Important note: Information in this article was accurate in January 2002. The state of the art may have changed since the publication date. Update from the 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Joseph Cofrancesco, Jr., M.D., M.P.H. The Hopkins HIV Report - January 2002
The 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held in Athens, Greece on October 23-26, presented a number of well conducted studies that provide further hints into the pathogenesis of antiretroviral complications.
Thyroid
Two studies reported an increased prevalence of thyroid abnormalities in HIV infected patients. An evaluation of 221 consecutive patients (132 men, 59 women) found 12 with clinically apparent hypothyroidism, 7 with sub-clinical hypothyroidism, and 8 with transient abnormalities. Overall, 7.9% of men and 8.6% of women were hypothyroid. [Esnault JL, et al. Abstract 16]. Another 18 month study of 80 patients (65 male) on ART found 11 with autoimmune thyroiditis (transient in 9), 4 with hypothyroidism, 4 with "euthyroid-sick syndrome," and 4 with mild primary hyperthyroidism. A high prevalence of autoantibodies was seen, and the TSH was not found to be a sensitive screening test [Liognon M, et al. Abstract 80]. While these data are interesting, the message is unclear. Most patients were asymptomatic and abnormalities were often transient. However, hypo- or hyper thyroidism should be considered in a patient presenting with compatible symptoms.
A nested sub-study within HIV-NET in Thailand found that the IDV dose schedule did not have an impact on renal stone formation. One hundred sixty-four patients receiving AZT+3TC plus IDV 800 tid or IDV/RTV 800/100 mg bid were followed for 64 weeks [Boyd M, et al. Abstract 10]. There was no difference in the incidence of kidney stones (17% tid vs. 22% bid) nor in IDV crystalluria (40%). Of concern, 27% of patients had at least a 25% decrease in creatinine clearance. Women were more likely to experience renal insufficiency than men (OR 2.3, 95% CI 1.3-4.2), and a multivariate analysis found that female sex was associated with pyuria (OR 2.0, 95% CI 1.3-3.2), hematuria (OR 3.2, 95% CI1.6-6.3), and crystalluria (OR 2.3, 95% CI 1.3-4.2). Reduced baseline creatinine clearance was not associated with worsening renal function at week 64. However, the increased risk among women has important clinical implications, and the finding of a 25% loss of renal function is concerning.
Furthermore, several unanswered questions remain. Were patients adequately hydrated? Does the early finding of crystalluria require that IDV be stopped? Can we prevent or slow deterioration of renal function with aggressive hydration? Finally, the creatinine clearance formula is affected by fat free mass, which can change with HAART.
A number of carefully-conducted studies suggested varying mechanisms for PI-induced insulin resistance. Most studies evaluated IDV, which may be the worst offender in this class. Potential mechanisms include:
Direct inhibition of the Glut-4 transport, studied in Xenopus laevis oocytes [Murata H, et al. Abstract 1] and rodents [Hruz PW, et al. Abstract 2];
Acute decrease in total and non-oxidative insulin-stimulated glucose disposal, as measured by a sophisticated euglycemic, hyperinsulinemic clamp technique in 6 HIV-negative volunteers after a single oral dose of IDV 1200 mg, randomized in a double-blind, crossover fashion [Noor MA, et al. Abstract 3];
Skeletal muscle insulin resistance, measured by reduced glucose uptake and impaired intracellular glucose phosphor-ylation using PET scans and the insulin clamp in 5 subjects on HAART compared to 6 untreated HIV-infected subjects [Behrens G, et al. Abstract 4];
Hepatic insulin resistance and impaired peripheral glucose disposal suggested by similar hepatic glucose production in 18 male patients with lipodystrophy and
18 HIV-infected males without lipodystrophy, despite increased fasting insulin levels in the former group [Hugaard SB, et al. Abstract 5].
Taken together, there are multiple, complex and possibly interactive hypotheses to explain the mechanisms for PI induced insulin resistance.
Mitochondrial damage can lead to lactic acidemia and may play a role in fat atrophy. Walker evaluated mitochondria (mt) DNA depletion in HepG2 hepatoma cells grown in a combination of NRTIs at concentrations equivalent to one third, full, and 10-fold steady state peak plasma levels in humans [Abstract 18]. MtDNA depletion was greatest with ddI, followed by d4T, and lowest for 3TC and AZT. The highest lactate levels were seen with ddI and ddI/3TC. AZT induced morphologic changes, but no changes in mtDNA. Cells grown in the presence of EFV demonstrated no changes, and ABC was not tested. With the exception of the ddI/d4T combination, which had the same effect as with ddI alone, combinations of NRTIs exhibited increased toxicity compared to individual drugs, and changes reversed when drugs were withdrawn. In a separate study, tenofovir, even at high doses, did not affect mtDNA [Biesecker G, et al. Abstract 37].
In vivo changes are often different than in vitro. However, this study demonstrates that nucleosides damage mitochondria. The damage is worse with combination therapy and varies according to the NRTIs used.
Protease Inhibitors: Michael Dube [Abstract 14] reported 48-week data on sophisticated body and metabolic evaluations of 14 non-diabetic, PI naive patients (12 men, 2 women) with CD4 counts >100 cells/mm3 (mean 264) and mean HIV RNA 5.0 log10 c/mL who were receiving open label ABC+ 3TC+APV 1200 mg bid. CD4 cells increased in all subjects, and 11 of 14 had viral loads <400 c/mL, and 9 had <50 c/mL. There was no short-term insulin resistance, but insulin resistance did occur by week 48, possibly due to weight gain. There was a trend toward increased fasting insulin levels without change in fasting glucose. On average, subjects’ weight increased 5 kg. Bone content increased minimally (0.18 0.14 p=0.02), total/HDL cholesterol ratios did not change, and no subject reported loss of leg or face mass. This is an interesting study, but is limited by the open-label, non-comparative design and the small sample size.
Although PIs produce insulin resistance, the strength of the effect varies within the class. In an in vitro study [Caron M, et al. Abstract 24], IDV had a negative effect on a number of different adipocyte functions (adipogenesis, insulin action on MAP and kinases, expression of SREBP-1, PPAR, and apoptosis in 3T3-F442 adipocytes) in a dose-dependent fashion. Nelfinavir (NFV) had a less pronounced effect, and amprenavir (APV) lower still. Long-term treatment of cells with IDV or NFV, but not APV, promoted cell apoptosis (fat cell death). Treatment with rosiglitazone prevented these effects.
AZT/3TC/ABC and Switch Studies: A 48-week open-label study suggested that lipid profiles and self-reported body shape improve after switching to a triple nucleoside regimen while maintaining viral suppression on an earlier HAART regimen [Lafeuillade E, et al. Abstract 28]. Subjects were randomized to continue their current regimen or change to AZT/3TC/ABC if their CD4 count was >100 cells/mm3 and HIV RNA was <500 c/mL for 6 months and <50 c/mL at the time of switch. Between groups, there were no baseline differences in self-reported body changes, but by week 48, 42% of subjects on their original regimen reported >1 symptom of lipodystrophy, compared with 28% of those who switched (P=0.033). Reductions in cholesterol and triglycerides occurred more often in the switch group: Cholesterol –0.80 vs –0.44 mmol/L (p<0.0001), triglycerides – 0.17 vs + 0.01 mmol/L (p=0.006). However, important data are missing:
Initial regimens were reported to "usually" be 2 NRTIs + 1 PI, with NFV being the most frequently used PI. The NRTI backbone usually consisted of AZT/3TC, but 15% were on d4T/ddI. We do not have the specifics of or sub-analysis based on initial regimen or initial CD4 count/viral load. It is not clear that the lipid changes are clinically significant. This study was open-label, making reports of body shape changes unreliable and potentially biased, and adherence, diet, and exercise would all need to be considered in interpreting results.
Anabolic Steroids: Anabolic steroids used to treat wasting have been proposed as a treatment for lipodystrophy. Ninety-two subjects with 10% unintentional weight loss received oxymetholone 50 mg bid or tid in a double-blind, placebo-controlled phase II trial [Hengge UR, et al. Abstract 70]. After 16 weeks, there were significant increases in body cell mass and lean body mass, with no change in total body fat. Grade 3 or 4 toxicity was seen in 2 (7.4%) in the bid arm and 6 (21%) in the tid arm. In a related study, patients who received testosterone cypionate had less subcutaneous arm/leg fat, lower HDL cholesterol levels, and higher triglycerides, insulin, and C-peptide levels (p<0.05) [Ford P, et al. Abstract 62]. However, this was an observational study, and the patients in the two groups were likely very different. We do not have data on the indications for anabolic steroid use nor the dose(s) given.
Anabolic steroids are an excellent treatment for patients with muscle wasting. Most are inexpensive and, with proper monitoring, can be used safely. However, anabolic steroids do not appear to improve "lipodystrophy."
Human Growth Hormone (HGH): HGH data have been presented elsewhere [Lo JC, et al. J Clin Endocrinol Metab 2001 Aug;86(8):3480-7]. K Mulligan reported the 6 month impact of HGH (3 mg/day) in 5 patients with fat accumulation [Schwartz JM, et al. Abstract 26]. HDL cholesterol and triglycerides increased, as well as total and LDL cholesterol. Glucose homeostasis worsened due to increased hepatic gluconeogenesis and peripheral insulin resistance. There may be a role for this potent but expensive agent in patients with pure fat accumulation, but it must be used with caution, as such patients often have insulin resistance.
Thiazolidinediones (rosiglitazone and pioglitazone): As noted above, the unfavorable in vitro effects of IDV, NFV and APV can be prevented if fat cells are co-treated with rosiglitazone [Caron M, et al. Abstract 24].
Pioglitazone (30 mg/d x 3 months then 45 mg/d x 3 months) given to 9 subjects on HAART with lipodystrophy was well tolerated and resulted in no change in the insulin resistance index, which was normal at baseline [Calmy A, et al. Abstract 43]. Six subjects reported subjective improvement in fat distribution, but there were no improvements in objective measures (anthropometrics or DEXA).
In a review from a Texas HIV clinic, 9 normoglycemic patients with baseline insulin resistance and lipodystrophy received rosiglitazone [Visnegarwala F, et al. Abstract 124]. After a median treatment of 24 weeks, 4 of 9 reported subjective improvement in lipoatrophy, and there was a trend towards a decrease in waist/hip ratios; there were no changes in cholesterol and no reported toxicity.
Metformin: Martinez [Abstract 29] reported on a blinded study of 51 subjects with abdominal fat accumulation and plasma triglycerides >200 mg/dL on stable PI-containing regimens, randomized to receive metformin 850 mg, gemfibrozil 600 mg or placebo (all bid). Twelve-month results demonstrated negligible effects on triglycerides and insulin resistance. Sonography showed no effect found in regional fat. In contrast, Hadigan reported 9-month data on 19 subjects who previously completed a double blind, randomized 3-month trial of metformin leading into open-label treatment [Abstract 69]. All patients had lipodystrophy and insulin resistance at entry. Metformin was well tolerated and lactic acid levels did not increase. Insulin AUC improved, and there was a reduction in waist circumference in patients who received 9 vs 6 months of metformin.
Metformin and the thiazolidinediones treat insulin resistance and may have a role in the treatment of lipodystrophy. Patients with documented insulin resistance are likely to benefit most. Taken together, these studies offer some hope for patients with or at risk for the metabolic and physical changes associated with "lipodystrophy," while demonstrating that well controlled, blinded randomized trials with objective endpoint measures are critically necessary.
"Lipodystrophy" describes a set of overlapping phenomena involving fat accumulation in some body parts, fat loss in others, with varying associated metabolic changes, and a solid understanding of these phenomena remains elusive. Metabolic changes influence physical changes and vice versa. Trials that are designed to address these complex issues are under way. Many of us left Athens hopeful that the scientific advances presented will be translated into clinically useful advances for our patients, but frustrated by the ever growing complexity of the field.
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Important note: Information in this article was accurate in January 2002. The state of the art may have changed since the publication date.
, and apoptosis in 3T3-F442 adipocytes) in a dose-dependent fashion. Nelfinavir (NFV) had a less pronounced effect, and amprenavir (APV) lower still. Long-term treatment of cells with IDV or NFV, but not APV, promoted cell apoptosis (fat cell death). Treatment with rosiglitazone prevented these effects.
