Changing from protease inhibitor treatment

Longer-term follow-up of patients with body fat changes who have switched from a protease inhibitor (PI) to a PI-sparing combination shows that body fat maldistribution does not improve after six to twelve months in the vast majority of cases.

Comparisons between these studies are difficult to make because studies used different methods to assess body fat changes, some studies lacked control groups and many studies were observational rather than randomised. Only one randomised study using the most reliable method for assessment of visceral and subcutaneous fat (MRI) has been conducted, and this study found no reduction in visceral fat.1 Studies of nucleoside analogue switching are discussed below.

Switch studies have shown variable trends in cholesterol and triglyceride levels. Randomised studies of abacavir substitution have shown significant reductions in total cholesterol, and two of three studies also showed a reduction in triglyceride levels.2 3 4 This has been confirmed in a sub-study of a large Spanish trial, in which levels of non-HDL cholesterol were reduced two years after replacing PIs with abacavir.5 The same study showed favourable increases in HDL cholesterol and in total to HDL cholesterol ratios after switching to efavirenz or nevirapine.

Reductions in cholesterol and triglyceride levels have been less consistent in studies of efavirenz or nevirapine substitution. Two randomised studies of nevirapine substitution have shown improvements in cholesterol and triglycerides, but only one of these studies included a comparison arm in which people remained on PI treatment.6 7 No randomised studies have shown cholesterol or triglyceride reductions after a switch to efavirenz. However, the majority of studies that have measured HDL cholesterol show a distinct class effect of NNRTIs: sustained increases in HDL cholesterol despite little reduction in total cholesterol.5

Insulin resistance does not necessarily improve after switching therapy. The only randomised study to report on insulin sensitivity found that it had improved 12 months after a switch to abacavir, efavirenz or nevirapine, but this study did not have a control group that remained on PI treatment.8 A cohort study in which all patients switched to efavirenz showed no improvement in insulin sensitivity after 12 months.9 In contrast, other uncontrolled cohort studies have reported improvements after switches to nevirapine or efavirenz.

In the majority of individuals who switch, viral load remains undetectable. One study found that individuals randomised to switch to efavirenz were significantly less likely to experience viral rebound within 48 weeks of switching when compared to those who remained on PI treatment.10 A similar trend was seen in two other randomised studies, one of efavirenz and one of nevirapine substitution.11 6 Two randomised studies of abacavir substitution have also reported superior viral load responses in the switch group.4 However one study of abacavir substitution showed that individuals with prior nucleoside analogue experience had a higher risk of viral rebound.3

Quite a few of the switch studies asked patients if they found it easier to adhere, or if the drugs were difficult to take, or if quality of life had improved. In each case they reported improved satisfaction with the new therapy, because it was easier to take.

Despite these advantages, however, a recent Italian study has suggested that switching from PI- to NNRTI-based therapy may be less effective than use of lipid-lowering drugs in managing lipid elevations. The study, which randomised 132 patients with high triglyceride and cholesterol levels to switch from their PI to nevirapine or efavirenz, or to add pravastatin (Lipostat) or bezafibrate (Bezalip) to their PI-based HAART regimen, showed greater decreases in triglycerides and LDL cholesterol in the NNRTI group.12

There was little evidence to support a switch from one protease inhibitor to another until the arrival of atazanavir. Individuals who switched from nelfinavir to atazanavir experienced significant lipid reductions within 12 weeks and average levels returned to pre-treatment baseline levels.13 See Atazanavir in A to Z of antiretroviral drugs for further details.

However, a primary analysis done midway through the 96-week ReAL study, in which some patients switched from twice-daily, existing ritonavir-boosted PI therapy to atazanavir, did not show significantly reduced abdominal visceral fat accumulation, although there were significant reductions in all fasting lipid levels.14  

In an attempt to explain poor results after stopping or switching PI therapy, Carr and colleagues have suggested that fat loss is either irreversible, or may take more than six months to reverse. Another possibility is that some aspects of fat and metabolic disorders may not be associated with either protease inhibitor treatment or with elevated lipids. Instead, NRTIs or other factors may play a role in causing these disorders.

References

  1. Carr A et al. A HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS 15: 1811-1822, 2001
  2. Lafeuillade A et al. Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study. HIV Clin Trials 4(1):37-43, 2003
  3. Opravil M et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. J Infect Dis 185: 1251-1260, 2002
  4. Clumeck N et al. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 15: 1517-1526, 2001
  5. Fisac C et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS 19: 917-925, 2005
  6. Barreiro P et al. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy. AIDS 14: 807-812, 2000
  7. Negredo E et al. Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine. AIDS 16(10): 1383-1389, 2002
  8. Martinez E et al. A randomized, double-blind, placebo-controlled, comparative study on the effects of metformin or gemfibrozil in lipodystrophic HIV-1-infected patients receiving protease inhibitors (PI). Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 702T, 2002
  9. Estrada V et al. Long-term metabolic consequences of switching from protease inhibitors to efavirenz in therapy for human immunodeficiency virus-infected patients with lipoatrophy. Clin Infect Dis 35: 69-76, 2002
  10. Becker S et al. Successful substitution of protease inhibitors with Sustiva (efavirenz) in patients with undetectable plasma HIV-1 RNA: results of a prospective, randomised, multicenter, open label study (DMP-266-049). 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 20, 2000
  11. Katlama C et al. Successful substitution of protease inhibitors with Sustiva (efavirenz) in patients with undetectable plasma HIV-1 RNA: results of a prospective, randomized, multicenter, open-label study (DMP 006-027). Thirteenth International AIDS Conference, Durban, abstract LB B7044, 2000
  12. Calza L et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS 19: 1051-1058, 2005
  13. 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
  14. Moyle G et al. Continuation of BID boosted PI vs switch to once-daily ATV/RTV for the management of lipodystrophy: 48 week primary analysis of the 96 week multicenter, open-label, randomized, prospective ReAL study. XVII International AIDS Conference, Mexico City, abstract MOPDB103, 2008
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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