The Body Habitus in Durban
Lipodystrophy prevention, prevalence and probable cause
The mystery of change in body habitus, accumulation of fatty tissue in areas such as the trunk, the neck, the breasts and the upper back accompanied by atrophy of adipose tissue in the face (Bichat's fat pad), the limbs and the pelvis/butt, was not resolved in Durban. But various studies addressed its probable etiology, pathogenesis, prevalence, and some studies addressed potential preventive strategies with a handful actually suggesting a therapeutic intervention. A panel of experts did not reach a consensus opinion on the definition of the syndrome, and controversy reigned when it came to how to use diagnostic tools to evaluate the syndrome. Patients tend to report more severe findings associated with the syndrome as compared to physicians, as was noted in a study conducted by Toby Kasper from GMHC (Abstract 1380). Anthropomorphic measurements like waist to hip ratio lacked specificity (Abstract 4246) in one study, whereas brachial and malar sonography had 85-88% sensitivity and 75-84% specificity (Abstract 4280); others argued for simpler office procedures such as measuring the waist circumference or obtaining serial photographs of patients to follow their change in body habitus.
Etiology and Pathogenesis
Various old theories which postulated a homology between the protease enzyme and several proteins involved in fat metabolism have been discarded as new studies indicate a potential role for mitochondria toxicity in the pathogenesis of the fat mal-distribution and the the metabolic irregularities. Mitochondrial toxicity is an acquired decrease in mitochondrial function (mitochondria are organelles within cells which produce ATP, the energy substrate of most living organisms) induced by NRTIs. This can result in several clinical syndromes like myopathy, neuropathy and lactic acidosis and possibly fat and lipid metabolism aberrations such as adipose tissue loss.
Mallal and Nolan from Perth, Australia, showed in a late breaker poster session (LB7054) impressive electron microscopy pictures of adipose tissue, taken from patients with clear symptoms of lipodystrophy. Both in patients treated with or without protease inhibitors (but always NRTIs), there were clear abnormalities in mitochondrial structure, together with an accumulation of lipid droplets (steatosis), compared with control specimens. Furthermore, there was an unexplained deposition of granular material on the inner aspect of the adipocyte membrane. Nucleoside analogues have been associated with lactic acidosis and hepatic steatosis, which is thought to relate to mitochondrial dysfunction caused by these agents inhibiting mitochondrial DNA polymerase gamma.
This problem has been reported with all the available nucleoside analogue combinations. Inhibition of this enzyme has been suggested to also be important in the pathogenesis of fat redistribution syndrome. A difference in relative incidence of lactic acidosis or hyperlactatemia between combinations has not been established. In a cross sectional survey of 211 asymptomatic patients, 161 (76%) of whom were on nucleoside analogue therapy, mild hyperlactatemia (defined as 2.1-5mmol/l) was present in 23% of treated and 8% of untreated patients. Serious hyperlactatemia (>5mmol/l) was observed in only one patient, which normalized without alteration of therapy. Of the patients with hyperlactatemia, 19% of ZDV recipients therapy, and 28% of d4T recipients had hyperlactatemia (Abstract 1234). The presence of elevated lactate in the absence of therapy is intriguing but may reflect laboratory issues, sampling variation (for example, use of cuffs or not), use of other mitochondrial toxins (such as alcohol), familial mitochondrial disease, recent exercise or the possibility that HIV infection alone may impact mitochondrial function.
A similar survey of 70 treated patients found lactate levels were >2.1 in 36% of patients and the anion gap widened in 19%. Three of four patients with lactate >3mmol/l and an anion gap of >12 had symptoms suggestive of drug toxicity such as fatigue, weight loss or myopathy (Abstract 1233). In eight patients with clinical lipodystrophy who were exercised to assess oxidative and glycolytic capacity in skeletal muscle tissue using ergometer cycling, oxygen consumption (VO2) and blood lactate (L) was measured. Before and after exercise, muscle biopsies were obtained to measure activity of citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HD) to assess mitochondrial oxidative capacity. The HAART treated HIV patients performed less work than healthy controls and had significantly higher baseline and post exercise lactates. Muscle biopsy data did not differ from controls. The absence of muscle abnormalities suggest that lactate elevations may have related to diminished hepatic clearance of lactate rather than excess production (Abstract 1232).
Bernasconi et al. (Abstract 703) confirmed earlier observations from other cohorts of an association between the development of lipoatrophy and the exposure to either d4T (OR 2.1) or d4T/ddI (OR 1.5). They furthermore showed a significant association between lipoatrophy and increased lactate levels, which was lacking in the situation of fat accumulation. In a multivariate analysis for fat accumulation only age >41 and intravenous drug use were associated. The association of fat loss and older age was noted by various studies, as were the use of stavudine or indinavir or ritonavir and the overall duration of HIV infection (Abstracts 704, 4215, 4245, 1382, 4242).
The SMART study (systematic monitoring of antiretroviral therapy) cohort of 207 subjects in Amsterdam found that only duration of ART, older age and weight at the time of initiation of HAART therapy were significantly associated with d4T use (Abstract 4247). In this study, however, the prevalence of lipodystrophy was low (15.5%) and the patients changed meds liberally due to side effects etc. or clinical parameters. Thus it was difficult to implicate a single class of drugs.
All in all, the weight of the evidence seems to suggests that d4T is implicated in fat loss especially in older persons. On the other hand, protease inhibitors are more strongly associated with fat accumulation and lipid disorders as was demonstrated by several studies (Abstracts 4281, 4232) where patients on PI-containing regimens were compared to those on PI-sparing regimens and found to have more frequent elevations in triglycerides and cholesterol and truncal adiposity. Women seem to experience more fat accumulation than men, who seem to suffer from more fat loss. This was reported by three groups of investigators (Abstracts 4212, 4273, 4272); one found fat loss in 44% of males and 23% of females. The difference among the genders remains unexplained.
Various investigators in Durban discussed treatment for the various aspects of the lipodystrophy syndrome, although a treatment for the underlying cause or a preventative strategy is still unavailable. The use of protease-sparing regimens was actively discussed and overall seemed to show a beneficial effect in the incidence of the syndrome without a negative effect on clinical or virological outcome, although the results were all preliminary and long-term outcome data are still not available. Lipid-lowering agents are being actively used to treat the lipid disorders and should be used with caution as many will interact with HAART; simvastatin levels, for example, can be elevated 2,500-fold in the presence of ritonavir and saquinavir. Thus pravastatin is recommended for treatment of hypercholesterolemia since it does not require the cytochrome p450 system for metabolism and was shown in several studies to effectively lower cholesterol levels in lipodystrophy patients (Abstracts 1438, 4277).
Treatments for fat atrophy are mostly cosmetic in nature, with cosmetic surgery and implants of human collagen or autologous fat implants being the most common, none of which received much attention in Durban. Stopping the HAART regimen was studied at the NIH among 26 male patients with viral loads <400 copies/ml sustained for one year; after 5.9 weeks of stopping therapy declines in lipid levels were noted (Abstract 4221), but there were no changes in insulin resistance and anthropomorphic measurements.
Deborah Cotton reviewed six studies that evaluated changing from a protease inhibitor to an NNRTI-containing regimen with a total of 307 patients and noted a mean decrease in cholesterol of 16% and in triglyceride levels of 27.6% in six months. Changes in body habitus were not uniform. In one sudy, where the PI was substituted for nevirapine, there were declines in serum triglycerides and increases in HDL cholesterol levels, but no change in LDL cholesterol and only a trend in reduction in fat as measured by DEXA.
These studies all are limited by the fact that they were uncontrolled and only the PI was substituted and lipodystrophy was already present, which may be irreversible once established, despite the potential causative agent being removed. Since it is unclear which of the classes of drugs are involved, or whether both are responsible, the inconsistent changes are not entirely unexpected.
Another potential agent for treatment of fat accumulation, which received some attention in Durban, was recombinant human growth hormone Serostim. This writer described 36 patients with lipodystrophy treated with Serostim for an average of 16 months, of whom 89% responded within 4 to 12 weeks with reductions in truncal adiposity, breast size and buffalo humps, without any significant changes in lipid levels or peripheral or facial fat loss (Abstract 4234). Bioelectric impedance analysis (BIAs) and serial photographs were used to follow changes in body habitus. Side effects included hyperglycemia, joint pains and carpal tunnel syndrome, most of which were reversible upon drug discontinuation or dose reduction. Most patients relapsed once the drug was stopped and required maintenance therapy with low dose Serostim to maintain the lipolytic effect.
Another investigator, Engelson, reported on the use of growth hormone and was able to demonstrate a 46% decrease in visceral adiposity and an 18% decrease in subcutaneous fat using DEXA and total body K+ (Abstract 1437). In a placebo-controlled trial Furrer showed that growth hormone reduced mean truncal fat by 2.4 kg, total mean fat by 2.6 kg but found no effect in subcutaneous fat or fasting lipid levels. All the effects were reversed upon drug discontinuation, except in one patient who continued arduous exercise in the gym (Abstract LB114).
The main problem associated with growth hormone in addition to the adverse effects is its exorbitant cost, which puts it out of reach to most patients; in addition its lipolytic effects may worsen the fat loss in the periphery or the face, yet to date it is the only agent which has a definitive effect in reducing the visceral and truncal fat accumulation which is most troublesome to patients.
In terms of the long-term cardiovascular complications of hyperlipidemia little was reported in Durban that would alter our thinking in terms of early intervention with HAART. One study suggested an abnormal carotid artery intima-medial thickening in patients with lipodystrophy, yet not significantly (Abstract 761). In addition, another study did not find the incidence of myocardial infarction to be significantly elevated although the length of follow-up was not adequate since it can take decades before the effects of hypercholesterolemia and hypertriglyceridemia are evident. In any case, elevated lipid levels should be treated aggressively in HIV-positive patients as their longevity is bound to be longer or as long as those of middle age or older HIV negative adults who develop this disorder during late adulthood.
One agent which recently received a lot of attention was metformin, an insulin sensitizing agent which has been used in diabetes mellitus as an oral hypoglycemia agent. The published study in JAMA was a pilot study of 26 individuals with HIV-associated lipodystrophy syndrome.1 The authors report that metformin (500mg twice daily) as compared to placebo reduced waist circumference, reduced visceral abdominal fat but no change was seen in VAT-SAT (subcutaneous adipose tissue) ratio. There was no significant effect of treatment on waist-hip ratio. Sixty-four percent (n=9) complained of mild to moderate diarrhea, which was reported to improve for most within 4 weeks, whereas 3 (27%) of 11 placebo patients experienced new or worsening diarrhea. There was no increase in lactate level associated with metformin therapy and both groups had mild decreases in lactate levels at three months. All patients in this study were receiving concomitant NRTIs; therefore, the absence of a significant effect on lactate levels provides some reassurance that low-dosage metformin can be used safely in this population.
Overall, our understanding of the lipodystrophy syndrome has improved after Durban, despite the innumerable of unanswered questions; practical diagnostic tests and procedures and simple interventions or strategies may help avert the complications or at least stall them temporarily. Early intervention in the recognition and treatment of the syndrome is required as long-standing aberrations in lipid metabolism or grotesque body habitus deformities due to fat accumulation or loss are bound to be irreversible.