Side-effects

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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 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 initiating ART, 33% of the nearly 400 patients 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.1 Reversible hyperbilirubinaemia, rated grade 3 and 4 occur in 35 to 47% of patients. This does not mean therapy should be discontinued or that there is actual liver disease. It is usually a benign development.

The risk of bilirubin elevations in individuals receiving atazanavir is dose-related, being most prevalent at higher drug concentrations.3 4 Data have also shown that it is more common in patients taking ritonavir-boosted atazanavir than those taking the drug without boosted atazanavir.5

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.6 A variant of the multidrug resistance gene 1 is also linked to atazanavir levels and the risk of hyperbilirubinaemia.7 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.8 This was confirmed in a similar, second study comparing the two drugs.9 Studies 043 and 045 also showed that atazanavir had a superior lipid profile to lopinavir, even when each drug is combined with ritonavir.10 1

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.11 These findings have been confirmed in at least three other studies.12 13 14 A case series of three protease inhibitor-experienced patients with ‘buffalo hump’ fat accumulation also provided evidence that switching to 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.15

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.2

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.16 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.17

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 cause for 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.18

Around 6% of patients taking atazanavir also develop a rash, which may require treatment to be discontinued in a few cases.19

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.20

References

  1. Johnson M et al. Atazanavir plus ritonavir or saquinavir, and lopinavir / ritonavir in patients experiencing multiple virological failures. AIDS 19: 685-694, 2005
  2. Squires K et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36: 1011-1019, 2004
  3. Gonzalez de Requena D et al. Atazanavir trough is associated with efficacy and safety: definition of therapeutic range. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 645, 2005
  4. Rendon A et al. Safety profile of atazanavir and correlation with plasma levels. 15th International AIDS Conference, Bangkok, abstract TuPeB4624, 2004
  5. Ward D et al. Hyperbilirubinemia among patients in the HIV outpatient study (HOPS) receiving atazanavir. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe2.1B02, 2005
  6. O'Mara E et al. Population pharmacodynamic assessment of atazanavir exposure, uridine diphosphatase-glucoronosyl transferase (UGT) 1A1 genotype and safety in healthy human subjects. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract A-1253, 2002
  7. Rodríguez-Nóvoa S et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS; 21(1): 41-46, 2007
  8. Murphy R et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS 17: 2603-2614, 2003
  9. Sanne I et al. Results of a phase 2 clinical trial at 48 weeks (A1424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 32: 18-29, 2003
  10. Nieto-Cisneros L et al. Antiviral efficacy, metabolic changes and safety of atazanavir versus lopinavir / ritonavir in combination with NRTIs in patients who have experienced virological failure with prior PI-containing regimen(s): 24-week results from BMX A1424-043. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 117, 2003
  11. Wood R et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr 36: 684-692, 2004
  12. Markowitz M et al. 48-week results of an atazanavir-based QD regimen in patients switching from BID-based HAART. Antivir Ther 8: S329, 2003
  13. Martinez E et al. Effects of switching to ritonavir-boosted atazanavir on HIV-infected patients receiving antiretroviral therapy with hyperlipidemia. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 850, 2005
  14. Gatell JM et al. Efficacy of atazanavir (ATV) based HAART in patients switched from a stable PI or boosted PI (PI/r) treatment. Planned week 24 analysis of a phase IIIb 48 week multicenter, open-label, randomized, prospective trial. The SWAN study. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe6.3C15, 2005
  15. Haerter G et al. Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir. AIDS 18: 952-955, 2004
  16. Jemsek JG et al. Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive, HIV-infected patients. Clin Infect Dis 42: 273-280, 2006
  17. Dube MP HIV-associated lipoatrophy: what are the kinder, gentler agents? Clin Infect Dis 42: 281-282, 2006
  18. Eholie SP et al. Acute hepatic cytolysis in an HIV-infected patient taking atazanavir. AIDS 18: 1610-1611, 2004
  19. Ouagari Z et al. Skin rash associated with atazanavir: report of three cases. AIDS 20: 1207-1208, 2006
  20. Noor MA et al. Maintenance of favorable in vitro metabolic profile of atazanavir when combined with low dose ritonavir. 15th International AIDS Conference, Bangkok, abstract ThOrB1356, 2004
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