Armed with a hell of a lot more data than President Bush had when he took us to war with Iraq, Bristol Myers Squibb gained FDA approval for their new protease inhibitor (PI) atazanavir (Reyataz®). It's the first new protease inhibitor to hit the market in almost 3 years (lopinavir/r, Kaletra®, was approved in September 2000). And it's the first once-daily, low pill count PI ever. For the treatment naive, atazanavir will be dosed at 400 mg QD (once a day). That's 2 pills once a day. Got that? 2 pills, once a day. Any of you that are on PIs know that this is an antiretroviral drug class revolution. So, you're asking yourself, "what's the catch?" Well, it's not a miracle in the resistance arena, but it does have a unique resistance pattern that emerges after its initial use, that leaves all other PIs as viable options. It also may offer some folks with mild to moderate PI resistance some choice. And boosted with ritonavir, may have a role in salve therapy. We'll discuss all of this below. It also causes this annoying increase in one's bilirubin levels. You know when babies are born with jaundice and have to be put under special lights? That's because their bilirubin levels are high. Atazanavir tends to cause the same thing (so can indinavir). For some people it can make their skin or eyes appear yellowish, for others it does not. This too, we'll discuss below. That's about as bad as the news gets.
The good news is that atazanavir does, or should I say doesn't do what the rest of the PI class does -- and that is, it doesn't raise cholesterol and triglycerides! So, for those of you who are suffering from through the roof lipids that cause you to have to take additional medications in order to stay on the drugs that control your HIV, this is very good news. For those of you who already have risk factors for heart disease, this is good news. And of course, for those of you who are sick of taking fifty million pills a day and don't have high level PI resistance, this is good news. One more piece of good news, atazanavir crosses the blood brain barrier and is found in cerebral spinal fluid and seminal fluid (cum).
Bristol Myers Squibb (BMS) has clinical trial data from several studies. Before we get into the lipid profiles and bilirubin issues, we'll look at the virologic results from the treatment naive trial BMS 034 and 008; and the treatment experienced trial BMS 043 and 045. Don't forget to refer to the glossary on page 8 (see PDF) for terms and abbreviations.
|Table I: ATV Efficacy Data|
Atazanavir should be taken with food (a light meal) once a day.
Mean HIV RNA log drop over 2 weeks (ATV alone) = 1.27 log10.
Mean HIV RNA log drop over course of 008 trial (triple combo) = 2.51 log10.
|BMS 034: ATV vs. EFV. Percent participants with VL <400 at week 48|
|BMS 008: ATV vs. NFV. Percent participants with VL <400 at weeks 48 and 108.|
|(Nukes: d4T/3TC)||Arm||ITT||OT (at wk 108)||CD4 (at wk 108)|
|Tx Experienced Trials BMS 043 and 045
BMS 043: ATV 400 mg QD vs. Kaletra 400/100 BID Plus 2 Optimal Nukes (previous failure of 1 PI). Percent of participants with VL <400 at week 24.
|BMS 045 (Optimized tx background): Percent with VL <400 and <50 at week 24 (Highly treatment experienced, significant resistance, with previous use of all drug classes).|
|n= 120||QD||ATV 300/RTV 100||64||39||83|
|n= 123||BID||LPV 400/RTV 100||62||42||90|
|n= 115||QD||ATV 400/SQV 1200||44||23||59|
From the data in Table I you can see that atazanavir performed as well as efavirenz and nelfinavir in the treatment naive trials. Atazanavir as a single agent did not perform as well as lopinavir/r (Kaletra) in the 043 trial, but that's to be expected. Remember that Kaletra is 2 drugs in one formulation -- 133 mg lopinavir/33 mg ritonavir in each capsule (3 caps twice a day is the typical dosage). Kaletra is an already boosted PI. The more direct comparison is shown in the early (24 wk) results of the 045 study with highly treatment experienced individuals. In that study, at least to this point, ATV/RTV appears to be competing well against LPV/RTV. 24 week data is less than 6 months. We'll have to wait and see how the next 6 months go before the salvage therapy jury comes in.
Simply put, if you're treatment naive and you didn't get infected with protease-resistant virus, atazanavir is a good first-line, or first PI-based treatment option. It may also be a good second-line PI on its own. But by the time you're resistant to several PIs, you'll have resistance to atazanavir as well. For those individuals who experienced treatment failure and had geno/phenotypable viral load, all had the I50L mutation which caused resistance to atazanavir, but increased susceptibility to other protease inhibitors. The I50L mutation also creates a "less fit" virus, meaning atazanavir resistance HIV does not replicate as well as wild-type virus. For treatment-experienced individuals, who already have protease inhibitor-resistant virus, atazanavir falls in line with the current body of knowledge regarding multiple PI mutations. Nelfinavir is the 1st to go, indinavir, ritonavir and saquinavir next, then amprenavir and lopinavir are last to go in the line of class cross-resistance. Of course, when PIs are boosted with ritonavir, the level of drug that is achieved in the blood can overcome low- to mid-level resistance. And don't forget, resistance is never all or nothing. It is a sliding scale of effectiveness that requires expertise to evaluate.
Editor's note: Please make sure your health care provider is not just reading the genotype report that says "resistant" or "sensitive." S/he needs to be able to evaluate the actual mutations or have someone with whom s/he consults in order to interpret a genotype. Phenotype results require less expertise to read because they are actually testing your virus against individual drugs.
Now that we've looked at the virologic efficacy of atazanavir compared with efavirenz, nelfinavir and lopinavir/r, let's take a look at the lipid info. Lipids are blood fats -- cholesterol and triglycerides that affect an individual's risk for coronary heart disease (CHD) and stroke. We have solid clinical evidence that protease inhibitors, as a class (and efavirenz), tend to increase blood fats in individuals who take them. This is no news flash to those of you on these meds, who may also be taking things like Pravachol® or Lipitor® to counter these side effects. Although there is still a lot of controversy amongst HIV experts as to how much elevated lipids (that are caused by antiretroviral therapy) contribute to increase risk for heart and vascular disease, there is no doubt that we know that if people have elevated lipids in the non-HIV world they have an increased risk for CHD. And, if our health care providers weren't worried, then why add additional drugs? So controversy aside, besides the low pill count and somewhat unique resistance profile, the main advantage of atazanavir over the rest of the PI class will be its favorable lipid profile. So let's look at that data, keeping in mind, that if you need to take a ritonavir-boosted ATV regimen some of the lipid benefits will be lost, but probably not all.
|BMS 034: Change in Lipids From Baseline ATV vs. EFV|
|At Week 24||ATV||EFV|
|LDL-c (bad stuff)||+1%||+18%|
|HDL-c (good stuff)||+13%||+24%|
|BMS 043: Change in Lipids From Baseline ATV vs. LPV/r|
|At Week 24||ATV||LPV/r|
|BMS 044: Improvement in Lipids After Switch From NFV to ATV|
|At Week 24||NFV -> ATV|
The biggest adverse event with atazanavir is the fact that a majority of people who have taken the drug have experienced elevated bilirubin levels. Bilirubin is a biproduct of liver function. Sometimes high bilirubin levels indicates that there is something wrong with the liver, sometimes it does not. Previous existing liver problems should be considered when starting atazanavir or any other medications that are metabolized in the liver. With atazanavir, the increased bilirubin levels are not associated with liver toxicity, but can cause some individual's skin or eyes to turn yellow. This condition is known as jaundice. When jaundice is associated with hepatitis or cirrhosis, it's a serious indicator of poor liver health. When it is associated with atazanavir use it is not dangerous. About 10% of people in atazanavir studies experienced jaundice; only about 1% of study participants stopped taking atazanavir as a result of jaundice. Up to 50% of people had low-level increases in their bilirubin; 25% had higher levels. Indinavir (Crixivan®) has a very similar mechanism and has been manageable for most individuals. The most important thing is to know that if you start ATV and wake up one morning with yellow eyes, don't panic. Call your doc and discuss how you want to go about managing the problem. In the treatment naive trials <1% of individuals discontinued therapy due to hyperbilirubin levels.
Along with good consumer and health care provider education, it is very important that case managers, social workers, mental health providers and substance abuse treatment providers understand this side effect. Far too many times our clients are accused of using drugs when, in fact, they are experiencing side effects from meds or other conditions. Just for the heck of it, imagine a diabetic, former drug user who comes into her/his substance abuse support group with an elevated blood sugar level that makes her/him drowsy and out of it and her/his eyes are yellow. Instead of a shot of insulin and a call to the doctor for out-of-control blood sugar and PI side-effect, s/he could wind up in detox. Crazier things have happened.
Other adverse events included the usual associated with protease inhibitors, but to no greater degree and often times lesser degree than other PIs. You know the drill, nausea, vomiting (very rare), diarrhea, headache. All in all, if you don't get the jaundice, ATV is looking like a very tolerable PI.
The old ddI wafers lower the amount of atazanavir in your body. I would have to ask, why are you still on the old formulation? However, if you are, take your ATV at least two hours after or one hour before your ddI. If you're on Videx EC the only reason to separate them is that you're supposed to take Videx EC on an empty stomach and ATV with food.
ATV and EFV: Unfortunately efavirenz lowers atazanavir levels. So the recommendation is to take ATV 300/RTV 100 with EFV 600 all together once a day with food. Do not take ATV and EFV together unless ritonavir is added to boost the ATV. This still allows for QD dosing, but may undo some of the lipid benefits.
ATV and SQV: Atazanavir increases the amount of saquinavir in your blood. So to mix these two you'll have to adjust the dose. This could be a good thing if you need higher levels of saquinavir to fight HIV. It also allows SQV to be dosed once a day. However, it can also increase side effects when a drug is boosted, so use with caution and under an HIV experts care.
ATV and RTV: Obviously, this is the boosted version of atazanavir therapy. The recommended dose is ATV 300 mg/RTV 100 mg. This is what is being studied in the trial BMS 045 reported on in Table I.
ATV and TDF: Again, unfortunately, tenofovir (TDF) appears to affect atazanavir levels. This is unfortunate because they are both very tolerable QD drugs. The studies to gain insight into exactly how to use these two drugs in combination are still ongoing. However, at the recent International AIDS Conference in Paris, Kate Squires, M.D. (from USC) reported on this drug to drug interaction. When 300 mg TDF is combined with 300 mg ATV/100 mg RTV (boosted regimen), ATV levels are reduced approximately 25%. However, this still gives blood levels of ATV that are 5 times higher than unboosted atazanavir. Therefore, she recommends using the 300/100 boosted dosing (like in the 045) study, in combination with tenofovir in treatment naïve individuals. Using TDF and ATV together without a ritonavir boost could lower ATV levels enough to risk treatment failure and development of resistance. If you are treatment experienced and have some protease resistance then it may take some more tweaking and consultation with resistance experts to figure out how to combine these two meds right now. There are studies underway that will address this issue. Keep in mind that these recommendations are from clinical experts, but are not yet FDA approved and do not appear in the package insert for atazanavir.
Do not take atazanavir with the following meds. Interactions could cause serious side effects or death:
Benzodiazepines: Versed®, midazolam, Halcion®, Triazolam
Ergot Derivatives (migraine Medications): dihydroergotamine, ergonovine, methylergonovine
GI Motility Agent: Propulsid® (cisapride)
Neuroleptic: Orap® (pimozide), Camptosar® (irinotecan), Vascor® (bepridel), Mevacor® (Lovastatin), Zocor® (Simvastatin), Crixivan® (indinavir)
Do not take atazanavir with the following meds because they lower the atazanavir level:
Rifampin, St. John's Wort, and AcipHex®, Nexium®, Prevacid®, Prilosec®, or Protonix®.
There are many other drug-to-drug interactions that require close monitoring or dose adjustment. The package insert that comes with your prescriptions (and that you need the hubble telescope to read) lists all of these interactions. This insert is also available on line at FDA.gov or BMS.com, or we can e-mail it to you. Send an e-mail to email@example.com and I'll shoot you a PDF file of the package insert.
Shelley Cohen Mckittrick is the Editor of Resolute! and The Director of Treatment Education at The PWA Coalition Colorado. She may be reached at 303.329.9379 or firstname.lastname@example.org.
Back to the Resolute! Summer 2003 contents page.