Report From the International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

Hopkins HIV Report 2006 Jan; 18(1):8-9

Joseph Cofrancesco, Jr., M.D., M.P.H. and Todd Brown, M.D.
Johns Hopkins

The 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held in Dublin on November 13-16, 2005, was a productive meeting, providing further insights into the complications of HIV treatment. A number of well conducted basic science and clinical studies were presented that may lead to improved treatment options for HIV-infected patients. The following is a report on the more clinically relevant abstracts.

HIV fat changes were first described as “fat redistribution,” with the assumption that the peripheral fat loss and central fat gain was linked and reciprocal. Many studies made this assumption in their methodology, and the term “lipodystrophy” was used for all fat changes. Some researchers still refer to HARS (HIV-associated redistribution syndrome). However, it has become increasingly clear that fat loss and fat gain are two distinct phenomena with different risk factors. Andrew Carr’s group reviewed data from all participants in the MITOX study, 98% of whom were male, which evaluated the effect of switching from stavudine (d4T) or zidovudine (AZT) to abacavir (ABC), and the ROSEY study, which found no effect of rosiglitazone on peripheral fat compared to placebo [Wand H, et al., Antivir Ther 2005; Suppl 3:L5 (abstract no. 3)]. The authors found that an increase in limb fat in men recovering from lipoatrophy was associated with an increase in subcutaneous abdominal fat as well as a modest increase rather than a reduction in visceral fat. Additionally, they found that risk factors were different for improvement in lipoatrophy (higher baseline body mass index) vs. decrease in visceral fat (higher limb fat mass, lower HDL cholesterol, higher insulin level, greater limb fat decreases). This suggests these fat changes are separate processes, and supports the newly emerging literature, especially the recently published FRAM study [Bacchetti P, et al. J Acquir Immune Defic Syndr. 2005 Oct 1;40(2):121-31]. Providers and researchers should look at fat loss and fat gain separately, and should avoid lumping them together with imprecise terms such as “fat redistribution” or “lipodystrophy.”

Nutritional Supplements

A number of small studies looked at use of nutritional supplements and body composition. Sakkas reported on a study of 33 HIV-infected men randomized to receive creatine monohydrate (loading dose of 20g/day for 5 days, then 4.8 g/day in repeated 6 week cycles) or placebo [Antivir Ther 2005; Suppl 3:L6 (abstract no. 6)]. After the first 2 weeks of the study, all subjects, with the exception of 7 who dropped out, underwent 12 weeks of supervised resistance training three times a week. Resistance training improved muscle size and strength; creatine increased lean body mass but did not increase strength. The implication is that we should not be recommending creatine to enhance muscle growth in our HIV-infected men, particularly since there is always doubt about the purity of supplements, and the potential toxicities are unclear. This study did report small increases in serum creatinine and triglycerides (TG) with the supplement. These results do emphasize that resistance training is a valuable way for people with HIV to maintain and build muscle and strength.

Uridine is the ‘hot’ compound for treating lipoatrophy. This supplement is purported to assist in recovery from mitochondrial damage, and preliminary results show promise. Sutinen reported on a study from Finland in which 20 men with lipoatrophy on either d4T or AZT were randomized to take the uridine-rich dietary supplement NucleomaxX (36 g tid for 10 days/month) or placebo for 3 months [Antivir Ther 2005; Suppl 3:L7 (abstract no. 7)]. The average increase in total limb fat by DXA for those receiving uridine was 21% compared to 7% in the placebo group. Intra-abdominal fat measured by MRI also increased significantly over the study period. There was no change in liver fat. This preliminary study suggests that this compound may be useful in helping those with lipoatrophy regain some lost fat. NucleomaxX was also associated with improvements in fat and blood mitochondrial DNA [McComsey G, et al. Antivir Ther 2005; Suppl 3:L49 (abstract no. 82)]. However, this study had a very small number of subjects. Additionally, NucleomaxX is not widely available, tastes bad, and is quite expensive. It may be that uridine will have better utility for the prevention of lipoatrophy rather than for recovery of lost fat. For clinicians in the US, it seems more reasonable to avoid medications toxic to mitochondria (especially d4T and AZT) than to add a supplement. An ACTG trial of uridine is planned.

Increases in Limb Fat With Lipid-Lowering Therapy

Quite unexpectedly, pravastatin was shown to increase limb fat by both DXA and computed tomography (CT) in a randomized, placebo-controlled study of 33 HIV-infected patients with hypercholesterolemia [Mallon PWG, et al. Antivir Ther 2005; Suppl 3:L15 (abstract no. 23)]. Despite a negligible effect on lipid parameters, the study’s primary endpoint, limb fat increased by an average 0.72 grams over 16 weeks in those randomized to pravastatin (40 mg qhs) compared to a nonsignificant 0.19 g increase in the placebo group. To put these results in perspective, this increase in limb fat was more than double what was seen after d4T discontinuation in the MITOX study. Further research is needed to confirm these findings and elucidate the underlying mechanism before it can be embraced by the clinical community.

Switch Studies

Continuing the theme that switching from medications that are associated with facial lipoatrophy is a viable option, Benn presented further data on the previously published RAVE study, which randomized patients to switch from d4T or AZT to ABC or TDF in a 1:1 randomized fashion [Antivir Ther 2005; Suppl 3:L7 (abstract no. 8)]. This substudy focused on 47 subjects and compared limb fat DXA measurements with 3D facial laser imaging at baseline and week 48. The authors found that switching was associated with improvements in facial volume similar to that seen with collagen injections, with no differences between ABC and TDF. Cheek volume changes correlated with limb fat changes. This study supports switching from a thymidine analog to either ABC or TDF, with no apparent difference between the two, for patients with lipoatrophy who can safely make such a switch.

Given the association of facial and limb fat, we may be able to extrapolate limb fat changes from other lipoatrophy switch and treatment studies to facial fat. In addition, a number of posters reported on improvement in lipids and other metabolic parameters when changing from d4T to TDF [da Silva B, et al. Antivir Ther 2005; Suppl 3:L38 (abstract no. 62); Libre JM, et al. Antivir Ther 2005; Suppl 3:L39 (abstract no. 63; Zhong L, et al. Antivir Ther 2005; Suppl 3:L40 (abstract no. 64]. Taken together, there is more than sufficient evidence that nucleoside analogs, especially d4T and to a lesser degree AZT, are associated with lipoatrophy, insulin resistance, and dyslipidemia, and that alternative NRTIs may be preferred, at least for initial therapy when patients have many options.

Lipids

Treatment of lipid abnormalities was also an important topic at this meeting. Michael Dubé reported on ACTG 5148, a 48-week, multicenter, open-label, prospective trial of extended released niacin in subjects with TG >200 mg/dL, but non-HDL cholesterol <180 md/dL, and LDL cholesterol <130 mg/dL [Antivir Ther 2005; Suppl 3:L9 (abstract no. 12)]. Patients received nutritional advice for the first 4 weeks (step 1), then niacin was titrated up to 2000 mg/day based on pre-established TG levels. The study participants were all male, with 61% white, 18% black, and 12% Hispanic. The authors found that extended-release niacin in doses of up to 2,000 mg/day, given with aspirin beforehand, was well tolerated and decreased TG by an average of 38%. HDL cholesterol increased by 15%, although LDL particle size and quantity did not change. Subtle changes seen in glucose metabolism at week 12 generally returned to baseline by week 48, although fasting insulin levels remained minimally elevated. These findings suggest a role for niacin in patients with a low HDL and a high TG. However, patients with high LDL cholesterol were excluded from this study, so it will be important to test this agent in combination with a statin and to further evaluate its effect on insulin resistance.

Insulin Resistance

Carl Grunfeld reported that a single dose of 1200 mg of amprenavir given to 6 healthy, male, HIV-infected volunteers in a double-blind, cross-over study did not decrease insulin-mediated glucose disposal ascertained by the eugylcemic hyperinsulinemic clamp technique [Lee GA, et al. Antivir Ther 2005; Suppl 3:L11 (abstract no. 15)]. This study should not be over-interpreted, however, as what happens over time in HIV-infected patients is far more complicated, and insulin resistance is likely to be due to a combination of effects. However, the authors had previously reported that a single dose of indinavir (IDV) did induce insulin resistance, [Noor MA, et al. AIDS. 2002 Mar 29;16(5):F1-8] and IDV has clearly been associated with insulin resistance clinically. The group plans on expanding these very labor- and time-intensive experiments in healthy volunteers with other, newer PIs, as well as PIs boosted with low dose ritonavir.

Mustafa Noor from Bristol-Myers Squib reported a randomized, cross-over study comparing atazanavir/ritonavir (ATV/r) (300/100 mg qd) and lopinavir/ritonavir (LPV/r) (400/100 bid) given for 10 days to 24 healthy, HIV-negative subjects [Antivir Ther 2005; Suppl 3:L11 (abstract no. 16)]. Treatment with ATV/r did not alter insulin sensitivity using the clamp technique, although TG did increase from 108 mg/dL at baseline to 140 mg/dL, with a small increase in insulin area-under-the-curve (AUC) during the oral GTT, another measure of insulin resistance. In contrast LPV/r was associated with significant decreases in insulin sensitivity, larger increases in insulin AUC, and greater increases in TG (to 161 mg/dL).

Bristol-Myers Squib reported on in vitro experiments studying insulin secretion in murine pancreatic beta-cells stimulated by glucose with or without amino acid costimulation in the presence of various PIs [Flint OP, et al. Antivir Ther 2005; Suppl 3:L32 (abstract no. 50)]. In this study the relative inhibition by protease inhibitors was RTV=LPV>IDV>ATV (the latter with very little inhibition). Taken together, these studies should remind providers that not all PIs have the same metabolic toxicities. Although there are PI class effects on insulin sensitivity, the magnitude of the effect varies considerably. Here, as with other studies, APV and ATV, even when boosted, appear to be less toxic than LPV/r.

Finally, Diop and colleagues compared actual blood glucose levels with those estimated by hemoglobin A1c (H A1c) six weeks later in HIV-infected and noninfected patients [Diop M-E, et al. Antivir Ther 2005; Suppl 3:L6 (abstract no. 5)]. They found that in HIV-infected patients H A1c underestimated glucose levels by an average of 12.3%. The authors suggest that this discrepancy is due to low-grade hemolysis induced by lamivudine, but further work is needed to clarify this mechanism. Nonetheless, clinicians should be aware of the possibility that use of H A1c may underestimate control of diabetes in HIV-infected patients.

Clinicians and patients in resource-rich nations continue to learn more about the science of metabolic toxicities, and are able to select treatment to avoid or treat toxicities. However, there is concern that patients in resource-limited countries, who have limited access to newer drugs, will inevitably experience many of these toxicities.

Summary

At this year’s meeting data were presented further reinforcing the concept that changes in subcutaneous fat and visceral fat are two different processes with different risk factors. New analyses of existing studies continue to show higher rates of limb fat loss with d4T, and to a lesser degree with AZT, compared to other NRTIs. In addition, data were presented that continue to demonstrate the benefit of switching from thymidine analogs to ABC or TDF as treatment for lipoatrophy. An interesting study suggested that pravastatin increased limb fat; this gain appeared to be greater than that accomplished with a switch from d4T to another NRTI. Several studies of nutritional supplements were presented. Supplementation with creatine resulted in increased lean body mass, but considering the possibility of impure commercially available products and unknown toxicities, it cannot be recommended. Uridine appeared to be beneficial in countering fat loss, but the commercially available supplements are expensive, difficult to find, and unpalatable. Niacin was shown to be beneficial in reducing TG and increasing HDL. Finally, several studies continue to show the propensity of PIs to induce metabolic toxicities, while emphasizing the differences among the individual PIs.

2006-01-10
HHR-2006-01-03

Copyright © 2006 - The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, the National Library of Medicine, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 2006. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2006. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.