The commonest side-effects of associated with atazanavir (Reyataz) are headache, nausea, rash, diarrhoea and vomiting. However, the 045 study concluded that gastrointestinal side-effects are less common in patients taking ritonavir (Norvir)-boosted atazanavir than those taking ritonavir-boosted lopinavir (Kaletra)^[1].

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 patients starting HIV treatment for the first time, 33% of around 400 patients taking atazanavir developed severe hyperbilirubinaemia, but less than 1% discontinued treatment due to bilirubin elevations, and only 5% developed jaundice^[2]. In a study of protease inhibitor-experienced patients, two thirds exhibited elevations in bilirubin, of whom 10% experienced very severe elevations^[3].

The risk of bilirubin elevations in individuals receiving atazanavir is dose-related, being most prevalent at higher drug concentrations^[4][5]. Recent data have also shown that it is more common in patients taking ritonavir (Norvir)-boosted atazanavir than those taking the drug without ritonavir boosting^[6]. However, if hyperbilirubinaemia is severe, discontinuation is preferred to dose reduction because reducing the drug dose may put the patient at risk of drug resistance and treatment failure.

People 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^[7]. A variant of the multidrug resistance gene 1 is also linked to atazanavir levels and the risk of hyperbilirubinaemia^[8]. For more information, see Uridine diphosphate glucuronosyltransferase 1A1.

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^[9]. This was confirmed in a similar, second study comparing the two drugs^[10]. Studies 043 and 045 also showed that atazanavir had a superior lipid profile to lopinavir, even when each drug is combined with ritonavir^[11][12].

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^[13]. These findings have been confirmed in at least three other studies^[14][15][16]. A case series of three protease inhibitor-experienced patients with ‘buffalo hump’ fat accumulation also provided evidence that switching two atazanavir can reverse fat redistribution, at least in part. All three patients experienced a decrease in these fat deposits and falls in blood lipids after switching to atazanavir, without significantly changing their diet or exercise regimens^[17].

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^[18].

The two groups of patients 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^[19]. However, this conclusion may be premature, since the study only lasted 48 weeks, and there are uncertainties surrounding the fat levels and CD4 cell counts of the patients at the start of the study^[20].

Other side-effects

A small number of patients 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 concern than other protease inhibitors.

Liver damage due to atazanavir treatment has only been reported in a single case. This involved a 56-year old HIV-positive woman with no other risk factors for liver-related side-effects^[21].

Around 6% of patients taking atazanavir also develop a rash, which may require treatment to be discontinued in a few cases^[22].

Atazanavir is not known to be associated with the development of insulin resistance. A test tube study has shown that this is unlikely to be affected by co-administration of atazanavir with ritonavir^[23].