patients with a high underlying cardiovascular risk due to other factors.2 Therefore, the clinical implications of the results of this abstract must take into account an individual patient's underlying cardiovascular risk. To give an estimate of the magnitude of the increased risk of heart attacks associated with the use of these drugs, the 1.9-fold (90%) increased risk associated with use of abacavir compares with a 2-3 fold increased risk of heart attack associated with current cigarette smoking. Thus, a patient who is a smoker and is using abacavir is at substantial risk of a heart attack. However, in this situation it would appear that for such a patient, stopping smoking would do more to reduce the risk of having a heart attack and other serious diseases more than by stopping abacavir. It is important to keep in mind that smoking has other detrimental health effects in addition to risk of heart attacks. A possible biological mechanism underlying the increased risk of a heart attack in association with use of abacavir and didanosine was not identified in the study and remains unknown, although the analyses did not suggest that known metabolic abnormalities were the culprits. The authors of the study1 recommend that patients receiving abacavir or ddI should consult their doctor, and discuss whether a modification of their anti-HIV drug regimen is appropriate. Patients should NOT stop any drug without prior discussion with their doctor. The authors are currently completing a manuscript detailing the findings, for submission to a peer-reviewed journal.

More Patients With High Viral Loads Experience Virologic Failure When Starting Therapy With an Abacavir-Based Regimen Than a Tenofovir-Based Regimen An Interview With Paul Sax, M.D. By Bonnie Goldman August 7, 2008

My name is Paul Sax. I'm the clinical director of the HIV program at Brigham and Women's Hospital in Boston, and an associate professor of medicine at Harvard Medical School. Today I presented the results of the ACTG 5202 study, comparing tenofovir/FTC [tenofovir/emtricitabine, Truvada] and abacavir/3TC [abacavir/lamivudine, Epzicom, Kivexa].1 It was a comparison of those two drugs in patients with viral loads greater than 100,000 copies/mL. Here are the basics of the study.

It was a four-arm study. Over 1,800 patients were randomized to one of four regimens: They either got abacavir/3TC plus tenofovir/FTC placebo, or tenofovir/FTC plus abacavir/3TC placebo. That was the nucleoside component. Then the third drug was either efavirenz [EFV, Sustiva, Stocrin] or boosted atazanavir [ATV, Reyataz]. The study started in 2005 and completed enrollment in November of 2007, and we expected to complete follow-up of the patients in the fall of 2009. In January of 2008, the Data Safety Monitoring Board [DSMB] reviewed this study and found an increased number of virologic failures in the abacavir/3TC arm.2 They said to us, "Instead of doing a four-arm comparison, why don't you combine it into two arms, tenofovir/FTC versus abacavir/3TC? Also, we would like you to unblind the nucleosides." So we did that. The results that I presented today were really that analysis of the nucleoside comparison in the greater than 100,000 viral load stratum. Patients were stratified at baseline by their screening viral loads. At baseline, the groups are pretty well matched. The one thing I want to mention is that only about 43% of patients were genotyped at entry. They had to be genotyped if they had recently acquired infection, or they got genotyped because it was standard of care at their site, but it otherwise wasn't specifically required. Our primary result -- which was time to virologic failure -- found that there was an excess number of virologic failures in the abacavir/3TC arm versus the tenofovir/FTC arm: 57 failures in the abacavir/3TC arm; 26 in the tenofovir/FTC arm and that was highly statistically significant at P = .0003. There was a hazard ratio for failure of over 2, for abacavir/3TC. We did a bunch of other analyses and they were all pretty much consistent. A couple of things to mention was that virologic failure happened regardless of whether it was early in the course of the treatment, or later in the course of treatment. Also, importantly, it did not seem to be caused by suspected abacavir hypersensitivity. There was 7% suspected hypersensitivity in both study arms, and most of the patients who had suspected abacavir [ABC, Ziagen] hypersensitivity did not have virologic failure. The other finding in the study, which was unanticipated, was that there was a shorter time to the first adverse event in the people who were receiving abacavir/3TC. Again, this was highly statistically significant. Most of these adverse events were metabolic in nature, with increases in lipids. It's unclear whether these are clinically significant, but nonetheless, there were also other side effects, such as body aches and pains, etc., that were seen more with abacavir/3TC than with tenofovir/FTC. There was one study death that was possibly related to abacavir/3TC after a suspected HSR [hypersensitivity reaction] and then rechallenged. Clearly, the study site did not realize that it was suspected HSR, and that's how that ended up happening. We did do extensive education, both before the trial started, during the trial, and of course, after this event, about how to manage abacavir hypersensitivity. It was not standard of care to do HLA-B*5701 testing when the study started, and we only started doing it towards the end of the study, after the presentation of the PREDICT data last year. That's in essence what the study showed: that there was a shorter time to virologic failure for these patients with high viral loads if they got abacavir/3TC versus tenofovir/FTC; that the hypersensitivity issue did not seem to explain the difference in the results; and finally, that more side effects were going on in the abacavir/3TC arm than in the tenofovir/FTC arm, and they happened sooner. The rest of the study keeps going. We're still going with the lower viral load stratum. We were assured by the Data Safety Monitoring Board that there didn't appear to be any kind of toxicity signal or efficacy signal that should make us stop. We're also continuing with the efavirenz versus the ritonaviry {RTV, Norvir]-boosted atazanavir comparison. As I said, the study will be completed in the fall of 2009. What's the take-home? What's a practicing physician to do? And what's a patient to do, if he or she is on Epzicom and doing fine? One post hoc analysis we did, which addresses that issue, showed that if patients have undetectable viral loads, measured at less than 50 copies/mL in our study, they did not have, at least at this point, an increased risk of virologic failure, whether they were on abacavir/3TC or tenofovir/FTC. That is an important sort of practical message for physicians and for patients, that if they have an undetectable viral load, they are tolerating it well and there are no other compelling issues to make them want to change, then they should stay with what they are on. The study, though, does address the issue of people who come into care with very high viral loads. I have to say, based on our prospective randomized double-blind study, which is kind of the best evidence you can get, it does appear that tenofovir/FTC is more effective virologically than abacavir/3TC, at least when combined with either efavirenz or boosted atazanavir.


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