Atazanavir

Atazanavir (Reyataz) is an antiretroviral drug from the class known as protease inhibitors. Protease inhibitors block the activity of the HIV protease (or proteinase) enzyme that HIV uses to break up large viral proteins so that new HIV particles can be formed. Inhibiting this action slows HIV replication and delays damage to the immune system.

Atazanavir was developed by Bristol-Myers Squibb, the makers of stavudine (d4T, Zerit) and didanosine (ddI, Videx/VidexEC). It was formerly identified as BM-232632.

In the European Union, atazanavir was approved for use in treatment-experienced people in 2004, at a dose of 300mg, boosted with 100mg ritonavir (Norvir) once a day. It was approved for use in treatment-naive people at the same dose in 2008.

In the United States, atazanavir was approved as an HIV treatment in 2003 without restrictions on its use. The licensed dosing is 300mg plus 100mg ritonavir once daily (for treatment-naive or treatment-experienced people) or 400mg once daily (for treatment-naive people). It is recommended that this drug be taken with food. It has also been approved for use in children six years of age and older.

Atazanavir co-formulated with cobicistat (150mg) as a boosting agent has been approved for use in the European Union and the United States under the brand name Evotaz. Approval was based on data showing equivalence between atazanavir boosted by cobicistat and atazanavir boosted by ritonavir. See Evotaz for further details of dosing and specific drug interactions resulting from the use of cobicistat.

Generic versions of atazanavir are also available in the European Union and United Kingdom..

Boosted atazanavir is no longer a preferred option for first-line treatment in US or European treatment guidelines and unboosted use of atazanavir is not recommended in treatment guidelines.

Effectiveness

Atazanavir (Reyataz) is an effective antiretroviral agent with comparable efficacy to other protease inhibitors and to non-nucleoside reverse transcriptase inhibitors (NNRTIs). It should be given in combination with other antiretroviral drugs, except in certain limited circumstances.

In 2007, the 96-week results of the AI424-089 trial showed that atazanavir taken alone or boosted with ritonavir (atazanavir/r) once-daily as part of an antiretroviral regimen is safe and effective in treatment-naive, HIV-positive individuals, including those with advanced HIV disease. (Malan)

The trial compared atazanavir/ritonavir 300/100mg once daily with atazanavir 400mg once daily in treatment-naive participants. In both study arms, once-daily lamivudine (3TC), and extended release stavudine were also given. At baseline, roughly half the participants had an average CD4 cell count around 200 cells/mm³ and a viral load above 100,000 copies/ml. 

At 96 weeks, boosted atazanavir showed a trend toward a higher rate of viral suppression, fewer virological rebounds, and less protease inhibitor or nucleoside analogue resistance. There was no statistically significant difference in the number of study participants achieving a viral load less than 50 copies/ml by intent-to-treat analysis. There were fewer virologic failures among people taking boosted atazanavir.

Atazanavir/ritonavir has been shown to be non-inferior to lopinavir/ritonavir in previously untreated people and treatment-experienced people, but with a lower incidence of cholesterol elevation and gastrointestinal adverse events such as diarrhoea and nausea. (Molina) (Nieto-Cisneros)

Atazanavir/ritonavir is recommended as a third agent for use in combination with tenofovir disoproxil/emtricitabine in first-line antiretroviral treatment in British HIV Association guidelines and is recommended as an alternative to the preferred first-line options of an integrase inhibitor or booster daruanvir (Prezista) in US treatment guidelines.

Atazanavir/ritonavir has also been tested in a two-drug regimen in combination with lamivudine. The randomised ATLAS-M study compared atazanavir/r plus lamivudine to a three-drug regimen of atazanavir/r and two NRTIs in virologically suppressed people. The 96-week study found that treatment with the two-drug regimen resulted in a significantly higher rate of viral suppression (Fabbiani). The regimen is recommended by the European AIDS Clinical Society for people who have been virologically suppressed on three-drug treatment for at least six months.

Ritonavir-boosted atazanavir-based therapy is safe and well tolerated in people with hepatitis B or hepatitis C virus infection. Similar rates of liver enzyme elevations were seen in a group of 180 people with hepatitis co-infection and 124 people who were not co-infected, with similar withdrawal rates in the two groups. (Perez-Elias)

Atazanavir is also safe and effective in HIV-positive people with liver cirrhosis, according to a retrospective Spanish study presented in 2007. The investigators found that people with cirrhosis who received atazanavir had both an immunological and virological response to the drug, but did not experience any clinically significant liver-related side effects. (Hermida)

Taking it

Atazanavir is approved for use by treatment-naive and treatment-experienced people in the United States and the European Union.

In the European Union, boosted atazanavir (Reyataz) is taken once daily as one 300mg capsule with a 100mg dose of ritonavir. It can also be dosed with two 150mg capsules plus one 100mg ritonavir (Norvir) capsule once a day.

Atazanavir can also be taken once daily as a single fixed-dose combination pill with the boosting agent cobicistat. This product is approved in the European Union as Evotaz. See Evotaz for further details.

In the United States, the approved dosing for treatment-naive people is 300mg atazanavir/100mg ritonavir once daily with food or atazanavir 400mg once daily with food. If taken in combination with efavirenz or tenofovir, both of those drugs are dosed normally, but the recommendation is to use boosted atazanavir (300mg/r 100mg once daily).

Treatment-experienced people should take 300mg atazanavir/100mg ritonavir daily with food. Unboosted atazanavir is not recommended.

Atazanavir should not be taken with proton pump inhibitors or antacids unless boosted by ritonavir or cobicistat.

Atazanavir should not be used in people with severe liver damage. A dose reduction to 300mg once daily should be made for someone with moderate liver damage (Child-Pugh Class B). In cases of mild liver damage, it should be used with caution.

Treatment-naive people with end-stage renal disease managed with haemodialysis should receive 300mg of atazanavir with 100mg of ritonavir. Atazanavir should not be given to treatment-experienced people with end-stage renal disease managed with haemodialysis. (Bristol Myers-Squibb)

Side effects

The commonest side effects associated with atazanavir (Reyataz) are headache, nausea, rash, diarrhoea and vomiting. However, the 045 study concluded that gastrointestinal side effects are less common in people taking ritonavir-boosted atazanavir than those taking ritonavir-boosted lopinavir (Kaletra). (Johnson)

The major side effect associated with atazanavir treatment is hyperbilirubinaemia, an elevation of bilirubin levels in the blood. Bilirubin is a waste product from the breakdown of red blood cells. Although it is not clinically harmful, trials have shown that up to 45% of people who take atazanavir can develop hyperbilirubinaemia. Elevated bilirubin levels can cause jaundice, a yellowing of the skin and the whites of the eyes.

Hyperbilirubinaemia tends to emerge within the first week of starting atazanavir treatment, but does not always cause jaundice. In one large study of people initiating antiretroviral therapy, 33% of the nearly 400 people developed severe hyperbilirubinaemia, but less than 1% discontinued treatment due to bilirubin elevations, and only 5% developed jaundice. (Squires)

Atazanavir is less likely to cause increases in cholesterol and triglycerides than older protease inhibitors. (Murphy) (Sanne) (Nieto-Cisneros)

Lipid increases are reversed after switching from other protease inhibitors. (Wood) (Markowitz) (Martinez) (Gatell)

Atazanavir also has fewer effects on blood lipid levels than the NNRTI efavirenz (Sustiva). (Squires) However, the ACTG 5224 study found that atazanavir treatment was associated with significantly greater increases in abdominal fat when compared to efavirenz. (McComsey)

A small number of people treated with atazanavir have developed cardiac disturbances. Electrocardiogram monitoring is recommended for people with existing heart conditions or who are taking medication known to affect heart function. However, a panel of experts who assessed atazanavir for approval found that it did not provide any greater cause for concern than other protease inhibitors.

Around 6% of people taking atazanavir also develop a rash, which may require treatment to be discontinued in a few cases. (Ouagari)

Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to atazanavir (Reyataz) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

Studies of viral isolates have found that viruses resistant only to nelfinavir and ritonavir were more likely to be susceptible to atazanavir than viruses resistant to three or more protease inhibitors. (Colonno, 2002) (Naeger) (Pellegrin) (Colonno, 2003)

Drug interactions

Like other protease inhibitors, atazanavir (Reyataz) is metabolised through the cytochrome P450 system, and is a specific inhibitor of the CYP3A4 enzyme. This means that it may interact with a wide variety of drugs also metabolised through this pathway.

Many other drugs using the CYP3A4 enzyme should not be given with atazanavir, as their levels may be increased in the body. These include:

• alfuzosin
• astemizole
• bepridil
• cisapride
• colchicine in people with renal or hepatic impairment
• ergotamine tartrate (Cafergot / Migril)
• flecainide acetate (Tambocor)
• fluticasone propionate (Flixotide)
• halofantrine
• hypericin (St John’s wort)
• lovastatin
• lumefantrine
• midazolam (Hypnovel)
• pimozide (Orap)
• propafenone (Arythmol)
• quinidine (Kinidin Durules)
• rifampicin (Rifadin / Rimactane)
• simvastatin (Zocor)
• terfenadine
• triazolam
• voriconazole (Vfend).

Atazanavir also inhibits P-glycoprotein and the multidrug resistance-associated protein, which pump foreign substances, including some drugs, out of cells. This could explain the observation that the blood disorders caused by many chemotherapy drugs are more severe in people taking protease inhibitors.

When atazanavir is taken with drugs to treat acid reflux disease and related symptoms, the AUC of atazanavir decreases significantly. Studies have shown that taking atazanavir with proton pump inhibitors such as omeprazole (Losec) and esomeprazole (Nexium) or H2-receptor blockers (e.g. ranitidine/Zantac and cimetidine/Dyspamet, Tagamet) results in lowered blood atazanavir concentrations in HIV-negative people.

Proton pump inhibitors should not be used in treatment-experienced people receiving atazanavir. In treatment-naive people, the proton pump inhibitor dose should not exceed a dose comparable to omeprazole 20mg and must be taken approximately 12 hours prior to the atazanavir/ritonavir 300/100mg dose.

According to the Bristol-Myers Squibb package insert, treatment-naive people taking omeprazole (or other proton pump inhibitor drugs) with an atazanavir-containing regimen decrease atazanavir exposure by 30 to 65%. When use of the two drugs is unavoidable, the drugs should be taken 12 hours apart, close clinical monitoring is recommended, and an increase in the atazanavir dose to 400mg boosted with 100mg ritonavir is recommended.

In treatment-experienced people on an atazanavir-containing regimen, the H2-receptor antagonist dose should not exceed the dose-equivalent of 20mg famotidine taken twice daily. Atazanavir and ritonavir should be administered simultaneously with, or at least 10 hours after, the H2-receptor antagonist.

Sildenafil is contraindicated when used for treatment of pulmonary arterial hypertension.

Atazanavir is contraindicated for use with the hepatitis C direct-antiviral combination elbasvir/grazoprevir (Zepatier). Use of simeprevir (Olysio) with atazanavir is not recommended. The daily dose of daclatasvir (Daklinza) should be reduced to 30mg when used with atazanavir.

Some drugs require dose adjustments when taken with atazanavir. The following drugs need to be taken at lower doses:

• Clarithromycin (Klaricid / Klaricid EC): the dose should be halved.
• Diltiazem (Tildiem / Angiozem / Optil): the dose should be halved.
• Rifabutin (Mycobutin): the dose should be reduced by up to 75% (150mg every day or three times a week) when atazanavir is dosed at 400mg once daily. (Agarwala, 2002)

Atazanavir has been observed to increase levels of the hormonal contraceptives ethinylestradiol and norethindrone. No guidance is available at present on appropriate dose reductions or interactions with other contraceptives.

There have also been at least three case reports of elevated levels of buprenorphine, which is used to treat opiate addiction, in people taking atazanavir. (Bruce) A dose reduction may be necessary. In contrast, no dose adjustment of methadone (Methadose) is needed. (Friedland)

Pregnancy

Owing to substantial variations in drug levels during pregnancy, atazanavir should only be used with a boosting dose of ritonavir. Therapeutic drug monitoring of atazanavir levels is advised if atazanavir is used with tenofovir disoproxil, as tenofovir disoproxil may reduce atazanavir levels.

Children

Atazanavir is available in powder form for children, to be dosed with food. Children weighing 15-35kg should receive oral capsules (200mg) and children weighing above 35kg should receive the adult dose of 300mg, with either dose boosted by 100mg of ritonavir.

Atazanavir boosted by ritonavir combined with two nucleoside reverse transcriptase inhibitor (NRTIs) is a preferred first-line treatment regimen for children aged 3-6 years and an alternative option for children aged 6-18 years in European (PENTA) treatment guidelines. US guidelines recommend atazanavir boosted by ritonavir as a preferred option for children aged 3 years and over weighing less than 25kg and as an alternative option for children aged 3 years and over weighing more than 25kg.

Atazanavir cannot be used in infants because of the risk of kernicterus, a type of brain damage caused by excess levels of bilirubin. 

The safety profile of atazanavir in children is similar to adults. The most commonly observed moderate to severe side effects are cough (21%), fever (19%), jaundice (13%), diarrhoea (8%), vomiting (8%), headache (7%), and runny nose (6%). Increased levels of bilirubin were found in the blood of 49% of individuals. In the P1020A study, 8.5% of individuals had a bilirubin level more than five times the upper limit of normal. (Rutstein)