Lipodystrophy and adverse drug reaction data presented at the 42nd ICAAC

13 November 2002. Related: Conference reports, Side effects, Lipodystrophy and metabolic complications, ICAAC 42nd San Diego 2002.

Graeme Moyle, MD, for HIVandhepatitis.com

The last hours of the 42nd ICAAC conference in San Diego was the somewhat disappointing timing for the poster session that covers what is to many patients the most important aspect of the long-term management of HIV disease. However, over the course of the other days there was a range of presentations that included valuable information on lipid abnormalities, morphological change and mitochondrial disease.

Lipid disturbances

Differentiation of drugs on the basis of lipid abnormalities remains challenging. Within the protease inhibitor class there are a number of comparative studies that enable differentiation between drugs. Kaletra causes greater rises in triglycerides and cholesterol than nelfinavir (Abbott M98-863 study), nelfinavir causes greater rises in cholesterol and triglycerides than the experimental protease inhibitor atazanavir (atazanavir 008 study).

The effect of Lopinavir (Kaletra) on lipid elevation may be exposure specific. Two studies evaluating lopinavir pharmacokinetics and changes in lipids and body composition demonstrated an association between higher lopinavir trough or mean exposures and higher cholesterol or triglycerides elevation.

In one study of 21 individuals where pre- and four hour post-observed dose levels of lopinavir were evaluated in individuals stable on Kaletra based therapy for at least three months, the lopinavir Cmin was higher (4.13 mg/ml) in individuals with triglycerides above 400 mg/dl compared with the Cmin in individuals with triglycerides values below this value (Cmin in 2.64 mg/ml) (p = 0.05)(Abstract H. 1916).

In a second study of 22 individuals receiving Kaletra there was a correlation demonstrated between the mean lopinavir plasma concentration and risk of developing elevated fasting cholesterol, the percent increase in cholesterol from baseline and the percent increase in triglycerides from baseline. No significant correlation was observed between changes in body fat as assessed by CT scan at multiple body sites and plasma lopinavir concentration (abstract H. 1920).

These data raise the possibility that therapeutic drug monitoring of lopinavir levels may have some value in managing dyslipidaemia in individuals receiving Kaletra who do not have other protease inhibitor options. The difficulty however is that the majority of these individuals are likely to be individuals in the salvage setting where higher levels of lopinavir are required to overcome pre-selected protease inhibitor resistance and where reducing drug exposure is likely to impact therapeutic efficacy. Additionally, the fixed dose packaging of Kaletra makes dose adjustment challenging.

New information from the MaxCmin study indicated that not all ritonavir-boosted protease inhibitor-based regimens have the same impact on lipids. This was a randomised open-label comparative study of ritonavir 100 mg twice daily boosting either saquinavir 1000 mg twice daily or indinavir 800 mg twice daily in individuals with a range of different treatment backgrounds.

Total cholesterol and LDL cholesterol rose only modestly (less than 10%) in individuals who received saquinavir but increased 15-20% in those who received indinavir. These differences were statistically significant. Triglyceride increases were also significantly smaller in the saquinavir treated group. Efficacy data from the study favoured saquinavir, as fewer individuals discontinued this agent due to adverse events.

Agouron and efavirenz: effect on fasting lipids

Two studies compared the effect of nelfinavir with efavirenz on fasting lipid levels over 16 to 24 weeks of follow-up. In study AG 1127, a randomised comparison of nelfinavir (n=102) and efavirenz (n=101) with AZT+3TC in treatment naïve patients, the total cholesterol rose by a similar amount in individuals randomised to nelfinavir (29 mg/dl) and efavirenz (31 mg/dl).

The proportion of patients who achieved the NCEP recommended intervention level of greater than 240 mg/dl was 19% in the nelfinavir group and 16% in efavirenz group. For LDL cholesterol, the mean change in the nelfinavir group was 23 mg/dl but only 12 mg/dl in patients randomised to efavirenz (p = 0.04).

The proportion of patients achieving the NCEP recommended intervention level for LDL cholesterol of >160 mg/dl was 16% in the nelfinavir group and 8% in the efavirenz group, these differences not being significantly different.

For HDL cholesterol, the mean change in the nelfinavir group was 5 mg/dl where HDL rose by 10 mg/ dl in the efavirenz group (p = 0.02). The mean change in triglycerides was smaller in the nelfinavir group (18mg/dl) compared with the efavirenz group (38mg/dl) (p = 0.3) but similar proportions of patients had fasting triglycerides values above 200 mg/dl, 30% and 23% for the nelfinavir and efavirenz groups, respectively.

In a multivariate logistic regression model, baseline LDL cholesterol was the strongest predictor of achieving an LDL in the NCEP recommended intervention range (Abstract H 1914).

Efavirenz improves HDL:LDL ratio

A small study of 17 individuals treated for 16 weeks with efavirenz-based therapy reported more detailed information regarding changes in lipid particle subfractions. Individuals in the study experienced a 22% rise in total cholesterol and a 44% rise in triglycerides levels.

Whilst the LDL cholesterol rose by 17%, the HDL cholesterol rose by 35% leading to an improved HDL:LDL ratio. Sub-fractional analysis indicated that the LDL particles rose only modestly and most of the LDL rise was made up by large LDL, a subfraction of low atherogenic risk. Amongst the HDL fractions the largest rise was seen amongst larger HDL particles, the most cardioprotective subfraction (Abstract H 1917).

A third study also supported the evidence that efavirenz improved lipid profile by substantially increasing the HDL fraction relative to the LDL cholesterol (abstract H 1918).

Atazanavir vs efavirenz: effects on fasting metabolic profiles

The BMS 034 study provided a randomised comparison of the fasting metabolic profile of individuals commencing AZT +3TC with either the investigational protease inhibitor atazanavir or efavirenz.

Total cholesterol raised by a mean 2% in the atazanavir group and a mean 21% with efavirenz. These changes were made up of LDL cholesterol, which increased by 1% with atazanavir and 18% with efavirenz, and HDL cholesterol which increased by 13% with atazanavir and 24 % with efavirenz over 48 weeks of follow-up (p < 0.0001).

Triglycerides levels actually fell in the atazanavir group by 9% abut rose by 23% in efavirenz treated patients (p < 0.0001). Differences in fasting glucose and insulin were not observed.

Dyslipidaemia

There was limited new information about the management of dyslipidaemia.

Dietary advice and exercise is, of course the first line of therapy, the basic intervention.

A study looking at the impact of dietary advice in people with HIV infection, on therapy and who had either cholesterol > 200 mg/dl or triglycerides values > 200 mg/dl reported data. The study included 161 individuals who are evaluated from baseline to three months with follow-up to six months on 70 individuals.

Patients were evaluated by whether they reported good adherence to the dietary advice or poor adherence to dietary advice. Individuals who adhered to dietary advice saw an 11mg/dl (~5%) median decline in cholesterol at three months relative to a change of just 1mg/dl decline in those who adhered poorly to dietary advice.

Benefits to triglycerides levels were 12 mg/dl (~3%) in individuals in adhered to dietary advice and 1mg/dl in those who did not. Body mass index fell by one unit over three months and two units over six months in individuals who followed dietary advice and fell by _ unit at three and six months in those who did not follow dietary advice, the BMI remaining in the normal range throughout.

These indicate that dietary advice does provide some useful benefits with regard to cholesterol and triglycerides but that changes are modest and many individuals find it difficult to adhere to dietary advice. For example, at three months 58 individuals in the cohort adhered well to dietary advice but 103 individuals had poor adherence to dietary advice (Abstract H 1933).

A previous study with pravastatin plus dietary advice vs. dietary advice alone indicated that individuals who received a pharmaceutical intervention for dyslipidaemia were less likely to adhere to dietary advice (Moyle et al, AIDS 2001).

A clinical cohort analysis of 93 individuals stable on protease inhibitor-based regimens and with triglycerides levels >300 mg/dl and/or cholesterol >280 mg/dl. Patients were given dietary advice and either statins (pravastatin 20 mg qd (n=22), atorvastatin 20 mg qd (n=19)) or fibrates (bezafibrate 400 mg qd (n=27), fenofibrate 200 mg qd (n=25)), in a non-randomised manner.

Over 12 months, statins reduced triglycerides by 39% and cholesterol by 30% and fibrates reduced triglycerides by 40% and cholesterol by 29%, respectively. Reductions in both groups being significant relative to baseline. No differences between choice of fibrate or statin were observed, despite the low dose of pravastatin (normal dose 40 mg daily) and relatively high dose of atorvastatin (recommended starting dose 10 mg in the presence of protease inhibitors) used. Adverse events were uncommon with only six individuals failing to complete 12 months of follow-up.

Morphological changes

Several approaches to the management of morphological change were reported.

Two previously reported randomised studies of substitution of thymidine analogues, or specifically d4T, with abacavir had indicated some modest improvement in fat mass as measured by DEXA scan over six to 12 months (Carr et al JAMA 2002, Moyle et al, World AIDS conference, Barcelona 2002).

Two further cohort studies reported on this management approach at the ICAAC meeting. It is a pity that control populations to gain better understanding of these outcomes were not included in the larger of these studies.

Switch from d4T to abacavir or zidovudine: 48-week data

A cohort study of 118 individuals who switched from d4T to (predominantly) abacavir oir zidovudine was followed by DEXA scans. Details of this cohort followed to 24 weeks were reported at the 9th Retrovirus Conference in Seattle earlier this year.

Updated results to week 48 indicated that, relative to baseline, arm fat had increased by 35%, and leg fat by 12%. Abdominal CT scan results indicated a median increase in subcutaneous fat of 4% and a median decrease in visceral fat of 2%. owever, these changes are likely to be within the variances of the test.

Viral load data indicated that 5% of individuals rebounded over 400 copies/ml and 13% of individuals had values above 50 copies/ml at week 48 (Abstract H. 1929). A subgroup of 16 individuals who replaced d4T with abacavir had mitochondrial DNA levels determined from fat, muscle and PBMC at baseline and week 48 using real-time PCR.

Both HIV negative and HIV-positive antiretroviral naive controls were also assessed.

At baseline only seven of the 16 patients entering the cohort demonstrated decreases in mitochondrial respiratory chain complexes one, two or three or decreased citric synthetase (another mitochondrial enzyme). The baseline mitochondrial DNA content in PBMC’s was similar to controls and rose significantly over 48 weeks of treatment. The mitochondrial DNA per fat cell was reported to be markedly reduced at baseline compared to control patients and rose significantly over the course of 48 weeks, but to levels which remained approximately 50% of control values. Muscle mitochondrial DNA was similar to control values at baseline and rose over 48 weeks to values 100% higher than control patients.

Correlation of the data with clinical changes was not reported. The meaning of mitochondrial DNA values that are higher than control values is not known (Abstract H 1930).

A second fat biopsy study found that levels of circulating tumour necrosis factor receptors type I and II were higher in individuals with more extensive and diffuse fat cell apoptosis on fat biopsy samples. As tumour necrosis factor exerts its apoptotic effects by triggering the release of pro-apoptotic mitochondrial factors, these data may provide some linkage with the changes in mitochondrial mass observed in fat cells (abstract H 1915).

Effects on lipoatrophy following d4T switch to abacavir

A case control study of 30 individuals who switched from d4T-based regimens to abacavir compared with 22 individuals who continued on d4T-based regimens was reported.

No significant differences in changes in cholesterol or triglycerides were observed although lactate levels declined significantly in the group who modified therapy. 43% of cases and 28% of controls reported improvement in their lipoatrophy after six months, although details of how this was assessed were not adequately provided (abstract H 1928).

Treatment of facial lipoatrophy

Plastic surgery offers the best “quick fix” approach for improving facial lipoatrophy. A range of different techniques has been suggested, with the most commonly reported method being the sub-dermal injection of polylactic acid (NewFill™).

Polylactic acid (NewFill)

A randomised study of immediate vs delayed polylactic acid therapy in 30 individuals with facial lipoatrophy was reported. Improvements in appearance were reported by patient’s self-assessment and by independent assessment of photographs. These improvements coincided with declines in anxiety and depression scores as measured by the HADS scale and in increases in facial skin thickness measured by ultrasound (H-1934).

Human growth hormone (Serostim)

A randomised study of 12 lipoatrophic patients with stable weight who received an initial induction period of 4mg/day of recombinant human growth hormone (Serostim) followed by maintenance doses of either 4mg/alternate days, 4mg/ twice-weekly or placebo for a further 12 weeks.

During the initial induction phase, patients gained lean body mass and two to three kilograms of weight, with a decline in truncal fat and improvements in total and LDL cholesterol values.

The self assessed visual analogue scales indicated that patients felt that their physical appearance had improved in a range of body areas including the face. These improvements tended to be maintained over the course of 12 weeks by continued alternate day growth hormone whereas the benefits, in terms of both objective and subject evaluations, were lost in individuals who discontinued growth hormone.

However, at 48 weeks of follow-up, when individuals had been off therapy for a minimum of 24 weeks, it was noted that the patients had tended to maintain the weight that they had gained on growth hormone, but lost lean body mass from their peak 12 weeks values and had increased fat mass relative to baseline values.

Fat gains included increases in both leg and arm fat of approximately 20% (H-1935). These data suggest that further investigation of the benefits of growth hormone in lipoatrophy should be pursued.

References:

Unless otherwise noted, all references are to the programme and abstracts of the 42nd ICAAC. September 27 – 30, 2002, San Diego, CA.

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