Kaletra vs. Reyataz
May 22, 2004
First and foremost, thank you very much for all you do for the HIV community. I sincerely appreciate this forum and all that you do.
After starting therapy in 2000 after pneumocystis I have been been on six cocktails, (1)trizivr, (2)3tc/d4t/viramune, (3)3tc/d4t/sustiva, (4)3tc/d4t/ddI, (5)3tc/viread/kaletra and (6)3tc/d4t/sustiva/kaletra, all stopped due to high liver enzymes. Of note, I've been tested for HEP 3 times and each time the test was neg. An ultrasound showed "fatty," benign tumors, a "fatty liver." Oddly, with this sixth cocktail, 3tc/zerit/susitva/kaletra my liver has relatively tolerated it it for almost a year.
In that time my VL has fluctuated between 500 and 5,000 and TCells vary between 450 and 630 with my latest labs showing VL of 503 and TCells 623, best labs in 4 yrs. My ID Doc still doesn't like the fact that I've never achieved "undetectable." Also, my cholesterol is 370 and trygl are 1,100. He, and I agree, think that because my liver enzymes are somewhat high on this cocktail and my need for optimum plasma levels of meds is significant has opted to change my antiretroviral meds instead of lipid lowering meds.
A genotype , which oddly was done with only 503 VL showed "no evidence of resistance" to the Nukes and PI's but "possible resistance to the NonNukes and a "relevant protease mutation" of "L63P." I found it odd that a previous phenotype showed 3tc to be less than 100% but it didn't show in the gene screen.
He wants to switch from Kaletra to Reyataz while remaining on 3tc/zerit/sustiva. I mentioned the "possible resistance" to the NonNukes as NonNukes may lower PI's but he seemed unconcerned.
My questions are: 1) Does this sound like a good option? 2) I'm allergic to sulfa drugs, bactrim/pentamadine, and abacavir...how does this bode for reyataz? 3) Would switching to fuzeon from sustiva be wise or should I wait for newer PI's and NonNukes? 4) Do my numbers even warrant considering Fuzeon at this time or is the lack of achieving "undetectable" taking priority? 5) What does the L63P relevant protease mutation mean with regards to other PI's? 6) What is your opinion regarding Kaletra vs. Reyataz? 7) As I have changed cocktails because of liver enzymes and not resistance issues how does this bode for future meds in the "pipeline." I'm sorry this question is so long but I really tried to be specific and hope I'm addresing valid concerns. I hope you can find the time to answer some of my questions. Again, I really sincerely thank you for any help you can offer and greatly appreciate all that you do. Thanks.
Response from Dr. Cohen
Some very important and difficult questions you pose here. Let's take them on in your order.
First using Reyataz (also called atazanavir here I'll abbreviate it as ATV to have less typing!) instead of Kaletra (also called Lopinavir/ritonavir and I'll abbreviate as LPV) requires a bit of background and discussion. There have been two studies comparing ATV to LPV. Both were done in people with at least one prior protease inhibitor used in the past relevant to your circumstance. One study was done where ATV was taken without low dose ritonavir (also called "boosted atazanavir" as the low dose ritonavir acts to boost the blood levels of the atazanavir compared to when it is taken without the booster) and the other was done comparing ATV boosted to unboosted to LPV. And the summary conclusion from both studies is that, when you are dealing with the risk for any degree of PI resistance, it is far better to use boosted ATV. The boosted levels improve the success rates as compared to what was seen when the drug was given unboosted. In addition, you are taking Sustiva, which actually acts to lower the blood levels of ATV, as it does for LPV and other protease inhibitors. Therefore, the use of ATV plus Sustiva requires the use of boosted ATV. It also requires adjusting the dose of LPV upwards to four caps twice a day. You didn't mention these dose changes and perhaps that is already done. I wanted to ensure that was the case.
Now, in the head to head study comparing these two PIs it was seen overall that they had similar response rates. This was particularly noted for those with minimal PI resistance. For those with extensive levels of PI resistance, there was a point at which LPV had retained greater activity than ATV. For those with less PI resistance and your resistance test would suggest few PI mutations ATV boosted and LPV did similarly well. However, while the virologic response rates were similar, ATV does have one potential advantage here, which is that the blood cholesterol and more so the triglyceride measurements may be better with ATV than LPV, even when using boosted atazanavir. And since the blood lipids are part of what is problematic for you this substitution seems reasonable to try given the expectation of similar potency and improved lipids. Now it is fair to point out that much of the info we have about comparing ATV to LPV happened on regimens that did not also contain Sustiva and there is a chance that the addition of this drug to either PI may alter the profile in ways that are not yet clear. There are studies going on about these combinations at this time and we should soon know if there are any unexpected findings about them.
However, I will add that your viral load of as high as 5 thousand while on Sustiva suggests you have NNRTI / Sustiva resistance. In general when there is a viral load of that degree while taking a "nonnuke" there is nonnuke resistance. You mention something about NNRTI resistance although I'm not sure of the details. But if there is NNRTI resistance there is little point to continuing the drug. Indeed at least in terms of drug levels, Sustiva lowers the levels of the PIs and that likely gets in the way for their ability to control HIV to some extent. And Sustiva does have some ability to increase cholesterol another reason to consider stopping it.
2. ATV has no similarities to the drugs you mention that you are allergic to and the rate of rash on ATV has been very low so this issue should not pose a problem to this substitution.
3/4. This question is about using Fuzeon (also called T-20 or enfuvirtide I'll abbreviate as ENF) instead of the Sustiva. Now, you don't mention what genotypic change was seen on the current or any former genotype that led to the conclusion about reduced susceptibility of the NNRTIs. However, as I mentioned above there is room for concern that Sustiva is adding little to your current regimen activity. In contrast, ENF would be fully potent here. As for when to start on it the short answer is anytime you are changing from one regimen to the next and have triple class exposure / resistance it is reasonable if not actually quite important to seriously consider adding ENF. The studies done show pretty clearly that using this drug on average doubles the chance to establish viral suppression. Now, it is an injectable and for some that leads to an understandable desire to defer. Nevertheless if the goal is to achieve complete viral suppression so as to create a regimen that might last for years and decades using ENF would increase the odds in your favor considerably. And while your CD4 count is high enough so that you don't "need" ENF now our experience shows us that starting it with a higher CD4 count actually improves the response rate when it is used. So while you can defer to some future regimen you'll enjoy more activity from it by not deferring it. And at least in terms of the toxicity issues you raise ENF does not add to concerns about lipids and it is unlikely to aggravate your liver either. It might allow you to alter your regimen and minimize the use of drugs that have led to the problems you're dealing with.
5. The L63P mutation is of uncertain significance it appears to reflect what we've seen on many others who have been on LPV as their first PI it is difficult for HIV to create resistance to this drug if it is the first PI used. And so this mutation has been seen in other settings and may reflect the attempt by HIV to find PI resistance. But as you note out tests suggest that our PIs are still fully active despite this mutation.
6. As for LPV versus ATV I think I covered this above. Both are great drugs and have provided us far greater ability to control HIV than was seen in the early era of the PIs we had available to us before LPV was available. I think there are reasons to use them both. And hopefully one or the other will accomplish your goal of viral control and long term safety - the goal of all antiviral options.
Finally you are changing due to concern about safety but since your viral load is not fully controlled it seems to be you are also changing with some concerns about prior resistance. For example we've learned that even if your current resistance test doesn't see a certain mutation, we need to assume that you are engaging in a battle to control the virus population with all of the mutations ever seen not just those on the current test. These virus populations have a way to hide and not disappear. So I think here you are actually changing for both reasons. And getting that viral load to undetectable will at least minimize the risk for allowing HIV to find even more mutations. And if you can find a safe way to control HIV you might have a regimen that allows you to not need to change so often
Good luck. Hope that helps.
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