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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Clin Infect Dis. Author manuscript; available in PMC Jun 17, 2008.
Published in final edited form as:
PMCID: PMC2430521
NIHMSID: NIHMS49771

Effect of Reducing the Dose of Stavudine on Body Composition, Bone Density and Markers of Mitochondrial Toxicity in HIV-infected Subjects- a Randomized, Controlled study

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.

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 (15). 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(610). 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 <50 copies/mL (or bDNA <75 copies/mL). In addition, patients had to have at least one of the following markers or risk factors for mitochondrial toxicity: 1) lipoatrophy as defined by self-report by the subjects of fat loss in the face, extremities and/or buttocks, and confirmed by the investigator; 2) two consecutive lactate levels > 1 X upper limit of normal; 3) regular excessive use of alcohol within the past 12 months prior to study, as defined by alcohol intake on >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 <60 kg; switch arm), or to continue the standard dose (continuation arm) for the 48-week study duration. Subjects were asked to remain on all other ART for the duration of the study. The study drugs (d4T at standard and low-dose) were provided free of charge by Bristol Myers Squibb to all study participants. The randomization schedule was prepared by the study data manager who was not linked with patient care. The study was approved by the Institutional Review Board of both institutions, and all subjects provided written informed consent prior to enrollment.

Clinical Assessment

After screening for eligibility, subjects were followed at weeks 0 (entry), 4, 12, 24, 36 and 48. At each visit, clinical assessment and laboratory tests (complete blood count, electrolytes, renal and liver tests) were performed. CD4 count and HIV-RNA were measured at weeks 0 and 48. Subjects with confirmed HIV-virologic failure had an HIV-genotype performed. Adherence to study drugs was assessed at every visit by count of dispensed and returned pills

Collection of Mitochondrial Markers

Peripheral blood mononuclear cells (PBMCs) were collected at entry and Week-48 of the study. Subcutaneous fat was obtained from a 6-mm skin punch biopsy in the upper outer quadrant of the buttocks at entry and Week-48. The fat samples were separated from the overlying skin and placed in a −70°C freezer until batch processing at the end of study. Fasting pyruvate and lactate were collected at rest and after a 10-minute exercise (walking up and down stairs at a fast rate) at study entry and Week 48. Fasting was defined as ≥8 hours since oral intake of anything other than water. Venous lactate levels were determined using ACTG guidelines (13) and levels were determined in real time at each site’s laboratory.

DNA isolation and mtDNA assays

The mtDNA assays were performed on batched specimens at the end of the study as described previously (14). The laboratory personnel were blinded to all sample characteristics. Briefly, total DNA was extracted with the QIAamp DNA isolation kit (Quiagen, Hilden, Germany). MtDNA and nDNA copy numbers were determined by quantitative PCR using the ABI 7700 sequence detection system (Applied Biosystems, Foster City, CA). The mtDNA ATP-6 gene was amplified and quantified with a FAM-fluorophore labeled probe. For the quantification of nDNA, exon 8 of the GAPDH-gene was amplified and quantified using a VIC-fluorophore labeled probe. Amplifications of mitochondrial and nuclear products were performed separately in optical 96-well plates (Applied Biosystems). All samples were run in triplicate. Absolute mtDNA and nDNA copy numbers were calculated using serial dilutions of plasmids with known copy numbers of mtDNA and nDNA.

Determination of Clinical Lipoatrophy and Lipohypertrophy

A questionnaire examining subject’s body fat loss and/or accumulation was completed separately and independently by patients and physicians. A lipoatrophy score was calculated based on questions about fat loss in the arms, legs, buttocks and face. Assessments within each of these sites were rated as “0” for “absent”; “1” for “mild”; “2” for “moderate” and “3” for “severe”. Thus, the lipoatrophy score could vary between 0–12. A similar lipohypertrophy score was calculated based on questions about fat gain in the abdomen, neck, and breasts as well as the presence of body lipomas. The total lipohypertrophy score could vary between 0–12.

Metabolic assessments

Fasting lipids were performed at study entry and weeks 24 and 48. Non-HDL cholesterol was derived by subtracting the HDL cholesterol value from the total cholesterol value. Total and regional body fat, LBM and BMD were measured by a whole-body dual-energy x-ray absorptiometry (DEXA) at baseline and week-48. Due to mechanical variances, all subjects were consistently scanned using the same machine at each time point. The DEXA scans were standardized, calibrated against a common standard and read centrally by Tufts University. The central reader was blinded to the timing of DEXA and the study arm.

Statistical analysis

Changes in fat and PBMC-mtDNA levels were the primary endpoints in this study, on which sample size calculation was based. In order to account for the levels of mtDNA at baseline, we also assessed percent change from baseline in mtDNA. Secondary endpoints were changes in fasting cholesterol, triglycerides, non-HDL and HDL cholesterol, lactate, lactate/pyruvate ratio, DEXA-measured changes in limb fat, LBM and BMD, CD4+ cell counts and HIV-RNA levels.

Using a p value of 0.05, a sample size of 22 was needed to provide 80% power to detect a 50% change from baseline and between-arms in fat-mtDNA levels. We used Wilcoxon Signed Rank test to compare differences between groups of variables, Mann-Whitney U test for between-group differences and Spearman Rank Correlation for correlations between variables. To determine possible confounding effects of variables on the endpoints, linear regression analysis was used. We did not adjust p-values for multiple comparisons. Unless stated, results are presented as median and range. All analyses were carried out using SAS, v.8.2 (The SAS Institute, Carey, NC).

RESULTS

Between Nov 2004 and Dec 2005, 26 subjects were screened, all of whom were randomized. Of these, two subjects withdrew consent before starting study drugs and were excluded from the analysis. Overall, 24 patients (79% men, 79% African Americans, age 36 yrs) were enrolled (switch arm 15); 21 completed the study. One subject in the switch arm withdrew at week 4 for personal reasons and scheduling conflict. Another subject in the switch arm died from overdose of illegal drugs and respiratory failure at week-37 that was unrelated to study participation. A third subject in the continuation arm withdrew at week 4 due to incarceration. No subject discontinued study drugs due to adverse effects.

Of the 24 subjects in the trial, 21 (88%) were found to have lipoatrophy at study entry, and 13 (62%) of these were randomized to the switch arm. The study groups had similar baseline demographics and laboratory indices, except for BMI (higher in the switch; p=0.003), total LBM (higher in the switch; p=0.04), and triglycerides (higher in the switch, p=0.02) (Table 1). Only two subjects (one per arm) were receiving a d4T dose of 30 mg BID at study entry (weight <60 kg). Four others were receiving concomitant ddI (2 patients per arm). Four patients on the switch arm and two on the continuation arm reported “social alcohol use” at study entry; none reported heavy use. The median baseline CD4 count was 558/mm3 (IQR 207-1698), and all subjects had HIV-1 RNA below the level of detection (< 50 copies/mL at the Case site and <75 copies/mL at the UPenn site) at study entry. CD4 count did not change between baseline and week-48. However, at 48 weeks six subjects (4/15 or 27% in the switch arm vs. 2/9 or 22% in the continuation) had lost virologic control with a median HIV-RNA of 972 (range 60– 49,400) copies/mL. Genotype was able to be performed on only the 2 subjects with HIV-1 RNA > 1,000 copies/mL, and identified no resistance mutations. All 6 subjects reported missing several doses, and pill count identified an adherence of <80% of the doses on all these subjects vs. >90% adherence in subjects who maintained virologic control.

Table 1
Baseline demographics, HIV and metabolic characteristics of all study participants

All subjects maintained their ART unchanged. Median (range) d4T duration was 55 months (range 21–126 months). There were no significant changes in serum creatinine, bilirubin, liver enzymes or creatinine kinase between weeks 0 and 48. None of the subjects, including the four with lactate >2.0 mmol/L at baseline exhibited symptoms suggestive of mitochondrial toxicity, such as anorexia, weight loss, nausea, vomiting, or abdominal pain. There was no change in alcohol consumption during the study.

Markers of mitochondrial function

Figure 1 illustrates the percent changes from baseline in fat-mtDNA levels. As seen in Table 2, at week 48, although there were no significant between-group differences, both median fat-mtDNA and lactate improved in the switch group [+40 (range −49,261) copies/cell; p= 0.02 and −0.27 (range 0.25, −1.2) mmol/L; p= 0.01, respectively). The percent change from baseline to week-48 in fat-mtDNA levels also increased in the switch arm [+67% (−34 to 356); p=0.01]. No changes from baseline in levels of fat-mtDNA or lactate were seen in the continuation arm. The four subjects with lactate > 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 post-exercise 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).

Figure 1
Percent Change from baseline in fat mtDNA levels in each of the study arms
Table 2
Changes in Metabolic and Mitochondrial Parameters from Baseline to Week 48 for the 21 subjects who completed the study

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

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 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, 1517). 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 (68).

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.

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, low-dose 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.

Acknowledgments

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.

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