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Switch from d4T to Abacavir: changes in fat and mitochondria
Reported by Jules Levin
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Brief summary of report: Two studies were reported on at ICAAC by Grace McComsey, both of which evaluated change in body fat composition and mitochondrial number, content, and function in patients with lipoatrophy (fat loss) who were taking a regimen including d4T and substituted abacavir or AZT for the d4T. Patients switching to abacavir on average had significant gains in fat as measured by DEXA in the arms, legs, and trunk (shoulder to waist). In the 48 weeks of the study as measured by patient self-report, it appears as though some patients experienced appreciable improvement, and a number of patients experiencing no worsening, and some patients experienced continued fat loss. The percentages of fat gain are reported below. Abacavir was much more successful than AZT in fat gain. Facial fat change was assessed only by patient self-report, and 27% of patients reported fat gain. The second study examined 16 patients from the first study and found that these patients had dysfunctional and reduced numbers of mitochondria. The number of mitochondria DNA increased in fat tissue, muscle tissue, and in blood cells (PBMC) after switching from d4T to abacavir or AZT, but almost all the patients in the substudy switched to abacavir (14/16). Increases in fat cells were significant but did not reach normal levels in 48 weeks. It appears as though changes in fat tissue may be the most reliable measure of changes in mtDNA as it relates to fat loss in HIV+ individuals, rather than changes in blood cells (PBMC). This study ended at week 48, so future responses such as 2-5 years out cannot be evaluated. We cannot evaluate if normal fat levels can be regained after for example 7-10 years.
As we know, due to HAART HIV-infected individuals are living healthier, more productive, and longer lives. HAART has long-term effects of HAART and it's important for patients to be knowledgeable about this and factor this into treatment decision making. Lipodystrophy includes fat accumulation and fat loss. Lipoatrophy, which is another word for fat loss, refers to loss of fat in the HIV-infected individual's face, arms, legs, and buttocks. This can very much affect a patient's well being and can be stigmatizing.
At ICAAC, Grace McComsey (Case Western University) reported on 2 interesting studies regarding switching from d4T to abacavir and fat loss (H-1929m H-1930). The TARHEEL study was designed to evaluate the affect on lipoatrophy (fat loss) and lactate after substitution of d4T or d4T and another agent with abacavir or AZT (as Combivir). All patients had lipoatrophy with oe without lactate levels above normal (2.2 mmol/l). The presence of fat loss was assessed by physician exam or patient report. Physical signs of lipoatrophy were determined by change in percent of fat using full-body dual-energy x-ray absorptiometry (DEXA), single abdominal computerized axial tomography (CT) scan, anthropometric measurements, and patient self-reports using a Body Image Questionaire. Patients with lactate <2.2 mmol/l could have discontinued ART until lactate was <2.2 or until patient was asymptomatic. ART was then resumed substituting abacavir or AZT for d4T and restarting all other ART drugs. 16 patients had lactate at baseline >2.2, and 13 of these 16 also had lipoatrophy. 102 patients had lipoatrophy of the 118 enrolled. AZT-naive patients substituted AZT for d4T, and AZT-experienced or intolerant patients substituted abacavir for d4T. 118 patients enrolled in study and 93 completed 48 weeks. 25 patients discontinued prematurely: 5 due to abacavir hypersensitity and 1 due to viral failure
Patients wee 43 years of age; 70-85% male; 50-70% white. Patients who did not discontinue ART due to elevated lactate (on average for 31 days) had undetectable HIV RNA and patients who discontinued had detectable HIV RNA. 40-45% of patients had symptoms of hyperlactatemia.
TIME ON d4T
82% of patients had been on d4T for greater than 2 years before switching to abacavir or AZT, and 12% had been on d4T for 1-2 years. 75% switched to abacavir and 25% to AZT.
RESULTS
24 week results presented at the Retrovirus Conference in February 2002 found the average percent increase in fat in the arm, leg, and trunk assessed by DEXA was increased from study entry by 20% (arm), 8% (trunk), and 5% (leg). On average fat gain increased from week 24 to 48, and at week 48 patients who switched from d4T to abacavir had increases in regional fat of 37% in arms, 15% in legs, and 19% in trunk. Patients who switched from d4T to AZT showed injcreases of 17% (arms), 7% (leg), and 16% in the trunk.. Patients who switched to abacavir saw more fat gain than patients switching to AZT, suggesting that abacavir is more effective in improving fat. Subcutaneous fat in the abdomen increased on average by 23.5 cm as measured by CT.
Interesting results came from the Body Image Questionaire (face, arms, legs, buttocks). At the study beginning, 50-60% of patients reporting they observed they had lost some or a lot of fat. After 24 weeks, following the switch from d4T to abacavir or AZT, 20-30% of patients reported they gained some or a lot of fat: 27% reported improvement in the face, 20% in legs, 22% in arms, and 19% in buttocks. 20-30% of patients reported some or a lot of fat loss, and 50-60% of patients reported they saw no change in fat, presumably they saw no improvement but also no worsening. In sum, after 24 weeks some patients reported fat gain (20-30%), some patients reported fat loss (20-30%) and the rest reported no change. At week 48, the percentages reported by patients were about the same so there wasn't a report of further improvement between week 24 and 48. This raises the question -- if fat gain will continue to improve but this question can't be answered because the study stopped at week 48.
It's difficult to assess the effect of the treatment switch on lactate because some patients with elevated lactate stopped their ART before the switch. But while on abacavir or AZT the patients who previously experienced elevated lactate on d4T did not experience increases while on AZT or abacavir, and lactate levels continued to decline after starting the substituted abacavir or AZT. Laboratory abnormalities most frequently associated with sympotomatic hyperlactatemia improved following the discontinuation of d4T and starting abacavir or AZT (AST/ALT, anion gap, bicarbonate).
The abstract reported that the average HIV viral load remained undetectable <(50 copies) throughout the study for patients who had not interrupted therapy due to elevated lactate before switching to abacavir or AZT.
Although the study ended at week 48 so it's not possible to assess further improvements, further analysis is ongoing to find factors that might predict why some patients had fat gain and others did not. Possible predictors include protease inhibitors vs no protease inhibitor use, age, gender, duration of treatment, duration of d4T use how much fat was lost up front before the switch, cwhether the combination of protease inhibitor and nukes are synergistic. Since the study is ended, it cannot answer the question of whether its possible to replace all the fat lost, or how long that would take. It's possible it could take more than 48 weeks for some patients to begin to see fat gain. It's also possible that fat loss is irreversible for some patients. If regaining all the fat lost is possible it could take a number of years, perhaps up to 10 for some patients, but we can't answer that question with this study.
MITOCHONDRIAL CHANGE
NRTIs (nukes) have been shown in studies in the laboratory to inhibit mitocondrial DNA replication (d4T>AZT>abacavir). The second study reported by McComsey was a substudy of the first and evaluated the mitochondrial number and function in blood (PBMCs), muscle tissue, and fat tissue in patients while still on d4T and after switching to abacavir or AZT. The change in fat tissue appears to be the most crucial measure. The fat and muscle tissue were taken by cutting a 1 inch incision, not by biopsy, in the lateral aspect of the thigh. 14 of the 16 patients in this substudy switched to abacavir and 2 switched to AZT. 13 of the 16 had lipoatrophy. It has been suggested that mitochondrial loss or dysfunction might be a contributing factor to lipoatrophy, but the link has not been strongly established.
3 patients had HCV. The liver contains mitochondria, and dysfunction or decline in the number of mitochondria in liver cells might impair liver function. Individuals with HCV/HIV coinfection may experience greater impairment of the liver due to the HCV and having taken nuke therapy for their HIV. This is reflected in 2 studies finding that coinfected patients experienced greater loss of fat, abnormal cholesterol and triglycerides, and glucose.
These patients ranged in age from 37 to 57 (average 44 years). 11 of the 16 patients were white and 5 were black. 9 patients had >500 CD4s, 6 had 200-500 CD4s, and 1 patient had <200 CD4s (average 580 CD4s). HIV viral load was 52 copies/ml. Average lactate was 1.65 mmol/l. At week 48, DEXA (n=13) from these patients showed average increases in fat from week 0 to week 48 of 23% in the arms, 10% in the leg, and 18% in the trunk (shoulder to waist).
McComsey found that the 16 patients had dysfunctional or poorly functioning mitocondria while on d4T than in HIV-negative individuals. She did this by assessing the amount of 7 enzymes in the PBMC and muscle and fat tissue in the 16 HIV+ patients with lipoatrophy and in control study subjects. The control study subjects' samples included PBMC, muscle and fat tissue from HIV-negative individuals, and PBMC from HIV+, ART naive individuals, and PBMC from HIV+ individuals on d4T for >6 months with no symptoms of lipoatrophy (n=49). The average baseline values for each of the 7 enzymes in the patients was less than the average values of the 7 enzymes taken from the control study subjects. 7 of 16 patients had significantly reduced enzyme levels. This suggests that the mitochondria in the 16 patients were not functioning properly. One affect of poorly functioning mitochondria can be a patient experiencing less physical energy. Mitochondria are contained in cells and function to provide energy for the body.
PBMC
The mitochondria (mt) DNA copies per cell for PBMC was very low at baseline for the 16 patients as well as for the HIV+ ART-treated patients without lipoatrophy, and for the HIV+ ART-naive patients. The HIV-negative study subjects had 7 times the amount of mtDNA copies as all the HIV+ patients. 48 weeks after switching to abacavir or AZT the mtDNA copies per cell in PBMC (peripheral blood mononuclear cells) increased 4-fold from 64 to 256 (n=13), p=0.0001. At baseline mt DNA copies were 64 in the 16 patients, 73 in the HIV+ ART naive subjects, and 120 in the subjects on d4T for >6 months with no signs of lipoatrophy. This data suggests that patients with HIV experience reduced mtDNA before starting HIV therapy. There was a great amount of variability in the number of mtDNA between patients in cells in the blood suggesting that evaluating blood cells (PBMCs) is not a reliable test for evaluating mitochondrial changes.
MUSCLE
The patients who had been on d4T and had lipoatrophy an increase in mtDNA. They experienced an increase in mtDNA copies per muscle genome from baseline to week 48 from 2305 at week 0 to 3754 (p=0.01). The control study subjects had an average of 3927. There was not much variability in the between patients in the number mtDNA.
FAT TISSUE
There is controversy surrounding whether measuring mtDNA changes in blood (PBMC) or fat tissue is more reliable, but it appears is that measuring changes fat tissue is more reliable to evaluate changes in fat for the HIV+ person with lipoatrophy. The average number of mtDNA copies per fat tissue cell in HIV-negative individuals was 921. For the patients who were on d4T & had lipodystrophy the number of mtDNA copies were 194 at week 0 and increased to 453 at week 48 after switching to abacavir. That's an increase of 140%. However, the number of mtDNA copies was still 50% less than that in HIV-negative individuals. The study reported there was a correlation between mtDNA levels in muscle at week 48 and DEXA improvements in arm, leg, and trubk. I think McComsey is now studying the correlation between the increase in mtDNA in fat tissue in these study patients and the DEXA improvements seen by these patients in the first study to see if there is a direct correlation between increased mtDNA and fat changes. Since average mtDNA copies in muscle returned to normal, although thyere was patient variability, and fat tissue improved to 50% of normal, mtDNA in fat tissue might return to normal given more time.
Other factors affect mtDNA function and number including genetics and environmental factors.
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