Atazanavir (Reyataz)

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. For more information on how protease inhibitors work, see Protease inhibitors in the section Ways of attacking HIV.

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 400mg once daily for treatment-naive people and 300mg plus 100 mg ritonavir once daily for treatment-experienced 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 under the brand name Evotaz. See Evotaz for further details of dosing and specific drug interactions resulting from the use of cobicistat.

Generic versions of atazanavir are due to become available for prescribing in the United Kingdom during 2018 and it is likely that most people taking atazanavir will be switched to these products.

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.[ref]

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.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

protease

An enzyme that HIV uses to break up large proteins into smaller ones from which new HIV particles can be made.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

treatment-naïve

A person who has never taken treatment for a condition.

resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

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.[ref] [ref]

Atazanavir/ritonavir is recommended as a third agent for use in combination with tenofovir/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.

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.[ref]

Atazanavir is also safe and effective in HIV-positive people with liver cirrhosis, according to a retrospective Spanish study presented in 2006. 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.[ref]

Taking it

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

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).

If using unboosted atazanavir, treatment-naive people should avoid the combination of enteric-coated didanosine with tenofovir.[ref]

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

Experimental doses of 300 or 400mg atazanavir plus 200mg ritonavir have been shown to improve atazanavir exposure in people with suboptimal levels on the standard boosted dose.[ref]

A dosing study in HIV-negative volunteers found that taking 400mg atazanavir with food increased drug concentrations by 35 to 70%, so taking the drug without food could result in failing to meet the necessary pharmacokinetic targets for efficacy. Atazanavir should also not be taken with proton pump inhibitors or antacids as the AUC of atazanavir is decreased with co-administration.

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.[ref]

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 (Norvir)-boosted atazanavir than those taking ritonavir-boosted lopinavir (Kaletra).[ref]

Hyperbilirubinaemia

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.[ref]

It has been shown that those with a particular version of the gene for an enzyme involved in bilirubin metabolism are at an elevated risk of developing hyperbilirubinaemia when taking atazanavir.[ref] A variant of the multidrug resistance gene 1 is also linked to atazanavir levels and the risk of hyperbilirubinaemia.[ref] Polymorphisms at MDR1-3435 significantly influence atazanavir plasma concentrations, as do other factors. The risk of severe hyperbilirubinaemia is further increased in the presence of the UGT1A1-TA7 allele.

Lipodystrophy

Several comparative studies have suggested that atazanavir may not disrupt lipids to the same extent as other protease inhibitors. In a study comparing atazanavir and nelfinavir (Viracept), atazanavir was not associated with any significant increases in cholesterol or triglyceride levels. In contrast, significant lipid elevations occurred in the nelfinavir arm.[ref] This was confirmed in a similar, second study comparing the two drugs.[ref] Studies 043 and 045 also showed that atazanavir had a superior lipid profile to lopinavir, even when each drug is combined with ritonavir.[ref]

There is also some evidence that atazanavir can reverse lipid increases caused by other protease inhibitors. In one study, switching from nelfinavir to atazanavir-based therapy returned lipids to pre-treatment levels after three months, while maintaining viral suppression for at least 36 weeks after the switch.[ref] These findings have been confirmed in at least three other studies.[ref] [ref] [ref]

Atazanavir also has fewer effects on blood lipid levels than the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva). For example, one large study comparing efavirenz and atazanavir found that efavirenz recipients were significantly more likely to experience increases in low-density lipoprotein (LDL or ‘bad’) cholesterol and triglycerides. However, the rate of discontinuation was similar in the two arms of the study.[ref]

The two groups of participants also had similar increases in the levels of fat under the skin and around the organs, suggesting that both atazanavir and efavirenz may reduce the risk of fat loss due to nucleoside reverse transcriptase inhibitor (NRTI) treatment.[ref]

Other side-effects

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.[ref]

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.[ref] [ref] [ref] [ref]

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.

This advisory was issued despite an earlier study carried out in HIV-positive people that failed to show reduced atazanavir levels when combined with low-dose ritonavir.[ref] In that study, proton pump inhibitors did not have a significant effect on the outcomes of antiretroviral therapy containing ritonavir-boosted atazanavir.[ref] The study investigators claim that the effects of omeprazole may be less important in people with HIV because of possible reduced stomach acid levels. Differences in study design and variability in drug levels may have also led to confusion over the relationship between these drugs.[ref]

When atazanavir is dosed with efavirenz (Sustiva), atazanavir levels are reduced by around 70%. Adding low-dose ritonavir counteracts this effect in HIV-negative volunteers, but a small study has found that this may not be the case in people with HIV.[ref] [ref] [ref] A similar effect of nevirapine has also been seen in a small study. Both drugs are CYP3A4 inducers, which means that they speed up metabolism of other drugs metabolised by the same route.[ref]

Combining atazanavir with tenofovir (Viread) may put an individual at risk of treatment failure, since tenofovir can reduce atazanavir levels by up to 40%.[ref] [ref] Atazanavir can also increase the likelihood of tenofovir-associated adverse events, including kidney disorders. Doctors should consider boosting atazanavir levels with ritonavir, if atazanavir and tenofovir must be used together, although studies have shown that this is not always successful in restoring atazanavir levels.[ref]

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.[ref]

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.[ref] A dose reduction may be necessary. In contrast, no dose adjustment of methadone (Methadose) is needed.[ref]

Children

Atazanavir boosted by ritonavir combined with two nucleoside reverse transcriptase inhibitor (NRTIs) is a preferred first-line treatment regimen for children aged 6-18 years in US and European (PENTA) treatment guidelines.

Atazanavir dosing in children up to age 18 is based upon body weight, but should never exceed the adult recommended dose. Atazanavir with ritonavir-boosting can be used in all children 6 to 18 years, regardless of antiretroviral experience.

Atazanavir should always be taken with food. Weight-based dosing can be found at the Bristol-Myers Squibb website: http://packageinserts.bms.com/pi/pi_reyataz.pdf or at the website of the National Institutes of Health (NIH): http://aidsinfo.nih.gov.

In the US, if a treatment-naive individual aged 13 years and older and weighing at least 39kgs cannot tolerate ritonavir, the recommended dose is atazanavir 400mg once daily with food.

The use of atazanavir is not recommended in children younger than 6 years; without ritonavir in children from 6 to 12 years, or for any child whose weight is less than 25kgs.

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.[ref]

 

Pregnancy

Owing to substantial variations in drug levels during pregnancy atazanavir should only be used with a boosting dose of ritonavir.

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