Protease inhibitor therapy-associated lipodystrophy, hypertriglyceridaemia and diabetes mellitus

Intensive combination therapy including a protease inhibitor is considered a standard of care in HIV-1 infection. Recently, an association has been noted between protease inhibitors and a syndrome consisting of peripheral lipodystrophy, hypertriglyceridaemia and diabetes mellitus [1–3]. Protease inhibitor-induced lipodystrophy is a cutaneous disorder characterized by disappearance of subcutaneous fat from the face and occasionally from the lower part of the body as well as by a sudden increase in waist size (truncal obesity or ‘crix-belly'), or the development of a fatty mass (`buffalo hump') at the back of the neck. These disorders affect quality of life and drug adherence by causing noticeable disfigurement. Hyperlipidaemia and diabetes of variable severity constitute, in the long term, potentially life-threatening metabolic disorders. A retrospective follow-up study was carried out in a series of 324 patients treated by two reverse transcriptase inhibitors (RTI) and a protease inhibitor [33 women (median age, 33 years), and 291 men (median age, 36 years)]. We attempted to investigate the various qualitative and quantitative interrelations of the components of this syndrome as induced by indinavir (800mg three times daily), ritonavir (600mg twice daily) and saquinavir (600mg three times daily). Patients with pre-existing diabetes were excluded from the study. The overall relative incidence of lipodystrophy was 11.57% (28 out of 242), which was induced by indinavir and ritonavir, but not saquinavir, being of limited absorption. This occurred after a protease inhibitor exposure of 4.7 ± 2.5 months (range, 2–10 months). No case of buffalo hump was detected (out of 28 patients; 95% confidence interval, 0–12) amongst the observed clinical varieties of lipodystrophy (Table 1). The respective protease inhibitor withdrawal in eight patients led to clear (four patients), minimal (three patients) and negligible (one patient) clinical amelioration (follow-up, 4.2 ± 1.6; range, 3–8 months). Protease inhibitor was discontinued due to disfigurement in one patient.Table 1: Overall incidence of protease inhibitor therapy-induced disorders. Diabetes mellitus was diagnosed shortly after its onset, since measurement of blood sugar levels has always been amongst the routine follow-up examinations, occurring after an overall exposure of 5.5 ± 3.0 months (range, 2–12 months), and was presented concurrently both in lipodystrophic and non-lipodystrophic protease inhibitor-treated patients. It affected 32.14% of the lipodystrophic patients (nine out of 28), all of them being under indinavir treatment, and was expressed before (three patients), simultaneously (one patient), and after lipodystrophy development (five patients). The remaining diabetes cases were 26 non-lipodystrophic protease inhibitor-treated patients (Table 1). Disease severity, when estimated in terms of elevated fasting blood glucose, revealed mild diabetes equally distributed amongst the disorder subgroups. The overall mean value of blood sugar was 130.8 ± 10.9 mg/100 ml (range, 120–188 mg/100 ml; cut-off, 110 mg/100 ml). Protease inhibitor-induced hyperglycaemia was controlled by diet alone. Fasting hypertriglyceridaemia (>150 mg/dl) was detected in all patients with diabetes as well as amongst all patients with lipodystrophy. Accordingly, the empirical probability for complete syndrome expression was 5.7% (nine out of 158), affecting only indinavir-treated patients. The respective relative incidence of this side-effect alone was 35.5% (115 out of 324), being the most common disorder. Either alone or in coexistence, the incidence rates of hypertriglyceridaemia fluctuated significantly amongst the three protease inhibitor groups (Table 1). Increased concentration levels were not homogeneously distributed when studied by disorder category. The difference between the triglyceride levels in the 28 lipodystrophy cases (436.86 ± 215.36 mg/dl; range, 178–1987 mg/dl) and those presenting only increased total triglyceride levels (115 patients; 311.2 ± 135.5 mg/dl; range, 160–888 mg/dl) was significant [P < 0.01, Bonferroni P value, one-way analysis of variance (ANOVA)], whereas the diabetes group values (26 patients; 403.5 ± 317.4 mg/dl; range, 162–1465 mg/dl) did not differ from any of the former groups in paired comparisons, implying a synergistic metabolic defect. For hyperglyceridaemia, the duration of protease inhibitor exposure was difficult to determine because the test was routinely requested for all patients after the diagnosis of the first cases of diabetes. None of the above defects was influenced by patient age or gender. Regarding previous RTI therapy duration at baseline (i.e., before starting protease inhibitor treatment), it was found that lipodystrophic patients (therapy duration, 34.36 ± 14.23 months; range, 12–64 months) were significantly more experienced (P = 0.0005) than the remaining syndrome population (i.e., those presenting at least one metabolic disorder: 141 patients; 22.24 ± 16.9 months; range, 2–108 months). However, therapy-naive cases were equally distributed between these groups (one out of 28 versus 22 out of 141). CD4 cell counts at baseline were significantly reduced among lipodystrophy cases (184.7 ± 142.8 × 106/l; range, 6–457 × 106/l) when compared with the diabetes group (360.8 ± 189.3 × 106/l; range, 53–692 × 106/l) or with the hypertriglyceridaemia group (348.1 ± 221.4 × 106/l; range, 19–979 × 106/l). A statistical homogeneity (one-way ANOVA) was detected amongst the two latter groups and the complication-free patients (155 patients; 385.1 ± 229.5 × 106/l; range, 3–950 × 106/l). The significant difference in exposure between RTI and protease inhibitors is indicative of a causative association between lipodystrophy and protease inhibitors, although a synergistic action cannot be excluded. Longer duration of HIV-1 infection and the concomitant immunological and metabolic changes might be considered as the main lipodystrophy precipitating factors [1–3]. Synergism between diabetes and hypertriglyceridaemia is expected even amongst immunocompetent patients [2]. V. A. Paparizos K. P. Kyriakis* C. Botsis V. Papastamopoulos M. Hadjivassiliou N. G. Stavrianeas