Important note: Information in this article was accurate in January 2005. The state of the art may have changed since the publication date.
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Researchers from around the worldgathered in Washington, D.C. in October for the 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. This article will focus on the research with clinical relevance.
Effects of Specific Medications
The impact of specific antiretroviral medication on insulin resistance was further clarified. In healthy volunteers, a single high dose of 800 mg of ritonavir was found to induce insulin resistance [Lee, GA, et al. Antiviral Therapy 2004; 9(6):L6 (Abstract 7)]. Indinavir/ritonavir also induced insulin resistance, but atazanavir/ritonavir did not. [Droan DA, et al. Antiviral Therapy 2004; 9(6):L6 (Abstract 6)]. Although insulin resistance is thought to be a class effect, there are clearly differences among protease inhibitors (PIs). Low-dose ritonavir and atazanavir do not appear to affect insulin sensitivity, whereas indinavir and high-dose ritonavir do.
There are increasing data suggesting that the choice of the nucleoside analogs is also important in the development of insulin resistance. In an analysis of 1,288 participants in the Multicenter AIDS Cohort Study (MACS), insulin resistance was independently associated with cumulative PI use as well as cumulative NRTI use, with the strongest effect on insulin resistance seen with cumulative stavudine exposure [Brown TT, et al. Antiviral Therapy 2004; 9(6):L8 (Abstract 10)] .
Subjects in the SOLO study who completed at least 48 weeks of once daily fosamprenavir 1400mg + ritonavir 200 mg were followed to week 120. The nucleoside back bone was abacavir (ABC) + lamivudine (3TC) in 83% of subjects. The 174 subjects demonstrated increases in HDL cholesterol (+13 mg/dL by week 120), and the proportion of subjects with a TC:HDL ratio >6.5 did not increase and was quite low (9%) at week 120 [Flamm J, et al. Antiviral Therapy 2004; 9(6):L57 (Abstract 99)]. Altogether, 18% of subjects reported fat accumulation and 5% reported fat loss; these changes did not increase from week 48 to 120 [Walmsley S, et al. Antiviral Therapy 2004; 9(6):L32 (Abstract 50)]. Taken together, the data suggest that fosamprenavir, even when boosted by low-dose ritonavir, has only a modest impact on lipids. The lack of fat loss no doubt stems from the fact that ABC/3TC was used as the nucleoside backbone. We do need to remember that LDL cholesterol and DEXA data were not presented, and only those successful at week 48 were followed until week 120.
Finally, there are increasing data that switching to tenofovir DF (TDF) can help to prevent or reverse some NRTI-associated complications. In one small study, 11 male and 6 female subjects changed from varying NRTI backbone drugs to TDF-containing regimens for a variety of reasons (e.g. failure, side effects). These subjects experienced no change in body mass, weight or bone density, but had increased total, limb and trunk fat by DEXA as well as decreases in cholesterol levels [Tsekes G, et al. Antiviral Therapy 2004; 9(6):L29 (Abstract 46)]. Similarly, Gilmore and colleagues presented 48-week data demonstrating that a switch from d4T to TDF led to a more favorable lipid profile [Gilmore J, et al. Antiviral Therapy 2004; 9(6):L58 Abstract 102)]
Treatment for Fat Accumulation
Previous trials have demonstrated reductions in central and dorsocervical fat with the use of Growth Hormone (GH), but at the expense of significant side effects, including insulin resistance, high cost, and loss of subcutaneous fat. Grinspoon and colleagues presented a multicenter, randomized trial of a GH releasing factor (GHRF) [Antiviral Therapy 2004; 9(6):L4 (Abstract 2)]. Sixty-one subjects with central adiposity were randomized to receive daily subcutaneous injections of placebo, 1.0 mg, or 2.0 mg of TH9507 (Theratechnologies, Montreal). At 12 weeks, there was a 16% decrease in visceral fat and an increase in limb muscle mass as measured by CT in the 2.0 mg group and no significant change in the placebo group. Although IGF-1 levels increased in the 1 mg dose, changes in body composition did not reach significance at this dose. Importantly, there were no significant changes in limb fat, glycemic control, or markers of insulin resistance. This proof-of-concept study suggests GHRF analogs may be safe and effective to reduce visceral fat without the risk insulin resistance or lipoatrophy, but larger trials of longer duration are needed.
NRTIs and Mitochondrial Toxicity
It is generally accepted that NRTIs, by damaging mitochondrial DNA, are linked to a number of complications, including fat loss and lactic acidosis. Data implicating the thymidine analogs (stavudine [d4T] and zidovudine [AZT]) were presented at this meeting. A study of healthy volunteers receiving d4T/3TC or AZT/3TC for six weeks demonstrated inhibition of mitochondrial RNA transcription in adipocytes [Mallon PWG, et al. Antiviral Therapy 2004; 9(6):L11 (Abstract 15)]. Similarly, in a study of 87 HIV-infected patients, both AZT and d4T were associated with mitochondrial depletion in adipocytes, with a larger effect seen with d4T. In contrast, exposure to non-thymidine analog-containing regimens was not associated with effects on mitochondria [Hammond E, et al. Antiviral Therapy 2004; 9(6):L11 (Abstract 16)]. Although these data are from cell lines, there is growing evidence from clinical studies as well that the thymidine analogs are toxic to mitochondria, with d4T being the worst offender. Providers need to be aware of these issues when selecting a nucleoside backbone or when assessing a patient with evidence of early nucleoside toxicity.
There is continuing interest in the potential utility of uridine, a pyrimidine precursor, to protect mitochondria. A group in Germany was able to block a number of markers of mitochondrial damage in cell culture by pre-treating with uridine [Walker UA, et al. Antiviral Therapy 2004; 9(6):L10 (Abstract 14)]. It is premature to recommend this product for patients, but human studies are underway.
Many small studies suggest a restorative benefit from various face- or body-filling compounds [Mest DR, et al. Antiviral Therapy 2004; 9(6):L36 (Abstract 59); Casavates LC, et al. Antiviral Therapy 2004; 9(6):L37 (Abstract 60); Guaraldi G, et al. Antiviral Therapy 2004; 9(6):L50 (Abstract 87)]. Guaraldi presented data from a prospective, 24-week, partially randomized trial using three different face fillers [Antiviral Therapy 2004; 9(6):L9 (Abstract 12)]. Patients with “adequate fat” received autologous fat transplants. Those without adequate fat were randomized 1:1 to receive polylactic acid (PLA), a reabsorbable compound now FDA-approved as Sculptra, or polyacrylamide (PCA I), a non-reabsorbable compound. Ultrasound measurement suggested that all three compounds appeared to restore facial volume to a similar degree, with no differences between groups. Interestingly, fat transplant subjects were less satisfied. No serious adverse events were reported. However, 4/24 (16%) of the fat transplant patients developed what is now being referred to as “hamster syndrome,” that is, fat hypertrophy of the cheeks accompanying fat re-accumulation at the donor site. For that reason, it was suggested that the dorsocervical area should not be used as the fat donor site. Nine of the 24 patients required a “retouch” for aesthetic reasons, and 12/24 reported mild edema. Forty percent (8/20) of the PLA patients had non-absorption nodules in cheeks. It should be noted that those receiving fat were not randomized and may well be different in the physiology of their fat cells and in etiology of their fat gain. Other subjects were excluded if the treating physicians did not believe subjects “would benefit.” Moreover, the study was only 24 weeks in duration. Much longer follow-up will be required to determine the relative merits of specific compounds. Patients and clinicians will continue to have difficult times determining which compound is best, as most trials are small, uncontrolled or non-randomized, and of relatively short duration.
Structured treatment interruption (STI) continues to be a promising method in selected patients to prevent or reverse complications of therapy. Patients enrolled in an STI protocol involving four cycles (two months on/one month off) followed by permanent discontinuation of ART, showed rapid improvements in lipid profiles and abnormal fat distribution, which were persistent at one year [Milinkovic A, et al. Antiviral Therapy 2004; 9(6):L47 (Abstract 81)]. All subjects had been on d4T/3TC and a PI (indinavir-10, nelfinavir-3). Another STI protocol that was designed to assess the impact of interleukin-2 (IL-2) on viral parameters showed that triglycerides and LDL and total cholesterol all improved within the first 4 weeks of interruption, and improvements were maintained at week 48. There was no change in insulin resistance. IL-2 had no affect on these changes [Tebas P, et al. Antiviral Therapy 2004; 9(6):L13 (Abstract 20)]. Unfortunately, many patients are not appropriate candidates for treatment interruptions due to low CD4 nadirs, high baseline viral loads, or a history of OIs; and treatment interruption may increase the risk of drug resistance. However, for those who can afford an interruption, it is helpful to know that metabolic parameters improve quickly and that fat accumulation or lipoatrophy may slowly improve.
Several abstracts confirmed an increased cardiovascular risk in HIV-infected patients. Parenti presented data on HIV-infected men receiving over 24 months of PI-containing HAART who had no cardiac symptoms [Antiviral Therapy 2004; 9(6):L65 (Abstract 116)]. Among these subjects 60% had increased coronary artery calcification, a marker of atherosclerosis. However, Mangili demonstrated a similar prevalence of coronary calcium but found no association with HAART [Antiviral Therapy 2004; 9(6):L67 (Abstract 119)]. Finally, an important finding from Boccara was that the presentation of the acute coronary syndrome may be different in HIV-infected patients [Antiviral Therapy 2004; 9(6):L68 (Abstract 121)]. In a case-control study of 50 HIV-infected and 50 seronegative patients undergoing percutaneous coronary intervention, HIV-infected patients were less likely to have an ST-elevation on EKG and were more likely to have a late diagnosis. Fortunately, re-stenosis rates after 1 year of follow-up did not differ.
The data on cardiovascular disease in HIV is evolving, but these data, along with the D:A:D study [Friis-Moller N, et al. N Engl J Med. 2003 Nov 20;349(21):1993-2003] suggest that clinicians need to have a high level of suspicion for coronary disease in HIV-infected patients.
Adverse Effects of Drugs used to treat Metabolic Abnormalities
HMG CoA-reductase inhibitors (“statins”) lower LDL cholesterol, but their effect on other HIV parameters is unknown. Iloejo conducted a cohort study of 272 HIV-infected patients, half of whom were exposed to statins, and found that statin exposure was associated with a blunting of the CD4 response to antiretrovirals (12% increase in cases vs 32% in controls) [Antiviral Therapy 2004; 9(6):L4 (Abstract 69)] . In another small study using cells cultured with ddI, d4T or ddC taken from patients receiving a statin or fibrate, there was a suggestion of additive toxicity when the statin was combined with a nucleoside analog [Susan-Resiga D, et al. Antiviral Therapy 2004; 9(6):L22 (Abstract 32)]. These were not randomized studies, and the clinical significance is unclear, but it does give us pause, as we increasingly add these medications to our patients’ complex drug regimens. We are learning of a number of effects that statins may have in HIV-negative individuals, and there is growing evidence that they are anti-inflammatory. This may be one of the reasons statins impact CD4 counts and viral load measurements in HIV positive individuals, though intra-cellular interactions are only beginning to be explored.
This year, there was a large presence of investigators from developing countries, where complications of HAART have not been as well studied. In a cohort of antiretroviral-naïve patients in South India assessed after 6 months of therapy, both efavirenz and nevirapine treatment was associated with increased fasting glucose values, but only efavirenz-treated subjects showed increases in body fat or LDL and HDL cholesterol [Saghayam S, et al. Antiviral Therapy 2004; 9(6):L38 (Abstract 62)]. In HIV-infected Thai patients, the prevalence of metabolic and morphologic abnormalities was similar to those seen in Western populations and was associated with PI-based or d4T-containing regimens [Homasanit M, Antiviral Therapy 2004; 9(6):L37 (Abstract 61)]. These issues are increasingly challenging in resource-limited nations. HAART options are limited to generic formulations and often selected by governmental agencies. Options for switching medications may not be available. Treating HIV and preventing disease progression remain paramount; however, providers will need to be aware of complications as they are likely to become prevalent. Health officials may wish to consider the cost of long-term complications when selecting antiretroviral medications for their nation.
The complexity of HIV-associated complications is apparent. This workshop shed further light on the role of specific antiretroviral agents or classes of agents in the emergence of these complications. Although insulin resistance is often thought of as a complication associated with protease inhibitors, there are clear differences among the PIs, and nucleoside analogs may also play a role. Ritonavir-boosted fosamprenavir or atazanavir appear to have only minimal effects on insulin resistance and lipid elevations. The data continue to implicate thymidine analogs, particularly stavudine, in causing mitochondrial damage and resulting clinical syndromes. Switching from another NRTI to tenofovir or abacavir may help with these complications. There were encouraging data on treatment of fat accumulation with growth hormone releasing factor and lipoatrophy using “filling” compounds or fat transplants, but long-term benefit needs to be established. Studies continue to show an increased risk of cardiovascular disease with HIV infection, and in some cases with HAART, and one study suggested that HIV-infected patients may have an altered presentation of acute coronary syndrome compared to uninfected patients. Taken together, it is clear that the selection of HAART is important not only to control the virus, but to limit long-term toxicities. However, patient and disease factors cannot be ignored. This workshop provided important basic science and clinical data that will help us better understand the long-term complications of HIV therapy.
NOTE: All accepted abstracts from the 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV will be published in the journal, Antiviral Therapy
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