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NIH Public Access Author Manuscript Clin Infect Dis. Author manuscript; available in PMC 2008 June 17.

NIH-PA Author Manuscript

Published in final edited form as: Clin Infect Dis. 2008 April 15; 46(8): 1290–1296.

Effect of Reducing the Dose of Stavudine on Body Composition, Bone Density and Markers of Mitochondrial Toxicity in HIVinfected Subjects- a Randomized, Controlled study GA McComsey1,2, V LoRe III3, M O’Riordan1, UA Walker4, D Lebrecht4, E Baron2, K Mounzer5, and I Frank3 1Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA 2Case Western Reserve University, Cleveland, Ohio, USA 3University of Pennsylvania, Philadelphia, PA, USA 4Medizinische Universitätsklinik, Freiburg, Germany


5Jonathan Lax Treatment Center, Philadelphia FIGHT, Philadelphia, PA, USA

Abstract BACKGROUND—Stavudine (or d4T) is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to d4T, but it is unclear if switching to a lower dose can reduce these toxicities while maintaining HIV virologic suppression. METHODS—HIV+ subjects receiving standard dose d4T with undetectable HIV-1 RNA for ≥ 6 mo were randomized 3:2 to half the d4T dose (switch arm) or maintain the dose (continuation arm) while continuing the remaining antiretrovirals. Fasting lactate, pyruvate, lipids, whole body DEXA and mitochondrial DNA (mtDNA) in fat and PBMCs were obtained at baseline and Week 48. Change from baseline to Week 48 was compared within- and between-groups.


RESULTS—24 pts (79% men, 79% African Americans, age 45 yrs) were enrolled: switch arm (n = 15), continuation arm (n = 9). Median (range) d4T duration was 55 (21–126) months. Median CD4 count was 558/mm3 (207–1698). At baseline, the arms were similar in demographics and laboratory indices except BMI, total lean body mass (LBM), and triglycerides (higher in the switch arm). Three pts (2 in switch) discontinued due to study-unrelated reasons. CD4 counts remained unchanged. At 48 weeks, 6 pts (27% of the switch arm and 22% in the continuation arm) had detectable HIV-RNA; median 972 (60–49,400) copies/mL. All pts with detectable HIV-RNA reported significant lapses in adherence; none exhibited mutations on genotype. After the switch, significant changes from study entry to week-48 were noted only for lactate [−0.27 (range −1.2 to 0.25); p=0.02] and fat mtDNA [+ 40 (−49 to + 261) cps/cell; p=0.02). In the continuation arm, a significant loss of bone mineral density (BMD) at week 48 [−1.7% (−6.3% to 0.8%); p=0.02] was seen. The only significant between-group difference was the change from baseline in BMD (p=0.003) CONCLUSION—Reducing d4T dose by half increased fat mtDNA and decreased lactate suggesting improvement in mitochondrial indices while preserving HIV virologic suppression in subjects who maintained adherence. A significant loss of BMD was seen in pts on standard-dose d4T but not in those on low-dose. These results suggest that switching to low-dose d4T may improve mitochondrial indices while maintaining virologic suppression.

Corresponding author: Grace McComsey, Associate Professor of Pediatrics and Medicine, Case Western Reserve University, Cleveland, Ohio 44106; phone 216-844-3645; email: [email protected].

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Keywords


mitochondria; lipoatrophy; lipodystrophy; mitochondrial DNA

Introduction Several studies have established a link between the use of d4T and lipoatrophy. This is at least partially due to the ability of d4T to inhibit DNA polymerase gamma and mtDNA replication (1–5). Switches from d4T to NRTIs with less effect on DNA polymerase gamma have led to modest improvements in limb fat, mtDNA levels and adipocyte apoptosis(6–10). Although in developed countries, most subjects with lipoatrophy have substituted d4T with less toxic NRTIs, this may not be feasible in developing countries. A recent systematic review of nine clinical trials examining d4T use demonstrated that a dose of 30mg BID has equivalent efficacy to the 40mg standard-dose prescribed to adults weighing >60 kg, with some evidence of fewer side-effects, including neuropathy and to a lesser degree lipoatrophy (11). One trial switched virologically controlled subjects receiving d4T 40mg BID to either tenofovir or 30mg BID of d4T; no changes in mtDNA levels or lactate were found (12).


The current d4T label suggests dose reduction to 20mg BID for patients developing peripheral neuropathy on 40mg BID (dose reduction is to 15mg BID for individuals originally on 30mg BID). However, clinical experience with the use of 20mg bid d4T outside of neuropathy is lacking, and it is unclear if administration of a lower d4T dose (20mg for ≥ 60 kg; 15mg for < 60kg) would allow continued virologic suppression and lead to less mitochondrial toxicities. To address this question, we investigated the effect of reducing the d4T dose on metabolic parameters in subjects treated with d4T-based antiretroviral therapy (ART).

Population and study design


This was an open-labeled, randomized, controlled study. HIV-infected subjects (age ≥18 years) were recruited in the Special Immunology Unit of University Hospitals of Cleveland and in the MacGregor Clinic of the University of Pennsylvania, Philadelphia. Inclusion criteria included HIV infection, stable ART containing standard doses of d4T for ≥24 weeks, and HIV-1 RNA 3 days of each week of >40 g/day in a male or > 30 g alcohol/day in a female; 4) hepatitis C; 5) female gender; 6) overweight (BMI >25 kg/m2; or 7) use of didanosine (ddI) at screening. Exclusion criteria included acute illness, concurrent medications known to affect mitochondria, pancreatitis and peripheral neuropathy of > Grade 1. Subjects were randomized 3:2 to reducing the dose of d4T by half of the original dose (d4T 40 → 20mg BID in subjects ≥ 60 kg or 30 → 15mg BID in subjects 2.0 mmol/L at study entry remained asymptomatic for the study duration and required no discontinuation or change in ART. Three of them (all on switch arm) finished the study with lactate < 2 mmol/L, while one patient (on continuation arm) had a lactate of 2.5 mmol/L at week-48. Fasting pyruvate levels, lactate/pyruvate ratio, and postexercise lactate did not change in either arm. PBMC-mtDNA level did not change in either arm. There was no significant correlation between changes in fat-mtDNA and either changes in PBMC-mtDNA or lactate in either arm. Also, changes in fat-mtDNA and in lactate did not correlate with age, gender, limb fat, BMI, current use of NNRTIs or PIs, duration of exposure to d4T or to thymidine NRTIs. The only significant correlations with changes in fat-mtDNA were nadir CD4 count (r=0.94; p=0.005), and CD4 count at study entry(r=0.94; p=0.005). Body composition and Bone Mineral Density


At baseline, groups were similar with regards to total and regional body fat and BMD. There was no significant change within and between groups in BMI, lipoatrophy scores (by physician or patient), lipohypertrophy scores (by patient), absolute or % limb fat, trunk fat, total fat, or % limb/total fat at week 48. There was a modest but statistically significant between-arm difference in the physician-generated lipohypertrophy score [median −1 (range −3, 3) vs. 0 (0, 3); p=0.04 in the switch vs. continuation arm). In the continuation arm, a significant loss of BMD was observed at week 48 [−1.7% (− 6.3% to 0.8%); p=0.02], while BMD remained stable in the switch arm [0.0 % (−1.2, 4); p=0.37]. The between-group difference in the change of BMD was significant (p=0.003). There was no association between change in BMD and change in lactate or mtDNA from week 0 to 48, when analyses included either the entire cohort or the separate groups. There was also no correlation between changes in BMD and baseline or changes in BMI. Other Metabolic Parameters There were no significant, between-group or within-groups differences in change in blood pressure, cholesterol, HDL-cholesterol, triglycerides or glucose.

Discussion NIH-PA Author Manuscript

This is the first randomized, controlled trial to examine a switch to half of the standard d4T dose in order to alleviate metabolic toxicities in subjects who are virologically suppressed. Also our study was the first to examine the effect of d4T dose reduction on fat-mtDNA levels. Our results showed that reducing the d4T dose by half led to an increase in fat mtDNA and decrease in serum lactate while preserving HIV virologic suppression in subjects who maintained adherence. A significant loss of BMD was seen in patients receiving standard dose d4T but not in those on low-dose d4T. Importantly, this change in BMD was not correlated with changes in BMI or body composition. After 48 weeks of the switch to half of the standard dose of d4T in our study, we found a significant improvement in fat mtDNA and venous lactate levels. This does suggest an improvement in mitochondrial function in these individuals, and is in contrast to studies where switching to 30 mg dose of d4T did not lead to significant changes in mtDNA levels or lactate (12). However, our study is the first that investigated changes in mtDNA in the adipose tissue Clin Infect Dis. Author manuscript; available in PMC 2008 June 17.

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with this strategy. The earlier dose reduction study analyzed mtDNA in PBMCs (12). Mitochondrial toxicity is tissue-specific and thus far conflicting results have emerged from the investigations of PBMC-mtDNA (9,15–17). These conflicting results may be secondary to platelet contamination (18) or to the specific treatment responsible for the mitochondrial toxicity (17). In contrast, several groups have consistently found fat-mtDNA depletion in NRTI-treated subjects (4,9,19,20). This outlines the importance of assessing fat-mtDNA levels, and not only PBMCs. Improvements in fat-mtDNA levels did not correlate with adherence to ART or with HIV-RNA changes. Surprisingly, despite the significant improvement in mitochondrial function, no changes were seen in subjective or objective measurements of body composition. The majority of our subjects had lipoatrophy at baseline, and results were unchanged when we excluded the three subjects without lipoatrophy (results not shown). Although one could argue that recovery of limb fat is slow to occur, other studies in which d4T was switched to non-thymidine NRTIs were able to show a modest but significant change in limb fat after 48 weeks of the switch (6–8).


At baseline, the switch arm had higher BMI and LBM, and a trend towards a higher limb fat than the continuation arm. In some of the prior ART switch studies, baseline BMI was significantly and positively associated with change in limb fat (7), so that the slight difference in baseline limb fat in our study may have confounded the results. However, we found no correlation between changes in limb fat (absolute or %change) and baseline or changes in BMI. There was a remarkable variability in the observed changes of limb fat in both arms, but there were no clear outliers. This wide variability had been noted in other switch studies that reported ranges. In the TARHEEL study, leg fat changes after a d4T-to-abacavir switch were a median of +15% and a range of −53% to +206%% (6). Arm fat had similar variability; 38% (−37 to 174). In the MITOX study, no ranges were reported but the mean increase in limb fat at week-104 was 1.26 ± 2.02 kg (7). Hence, there is a consistent wide variability in the limb fat responses to ART-switch strategies.


Also, the effect on fat-mtDNA of switching to low-dose d4T was less than that previously reported with d4T discontinuation (9). When compared to the TARHEEL study (n=16), which observed an increase of 122% in fat-mtDNA after 48 weeks of discontinuation of d4T (9), the switch to low-dose d4T was associated with a smaller increase, with a median increase of 67% after the 48-week period of the study. The lack of body composition changes found in this study cannot be explained by variation in the study population, since age, d4T duration, and other characteristics were similar in both studies. Thus, although improvement in mitochondrial function is observed with the low-dose d4T in this study, it remains suboptimal when compared to other strategies such as substitution of non-thymidine NRTIs for d4T. This may also explain the lack of improvement in limb fat in this study. The apparent protection of low-dose d4T against the decrease in BMD seen over the 48-week of the study in the control arm is surprising given that the effect of NRTI doses on BMD has not been previously investigated. This is somewhat consistent with another study where patients receiving d4T or AZT therapy had a small, but significant decrement in BMD over the 104-week observation period, whereas those who switched to abacavir remained stable (7). A mitochondrial etiology of decreased BMD in HIV could indeed explain these findings. Thymidine analogues may affect bone metabolism indirectly, through their effect on mitochondria which maybe important in the development of reduced BMD (21). A large, cross sectional study of HIV+ men showed that an independent predictor of osteopenia is the presence of lactic acidosis (22), which may decrease bone formation and increase bone resorption (23). Further studies are required to test this potential association.

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The significant positive correlation found between fat mtDNA and CD4 count is consistent with the observation that advanced HIV disease is independently associated with lipoatrophy (24). In addition, lower CD4 count is predictive of hyperlactatemia/lactic acidosis (25). Thus the correlation we found between CD4 count and fat mtDNA further strengthen the suggestion that advanced HIV is associated with higher risk of ART-mitochondrial toxicity. With limited resources for HIV treatment in developing countries, low-cost treatment options such as stavudine still need to be pursued if safety can be improved by dose optimization. However, caution should be exerted as to the extent to which it would be safe to lower the dose (15–30 mg) as this low-dose strategy may be less tolerant to breaches in adherence. Despite the limitations of the small sample size and the open labeled nature of the study, this study provides valuable information as to the role of low-dose d4T in amelioration of metabolic parameters. The results suggest that the switch to half the standard-dose of d4T modestly but significantly improve mitochondrial indices without changes in body composition. The switch was able to mitigate the loss of BMD seen overtime with the standard dose d4T. Finally, lowdose d4T was not associated with loss of virologic control. For either of the d4T doses, subjects with low adherence to therapy exhibited higher risk of virologic failure. Acknowledgements


Sponsorship: This work was supported by Bristol Myers Squibb, the Case Western Reserve University Center for AIDS Research (CFAR) (AI36219), and the Clinical Core of the UPenn CFAR (AI45008). The mitochondrial assays were supported by NIAID AI- 60484 (GM). The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Dr McComsey has received research grant support and serves as consultant and speaker for Bristol Myers Squibb Co., GlaxoSmithKline, Gilead and Abbott. Dr Frank is a speaker and consultant for Bristol Myers Squibb.

REFERENCES


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A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006;20(16):2043–2050. [PubMed: 17053350] 9. McComsey GA, Paulsen DM, Lonergan TJ, Hessenthaler SM, Hoppel CL, Williams VC, Fisher RL, Cherry CL, White-Owen C, Thompson KA, Ross ST, Hernandez JE, Ross LL. Improvements in lipoatrophy, mitochondrial DNA content and adipose tissue apoptosis levels after replacement of stavudine with either abacavir or zidovudine. AIDS 2005;19:15–23. [PubMed: 15627029] 10. Cherry CL, Lal L, Thompson KA, McLean CA, Ross LL, Hernandez J, Wesselingh SL, McComsey G. Increased adipocyte apoptosis in lipoatrophy improves within 48 weeks of switching patients from stavudine to abacavir or zidovudine. J Acquir Immune Defic Syndr 2005;38(3):263–267. [PubMed: 15735442] 11. Hill A, Ruxrungtham K, Hanvanich M, Katlama C, Wolf E, Soriano V, et al. Systematic review of clinical trials evaluating low-dose stavudine as part of antiretroviral treatment Experts Opinion in Pharmacotherapy 2007;8(5):679–688. 12. Milinkovic A, Martinez E, Lopez S, de Lazzari E, Miro O, Vidal S, Blanco JL, et al. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Antivir Ther 2007;12(3):407–415. [PubMed: 17591031] 13. http://aactg.s-3.com/members/download/other/Metabolic/VenousLactateSOP.doc 14. Setzer B, Schlesier M, Walker UA. Effects of didanosine-related depletion on mtDNA in human T lymphocytes. J Infect Dis 2005;191:848–855. [PubMed: 15717258] 15. McComsey G, Bai R, Maa J-F, Seekins D, Wong L-J. Extensive Investigations of Mitochondrial DNA Genome in Lipoatrophy: Beyond mtDNA depletion. J Acquir Immune Defic Syndr 2005;39 (2):181–188. [PubMed: 15905734] 16. Cote HC, Brumme ZL, Craib KJ, Math M, Alexander CS, Wynhoven B, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. NEJM 2002;346:811–820. [PubMed: 11893792] 17. Cherry CL, Nolan D, James IR, McKinnon EJ, Mallal SA, Gahan ME, Lal Luxshimi, McArthur JC, Wesselingh SL. Tissue specific associations between mitochondrial DNA levels and current treatment status in HIV infected individuals. J Acquir Immune Defic Syndr 2006;42(4):435–440. [PubMed: 16810110] 18. Pinti M, Nasi M, Moretti L, Bellodi C, Troiano L, Mussinin C, Esposito R, Cossarizza A. Role of platlets contamination in assessing mtDNA content in peripheral blood mononuclear cells. Antiviral Therapy 2002;13:L15. 19. Nolan D, Hammond E, Martin A, Taylor, Hermann S, McKinnon E, Metcalf C, Latham B, Mallal S. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003;17(9):1329–1338. [PubMed: 12799554] 20. Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen U-P, Schöfer H, Setzer B, Venhoff N, Rickerts V, Staszewski S. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. JAIDS 2002;29:117–121. [PubMed: 11832679] 21. Pan G, Yang Z, Ballinger SW, McDonald JM. Pathogenesis of Osteopenia/Osteoporosis Induced by Highly Active Anti-Retroviral Therapy for AIDS. Ann N Y Acad Sci 2006;1068:297–308. [PubMed: 16831930] 22. Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS 2001;15:703–709. [PubMed: 11371684] 23. Bushinsky DA, Krieger NS, Geisser DI, et al. Effects of pH on bone calcium and proton fluxes in vitro. Am J Physiol 1983;245:F204–F209. [PubMed: 6881337] 24. Lichtenstein KA, Delaney K, Armon C, Ward D, Moorman A, Wood K, Holmberg SD. HIV Outpatient Study Investigators. Incidence of and Risk Factors for Lipoatrophy (Abnormal Fat Loss) in Ambulatory HIV-1-Infected Patients. JAIDS Journal of Acquired Immune Deficiency Syndromes 2003;32(1):48–56.


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25. Arenas-Pinto A and the International Lactic Acidosis Study Group. International Case-control Study of Lactic Acidosis and Severe Hyperlactatemia in Treated HIV-infected Adults. Abstract 806; The 14th Conference on Retroviruses and Opportunistic Infections; Feb 2007; Los Angeles, CA.

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Clin Infect Dis. Author manuscript; available in PMC 2008 June 17.

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NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1.

Percent Change from baseline in fat mtDNA levels in each of the study arms

NIH-PA Author Manuscript Clin Infect Dis. Author manuscript; available in PMC 2008 June 17.

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Table 1

Baseline demographics, HIV and metabolic characteristics of all study participants

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Characteristics

Total N=24

Switch N=15 n(%)

Continuation N=9 n(%)

p-value

Age (years; median, range)

45 (35–63)

46 (38–62)

44 (35–63)

0.63

Male sex

19 (79%)

12 (80%)

7 (78%)

1

Race / ethnicity White Black

5 (21%) 19 (79%)

5 (33%) 10 (67%)

0 (0%) 9 (100%)

179 (2–626)

177 (2–626)

180 (10–352)

0.68

111 (39–277)

111 (64–229)

101 (39–277)

1.00

558 (207–1698)

491 (207–1698)

593 (222–979)

0.81

8 (33%) 17 (67%)

5 (33%) 11 (73%)

3 (33%) 6 (67%)

Duration of NRTI (months; median, range)

82 (24–232)

72 (33–155)

94 (24–232)

0.81

Duration of thymidine NRTI (months; median, range)

72 (24–182)

66 (33–182)

94 (24–142)

0.95

Duration of d4T (months; median, range)

55 (21–126)

51 (21–126)

51 (24–116)

0.76

Duration of NNRTI (months; median, range)

9 (0–92)

9 (0–92)

8 (0–67)

0.62

Duration of PI (months; median, range)

46 (0–144)

45 (0–144)

73 (0–119)

0.72

Glucose (mg/dL; median, range)

80 (57–117)

82 (57–117)

77 (68–87)

0.23

(Triglycerides level mg/dL; median, range)

148 (52–777)

175 (52–777)

113 (63–181)

0.02

Cholesterol level (mg/dL; median, range)

192 (122–290)

214 (133–290)

176 (122–282)

0.24

HDL Cholesterol (mg/dL; median, range)

39 (28–94)

38 (28–75)

41 (32–94)

0.24

BMI (kg/m ; median, range))

25 (− 20,35)

26.6 (22,35)

23 (20,27)

0.003

Patient lipoatrophy score Physician lipohypertrophy score

5 (0,12) 1 (0,5)

5 (0,12) 1 (0,5)

5 (0,7) 0 (0,2)

0.59 0.05

Patient lipohypertrophy score

2 (0,9)

3 (0,9)

1 (0,3)

0.12

DEXA limb fat (grams; median, range) Trunk fat (grams; median, range)

5277 (2129–18992 8536 (2098–26464)

6047 (2129–18992) 9860 (2098–26464)

4721 (2327–8895) 5648 (2827–12973)

0.15 0.14

Lean Body Mass (grams; median, range)

59630 (39754– 74637)

62051 (39754– 74637)

51703 (41469–64277)

0.04

Total Body BMD (g/cm2; median, range)

1.18 (0.99–1.36)

1.18 (0.99–1.36)

1.18 (1.09–1.3)

0.59

Resting venous lactate (mmol/L; median, range)

1.16 (0.35–4.9)

1.3 (0.4–4.0)

1.0 (0.7–4.9)

0.47

Resting pyruvate (mmol/L; median, range)

0.09 (0.03–0.16)

0.10 (0.03–0.16)

0.09 (0.06–0.10)

0.39

Post exercise venous lactate (mmol/L; median, range) Fat mtDNA (copies/cell; median, range)

1.9 (0.45–4.5)

1.75 (0.96–4.5)

2.0 (0.45–3.9)

0.30

121 (60–179)

120 (60–174)

133 (68–179)

0.83

PBMC mtDNA (copies/cell; median, range)

22 (10–93)

23 (10–47)

21 (13–93)

0.9

0.12

Nadir CD4+ cell count (cells/uL; median, range) Known duration of HIV (months; median, range) CD4+ cell count (cells/ mm3;median, range) Antiretrovirals classes at entry NNRTI PI

2

1.0*

*

Comparison of PI vs. NNRTI; one subject was on PI+NNRTI


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Table 2

Changes in Metabolic and Mitochondrial Parameters from Baseline to Week 48 for the 21 subjects who completed the study


Variable BMI (kg/m2) Glucose (mg/dL) Triglycerides (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) Resting lactate (mmol/L) Resting pyruvate Fat mtDNA (copies/cell) % Fat mtDNA PBMC mtDNA (copies/cell) Lipoatrophy score (physician) Lipoatrophy score (patient) Lipohypertrophy score (physician) Lipohypertrophy score (patient) Total lean body mass (grams) Trunk fat (grams) Limb fat (grams) % Limb fat % Bone mineral density * within-arm changes; p

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