Side-effects

The commonest side-effects of Kaletra are diarrhoea and nausea. In the major studies of Kaletra, moderate or severe diarrhoea affected 12 to 27% of participants. Two to 7% of patients interrupted therapy because of diarrhoea, but only 1% of all participants in these trials stopped Kaletra treatment. Diarrhoea and loose stools are most common during the first two months of treatment, but many people experience ongoing problems. Nausea related to lopinavir treatment is also a common reason for interrupting treatment, occurring in 2 to 12% of study participants .

Fatigue, muscle weakness, headache, stomach pain and vomiting are less common side-effects associated with Kaletra in clinical trials.

Body fat changes and metabolic disorders have been associated with the protease inhibitors as a class. After 60 weeks on lopinavir, 7% of HIV-positive individuals in a major international study had developed body fat changes, the same rate of development as seen among people who received nelfinavir (Viracept).1 However in another study, 35% of patients experienced body fat changes after four years on Kaletra. 2

Elevated lipids, including high triglycerides and cholesterol levels, occur amongst 10 to 25% of people on Kaletra, particularly among those with high cholesterol or triglycerides before starting to take the drug.2 3 4 5

These lipid changes are mild in the majority of patients and only rarely lead to treatment discontinuation.6 7 There seems to be no correlation between blood concentrations of lopinavir and the severity of lipid elevations, suggesting that dose reductions are unlikely to moderate lipid increases.8 The low-dose ritonavir, rather than the lopinavir in Kaletra drives the increases in blood cholesterol and triglyceride levels.9 Kaletra is also associated with insulin resistance and the development of type II diabetes.10 For more details, see Metabolic changes while on ART.

The other key side-effect associated with Kaletra is elevated liver enzyme levels, which occurs most commonly among individuals co-infected with hepatitis B or C.2 11 12 As observed for lipid elevations, liver toxicity does not seem to be related to the levels of lopinavir in the blood, suggesting that dose adjustments are unlikely to be of benefit.13 However, liver problems are rare in patients taking Kaletra, with one study finding an incidence of severe liver abnormalities of less than one per 100 person-years of treatment.14

In ACTG 5142, lipoatrophy (defined as a 20% loss of limb fat at week 96), was experienced by 32% of the efavirenz + 2NRTI group, 17% of the Kaletra + 2 NRTI group, and 9% of the Kaletra/efavirenz group.15

When the incidence of lipoatrophy was analysed according to the second nucleoside analogue used, it was most commonly seen in patients who received d4T, 42% compared to 27% in the AZT group. Just 9% of tenofovir-treated patients developed lipoatrophy, a significantly lower proportion than was found in the AZT recipients.

Compared to EFV, LPV had less lipoatrophy when given with an NRTI. When lipoatrophy incidence was analysed according to pairings of drugs, it was evident that tenofovir recipients who received efavirenz were more likely to develop lipoatrophy (12%) than those who received Kaletra (6%). Similarly, AZT recipients who received efavirenz were also at greater risk of lipoatrophy (40% vs 16% for Kaletra recipients). The difference was less pronounced for d4T recipients (51% for efavirenz, 33% for Kaletra).

After 96 weeks those in the nucleoside-sparing arm had experienced an average 18% gain in limb fat (around 1kg), compared to a 9.8% gain in the Kaletra + 2 NRTIs group and a gain of 1.4% in the efavirenz group.

A surprising result was that the NRTI-sparing regimen (LPV+EFV) increased lipids significantly more than did the EFV+2 NRTIs or LPV+2 NRTIs regimens. Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol changes were not significantly different.

Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol elevations between the Kaletra and efavirenz arms were similar. The increase in HDL cholesterol was significantly greater in the Kaletra/efavirenz nucleoside-sparing arm.

References

  1. Bernstein B et al. Safety of Kaletra: data from phase II and phase III clinical trials. First International AIDS Society Conference on HIV Treatment and Pathogenesis, Buenos Aires, abstract 525, 2001
  2. Hicks C et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naïve patients: 4 year follow-up study. AIDS 18: 775-779, 2004
  3. Martinez E et al. Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clin Infect Dis 38: 1017-1023, 2004
  4. Montes ML et al. Lipid disorders in antiretroviral-naive patients treated with lopinavir/ritonavir-based HAART: frequency, characterization and risk factors. J Antimicrob Chemother 55: 800-804, 2005
  5. Valerio L et al. Lopinavir / ritonavir combination and total / HDL cholesterol ratio. J Infect 50: 229-235, 2005
  6. Lafeuillade A et al. Evolution of lipid abnormalities in patients switched from stavudine- to tenofovir-containing regimens. J Acquir Immune Defic Syndr 33: 544-546, 2004
  7. Bongiovanni M et al. Use of lopinavir / ritonavir in HIV-infected patients failing a first-line protease-inhibitor-containing HAART. J Antimicrob Chemother 55: 1003-1007, 2005
  8. Torti C et al. Lipid abnormalities in HIV-infected patients are not correlated with lopinavir plasma concentrations. J Acquir Immune Defic Syndr 35: 324-326, 2004
  9. Shafran SD et al. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med 6: 421-425, 2005
  10. Noor MA et al. The effects of protease inhibitors atazanavir and lopinavir / ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS 18: 2137-2144, 2004
  11. Meraviglia P et al. Lopinavir / ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Med 5: 334-343, 2004
  12. Seminari E et al. Steady-state pharmacokinetics of atazanavir given alone or in combination with saquinavir hard-gel capsules or amprenavir in HIV-1-infected patients. Eur J Clin Pharmacol 61: 545-549, 2005
  13. Gonzalez-Requena D et al. Liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection. AIDS Res Hum Retroviruses 20: 698-700, 2004
  14. Bonfanti P et al. Low incidence of hepatotoxicity in a cohort of HIV patients treated with lopinavir/ritonavir. AIDS 19: 1433-1434, 2005
  15. Haubrich R et al. Metabolic outcomes of ACTG 5142: a prospective randomised phase III trial of NRTI, PI- and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 38, 2007
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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