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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Clinical Science

Lack of Recurrence of Hyperlactatemia in HIV-Infected Patients Switched From Stavudine to Abacavir or Zidovudine

Lonergan, J. Tyler MD*; McComsey, Grace A. MD†; Fisher, Robin L. MSA‡; Shalit, Peter MD§; File, Thomas M. Jr MD||; Ward, Douglas J. MD¶; Williams, Vanessa C. MS‡; Hessenthaler, Siegrid M. MPH‡; Lindsey, Laura‡; Hernandez, Jaime E. MD‡; for the ESS40010 (TARHEEL) Study Team

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From the *Department of Medicine, Owen Clinic/University of California at San Diego Medical Center, San Diego, CA; †Department of Pediatric Infectious Diseases, Case Western Reserve University, Cleveland, OH; ‡GlaxoSmithKline, Research Triangle Park, NC; §Swedish Medical Center, Seattle, WA; ||Summa Health System, Akron, OH; and ¶Dupont Circle Physicians Group, Washington, DC.

Received for publication July 15, 2003; accepted April 14, 2004.

Supported by GlaxoSmithKline Research and Development.

The results of this study were presented in part in poster 92 at the Third International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Athens, October 2001; in poster 701T at the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, February 2002; as abstract and slide presentation 21 at the Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, September 2002 (Antiviral Therapy 2002;7:L13); in posters H-1929 and H-1930 at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, September 2002; as oral presentation 51 at the Second IAS Conference on HIV Pathogenesis and Treatment, Paris, July 2003; in poster 90 at the Fifth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Paris, July 2003; and as abstract/presentation 110 at the 41st Annual Meeting of the Infectious Diseases Society of America, San Diego, October 2003.

Reprints: J. Tyler Lonergan, Owen Clinic/University of California at San Diego Medical Center, 200 West Arbor Drive, San Diego, CA 92103–8681 (e-mail: tlonergan@ucsd.edu).

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Abstract

Summary: Stavudine (d4T) has been observed in clinical trials and cohort studies to be more often implicated in cases of hyperlactatemia than other nucleoside reverse transcriptase inhibitors, possibly because of its relatively greater propensity to induce mitochondrial toxicity. The ESS40010 study was a 48-week, open-label, switch study that assessed changes in serum lactate levels and signs/symptoms of hyperlactatemia after substitution of abacavir (n = 86) or zidovudine (n = 32) for d4T in 118 virologically suppressed HIV-infected patients (HIV-1 RNA <400 copies/mL) who had developed serum lactate concentrations ≥2.2 mmol/L (n = 16) or had remained normolactatemic (n = 102) after receiving ≥6 months of d4T-based treatment. Median serum lactate decreased significantly below baseline at week 24 (−0.15 mmol/L, P = 0.0002) and week 48 (−0.15 mmol/L, P = 0.0015). In 10 hyperlactatemic patients in whom d4T was discontinued, serum HIV-1 RNA levels rebounded over the ensuing 31 days, but virologic suppression (HIV-1 RNA <400 copies/mL) was regained when treatment using abacavir or zidovudine was subsequently instituted. In the group with elevated lactate at baseline, symptoms of hyperlactatemia improved in 8% to 23% of patients, did not change in 69%, and worsened in 8%. Serum transaminases, which had been elevated while patients received d4T, normalized after d4T discontinuation and remained in the normal range after the switch to abacavir or zidovudine. Overall, in patients with d4T-associated hyperlactatemia, stopping d4T results in normalization of lactate and a rebound in viral load; restarting treatment using abacavir or zidovudine subsequently maintains normal lactate levels and rapidly leads to a return of virologic suppression.

The nucleoside reverse transcriptase inhibitor (NRTI) stavudine (d4T) has proved in clinical trials to be useful when included as part of many highly active antiretroviral treatment (HAART) regimens. 1 However, several randomized clinical trials and cohort studies have shown that d4T places patients at a greater risk of developing hyperlactatemia (defined as confirmed lactate level ≥2.2 mmol/L) relative to other NRTIs. 2–6 Hyperlactatemia has been noted in 5% to 25% of patients treated with NRTIs, with most cases occurring in patients receiving d4T, often in combination with didanosine. 6,7 The increase in serum lactate may be caused primarily by an increase in endogenous lactate production and, to a lesser degree, by impairment in lactate clearance. 8 The risk of hyperlactatemia with d4T seems to parallel d4T’s greater propensity to inhibit mitochondrial DNA polymerase gamma compared with the NRTIs lamivudine, zidovudine, and abacavir (hierarchy of inhibition observed in enzyme assays and cell cultures: zalcitabine ≥ didanosine ≥ stavudine > lamivudine > zidovudine > abacavir). 9

In many patients, hyperlactatemia is asymptomatic and transient, but some patients develop clinical signs and symptoms of lactic acidemia, including nausea, vomiting, anorexia, abdominal pain, bloating, recent weight loss, dyspnea, fatigue, and tachycardia. 10–12 These symptoms may be accompanied by elevated serum transaminases and anion gap and decreased bicarbonate. Most patients with d4T-associated hyperlactatemia do not develop dangerously high lactate concentrations and tend to stabilize at low-grade elevation. 5 A few patients progress to a decompensated life-threatening lactic acidosis and hepatic steatosis, however. 12 In a review of 75 cases of NRTI-associated lactic acidosis and hepatic steatosis reported since 1991, 57 (76%) occurred after use of d4T. 13 Almost half (47%) of these cases resulted in death.

The ESS40010 (TARHEEL) study was a clinical trial designed to assess the reversibility of hyperlactatemia and lipoatrophy after the substitution of d4T with either abacavir or zidovudine in patients who had developed signs and symptoms of hyperlactatemia or lipoatrophy while receiving d4T treatment. Results presented below concentrate primarily on the hyperlactatemia objective of this study.

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METHODS

Study Population

Male and nonpregnant and nonlactating female patients at least 18 years of age were eligible to be screened for study enrollment if they (1) had HIV infection (documented by HIV-1 antibody enzyme-linked immunosorbent assay [ELISA] and confirmed by Western blot test of HIV-1 antibody or positive HIV-1 blood culture), (2) were able to read at a sixth-grade level, (3) had been taking a prescribed d4T-containing regimen consistently for ≥6 months immediately preceding study entry, and (4) had undetectable HIV-1 RNA (defined as <400 copies/mL) on the 2 most recent consecutive viral load measurements at least 1 month apart. Patients were enrolled if they had (1) positive physical examination findings showing at least 1 of the following: clinician-confirmed decrease of facial fat, decrease of fat in lower extremities, or decrease of fat in gluteal region; (2) patient self-report of at least 2 of the following: decrease of facial fat, decrease of fat in lower extremities, or decrease of fat in gluteal region; (3) patient self-report of at least 1 of the following: decrease of facial fat, decrease of fat in lower extremities, or decrease of fat in gluteal region plus at least 2 laboratory-confirmed occurrences of elevated lactate levels (≥2.2 mmol/L) during screening (before the baseline day [day 1 of treatment]); (4) patient self-report of at least 2 of the following: shortness of breath on exertion, generalized weakness, fast heart beat, recent weight loss of ≥10 lb within the previous 2 months, pain and/or bloating in the abdomen, nausea and/or vomiting and/or lack of appetite plus a confirmed elevation of lactate level ≥2.2 mmol/L at the screening visit; or (5) a confirmed serum lactate level >3.2 mmol/L at the screening visit.

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Study Design

In this multicenter, phase 4, open-label, switch study design, informed consent was obtained from patients before the conduct of any procedures, including screening activities. On study day 1, patients underwent a physical examination and were evaluated regarding demographic characteristics, baseline disease severity (Centers for Disease Control and Prevention [CDC] classification, HIV-associated conditions), and history of prior antiretroviral drug use. Thereafter, study visits were conducted at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. All laboratory draws from day 1 through week 48 were performed with patients fasting for at least 8 hours preceding the procedure. The study was conducted between July 2000 and February 2002 at 22 outpatient treatment sites in the United States. Before the initiation of the study procedures, the study protocol (ESS40010) was approved by the institutional review boards at each study site.

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Treatment Switch

Abacavir was administered as a single 300-mg tablet (Ziagen; GlaxoSmithKline, Research Triangle Park, NC) and zidovudine as 150 mg of lamivudine/300 mg of zidovudine in a single combination tablet (Combivir; GlaxoSmithKline). The decision about whether to use zidovudine or abacavir was left to the investigator based on the following guideline: zidovudine-naive patients were to be switched to zidovudine, and zidovudine-experienced or -intolerant patients were to be switched to abacavir.

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Assessment of Efficacy

Plasma HIV-1 RNA levels were measured at all study visits using the Roche polymerase chain reaction (PCR) assay, Amplicor HIV-1 MONITOR UltraSensitive version 1.0 (Roche Diagnostics, Branchburg, NJ), which has a lower limit of quantitation (LLOQ) of 50 copies/mL and a quantitation range of 50 to 75,000 copies/mL. If at any point during the study, HIV-1 RNA values were >75,000 copies/mL, the Roche AMPLICOR PCR Standard 1.0 assay (LLOQ = 400 copies/mL) was used.

In patients with confirmed serum lactate levels ≥2.2 mmol/L at the screening visit, it was up to the discretion of the investigator to discontinue therapy. Patients discontinuing d4T were considered likely to develop an elevation in their plasma HIV-1 RNA level. They could enter the study as long as their HIV-1 RNA was undetectable (defined as <400 copies/mL) on their 2 most recent consecutive measurements at least 1 month apart before the discontinuation of antiretroviral treatment. Once these patients started on study drug (defined as study day 1), loss of virologic control was defined as a plasma HIV-1 RNA level >1000 copies/mL on 2 occurrences at least 1 week apart without confounding factors, starting with their week 8 visit, except for those patients who had at least a 1-log10 decrease in HIV-1 RNA from their peak rebound level by their week 8 visit. Patients who continued to have a decrease in their HIV-1 RNA were considered to have reached a virologic end point only if they failed to attain a plasma HIV-1 RNA level of 1000 copies/mL or less by their week 24 visit or to have a subsequent elevation in HIV-1 RNA before week 24.

CD4+ lymphocyte counts were measured by flow cytometry at baseline and at weeks 8, 12, 24, and 48.

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Safety Assessment

At all study visits, patients were asked nonleading open-ended questions about the occurrence of adverse events and changes in concurrent medications and assessed for the appearance of HIV-associated conditions. Patients underwent fasting (8-hour) blood sampling for assessment of changes in standard laboratory and hematology parameters, hepatitis B surface antigen (HbsAg), hepatitis C antibody, and anion gap at screening; baseline; and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. Patients with confirmed lactate levels ≥2.2 mmol/L at the screening visit had the option to have all antiretroviral drugs discontinued. As per AIDS Clinical Trials Group (AACTG) guidelines, these patients had to have weekly repeat lactate levels performed at a central laboratory until lactate levels were <2.2 mmol/L on 2 consecutive tests (1 week apart), at which time, they could start study drug. In patients with symptoms of hyperlactatemia, lactate levels continued to be measured until patients were asymptomatic. Lipids (panel), insulin, free fatty acids, lipase, and C-peptide were assessed from blood samples at baseline and study weeks 8, 12, 24, and 48 or at an early termination visit; HbsAg and hepatitis C antibodies were evaluated at baseline and week 48 or at an early termination visit.

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Statistical Analysis

The patient screening questionnaire was summarized along with number and percentage of patients who reported at least 1 symptom of hyperlactatemia. Summary statistics for lactate levels (actual values and change from baseline) were calculated each week. The Wilcoxon signed-rank test 14 was used to test whether the change from baseline was different from 0. Changes were statistically significant if P < 0.05. Risk factors for hyperlactatemia (gender and race) were evaluated at baseline using logistic regression to calculate odds ratios, with 95% confidence intervals (CIs), comparing patients with serum lactate concentrations ≥2.2 mmol/L with patients with normal levels.

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RESULTS

The demographic and disease characteristics of the patients are presented in Table 1. A total of 138 patients were screened for the study, of whom 118 met the inclusion criteria. Most of these 118 patients were male (83%) and white (65%). Besides having undergone treatment with d4T, patients also had been exposed previously to the NRTIs zidovudine (52%) and lamivudine (90%), the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (33%) and nevirapine (27%), and the protease inhibitors (PIs) indinavir (45%) and nelfinavir (34%). At screening, 16 patients (14%) had confirmed elevated lactate levels ≥2.2 mmol/L, with a median lactate level of 2.90 mmol/L (range: 2.20–5.00 mmol/L). In the 102 patients (86%) with confirmed screening serum lactate levels <2.2 mmol/L, the median lactate level was 1.40 mmol/L (range: 0.40–4.20 mmol/L; any values ≥2.2 mmol/L in these patients were not confirmed). Ninety-seven percent (114/117) of the total study population had at least 1 symptom of lipoatrophy. Eighty-six patients (73%) were switched from d4T to abacavir, and 32 (27%) were switched to zidovudine, given as Combivir. The logistic regression analysis showed that women (compared with men) and African Americans (compared with other ethnic groups) were more likely to have high lactate serum concentrations (odds ratios, 2.63 [95% CI: 0.80–8.67] and 4.50 [95% CI:1.39–14.61], respectively), although only African-American ethnicity was statistically significant (P < 0.005).

Table 1
Table 1
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In the 16 patients who were hyperlactatemic during screening, the median lactate level at baseline (day 1) was 2.05 mmol/L (range: 1.10–3.30 mmol/L). Ten of these patients had lactate levels <2.2 mmol/L at baseline; all had discontinued antiretroviral therapy for a median of 31 days before being switched to either abacavir or zidovudine. The 6 other patients switched without interruption of therapy. Overall, 12 and 4 patients replaced d4T with abacavir and zidovudine, respectively. In the normolactatemia group, the median lactate level at baseline was 1.40 mmol/L and the range was 0.60 to 4.10 mmol/L (14 of these 102 patients had lactate levels ≥2.2 mmol/L at baseline; these levels, however, were not confirmed by a second measurement).

Serum lactate decreased gradually over the study period after the discontinuation of d4T and after the switch to abacavir or zidovudine. At 24 and 48 weeks, the median change from baseline in lactate in the hyperlactatemia group was −0.20 mmol/L and −0.80 mmol/L, respectively, and in the normolactatemia group, it was −0.10 mmol/L and −0.10 mmol/L, respectively (Fig. 1A). Four patients whose screening lactate was ≥2.2 mmol/L had at least 1 lactate measurement ≥2.2 mmol/L after switching to abacavir or zidovudine (see Fig. 1B). Lactate levels in these patients were generally below 2.2 mmol/L during most of the study, however. No confirmed lactate levels >2.2 mmol/L were observed 8 weeks after the switch, and all levels were <2.2 mmol/L at week 48 or at study discontinuation. In the 6 patients who were hyperlactatemic at screening who switched to abacavir or zidovudine without interrupting treatment, lactate levels remained within the normal range during 48 weeks of therapy. In the total population, median serum lactate decreased significantly below baseline at week 24 (−0.15 mmol/L, P = 0.0002) and week 48 (−0.15 mmol/L, P = 0.0015).

Figure 1
Figure 1
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At baseline, 38% of the hyperlactatemic patients and 46% of the normolactatemic patients (45% [52/116] of the total population) had at least 1 clinical symptom compatible with hyperlactatemia. When hyperlactatemia-related symptoms were assessed again at week 12, 8% to 23% of the group that had elevated lactate at baseline reported improvement, 69% reported no change, and 8% reported worsening (see Fig. 1C). In the normolactatemic group, 10% to 11% reported improvement, 60% to 63% reported no change, and 9% to 13% reported worsening (see Fig. 1D).

At baseline, the hyperlactatemia group had a slightly higher median anion gap than the normolactatemia group (18.5 mEq/L vs. 17.0 mEq/L), a slightly lower bicarbonate (23.3 mEq/L vs. 23.4 mEq/L), a higher alanine aminotransferase (ALT, 38.5 U/L vs. 32.0 U/L), and a slightly lower aspartate aminotransferase (AST, 28.5 U/L vs. 30.0 U/L). At 12 weeks, hyperlactatemic patients had median changes from a baseline of −1.0 mEq/L in anion gap, +1.65 mEq/L in bicarbonate, −10.50 U/L in ALT, and −6.00 U/L in AST (Table 2). At this time, lactate was −0.15 mmol/L below baseline. By week 48, anion gap in both groups had fallen to within the normal range or had not changed in 67% of patients and had increased in 33%; bicarbonate at week 48 had normalized or not changed from baseline in 100% of the hyperlactatemia group and 92% of the normolactatemia group; ALT had normalized or not changed from baseline in 92% and 95% of patients, respectively (increased in the remainder); and AST had normalized or not changed in 83% and 96% of patients, respectively (increased in the remainder). One patient in the normolactatemia group developed peripheral neuropathy during the study. There were no hyperlactatemia-related deaths or hospitalizations in either group.

Table 2
Table 2
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At baseline, median HIV-1 RNA levels were undetectable in the normolactatemia group. Median HIV-1 RNA levels were elevated in the hyperlactatemia group as a whole, however, because all antiretroviral therapy had to be discontinued for a median of 31 days in 10 of the 16 patients after screening (Fig. 2). After this viral rebound, HIV-1 RNA rapidly returned to undetectable levels once antiretroviral therapy was reinstituted with abacavir or zidovudine. At baseline, 89% and 71% of patients in the total population had HIV-1 RNA <400 copies/mL and <50 copies/mL, respectively (intention to treat [ITT]: observed analysis). At week 48, these percentages were 93% and 86%, respectively.

Figure 2
Figure 2
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DISCUSSION

The results of this study show that in patients with d4T-induced hyperlactatemia, discontinuation of d4T promptly results in a reduction in lactate levels and a rebound in viral load; once hyperlactatemia resolves, switching to either abacavir or zidovudine results in maintenance of normal lactate concentrations and regaining of virologic suppression over a 48-week period. This finding underscores the difference among NRTIs in their effect on serum lactate and supports the option of using NRTIs with the least effect on lactate in place of those with greater effects. It also suggests that changing from a hyperlactatemia-inducing NRTI to an antiretroviral drug of another class may not be necessary. Amelioration of d4T-induced hyperlactatemia by discontinuing d4T and then switching to abacavir or zidovudine has been reported in other studies. 5,15–17 Unlike the present study, however, these studies did not (1) measure the effect of the switch on efficacy, (2) monitor objective and subjective parameters to document improvement of hyperlactatemia, and/or (3) employ a normolactatemic group as a comparator to the hyperlactatemic treatment group. The hyperlactatemic potential of d4T also has been evidenced in a prospective comparative clinical trial between d4T and abacavir, each combined with lamivudine/nelfinavir, which showed at week 48 that the median serum lactate was more than 3-fold higher than baseline in the d4T-containing arm, whereas no differences from baseline were observed in the abacavir-containing arm. 18

In patients with elevated lactate concentrations who discontinued d4T plus all other antiretroviral drugs in their treatment regimen (10 of 16 hyperlactatemic patients), normalization of serum lactate occurred within approximately a 5-week period (median, 31 days). This is consistent with the time for resolution of d4T-induced hyperlactatemia described in other reports. 5 As would be expected, the lapse in treatment prompted virologic rebound in all patients who interrupted therapy. In view of the lesser effect of abacavir and zidovudine on serum lactate shown in this study, it may be postulated for patients with hyperlactatemia that d4T may be safely switched to either abacavir or zidovudine without treatment interruption to prevent loss of virologic suppression, drop in CD4 lymphocyte count, and potential development of mutations conferring antiretroviral resistance. Nevertheless, it should be cautioned that other studies have shown that zidovudine can occasionally increase lactate concentrations 7,19; the likelihood of abacavir doing so is lower. 7,20

With respect to laboratory changes, normalization of serum lactate concentrations after d4T withdrawal was associated with decreases in serum transaminases. Interestingly, reductions in transaminases also were observed in the normolactatemic group. Thus, it is possible that d4T treatment may have been responsible for elevation of transaminases in some patients. Changes in anion gap and bicarbonate were not clinically significant. Although routine testing of lactate levels is not generally recommended in most clinical settings, it is useful in patients with unexplained symptoms or unexplained elevated liver function test abnormalities. 21

In the hyperlactatemic group, symptoms associated with hyperlactatemia, especially abdominal pain and bloating, seemed to improve in some patients after discontinuation of d4T and during subsequent abacavir or zidovudine treatment. In the normolactatemic group, gastrointestinal adverse events generally showed no change after the switch in treatment. Assessment of hyperlactatemia based on symptoms alone may be unreliable, as evidenced in this study by the large proportion of normolactatemic patients who reported having 1 or more symptoms associated with abnormally high lactate concentrations. Despite their nonspecificity, however, symptoms may serve to prompt a workup for hyperlactatemia.

The odds ratio calculated in this study showed a greater risk for d4T-induced hyperlactatemia among women and African Americans, with only African ethnicity being statistically significant. Female gender (but not race) has previously been reported as contributing to the risk of NRTI-associated hyperlactatemia. 7 Using a Cox proportional hazards model, White et al 22 have shown that elevated lactate is an independent predictor of fat wasting (lipoatrophy). Almost all the patients evaluated in this study had 1 or more signs of lipoatrophy, which reversed at least partially over the course of the study. 23 Thus, it is possible that normalization of lactate levels may have contributed to this improvement in lipoatrophy. Other studies have shown elevated lactate concentrations to be predictive of peripheral neuropathy and osteopenia. 10,24

This study had a few limitations. The sample of patients in the hyperlactatemic subgroup was small. Hyperlactatemia is an uncommon finding in patients on NRTI therapy. Only patients with unexplained symptoms, particularly when combined with unexplained liver function test elevations, should be evaluated for this complication. Most of the patients with hyperlactatemia in this study were asymptomatic or presented with peripheral fat wasting only. Median AST and ALT values were elevated in the hyperlactatemia cohort as a whole, however. These values improved after therapy was discontinued (in 10 of the 16 hyperlactatemic patients) and remained within the normal range after the switch from d4T to abacavir or zidovudine. The number of patients switched to zidovudine relative to the number switched to abacavir was too small to allow differentiation of the effects of the 2 drugs on lactate or HIV-1 RNA levels. Nevertheless, improvement was observed in both groups. Patients may have been misclassified as having hyperlactatemia because of false lactate elevations. Even though we followed the AACTG-recommended protocol for lactate testing and lactate results were confirmed with a second measurement, we acknowledge that patients with mild asymptomatic hyperlactatemia without lipoatrophy may not actually require nucleoside changes. The risk factor analysis for hyperlactatemia in this study was limited, because comparisons were made in groups that were assembled together for different reasons. Another limitation of this study was the lack of a control arm. Other studies have shown continued loss of fat and worsening of hyperlactatemia in patients who remained on d4T, however. 5,16 There is no reason to believe that different clinical changes would have occurred in the patients in TARHEEL.

In conclusion, in patients with d4T-associated hyperlactatemia, discontinuation of d4T, followed by a switch to abacavir or zidovudine after normalization of lactate levels, results in continued maintenance of normal lactate concentrations. Resumption of antiretroviral treatment using abacavir or zidovudine also prompts a return of virologic suppression in patients who rebound after d4T withdrawal.

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ACKNOWLEDGMENTS

The authors thank the study participants, the study investigators and study site personnel, and the following TARHEEL study team personnel: Margaret Becker, Irvie Bullock, Julie Fleming, Keith Pappa, Carol Humphries, Ilisse Minto, Steven Ross, Lisa Ross, and Anne Stokley. They also thank Gary E. Pakes for his assistance in the writing of this manuscript.

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Keywords:

abacavir; Combivir; HIV infection; hyperlactatemia; lipoatrophy; stavudine; zidovudine

© 2004 Lippincott Williams & Wilkins, Inc.

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