The most eventful aspect of the 3rd IAS Conference in Rio de Janeiro for me was a missed connection and lost luggage for three days. However, we did deepen our understanding of fat and metabolic issues. And, of course, the weather and the Brazilians were beautiful.

Bone Loss

Bongiovanni evaluated potential predictors of bone demineralization in HIVinfected patients [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.2B08)]. Questionnaires, blood and urine samples, and blinded bone DEXA scans were performed on 161 consecutive HIVinfected outpatients aged 30 to 50 years. Of these, 48 were ART naïve and 113 were taking HAART; males were equally represented in each group (60% and 65% respectively). Using WHO criteria, approximately half had an abnormal DEXA: 65 had osteopenia (46% of naïve, 51% on HAART), but only 15 had frank osteoporosis (10% naïve, 9% HAART). Low bone density was associated with traditional risk factors: female gender, older age, and low body mass index. In addition, there was also a greater risk in patients with higher viral loads. HAART use was not associated with markers of bone metabolism. There was no comment on the specific HAART regimens used, cigarette smoking (another known risk factor) or protective factors such as exercise, calcium and vitamin use.

Similarly, a small cohort of 200 French patients (74% male, median age 43 years), selected from HIV-infected patients followed in the Bordeaux University Hospital, underwent DEXA between November and December 2004 [Dutronc H, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.2B19)]. Using WHO criteria, 80 patients (40%) had osteopenia while 21 patients (11%) had osteoporosis. Both studies show a relatively high prevalence of osteoporosis at approximately 10%, and even higher prevalence of osteopenia. Traditional risk factors are implicated. HIV seems to be playing a role, but neither study was powered nor designed to determine the effects of specific medications. Clinicians should be aware that osteoporosis will likely be an issue for some patients, particularly those with other risk factors. Fortunately, a higher risk for fractures, the only thing that really matters in the end, has not been yet demonstrated.

NRTIs And Toxicity

In a late breaker, Fisac reported on 71 treatment naïve subjects who were randomized in the open-label ABCDE study to take abacavir (ABC) vs stavudine (d4T) combined with efavirenz (EFV) and lamivudine (3TC) [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPeLB2.2B02)]. Baseline characteristics were similar in the 2 groups. At month 24, median insulin levels and Homeostasis Model Assessment of Insulin Resistance (HOMA–IR) (a measure of insulin resistance) increased significantly only in the d4T arm (+27% and +38%, respectively). Patients with “lipodystrophy” and increased waist-to-hip ratios had the highest increases. These results are consistent with a growing body of literature suggesting that the choice of NRTIs is important not only with respect to the risk of lipoatrophy but for glucose metabolism as well. As with other studies, d4T, but not ABC, is implicated as having negative metabolic effects.

Switching medications continues to be a strategy used to help reverse undesirable metabolic and fat changes associated with HIV treatment. Calza and colleagues evaluated 130 NNRTI-naïve patients who were stable on their first HAART regimen, but had hyperlipidemia [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuFo0105)]. Subjects were randomized to: switch from a protease inhibitor (PI) to nevirapine (NVP) (arm 1), switch from a protease inhibitor (PI) to efavirenz (EFV) (arm 2), or to remain on PI and add pravastatin (arm 3), or bezafibrate (arm 4). This open-label, 12-month study suggested that lipid-lowering medications were more effective than switching ART. Triglyceride levels (TG) were reduced 25%, 9%, 41% and 47% in arms 1-4, respectively, compared to baseline; there was a statistically significant difference between arms A-B and C-D. Comparable results were seen for LDL-cholesterol levels. As expected, switching to NVP resulted in greater reductions in TG than switching to EFV. Unfortunately, there were no data presented on the NRTI backbone or baseline PIs, and the sample size was relatively small, so comparison between individual arms could not be made.

It is not surprising that use of lipidlowering agents would have a greater impact than treatment switches, since switches, at best, can only return lipid levels to pretreatment baselines, whereas lipid-lowering agents can go further. Many patients have high lipid levels at baseline. However, for many patients, switching therapy will result in satisfactory reductions in lipid levels without the need for additional medications, with their cost and potential for toxicity and drug interactions. It should also be noted that when drug therapy is required for the treatment of hyperlipidemia, the choice of a statin vs a fibrate should not be made by coin-toss, as in this study, but should be based on the characteristics of the lipid profile. Statins are preferred for elevations in LDL cholesterol; fibrates are preferred for hypertriglyceridemia.

A series of studies reinforced the benefit of switching from d4T to tenofovir DF (TDF). GS 903e is an extension study of the large GS 903 trial comparing d4T versus TDF with 3TC/EFV in naïve subjects) [Madruga JVR, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.2B12)]. Both lipid levels and lipoatrophy improved in 85 subjects who had been on d4T but switched to TDF. The mean time on d4T before the switch was 152 weeks. At 48 weeks after switch, total cholesterol decreased by a mean of 38 mg/dL; triglycerides decreased by 72 mg/dL and LDL cholesterol by 16 mg/dL. There were no significant changes in HDL cholesterol or DEXA bone densities. There was a mean increase of 0.42kg in limb fat, also measurement by DEXA, at week 48.

Similarly, Palacios reported 48-week data on 237 patients, identified from a mulitcenter, prospective cohort of 1286 patients, who switched from d4T to TDF for lipoatrophy. [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.3C15)]. No patient withdrew for virologic failure. There were no significant changes in blood pressure, smoking (approximately 53% in each group), or diabetes between the two arms. However, the 10-year overall cardiovascular risk decreased from 7.2% to 6.8 %, accompanied by a decrease in total cholesterol and LDL cholesterol.

In a late breaker, Benn and colleagues reported the 3-D surface laser measurements for facial lipoatrophy performed at baseline and week 48 on 47 subjects (24 on ABC and 23 on TDF) from the larger RAVE study involving switches from a thymidine analog to ABC or TDF) [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPeLB2.3C02)]. They found no difference between treatment arms, with the mean volume over the cheek at week 48 similar to what would be expected for collagen injections. Sixty-nine percent of the subjects reported no change or improvement in facial appearance. There were no differences between study arms in baseline limb fat and both showed similar improvements (+0.36 kg). The amount of limb fat by DEXA correlated significantly with cheek volume. Although not surprising, taken together these studies demonstrate the value of eliminating thymidine analogs, especially d4T, for lipoatrophy and metabolic toxicities. The RAVE study suggests that ABC and TDF are equally non-toxic and may lead to a slow reversal of some of the fat changes. It should also be noted that investigators were looking for improvement or lack of progression, which is not the same thing as total reversal or normalization. Clinicians need to remain vigilant to notice early lipid or fat changes early, and to make the appropriate switches.

PIs and Toxicity

Not all switch studies involve a switch to an NNRTI, and not all PIs have the same lipid or glucose metabolism issues. Moebius reported the results of a very small prospective, open-label, 24-week cohort study of 33 antiretroviral-experienced patients with hyperlipidemia [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.4C20)]. Switching to atazanavir (ATV) lead to a rapid 45% decrease in TG levels and an 18% decrease in total cholesterol. HDL and LDL cholesterols did not change. There were no data presented on baseline regimens, the reason for switch, virologic outcomes, or whether the ATV was boosted. As with most studies, data on diet and exercise were also not provided. Nonetheless, these data are consistent with previously published data suggesting that ATV does not have a negative impact on lipids or TG and that switching to ATV can reverse previously induced changes.

Finally, more data were presented from the large, multicenter D:A:D study group [Sabin C, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.2B28)]. Using standard definitions, after adjustment for other factors PI exposure was a significant independent risk factor for diabetes mellitus (RR 1.06 per year). However, once TG levels were entered into the model, the PI effect disappeared. Traditional risk factors were significantly associated with the development of diabetes including older age, male sex, increased BMI and black race. As with other cardiovascular risk factors in this cohort, earlier calendar year was also a risk, which presumably reflects the use of more toxic medications available in prior years. The study suggests that diabetes and hypertriglyceridemia are related in many patients, and that some PIs are associated with hypertriglyceridemia and/or diabetes risk. This study does not specify the PI or the NRTI backbone used. As we are learning, not all agents within classes have the same degree of have class toxicities.

Vascular Disease

Kaplan and colleagues found an increased prevalence of subclinical carotid artery lesions in HIV-infected women in the Women’s Interagency HIV Study [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.3C12)]. Using B-mode ultrasound, carotid artery intima-media lesions were more common among HIV-infected (10%) than among HIV-negative women (2%), regardless of HAART exposure. Compared to HIV-negative women, HIV-infected women had a 4.18-fold higher risk of lesions after adjustment for age, race, BMI, and smoking. The clinical significance of these subclinical lesions is unclear, but the data supports the view that left unchecked both metabolic abnormalities and HIV infection contribute to vascular disease.

Reimbursement Issues

Lastly, in an intriguing study of the potential impact of government and insurance companies’ policies, Manfredi and colleagues evaluated recent changes in the Italian government’s reimbursement for lipid-lowering drugs [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe2.4C03)]. Free access to or reimbursement for statins, fibrates, and omega-3 fatty acids is now restricted to patients who need secondary prophylaxis because they have already had a vascular event, those with a genetically-proven familial dyslipidemia, or those with a 10-year risk of a primary cardiovascular event >20% as calculated by software developed for the general population. The authors noted that <5% of the HIV infected Italian cohort of >1,000 would meet these criteria for reimbursement. The authors conclude that the increased life expectancy achieved by HAART may be threatened by untreated lipid abnormalities. The impact of formulary restrictions, payment cutbacks with increased co-payments, and increased paperwork is not surprising to an American audience. Time will tell how these changes will affect our patients’ long-term health.

Summary

For bone loss, traditional risk factors continue to be implicated. HIV seems to be playing a role, but none of the studies was powered nor designed to determine whether a specific medication was implicated, or whether medication may be protective by controlling the contribution of inflammation caused by HIV. Providers need to be aware that osteoporosis is likely to be an issue for some patients. However, it is worth noting that a higher risk for fractures, which is what really matters,has not been demonstrated.

Additional evidence was presented indicating that NRTI selection is important not only for fat changes but also glucose metabolism. As with other studies, d4T is implicated as having negative effects, but not ABC or TDF. Methods to avert metabolic complications include switching anti-retrovirals. Data were presented showing the small lipid benefit of switching from PI to EFV or NVP compared to the addition of a lipid lowering agent. Despite this, practicality may lead to switching antiretrovirals as opposed to adding additional medications. A number of studies reported reduction in lipid and metabolic complications with a switch to TDF from other NRTIs, while another study suggested that ATV may be a may be a reasonable PI option for those with significant lipid or glucose issues. Finally, a report from the Women’s Interagency HIV Study suggests that HIV infection may increase the risk of vascular disease independent of HAART exposure.

20050901
JH2005-09-06

©1997-2005. 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 grants from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2005. 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, 2005. 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.