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Clinical Science

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy

John, Mina; Moore, Corey B.; James, Ian R.; Nolan, David; Upton, Richard P.; McKinnon, Elizabeth J.; Mallal, Simon A.

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From the Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Western Australia.

Received: 26 July 2000;

revised: 6 December 2000; accepted: 20 December 2000.

Requests for reprints to Dr S. Mallal, Department of Clinical Immunology, Royal Perth Hospital, Perth WA 6000, Australia.

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Objective: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients.

Design: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study.

Results: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8–4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses.

Conclusions: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

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Acute, severe lactic acidosis is a rare but potentially fatal complication of treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) in HIV-infected patients [1–5]. Severe lactic acidosis is typically symptomatic with nausea, vomiting, severe malaise and prostration and may occur precipitously after months or even years of NRTI treatment [5]. Recently, mild or moderate lactate elevation in NRTI-treated individuals has been reported [6–9]. The natural history of mild to moderate hyperlactatemia and its relationship to the risk of severe, life-threatening lactic acidosis is not known.

As lactate is the product of anaerobic glycolysis, hyperlactatemia in normal aerobic conditions may indicate mitochondrial dysfunction [10]. The mitochondrial basis of NRTI-induced hepatic steatosis, lactic acidosis and myopathy is well established, and several other adverse effects such as peripheral polyneuropathy and cardiomyopathy have also been linked to mitochondrial toxicity [11]. It has been hypothesized that some features of the ‘lipodystrophy syndrome’ are also tissue-specific mitochondrial toxicities caused by NRTI treatment [12–14]. As hyperlactatemia may be a correlate of mitochondrial dysfunction, we sought to determine the prevalence, longitudinal course and risk factors for the development of hyperlactatemia in a large HIV-infected population.

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Venous lactate concentration was measured in 349 participants of the Western Australian HIV Cohort Study [15] as part of routine outpatient review from January 1999 to June 2000. Visits typically occurred at intervals of 1–3 months for all patients. Clinic phlebotomists were instructed to ensure that patients were at rest for at least 10 minutes prior to extraction of a heparinized venous blood sample without a tourniquet or fist clenching. Samples were transported immediately to an adjacent laboratory and measured in a lactate biosensor using amperometric technology within minutes of collection. If there was a delay in immediate processing, the sample was put on ice and assayed within 20 minutes.

Comprehensive demographic, clinical and laboratory data are routinely collected on all participants of the Western Australian HIV Cohort Study, which was established in 1983 [14,15]. The variables relevant to this study include age; sex; body mass index; HIV- and non-HIV-related illnesses, including hepatitis B and C coinfection; history of antiretroviral drugs, including reason for therapy revision; history of prophylactic and non-HIV-related medications; serial CD4 T cell counts and plasma HIV RNA concentration [HIV Amplicor (Roche, Branchburg, USA), limit of detection < 400 copies/ml until November 1999, then Roche Amplicor HIV monitor Version 1.5 Ultrasensitive, limit of detection < 50 copies/ml]; and full blood picture and serum biochemistry, including liver function tests. All laboratory-derived data are electronically downloaded into the cohort study database.

The full study cohort comprised 349 active patients with 1379 lactate measurements between January 1999 and June 2000. Though lactate measurements done prior to January 1999 were recorded in the cohort database, they were not used in any analysis in this study. Highly active antiretroviral therapy (HAART) was defined as two NRTIs (stavudine or zidovudine with either lamivudine or didanosine) and a protease inhibitor (PI) or two NRTIs and abacavir or two NRTIs and a non-nucleoside reverse transcriptase inhibitor (NNRTI). Five patients who presented during the study period with acute symptomatic severe lactic acidosis were described separately and excluded from subsequent analyses. Cross-sectional analysis was restricted to those patients who were antiretroviral naive or those who had been on their current HAART regimen for at least 30 days at the time of their lactate measurement. Patients who were not on any current therapy (but were not treatment naive) or those not on HAART as defined above were not included in these analyses. The multiple linear regression model and non-linear mixed model of lactate concentrations over time were further restricted to only HAART-treated patients.

A review of the medical records of all patients who had HAART revised during the study period was undertaken to confirm reason(s) for revision, as recorded in the study database.

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Statistical analyses

Cross-sectional comparisons and linear mixed model analyses were carried out using the SAS statistical package (SAS Institute, Cary, North Carolina, USA). In cross-sectional analysis, the mean of the consecutive lactate measurements taken while the patient was on current therapy was used as a single value for each individual. ANOVA was used to assess significant differences in the averages between treatment groups. For the longitudinal analysis, both mixed effects linear and non-linear models of the growth in lactate measurements were used. When considering time from HAART, a non-linear growth model of the form lactate = a [1 – b exp(–kt)] was fitted using the S-PLUS statistical package [16]. The coefficients a and b in this model were assumed to be random, varying about a population average according to the individual, but k was taken to be fixed across individuals; t was time. The model allows individual variation in initial lactate measurements and in the value at which the measurements may level off over time. Estimates of the population averages of these parameters for each treatment regimen allowed comparison of the trends using standard large-sample Wald tests. Linear mixed models comparing effects after the initial increase in lactate levels were fitted using SAS.

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Patient characteristics and distribution of current antiretroviral treatment is shown in Table 1.

Table 1
Table 1
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In 516 patient-years of observation and routine lactate measurement, five patients, three male and two female, had lactate elevation above 5 mmol/l (laboratory healthy reference range 0.3–1.3 mmol/l). One male patient had non-Hodgkin's lymphoma with widespread hepatic metastases and multiorgan failure. Another male patient had advanced AIDS, refractory cytomegalovirus encephalomyelitis and cardiomyopathy. Neither of these patients were taking antiretroviral therapy and it was thought that the lactic acidosis was a consequence of their underlying illnesses. The third male patient had a history of alcohol abuse, alcohol-induced hepatitis and had one lactate level of 9.3 mmol/l after acute alcohol intoxication. He was not compliant with his prescribed antiretroviral therapy during this time. His lactate levels subsequently declined rapidly to < 2.00 mmol/l. The two remaining patients, both female, experienced typical NRTI-induced lactic acidosis/hepatic steatosis, giving an incidence rate of 3.9 per 1000 person-years. In one, symptoms of nausea and abdominal discomfort began 6 months after commencing stavudine and nelfinavir and were rapidly progressive. Venous lactate concentration was 6.4 mmol/l at diagnosis but was 1.6 mmol/l 1 month earlier and was 1.9 mmol/l 5 months earlier (when asymptomatic). The other female patient had been taking stavudine, lamivudine and nelfinavir for 1 year. Acute-onset severe malaise, vomiting, abdominal pain and clinical hepatomegaly prompted urgent lactate measurement, which showed the patient had a lactate concentration of 8.2 mmol/l. There was also massive hepatomegaly on abdominal ultrasound. No prior lactate measurements were available for this patient; however, the calculated anion gap in serum samples taken a month before presentation with fulminant lactic acidosis was within normal range. Both patients with severe NRTI-induced lactic acidosis/hepatic steatosis had serum bicarbonate < 20 mmol/l and had NRTI permanently discontinued. The multiple lactate values of all five patients with severe lactic acidosis were removed from all subsequent analyses.

A further five patients in the cohort had revision of NRTI by their physician during the study period because of symptoms that were thought to be related to moderate hyperlactatemia (2.8–4.1 mmol/l) and/or hepatic steatosis. All patients had nausea and/or abdominal discomfort, abnormal liver function tests and an appearance suggestive of hepatic steatosis on abdominal ultrasound. All five had their stavudine replaced by zidovudine or abacavir, with relief of symptoms and subsequent fall in lactate levels, though two patients had transient rises to 4.2 mmol/l at 9 months later and 3.5 mmol/l at 11 months later, respectively. No patients in the cohort had revision of HAART because of asymptomatic hyperlactatemia detected on study monitoring tests.

There was an average of 4.2 consecutive lactate measurements taken per patient during the 18-month observation period. The mean of consecutive lactate measurements for each individual was calculated. Of the 344 patients who never had a lactate level > 5 mmol/l, 39.8% had a mean lactate concentration between 1.5 and 2.5 mmol/l, 4.4% between 2.5–3.5 mmol/l and none between 3.5 and 5 mmol/l during the study period. However, 65.0% had a lactate concentration above 1.5 mmol/l, 18.3% above 2.5 mmol/l and 5.7% above 3.5 mmol/l on at least one occasion.

Mean lactate concentrations on current therapy were compared between various HAART regimens, stratified by drugs and drug classes that are used in mutually exclusive groups (see Table 2). In an analysis of combined groups, all patients treated with stavudine-containing HAART (with either a PI or a NNRTI) had a higher mean lactate concentration (n = 140; 1.65 mmol/l) compared with those on zidovudine-containing HAART (n = 101; 1.45 mmol/l) and those who were antiretroviral naive (n = 73; 1.34 mmol/l) (P < 0.05, ANOVA). There was no significant difference between zidovudine-treated and treatment-naive patients. Mean lactate concentrations associated with use of lamivudine versus didanosine and PI versus NNRTI versus abacavir (matched for concurrent NRTI) were not significantly different. Similarly there were no significant differences between those on different individual PIs or individual NNRTIs (data not shown).

Table 2
Table 2
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The longitudinal profile of lactate levels was analysed and plotted using the non-linear mixed effects growth model described earlier. Figure 1 shows that population average curves of lactate values rise from time of starting a HAART regimen. Patients were stratified into stavudine- or zidovudine-treated groups and data were included only for patients who did not change their treatment regimen. There was no significant difference in the average lactate values at the commencement of HAART (P = 0.67; combined estimate 0.74 mmol/L, SE = 0.24 mmol/l). However, there was a significant difference between the estimated long-term population average lactate concentrations (1.63 mmol/l in stavudine users, 1.40 mmol/l in zidovudine users: difference 0.23 mmol/l; P < 0.01). Individual averages varied about these population averages with standard deviations of 0.47 mmol/l for those using stavudine and 0.44 mmol/l for zidovudine.

Fig. 1
Fig. 1
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In view of the time taken for equilibration of lactate concentration after starting HAART, a multiple linear mixed model with individual specific coefficients was used to identify the predictors of venous lactate concentration with the data values restricted to only those obtained after at least 9 months of therapy. This negated possible effects of rising unstable levels of lactate in the early months of HAART. Multiple potentially predictive immunological and viral factors were examined in the model. Treatment with stavudine was associated with an estimated 0.36 mmol/l higher lactate concentration compared with zidovudine (P = 0.003), consistent with the finding from the growth model. However, no other variables were found to be significantly associated with chronic hyperlactatemia, including use of PI or NNRTI, age, sex, AIDS, duration of AIDS and HIV infection, number of past opportunistic infections, nadir CD4 cell count, peak plasma HIV RNA concentration, hepatitis B or hepatitis C coinfection, mean corpuscular volume and serum alanine aminotransferase. Adjustment for duration of total NRTI exposure or duration of past zidovudine use in stavudine users did not abrogate the results of the analysis, indicating that the increased risk associated with stavudine use was not confounded by the longer history of NRTI exposure in a proportion of stavudine users.

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Under normal conditions in aerobic tissues, the pyruvate generated by glycolysis is largely metabolised oxidatively in mitochondria. Lactate is the end-product of cytoplasmic glucose metabolism and lactate production is favored in anaerobic conditions. At rest, lactate concentration in venous blood reflects the equilibrium maintained between the rate of lactate production in several metabolically active tissues (in turn dependent on mitochondrial function and cellular oxygen levels) and the rate of lactate utilization by liver and renal cortex [17]. Lactate concentration is normally maintained within a narrow physiological range, with constant (basal) turnover estimated at 1 mEq/min (1 mmol/min). However, under various conditions of lactate excess, hepatic and renal clearance of lactate may be augmented and other organs that are normally lactate producers, such as skeletal muscle, can become important lactate consumers. Hence large (up to 100-fold) acute elevations in lactate after vigorous exercise are rapidly re-equilibrated, indicating the efficiency of lactate regulation, which is thought to be part of a generalized homeostatic system regulating organic acids via systemic pH [17].

It is possible that continuous and chronic excess of lactate could lead to a progressive increase in the ‘set-point’ of homeostatic control, as in the case of other tightly regulated biological molecules. Though the majority of patients in this study had lactate levels above the reference range at some time during the observation period, average levels did not stay at 3.5–5 mmol/l in any patient. Chronic mild hyperlactatemia with lactate concentrations of 1.5–3.5 mmol/l, maintained over many months, was the most common pattern of hyperlactatemia observed. The longitudinal data confirm that lactate concentrations do rise overall from the pretreatment baseline but are largely maintained at only mildly elevated levels in the long term. Presumably, homeostatic mechanisms are preserved enough to compensate, at least partially, for lactate excess in most patients. The primary cause(s) of this net rise in lactate – increased production and/or reduced clearance – is not known. A study of exercise physiology has shown that skeletal muscle is probably not a major source of excess lactate production in NRTI-treated HIV-infected patients, as their oxidative phosphorylation, lactate/pyruvate production and lactate clearance following exercise was not significantly different from matched controls [18].

In contrast to the common form of mild stable hyperlactatemia, severe lactic acidosis appears to indicate an extreme, decompensated metabolic state in which homeostasis is lost completely. Notably, NRTI-induced severe lactic acidosis is almost always accompanied by massive hepatic steatosis and frequently by hepatic failure [1–5]. The liver has limited lactate clearance capacity in these circumstances and hence becomes a net lactate producer. The extent of mitochondrial toxicity in hepatocytes may be the key determinant of risk of decompensation into severe lactic acidosis in NRTI-treated patients [19].

The predominant risk factor for developing chronic hyperlactatemia was the use of stavudine compared with zidovudine; this was found in three separate analyses and after adjustment for the potential confounding effect of duration of past and total NRTI exposure. Moreover, the change from stavudine to zidovudine in five patients with moderate hyperlactatemia may make our estimates of the differences between the two drugs conservative. Differences between zidovudine and stavudine are most easily detected in observational cohort data, as they are never used together. The independent contribution of concurrent agents in HAART may be difficult to determine. However, we found no significant difference in risk of chronic hyperlactatemia between other largely ‘mutually exclusive’ or competing antiretroviral drugs, namely lamivudine versus didanosine, PI versus NNRTI versus abacavir, individual PI and individual NNRTI. This suggests that these agents have differences that are too small for our analyses to detect, have no contribution to hyperlactatemia or all have exactly equivalent effects. It is possible that we did not have the power to detect the contribution of agents used by only a small number of patients, such as didanosine, abacavir and efavirenz.

The risk profile of hyperlactatemia mirrors that of some features of the ‘lipodystrophy syndrome’ in our cohort. The possible mitochondrial basis of lipodystrophy is, in part, predicated on the observation that use of NRTI is a sufficient condition, and an independent risk factor, for the development of progressive subcutaneous fat wasting, ‘buffalo humps', breast enlargement and focal lipomatoses in HIV-infected patients [14,20–22]. In our previous analysis of the predictors of progressive subcutaneous wasting in the Western Australian HIV Cohort, longer duration of NRTI therapy conferred a significantly greater risk of developing both clinically apparent fat wasting and lower subcutaneous limb fat measured by dual energy X-ray absorptiometry (DEXA). Within the NRTIs, stavudine was consistently associated with a greater risk of fat wasting compared with zidovudine [14]. Though stavudine is also the predominant risk factor for chronic hyperlactatemia, a causal relationship between chronic hyperlactatemia (as a correlate of mitochondrial toxicity) and lipodystrophy is not proven by these findings. It is possible that lipodystrophy and hyperlactatemia are both associated with stavudine but are pathogenically completely distinct or reflect different tissue-specific effects of stavudine and other NRTIs. Our previous study also suggested that fat wasting may be related to an interaction between PI and NRTI drugs, either by distinct but additive mechanisms or by PI-mediated exacerbation of a slower (mitochondrial) NRTI toxicity [14]. The lack of any detectable influence of PI on lactate concentrations argues against the latter possibility.

It is unlikely that the population distribution of lactate values is skewed to a higher range only because more measurements were taken in those with very high lactate levels. All patients who ever experienced a lactate level > 5 mmol/l were highly symptomatic and had lactate measures taken outside of the routine study protocol. These patients’ lactate values were removed from all subsequent analyses, leaving predominantly asymptomatic patients who had routine lactate measurements only. In any case, the multiple measurements taken in individuals were appropriately taken into account in the analyses either via averaging or through the longitudinal random effects (mixed) models.

The subsequent stable course of chronic hyperlactatemia, on average , is unlikely to be a result of revision of therapy in those with rising lactate concentrations, as asymptomatic hyperlactatemia alone did not cause therapy revision in any patient. However, the incidence of fulminant lactic acidosis/hepatic steatosis induced by NRTI may be underestimated in our cohort as five patients with moderate symptomatic hyperlactatemia had their (stavudine) therapy changed. It is possible that these patients would have progressed to severe fulminant lactic acidosis/hepatic steatosis if therapy were not revised. Of note, a preceding gradual rise in plasma lactate levels or in anion gap while asymptomatic was not detected in the two patients who had severe NRTI-induced lactic acidosis/hepatic steatosis. The data suggest that chronic hyperlactatemia found by routine testing in asymptomatic patients at 1–3 monthly intervals has poor sensitivity for, and given the rarity of severe lactic acidosis/hepatic steatosis, very poor positive predictive value for identifying cases of future symptomatic lactic acidosis/hepatic steatosis.

This longitudinal study shows that acute, severe NRTI-induced lactic acidosis/hepatic steatosis is a rare event in a centre where there is a high degree of awareness of this condition. A venous lactate concentration that is > 5 mmol/l indicates a state of widespread cellular energy deficit and metabolic decompensation. Uncommonly, patients may present with less severe symptoms, hepatic steatosis and only mild to moderate hyperlactatemia (2.8–4.1 mmol/l in our study) and tolerate a revision, rather than cessation, of NRTI. It is not certain if this represents an earlier phase in the natural history of severe lactic acidosis in some patients [7]. However, the fulminant form may still occur very precipitously, so diagnosis ultimately relies on having a high index of suspicion about suggestive symptoms in any patient taking a NRTI. In contrast, the incidental finding of mild to moderate hyperlactatemia without symptoms in patients taking HAART does not necessarily portend a progression to severe decompensated lactic acidosis. Based on the 516 patient-years of observation in this study, asymptomatic hyperlactatemia is stable (maintained at an average of 1.5–3.5 mmol/l) in the vast majority of patients without revision of therapy.

The mechanism by which chronic hyperlactatemia occurs in patients on HAART is not known but may be a correlate of tissue-specific mitochondrial toxicities of NRTI. Further studies to elucidate both the tissue source(s) of plasma lactate in NRTI-treated patients and the lactate clearance mechanisms may help to unravel the biological significance of chronic hyperlactatemia in this setting.

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We are grateful to Associate Professor Martyn French for helpful comments on the manuscript, John Blennerhasset for supervision of lactate assays and all the staff and patients of the Department of Clinical Immunology, Royal Perth Hospital who participated in this study.

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Nephrology Dialysis Transplantation, 22(2): 649-651.
HIV Medicine
Viral efficacy maintained and safety parameters improved with a reduced dose of stavudine: a pilot study
Ait-Mohand, H; Bonmarchand, M; Guiguet, M; Slama, L; Marguet, F; Behin, A; Amellal, B; Bennai, Y; Peytavin, G; Calvez, V; Pialoux, G; Murphy, R; Katlama, C
HIV Medicine, 9(9): 738-746.
Revista Clinica Espanola
Report of three cases of hyperlactacidemiae/lactic acidosis after treatment of hepatitis C with pegylated interferon and ribavirin in HIV coinfected patients
Ramirez, MLM; Zapata, MR
Revista Clinica Espanola, 202(): 543-545.

Progress in Cardiovascular Diseases
Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy
Lewis, W
Progress in Cardiovascular Diseases, 45(4): 305-318.
Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine
Gerstoft, J; Kirk, O; Obel, N; Pedersen, C; Mathiesen, L; Nielsen, H; Katzenstein, TL; Lundgren, JD
AIDS, 17(): 2045-2052.
Canadian Medical Association Journal
Adverse effects of antiretroviral therapy for HIV infection
Montessori, V; Press, N; Harris, M; Akagi, L; Montaner, JSG
Canadian Medical Association Journal, 170(2): 229-238.

Cardiomyopathy, nucleoside reverse transcriptase inhibitors and mitochondria are linked through AIDS and its therapy
Lewis, W
Mitochondrion, 4(): 141-152.
Current HIV Research
Oral glucose loading for detection of mitochondrial toxicity during HAART in HIV-infected patients
ter Hofstede, HJM; Borm, GF; Koopmans, PP
Current HIV Research, 5(4): 389-393.

Scandinavian Journal of Infectious Diseases
Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity
Maagaard, A; Kvale, D
Scandinavian Journal of Infectious Diseases, 41(): 808-817.
Food and Chemical Toxicology
Co-factors for abnormal lactate levels among persons with HIV disease at a tertiary HIV care setting in South India
Sundaram, M; Srinivas, CN; Shankar, EM; Deepak, M; Murugavel, KG; Balakrishnan, P; Solomon, S; Kumarasamy, N
Food and Chemical Toxicology, 46(8): 2823-2825.
Sexually Transmitted Infections
Mitochondrial toxicity and HIV therapy
White, AJ
Sexually Transmitted Infections, 77(3): 158-173.

Clinical Infectious Diseases
Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: A case-control study
Bonnet, F; Bonarek, M; Morlat, P; Mercie, P; Dupon, M; Gemain, MC; Malvy, D; Bernard, N; Pellegrin, JL; Beylot, J
Clinical Infectious Diseases, 36(): 1324-1328.

American Family Physician
Managing issues related to antiretroviral therapy
Lesho, EP; Gey, DC
American Family Physician, 68(4): 675-686.

HIV-associated neuromuscular weakness syndrome
Simpson, D; Estanislao, L; Evans, S; McArthur, J; Marcus, K; Truffa, M; Lucey, B; Naismith, R; Lonergan, JT; Clifford, D
AIDS, 18(): 1403-1412.
Clinical Infectious Diseases
A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa
Bolhaar, MG; Karstaedt, AS
Clinical Infectious Diseases, 45(2): 254-260.
Canadian Medical Association Journal
Symptomatic hyperlactatemia in an HIV-positive patient: a case report and discussion
Antoniou, T; Weisdorf, T; Gough, K
Canadian Medical Association Journal, 168(2): 195-198.

Sexually Transmitted Infections
Lactic acidosis in HIV infected patients: a systematic review of published cases
Arenas-Pinto, A; Grant, AD; Edwards, S; Weller, IVD
Sexually Transmitted Infections, 79(4): 340-344.

Netherlands Journal of Medicine
Antiretroviral therapy in HIV patients: aspects of metabolic complications and mitochondrial toxicity
ter Hofstede, HJM; Burger, DM; Koopmans, PP
Netherlands Journal of Medicine, 61(): 393-403.

Journal of Antimicrobial Chemotherapy
Starting highly active antiretroviral therapy: why, when and response to HAART
Mocroft, A; Lundgren, JD
Journal of Antimicrobial Chemotherapy, 54(1): 10-13.
Annales De Biologie Clinique
Hyperlactatemia and lipodystrophy in HIV-positive persons
Marceau, G; Jacomet, C; Ughetto, S; Roszyk, L; Dastugue, B; Laurichesse, H; Sapin, V
Annales De Biologie Clinique, 62(4): 471-478.

Skin lesions as another possible clinical manifestation of mitochondrial toxicity in an HIV-infected patient
Bachmeyer, C; Orlandini, V; Grimaldi, D; Bonnard, P; Moguelet, P; Aractingi, S
Dermatology, 214(2): 189-190.
Lactate levels in children with HIV/AIDS on highly active antiretroviral therapy
Desai, N; Mathur, M; Weedon, J
AIDS, 17(): 1565-1568.
Antimicrobial Agents and Chemotherapy
Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single- and three dual-NRTI treatments
Note, R; Maisonneuve, C; Letteron, P; Peytavin, G; Djouadi, F; Igoudjil, A; Guimont, MC; Biour, M; Pessayre, D; Fromenty, B
Antimicrobial Agents and Chemotherapy, 47(): 3384-3392.
Clinical Infectious Diseases
Nucleoside-related mitochondrial toxicity among HIV-Infected patients receiving antiretroviral therapy: Insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA
Montaner, JSG; Cote, HCF; Harris, M; Hogg, RS; Yip, B; Harrigan, PR; O'Shaughnessy, MV
Clinical Infectious Diseases, 38(): S73-S79.

Laboratory Investigation
Prospective evaluation of blood concentration of mitochondrial DNA as a marker of toxicity in 157 consecutively recruited untreated or HAART-treated HIV-positive patients
Chiappini, F; Teicher, E; Saffroy, R; Pham, P; Falissard, B; Barrier, A; Chevalier, S; Debuire, B; Vittecoq, D; Lemoine, A
Laboratory Investigation, 84(7): 908-914.

HIV Medicine
Limitation of exercise capacity in nucleoside-treated HIV-infected patients with hyperlactataemia
Duong, M; Dumas, JP; Buisson, M; Martha, B; Piroth, L; Grappin, M; Waldner, A; Chavanet, P; Portier, H
HIV Medicine, 8(2): 105-111.

New England Journal of Medicine
Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients
Cote, HCF; Brumme, ZL; Craib, KJP; Alexander, CS; Wynhoven, B; Ting, LL; Wong, H; Harris, M; Harrigan, PR; O'Shaughnessy, MV; Montaner, JSG
New England Journal of Medicine, 346(): 811-820.

Drug Safety
Protease inhibitor-induced diabetic complications - Incidence, management and prevention
Lien, LF; Feinglos, MN
Drug Safety, 28(3): 209-226.

Antiviral Therapy
Asymptomatic hyperlactataemia: predictive value, natural history and correlates
McComsey, GA; Yau, L
Antiviral Therapy, 9(2): 205-212.

Current Pharmaceutical Design
Hepatotoxicity of antiretroviral drugs
Abrescia, N; D'Abbraccio, M; Figoni, M; Busto, A; Maddaloni, A; De Marco, M
Current Pharmaceutical Design, 11(): 3697-3710.

Clinical Endocrinology
Thyroid function in human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): a longitudinal study
Madeddu, G; Spanu, A; Chessa, F; Calia, GM; Lovigu, C; Solinas, P; Mannazzu, M; Falchi, A; Mura, MS; Madeddu, G
Clinical Endocrinology, 64(4): 375-383.
Clinical Infectious Diseases
Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients
McGovern, BH; Ditelberg, JS; Taylor, LE; Gandhi, RT; Christopoulos, KA; Chapman, S; Schwartzapfel, B; Rindler, E; Fiorino, AM; Zaman, MT; Sax, PE; Graeme-Cook, F; Hibberd, PL
Clinical Infectious Diseases, 43(3): 365-372.

American Journal of Physiology-Heart and Circulatory Physiology
Defective mitochondrial DNA replication and NRTIs: pathophysiological implications in AIDS cardiomyopathy
Lewis, W
American Journal of Physiology-Heart and Circulatory Physiology, 284(1): H1-H9.
Antiviral Therapy
Hyperlactataemia in HIV-infected patients: the role of NRTI-treatment
Vrouenraets, SME; Treskes, M; Regez, RM; Troost, N; Smulders, YM; Weigel, HM; Frissen, PHJ; Brinkman, K
Antiviral Therapy, 7(4): 239-244.

American Journal of Gastroenterology
Management and treatment of hepatitis C virus infection in HIV-infected adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office
Burgess, J; Davey, V; Raab, C; Deyton, LR; Wright, TL; Ho, SB; Garcia-Tsao, G; Dominitz, J; Tien, PC; Lampiris, H; Jensen, P; Currie, S
American Journal of Gastroenterology, 100(): 2338-2354.
Antiviral Therapy
Possible ways nucleoside analogues can affect mitochondrial DNA content and gene expression during HIV therapy
Cote, HCF
Antiviral Therapy, 10(): M3-M11.

Expert Opinion on Drug Safety
Mitochondrial disease in the offspring as a result of antiretroviral therapy
Venhoff, N; Walker, UA
Expert Opinion on Drug Safety, 5(3): 373-381.
AIDS Research and Human Retroviruses
Mitochondrial Oxidative Phosphorylation Protein Levels in Peripheral Blood Mononuclear Cells Correlate with Levels in Subcutaneous Adipose Tissue within Samples Differing by HIV and Lipoatrophy Status
Shikuma, CM; Gerschenson, M; Chow, D; Libutti, DE; Willis, JH; Murray, J; Capaldi, RA; Marusich, M
AIDS Research and Human Retroviruses, 24(): 1255-1262.
Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals
Noguera, A; Fortuny, C; Munoz-Almagro, C; Sanchez, E; Vilaseca, MA; Artuch, R; Pou, J; Jimenez, R
Pediatrics, 114(5): E598-E603.
Clinical Chemistry and Laboratory Medicine
The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy
Dube, MP; Kitch, DW; Parker, RA; Alston-Smith, BL; Mulligan, K
Clinical Chemistry and Laboratory Medicine, 43(9): 947-952.
Medical Clinics of North America
Metabolic acidosis: Differentiating the causes in the poisoned patient
Judge, BS
Medical Clinics of North America, 89(6): 1107-+.
Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy
Arenas-Pinto, A
AIDS, 21(): 2455-2464.

Clinical Infectious Diseases
Lactacidemia in asymptomatic HIV-infected subjects receiving nucleoside reverse-transcriptase inhibitors
Boffito, M; Marietti, G; Audagnotto, S; Raiter, R; Di Perri, G
Clinical Infectious Diseases, 34(4): 558-559.

Jaids-Journal of Acquired Immune Deficiency Syndromes
Random venous lactate levels among HIV-positive patients on antiretroviral therapy
Harris, M; Chan, KJ; Tesiorowski, AA; Hogg, RS; Rosenberg, FM; Yan, CC; Montaner, JSG
Jaids-Journal of Acquired Immune Deficiency Syndromes, 31(4): 448-450.

Progress in Cardiovascular Diseases
HIV infection and lipodystrophy
Kotler, DP
Progress in Cardiovascular Diseases, 45(4): 269-284.
Clinical Infectious Diseases
The relationship between nucleoside analogue treatment duration, insulin resistance, and fasting arterialized lactate level in patients with HIV infection
Lo, JC; Kazemi, MR; Hsue, PY; Martin, JN; Deeks, SG; Schambelan, M; Mulligan, K
Clinical Infectious Diseases, 41(9): 1335-1340.

Samj South African Medical Journal
Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy
Eshun-Wilson, I; Soentjens, P; Zeier, M; Taljaard, J
Samj South African Medical Journal, 95(): 929-930.

Clinical Infectious Diseases
Metabolic acidosis in HIV-infected patients
Bonnet, F; Bonarek, M; Abrij, A; Beylot, J; Morlat, P
Clinical Infectious Diseases, 34(9): 1289-1290.

Clinical Infectious Diseases
A cautionary tale: Fatal lactic acidosis complicating nucleoside analogue and metformin therapy
Worth, L; Elliott, J; Anderson, J; Sasadeusz, J; Street, A; Lewin, S
Clinical Infectious Diseases, 37(2): 315-316.

Hyperlactataemia during antiretroviral therapy: Incidences, clinical data and treatment
Gerard, Y; Viget, N; Yazdanpanah, Y; Ajana, F; de la Tribonniere, X; Bocket, L; Deuffic-Burban, S; Dos Santos, A; Ballester, L; Mouton, Y
Therapie, 58(2): 153-158.

International Journal of Infectious Diseases
Consecutive blood lactate assessment in HIV-infected children: correlation with therapy and clinical characteristics
Rosso, R; Ferrazin, A; Di Biagio, A; Bassetti, M; Bassetti, D
International Journal of Infectious Diseases, 9(3): 173-175.
Antiviral Therapy
K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavuldine
Roge, BT; Katzenstein, TL; Obel, N; Nielsen, H; Kirk, O; Pedersen, C; Mathiesen, L; Lundgren, J; Gerstoft, J
Antiviral Therapy, 8(2): 173-182.

Nature Clinical Practice Endocrinology & Metabolism
Therapy Insight: body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy
Falutz, J
Nature Clinical Practice Endocrinology & Metabolism, 3(9): 651-661.
Jaids-Journal of Acquired Immune Deficiency Syndromes
Mitochondrial toxicity in the era of HAART: Evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy
Montaner, JSG; Cote, HCF; Harris, M; Hogg, RS; Yip, B; Chan, JW; Harrigan, PR; O'Shaughnessy, MV
Jaids-Journal of Acquired Immune Deficiency Syndromes, 34(): S85-S90.

HIV Clinical Trials
First-line therapy and mitochondrial damage: Different nucleosides, different findings
Blanco, F; Garcia-Benayas, T; de la Cruz, JJ; Gonzalez-Lahoz, J; Soriano, V
HIV Clinical Trials, 4(1): 11-19.

HIV Medicine
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005)
Gazzard, B
HIV Medicine, 6(): 1-61.

Clinical Infectious Diseases
Risk factors for and outcome of hyperlactatemia in HIV-infected persons: Is there a need for routine lactate monitoring?
Imhof, A; Ledergerber, B; Gunthard, HF; Haupts, S; Weber, R
Clinical Infectious Diseases, 41(5): 721-728.

HIV Clinical Trials
Mild to moderate symptoms do not correlate with lactate levels in HIV-positive patients on nucleoside reverse transcriptase inhibitors
Tan, D; Walmsley, S; Shen, S; Raboud, J
HIV Clinical Trials, 7(3): 107-115.

International Journal of Infectious Diseases
Risk factors for mortality in symptomatic hyperlactatemia among HIV-infected patients receiving antiretroviral therapy in a resource-limited setting
Manosuthi, W; Prasithsirikul, W; Chumpathat, N; Suntisuktappon, B; Athichathanabadi, C; Chimsuntorn, S; Sungkanuparph, S
International Journal of Infectious Diseases, 12(6): 582-586.
Journal of Human Virology
Chronic stavudine exposure induces hepatic mitochondrial toxicity in adult Erythrocebus patas monkeys
Gerschenson, M; Nguyen, VT; St Claire, MC; Harbaugh, SW; Harbaugh, JW; Proia, LA; Poirier, MC
Journal of Human Virology, 4(6): 335-342.
Jaids-Journal of Acquired Immune Deficiency Syndromes
Mitochondrial damage associated with long-term antiretroviral treatment: Associated alteration or causal disorder?
Vittecoq, D; Jardel, C; Barthelemy, C; Escaut, L; Cheminot, N; Chapin, S; Sternberg, D; Maisonobe, T; Lombes, A
Jaids-Journal of Acquired Immune Deficiency Syndromes, 31(3): 299-308.

AIDS Patient Care and Stds
Fatal lactic acidosis associated with antiretroviral therapy
Sharma, RS; Smina, M; Manthous, CA
AIDS Patient Care and Stds, 16(): 515-517.

Clinical Infectious Diseases
Suitable monitoring approaches to antiretroviral therapy in resource-poor settings: Setting the research agenda
Kent, DM; McGrath, D; Ioannidis, JPA; Bennish, ML
Clinical Infectious Diseases, 37(): S13-S24.

Antimicrobial Agents and Chemotherapy
Hyperlactatemia and human immunodeficiency virus infection: Lessons from the era of antiretroviral monotherapy
Chariot, P; Bourokba, N; Monnet, I; Gherardi, R
Antimicrobial Agents and Chemotherapy, 46(): 3683.
Jaids-Journal of Acquired Immune Deficiency Syndromes
Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: Recommendations of an International AIDS Society-USA panel
Schambelan, M; Benson, CA; Carr, A; Currier, JS; Dube, MP; Gerber, JG; Grinspoon, SK; Grunfeld, C; Kotler, DP; Mulligan, K; Powderly, WG; Saag, MS
Jaids-Journal of Acquired Immune Deficiency Syndromes, 31(3): 257-275.

HIV Clinical Trials
Update on HIV lipodystrophy
Kravcik, S
HIV Clinical Trials, 5(3): 152-167.

Clinics in Laboratory Medicine
Differentiating the causes of metabolic acidosis in the poisoned patient
Judge, BS
Clinics in Laboratory Medicine, 26(1): 31-+.
Right ventricular volume and mass determined by one magnetic resonance imaging in HIV patients with possible right ventricular dysfunction
Kjaer, A; Lebech, AM; Gerstoft, J; Hesse, B; Petersen, CL
Angiology, 57(3): 341-346.

Journal of Medical Virology
Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons
Boulassel, MR; Morales, R; Murphy, T; Lalonde, RG; Klein, MB
Journal of Medical Virology, 78(9): 1158-1163.
HIV Medicine
Kinetics of lactate metabolism after submaximal ergometric exercise in HIV-infected patients
Bauer, AM; Sternfeld, T; Horster, S; Schunk, M; Goebel, FD; Bogner, JR
HIV Medicine, 5(5): 371-376.

Journal of Antimicrobial Chemotherapy
[C-13]methionine breath test: a novel method to detect antiretroviral drug-related mitochondrial toxicity
Milazzo, L; Piazza, M; Sangaletti, O; Gatti, N; Cappelletti, A; Adorni, F; Antinori, S; Galli, M; Moroni, M; Riva, A
Journal of Antimicrobial Chemotherapy, 55(1): 84-89.
AIDS Patient Care and Stds
Hepatic steatosis and HIV infection
Ristig, M; Drechsler, H; Powderly, WG
AIDS Patient Care and Stds, 19(6): 356-365.

Antiviral Therapy
Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors
Venhoff, N; Setzer, B; MelkaoUi, K; Walker, UA
Antiviral Therapy, 12(7): 1075-1085.

HIV Medicine
Risk factors for and clinical characteristics of severe hyperlactataemia in patients receiving antiretroviral therapy: a case-control study
Osler, M; Stead, D; Rebe, K; Meintjes, G; Boulle, A
HIV Medicine, 11(2): 121-129.
Critical Care
Continuing HIV therapy in the ICU
Soni, N; Pozniak, A
Critical Care, 5(5): 247-248.

Seminars in Liver Disease
Hepatotoxicity of nucleoside reverse transcriptase inhibitors
Montessori, V; Harris, M; Montaner, JSG
Seminars in Liver Disease, 23(2): 167-171.

Clinical Chemistry
Frequency, risk factors, and outcome of hyperlactatemia in HIV-positive persons: Implications for the management of treated patients
Marceau, G; Sapin, V; Jacomet, C; Ughetto, S; Cormerais, L; Regagnon, C; Dastugue, B; Peigue-Lafeuille, H; Beytout, J; Laurichesse, H
Clinical Chemistry, 49(7): 1154-1162.

Frequency, risk factors and features of hyperlactatemia in a large number of patients undergoing antiretroviral therapy
Manfredi, R; Motta, R; Patrono, D; Calza, L; Chiodo, F; Boni, P
AIDS, 17(): 2131-2133.

AIDS Research and Human Retroviruses
Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy
Miro, O; Lopez, S; Martinez, E; Rodriguez-Santiago, B; Blanco, JL; Milinkovic, A; Miro, JM; Nunes, V; Casademont, J; Gatell, JM; Cardellach, F
AIDS Research and Human Retroviruses, 19(): 1027-1032.

Journal of Clinical Virology
Serum L-lactate and pyruvate in HIV-infected patients with and without presumed NRTI-related adverse events compared to healthy volunteers
ter Hofstede, HJM; Willems, HL; Koopmans, PP
Journal of Clinical Virology, 29(1): 44-50.
Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis
Lonergan, JT; Barber, RE; Mathews, WC
AIDS, 17(): 2495-2499.

HIV Medicine
British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008
Gazzard, BG
HIV Medicine, 9(8): 563-608.
Journal of Acquired Immune Deficiency Syndromes
Long-term exposure to lifelong therapies
Powderly, WG
Journal of Acquired Immune Deficiency Syndromes, 29(): S28-S40.

Antiviral Therapy
Complications associated with NRTI therapy: update on clinical features, and possible pathogenic mechanisms
Nolan, D; Mallal, S
Antiviral Therapy, 9(6): 849-863.

Metabolic Syndrome and Related Disorders
Human Immunodeficiency Virus and Highly Active Antiretroviral Therapy-Associated Metabolic Disorders and Risk Factors for Cardiovascular Disease
Anuurad, E; Semrad, A; Berglund, L
Metabolic Syndrome and Related Disorders, 7(5): 401-409.
Clinical Infectious Diseases
Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: Report of 12 cases and review of the literature
Falco, V; Rodriguez, D; Ribera, E; Martinez, E; Miro, JM; Domingo, P; Diazaraque, R; Arribas, JR; Gonzalez-Garcia, JJ; Montero, F; Sanchez, L; Pahissa, A
Clinical Infectious Diseases, 34(6): 838-846.

Current Drug Metabolism
Combinations against combinations: Associations of anti-HIV 1 reverse transcriptase drugs challenged by constellations of drug resistance mutations
Maga, G; Spadari, S
Current Drug Metabolism, 3(1): 73-95.

Archives of Medical Research
Metabolic acidosis and hepatic steatosis in two HIV-infected patients on Stavudine (d4T) treatment
Cornejo-Juarez, P; Sierra-Madero, J; Volkow-Fernandez, P
Archives of Medical Research, 34(1): 64-69.
PII S0188-4409(02)00454-X
Scandinavian Journal of Infectious Diseases
Fatal nucleoside-associated lactic acidosis in an obese woman with human immunodeficiency virus type 1 infection on a very low-calorie diet
Sipsas, NV; Kosmas, N; Kontos, A; Eftychiadis, C; Agapitos, E; Kordossis, T
Scandinavian Journal of Infectious Diseases, 35(4): 291-293.
Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine
Walker, UA; Bauerle, J; Laguno, M; Murillas, J; Mauss, S; Schmutz, U; Setzer, B; Miquel, R; Gatell, JM; Mallolas, J
Hepatology, 39(2): 311-317.
Metabolic complications of HIV therapy in children
McComsey, GA; Leonard, E
AIDS, 18(): 1753-1768.

Antiviral Therapy
Mitochondrial effects of a 24-week course of pegylated-interferon plus ribavirin in asymptomatic HCV/HIV co-infected patients on long-term treatment with didanosine, stavudine or both
Ballesteros, AL; Miro, O; Lopez, S; Fuster, D; Videla, S; Martinez, E; Garrabou, R; Salas, A; Cote, H; Tor, J; Rey-Joly, C; Planas, R; Clotet, B; Tural, C
Antiviral Therapy, 9(6): 969-977.

Antiviral Therapy
Muscle and liver lactate metabolism in HAART-treated and naive HIV-infected patients: the MITOVIR study
Ghosn, J; Guiguet, M; Jardel, C; Benyaou, R; Zeller, V; Simon, A; Valantin, MA; Amellal, B; Assoumo, L; Hogrel, JY; Costogliola, D; Kotlama, C; Lombes, A
Antiviral Therapy, 10(4): 543-550.

Expert Opinion on Pharmacotherapy
Lactic acidosis related to nucleoside therapy in HIV-infected patients
Falco, V; Crespo, M; Ribera, E
Expert Opinion on Pharmacotherapy, 4(8): 1321-1329.

Clinics in Chest Medicine
Critical issues in nephrology
Peixoto, AJ
Clinics in Chest Medicine, 24(4): 561-+.
Canadian Medical Association Journal
HIV drug stavudine (Zerit, d4T) and symptoms mimicking Guillain-Barre syndrome
Wooltorton, E
Canadian Medical Association Journal, 166(8): 1067.

Toxicology Letters
Pharmacodynamic activity of drugs and ecotoxicology - can the two be connected?
Seiler, JP
Toxicology Letters, 131(): 105-115.
PII S0378-4274(02)00045-0
Revista Clinica Espanola
Symptomatic hyperlactatemia associated with the use of antiretroviral agents
Sierra, JO; Garcia, RR; Lopez-Medrano, F; de Lucia, AM; Vela, MI
Revista Clinica Espanola, 202(): 540-542.

Severe liver mitochondriopathy with normal liver histology and normal lactate levels in patients receiving nucleoside analogues
Batisse, D; Van Huyen, JPD; Piketty, C; Canali, GG; Karmochkine, M; Weiss, L; Bruneval, P; Kazatchkine, MD
AIDS, 16(): 2370-2371.

Clinical Infectious Diseases
Hyperlactatemia and antiretroviral therapy: The Swiss HIV Cohort Study
Boubaker, K; Flepp, M; Sudre, P; Furrer, H; Haensel, A; Hirschel, B; Boggian, K; Chave, JP; Bernasconi, E; Egger, M; Opravil, M; Rickenbach, M; Francioli, P; Telenti, A
Clinical Infectious Diseases, 33(): 1931-1937.

Annals of Internal Medicine
Guidelines for using antiretroviral agents among HIV-infected adults and adolescents - The panel on clinical practices for treatment of HIV
Dybul, M; Fauci, AS; Bartlett, JG; Kaplan, JE; Pau, AK
Annals of Internal Medicine, 137(5): 381-433.

Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors
Walker, UA; Setzer, B; Venhoff, N
AIDS, 16(): 2165-2173.

Current Drug Targets
Emerging drug toxicities of highly active antiretroviral therapy for human immunodeficiency virus (HIV) infection
Heath, KV; Montaner, JSG; Bondy, G; Singer, J; O'Shaughnessy, MV; Hogg, RS
Current Drug Targets, 4(1): 13-22.

Scandinavian Journal of Infectious Diseases
Natural history of hyperlactataemia in human immunodeficiency virus-1-infected patients during highly active antiretroviral therapy
Huynh, TK; Luttichau, HR; Roge, BT; Gerstoft, J
Scandinavian Journal of Infectious Diseases, 35(1): 62-66.
Lancet Infectious Diseases
Hyperlactataemia syndromes associated with HIV therapy
Ogedegbe, AEO; Thomas, DL; Diehl, AM
Lancet Infectious Diseases, 3(6): 329-337.

Nature Reviews Drug Discovery
Toxicity of antiretroviral therapy and implications for drug development
Carr, A
Nature Reviews Drug Discovery, 2(8): 624-634.
Scandinavian Journal of Clinical & Laboratory Investigation
Preanalytical handling of samples for measurement of plasma lactate in HIV patients
Andersen, O; Haugaard, SB; Jorgensen, LT; Sorensen, S; Nielsen, JO; Madsbad, S; Iversen, J
Scandinavian Journal of Clinical & Laboratory Investigation, 63(6): 449-454.
Mitochondrial dysfunction in AIDS and its treatment
Gerschenson, M; Brinkman, K
Mitochondrion, 4(): 763-777.
Antiviral Therapy
Mechanisms of HIV and nucleoside reverse transcriptase inhibitor injury to mitochondria
Moyle, G
Antiviral Therapy, 10(): M47-M52.

Current Pharmaceutical Design
Understanding and avoiding antiretroviral adverse events
Shibuyama, S; Gevorkyan, A; Yoo, U; Tim, S; Dzhangiryan, K; Scott, JD
Current Pharmaceutical Design, 12(9): 1075-1090.

Expert Opinion on Investigational Drugs
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Expert Opinion on Investigational Drugs, 10(8): 1443-1456.

International Journal of Std & AIDS
Fatal lactic acidosis associated with highly active antiretroviral therapy in patients with advanced human immunodeficiency virus infection in Taiwan
Sheng, WH; Hsieh, SM; Lee, SC; Chen, MY; Wang, JT; Hung, CC; Chang, SC
International Journal of Std & AIDS, 15(4): 249-253.

Clinical Nutrition
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Clinical Nutrition, 24(1): 5-15.
Journal of Medical Virology
Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy
Haugaard, SB; Andersen, O; Pedersen, SB; Dela, F; Richelsen, B; Nielsen, JO; Madsbad, S; Iversen, J
Journal of Medical Virology, 77(1): 29-38.
Revue Neurologique
Mitochondrial cytopathies associated with HIV infection
Gerard, Y; Melliez, H; Mouton, Y; Yazdanpanah, Y
Revue Neurologique, 162(1): 62-70.

Clinical Infectious Diseases
Lipodystrophy in a cohort of human immunodeficiency virus-infected Asian patients: Prevalence, associated factors, and psychological impact
Paton, NI; Earnest, A; Ng, YM; Karim, F; Aboulhab, J
Clinical Infectious Diseases, 35(): 1244-1249.

Biomedicine & Pharmacotherapy
Could antioxidant supplementation reduce antiretroviral therapy-induced chronic stable hyperlactatemia?
Lopez, O; Bonnefont-Rousselot, D; Edeas, M; Emerit, J; Bricaire, F
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Antiretroviral nucleoside and nucleotide analogues and mitochondria
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AIDS, 17(5): 673-677.

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García-Benayas, T; Blanco, F; de la Cruz, JJ; Soriano, V; González-Lahoz, J
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AIDS, 15(6): 795-797.

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Pedersen, BK; Røge, BT; Calbet, JA; Møller, K; Ullum, H; Hendel, HW; Gerstoft, J
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Current Opinion in Infectious Diseases
Hyperlactatemia syndromes in people with HIV infection
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Current Opinion in Infectious Diseases, 15(1): 23-29.

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Current Opinion in Infectious Diseases
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Current Opinion in Infectious Diseases, 16(1): 5-10.

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Kalkut, G
Current Opinion in Oncology, 17(5): 479-484.

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Absence of Sustained Hyperlactatemia in HIV-Infected Patients With Risk Factors for Mitochondrial Toxicity
Basar, M; Kashuba, A; Kondo, P; Martinez, A; Giardini, J; Quinn, J; Littles, M; Wingfield, H; Koletar, SL; Adult AIDS Clinical Trials Group A5129 Team, ; Wohl, DA; Pilcher, CD; Evans, S; Revuelta, M; McComsey, G; Yang, Y; Zackin, R; Alston, B; Welch, S
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JAIDS Journal of Acquired Immune Deficiency Syndromes
Lack of Recurrence of Hyperlactatemia in HIV-Infected Patients Switched From Stavudine to Abacavir or Zidovudine
Lonergan, JT; McComsey, GA; Fisher, RL; Shalit, P; File, TM; Ward, DJ; Williams, VC; Hessenthaler, SM; Lindsey, L; Hernandez, JE; for the ESS40010 (TARHEEL) Study Team,
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JAIDS Journal of Acquired Immune Deficiency Syndromes
Factors Associated With Mitochondrial Dysfunction in Circulating Peripheral Blood Lymphocytes From HIV-Infected People
Polo, R; Martinez, S; Madrigal, P; Gonzalez-Muñoz, M
JAIDS Journal of Acquired Immune Deficiency Syndromes, 34(1): 32-36.

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Higher-Than-Expected Rates of Lactic Acidosis Among Highly Active Antiretroviral Therapy-Treated Women in Botswana: Preliminary Results from a Large Randomized Clinical Trial
Wester, CW; Okezie, OA; Thomas, AM; Bussmann, H; Moyo, S; Muzenda, T; Makhema, J; Widenfelt, Ev; Musonda, R; Novitsky, V; Gaolathe, T; Ndwapi, N; Essex, M; Kuritzkes, DR; deGruttola, V; Marlink, RG
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Genetic and Functional Mitochondrial Assessment of HIV-Infected Patients Developing HAART-Related Hyperlactatemia
Garrabou, G; Morén, C; Gallego-Escuredo, JM; Milinkovic, A; Villarroya, F; Negredo, E; Giralt, M; Vidal, F; Pedrol, E; Martínez, E; Cardellach, F; Gatell, JM; Miró, Ò
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The Pediatric Infectious Disease Journal
Metabolic complications of antiretroviral therapy in children
The Pediatric Infectious Disease Journal, 22(1): 77-84.

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The Pediatric Infectious Disease Journal
Antiretroviral Therapy-Related Hyperlactatemia: in Reply
Fortuny, C; Noguera, A
The Pediatric Infectious Disease Journal, 23(4): 375-376.

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The Pediatric Infectious Disease Journal
Fatal lactic acidosis and mimicking Guillain-Barré syndrome in an adolescent with human immunodeficiency virus infection
Rosso, R; Di Biagio, A; Ferrazin, A; Bassetti, M; Ciravegna, BW; Bassetti, D
The Pediatric Infectious Disease Journal, 22(7): 668-670.

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The Pediatric Infectious Disease Journal
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The Pediatric Infectious Disease Journal
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Back to Top | Article Outline

hyperlactatemia; lactic acidosis; hepatic steatosis; HAART; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; protease inhibitors; mitochondrial toxicity; lipodystrophy; subcutaneous fat wasting

© 2001 Lippincott Williams & Wilkins, Inc.


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