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Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Reyataz (Atazanavir Sulfate, ATV)

Fall 2003/Winter 2004

Reyataz (atazanavir sulfate, ATV) was approved by the FDA in June 2003 as the first protease inhibitor (PI) to be taken once a day. For people who are just starting treatment, studies showed that Reyataz lowers viral load almost as well as Sustiva (efavirenz), a strong non-nucleoside, and almost as well as (although not better than) Viracept (nelfinavir), a relatively weak PI. These studies also showed that Reyataz may be the only PI that doesn't raise lipid levels (cholesterol, triglycerides). In one study, it actually improved lipids. Levels of bilirubin (a product of red blood cell breakdown) can increase in many people taking Reyataz. The drug has a favorable resistance profile in that its most common mutation doesn't cause cross-resistance to other PIs. Other mutations, however, can cause cross-resistance.


Background

Three critical studies led to the FDA's approval of Reyataz. One was a non-inferiority study. Using this increasingly popular trial design, study AI424-034 compared Reyataz to Sustiva, both taken with two NRTIs, in 810 people who had never been on antiretrovirals before. Unlike other comparative studies, this one was designed to show that Reyataz wasn't worse than Sustiva, even if it wasn't better. After 48 weeks, the two groups did just about as well, with no statistically significant difference -- 32% of people on Reyataz had viral loads below 50 compared to 37% of those on Sustiva. But the results were somewhat unsettling. While they did show that Reyataz wasn't inferior to Sustiva, the question was -- why did the people taking Sustiva in this trial do so poorly? In study DMP 266-006, for example, 64% of people on Sustiva and two NRTIs had viral loads below 50 at 48 weeks -- almost twice the rate seen in study AI424-034. Bristol-Myers Squibb (BMS), the manufacturer of both Sustiva and Reyataz, attributes Sustiva's (and Reyataz's) relatively poor performance to a problem with new procedures and vials used in the study.

A second study, AI424-008, compared two different doses of Reyataz to Viracept in 467 people who had never taken antiretrovirals before. Trial participants also took two NRTIs. After 48 weeks, there were no statistically significant differences between the three groups -- approximately 35% of people on either dose of Reyataz and 38% of those on Viracept had viral loads below 50. Again, Reyataz did about as well as the drug it was being compared to. Together with those of AI424-034, these results show that Reyataz can lower viral loads to below 50 copies in about a third of people who are just starting treatment, a modest response at best.

Lastly, study AI424-043 provided important, although incomplete, information about how Reyataz works in people who have used other PIs in the past. In this study, 300 people whose HIV wasn't responding to another PI switched to either Reyataz or Kaletra, in addition to two NRTIs. After six months, 34% of people taking Reyataz had viral loads below 50 compared to 50% of those on Kaletra. When the results of these three studies were presented to the FDA, the agency was convinced that Reyataz was comparable enough to Sustiva and Viracept to grant the drug approval for use in a first treatment regimen. But the FDA didn't have compelling information about how Reyataz should be used in people who had already taken, and failed, other protease inhibitors. Data that weren't presented in time for the drug's approval showed that boosting Reyataz with a small amount of Norvir (ritonavir) raised levels of Reyataz sufficiently to lower viral load in people who had previously failed multiple PIs. In fact, boosted Reyataz (300 mg Reyataz plus 100 mg Norvir once a day) performed as well as Kaletra. Because the FDA was unable to review this information (it was presented late), there are no current recommendations for the use of boosted Reyataz for people with multi-drug resistant virus.

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Concerns about Reyataz's side effects, cross-resistance, dosing, and other issues made some activists ask if there was enough information for full approval in June 2003. They wanted more studies to evaluate the short and long-terms risks and how best to use this drug. In May 2003, a group of activists sent a consensus letter to the FDA asking for postponement of full approval until more studies were completed. Despite these efforts, Reyataz was granted full approval weeks after receipt of the letter.


Side Effects

Reyataz's most common side effect is an increase in bilirubin, a substance produced when red blood cells are broken down. High levels of bilirubin can cause jaundice (yellowing of the skin and the whites of the eyes) -- the higher the bilirubin level, the more likely jaundice will appear. If the drug is stopped, bilirubin levels return to normal and the yellow color goes away. High bilirubin levels can also be a symptom of liver damage, so this unusual side effect raises concern about whether taking Reyataz could harm the liver. But so far, using Reyataz doesn't seem to have caused any liver damage. Among the studies done to date, about 40% of people taking Reyataz at the boosted dose and 47% of those taking the standard dose had bilirubin levels more than two and a half times above normal and 15% experienced jaundice. People starting Reyataz should closely monitor bilirubin levels and liver health. Reyataz should be used with caution in people with pre-existing liver problems such as hepatitis B or C, although no differences in bilirubin levels have been seen in people who are co-infected.

Unlike other PIs, Reyataz hasn't caused increases in blood fats (cholesterol, triglycerides) in clinical trials. In AI424-007 and 008, no elevations in lipids were seen after 48 weeks on Reyataz. Similar results have been seen in other studies of this drug. Furthermore, people taking Viracept for 48 weeks in study AI424-034 who switched to Reyataz had, on average, a 76% drop in total cholesterol, a 41% drop in LDL (bad) cholesterol, and a 50% drop in triglycerides 48 weeks after switching. These levels began to drop as early as four weeks after switching and were maintained for up to 108 weeks after switching. Unfortunately, despite these positive findings, some people on Reyataz have experienced increased fat in the upper back, neck, trunk, and breasts, as well as increases in blood glucose levels. More information from follow-up studies is needed to determine if Reyataz is a possible cause of these body-shape changes.

Other potential side effects include nausea, diarrhea, headaches, rash, and abdominal pain.


Drug Interactions

Reyataz interacts with other medications, including other antiretrovirals. Videx (ddI), Sustiva, and Viread (tenofovir) can each lower the amount of Reyataz in the blood. Videx's food restrictions are also quite different than those for Reyataz. Therefore, BMS recommends that Reyataz be boosted with low-dose Norvir when taken with Sustiva or Viread and that it be taken a few hours before or after Videx. Crixivan (indinavir), another PI, can also cause high levels of bilirubin and shouldn't be taken with Reyataz.

The list of other interactions includes rifampin, the antineoplastic Camptosar (irinotecan), Vascor (bepridil), the benzodiazepines Versed (midazolam) and triazolam (Halcion, Restoril, Dalmane, and others), ergot alkaloids (used to treat migraines), Zocor (simvastatin), lovastatin (Mevacor or Atocor), and St. John's wort (hypericum). Combining Reyataz with any of these drugs may cause serious or even life-threatening reactions.

Reyataz can also increase blood levels of antiarrhythmics (used to regulate an erratic heartbeat), the blood thinner warfarin, tricyclic antidepressants, Mycobutin (rifabutin), certain calcium channel blockers, Lipitor (atorvastatin), certain immunosuppressants, Viagra (sildenafil), the oral contraceptives ethinyl estradiol and norethindrone, and Biaxin (clarithromycin). Dose adjustments may be necessary to reduce the risk of side effects. Reyataz levels can decrease when taken with certain antacids and H2 receptor antagonists, so spacing your dose of Reyataz and these medications as far apart as possible is recommended.


When to Consider It

The most recent Department of Health and Human Services treatment guidelines don't discuss Reyataz in any detail or include it in any preferred or alternative regimens. That doesn't mean that the drug couldn't be useful in a first or later combination -- it's just that it was approved shortly before the revised guidelines were released. In fact, Reyataz may join Kaletra as a particularly versatile PI, valuable for people just starting treatment and for those whose virus is no longer responding to certain PIs. According to a member of the panel that drafts and approves the guidelines, Reyataz will probably be listed as an alternative protease inhibitor in future versions of the guidelines.

For people beginning treatment with a PI, Reyataz is appealing because of its once-a-day dosing, the fact that it doesn't seem to raise lipid levels, and its unique resistance profile. However, many healthcare providers are prescribing Reyataz in combination with low-dose Norvir in order to boost Reyataz levels in the body, making it even more powerful against HIV and prolonging the effect of therapy. While there is some concern that low-dose Norvir might "cancel out" Reyataz's minimal effect on lipid levels, data from clinical trials and anecdotal reports suggest that this isn't a big problem.

If your virus becomes resistant to Reyataz, you're still likely to respond to other PIs. In fact, some data suggest that HIV that becomes resistant to Reyataz may be even more sensitive to other PIs used down the line. And for people whose virus is already resistant to other PIs, early data suggest that Reyataz should still work. In one study of HIV isolated from 551 people, Reyataz worked against virus that was resistant to Viracept. What's more, the primary mutation that results in partial resistance to Reyataz (the I50L mutation) is believed to make the virus even more sensitive to other PIs, most notably Agenerase (amprenavir). However, cross-resistance is still possible, even if it's less common than with most other PIs. Several people who had been on antiretrovirals before and took Reyataz together with Invirase/Fortovase (saquinavir) developed cross-resistance to almost all of the PIs -- with the exception of Agenerase.


Good to Know

  • The original brand name chosen for atazanavir was Zrivada. The new name, Reyataz, may have been chosen because Zrivada didn't fly with focus group participants or because "Taz" was already being used as a nickname for the drug while it was in development.


Pregnancy

Reyataz is classified as an FDA pregnancy category B drug. Animal studies fail to demonstrate a risk to the fetus, but well-controlled studies of pregnant women haven't been conducted. Reyataz should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.


Dose

Reyataz comes in 100, 150, and 200-mg capsules. The once-a-day standard dose is 400 mg, usually taken as two 200-mg capsules. Reyataz should be taken with a light meal or snack -- meals of around 350 calories help make Reyataz more available in the body. When used with Norvir, the dose is two 150-mg Reyataz capsules plus one 100-mg Norvir capsule once a day.

Reyataz is not approved for pediatric use. Due to the risk of increased bilirubin, Reyataz should not be given to children under the age of 3 months.

FDA Approval: 2003

Manufacturer: Bristol-Myers Squibb

Patient Assistance Program: 877-758-7877





  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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