Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy
Lactic Acidosis International Study Group
Received 27 March, 2007
Revised 31 May, 2007
Accepted 15 June, 2007
Correspondence to Dr A. Arenas-Pinto, Centre for Sexual Health and HIV Research, University College London, The Mortimer Market Centre, London WC1E 6JB, UK. E-mail: AArenas-Pinto@gum.ucl.ac.uk
Background: Severe hyperlactataemia and lactic acidosis are rare serious complications of antiretroviral therapy (ART).
Methods: Lactic acidosis was defined as pH < 7.35, bicarbonate < 20 mmol/l and raised lactate; hyperlactataemia as two consecutive lactates > 5 mmol/l. The case–control study of 110 cases and 220 controls(two randomly selected from treated patients by centre and calendar year) from centres in 10 countries included 40 (36.4%) female cases and 40 female controls (18.2%) (P < 0.001). Median age was 42.4 years [interquartile range (IQR, 36.0–52.5] for cases and 40 (IQR, 35.0–47.1) for controls (P = 0.013). More cases were nonwhite (41.9%) than controls (31.2%) (P = 0.032). Cases had a shorter duration of exposure to dideoxynucleosides.
Results: After adjusting for age, gender and current CD4 cell count, hyperlactataemia/lactic acidosis remained associated with exposure to didanosine in every category of exposure duration but was most strongly associated with exposure < 12 months. In a separate multivariable model, apart from exposure to stavudine, didanosine, or even more strongly both, age above 40 years [odds ratio (OR), 2.6; 95% confidence interval (CI), 1.08–6.29], female gender (OR, 5.97; 95% CI, 1.92–18.5) and advanced immunosuppression were independent associations (CD4 cell count 200–349, 100–199 and < 100 cells/μl: OR, 3.89, 7.58 and 8.11, respectively).
Interpretation: Hyperlactataemia/lactic acidosis was associated with exposure to dideoxynucleosides, female gender, advanced immunosuppression and possibly ethnicity. This has important consequences for choice of ART in resource-limited settings. The association with shorter duration of exposure may support the hypothesis of susceptibility in a small proportion of patients.
Evidence has accumulated since the mid 1990s about the association between exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) and mitochondrial dysfunction. Several proposed NRTI-induced adverse drug reactions (ADR) have been attributed to mitochondrial toxicity, and lactic acidosis may be considered as the proof of the concept for the proposed association . Although uncommon, with reported incidence rates ranging between 1.3 and 10 episodes per 1000 person-years on antiretroviral therapy (ART), lactic acidosis is a life-threatening complication [2,3] with a case-fatality rate estimated at around 60% in HIV-infected individuals .
Hyperlactataemia and lactic acidosis have been attributed to almost all NRTI drugs currently in use. Combination ART has been the standard of care for more than a decade, but ART combinations are not randomly allocated; rather they follow biological rationale and historical trends, making it difficult to assess the effect of an individual drug on lactate metabolism and mitochondrial function in vivo. Nonetheless, almost all studies to date suggest that dideoxynucleosides, in particular stavudine, are associated with the development of severe lactic acidosis [3,5,6].
In the context of expanding access to ART, NRTI and particularly thymidine analogues (i.e. zidovudine and stavudine) are the cornerstone of first-line ART regimens originally recommended for resource-limited countries . More recent recommendations favour regimens based on abacavir or tenofovir over ones containing the thymidine analogues, on the basis of a lower risk of adverse events . However, the cost or availability of such alternatives makes this difficult to implement on a large scale. Consequently, it remains critically important to identify risk factors for NRTI-induced adverse events, quantify risk and produce evidence-based guidelines for their use. This multicentre, multinational case–control study sought to identify risk factors for confirmed severe hyperlactataemia and lactic acidosis in HIV-1-infected patients exposed to ART.
Participants and methods
For this retrospective case–control study, the main outcome was the first episode of lactic acidosis or severe hyperlactataemia for each case. All study participants were HIV-1-infected adults (older than 16 years) previously or currently taking ART. Lactic acidosis was defined as arterial blood pH < 7.35, blood bicarbonate < 20 mmol/l and blood lactate levels above the upper limit of the reference range in the relevant centre. Patients with hyperlactataemia were included if they had at least two consecutive readings of blood lactate > 5 mmol/l (450 mg/l) regardless of their acid–base status. The episode date for each case was the date when the case definition was met (i.e. the confirmatory reading > 5 mmol/l for hyperlactataemia or the date of the first low blood pH and bicarbonate for lactic acidosis). Clinical data were not included in the case definition. Symptoms associated with lactic acidosis and hyperlactataemia are mainly nonspecific and frequently seen in HIV-1-infected patients taking ART . In a retrospective study, it would have been difficult to assess their presence accurately. Hyperlactataemia and lactic acidosis were combined as a single outcome based on recommendations made by experts in the field  and also the biological plausibility of progression from hyperlactataemia to lactic acidosis. Cases diagnosed between 1997 and 2004 were included.
Two randomly selected controls were matched to their respective cases by centre and calendar year. Therefore, controls were patients receiving outpatient care or admitted to hospital during the same calendar year as the event in their respective case. The index date for controls was the date of the consultation or hospital admission closest to the diagnosis date of their respective case.
Information regarding past medical history, concomitant medical conditions and laboratory data was collected on a standardized proforma. ART exposure history, including duration of exposure to each drug, was recorded. Patients who stopped any NRTI within 4 weeks prior to the episode were considered as having current exposure to that drug. Laboratory values concerning acid–base balance and blood lactate level in cases were those at the time of confirmation of the diagnosis. Only 5 of the 19 participating centres performed blood lactate concentrations routinely for patients taking ART and, therefore, only a minority of controls had blood lactate results available at the time of their inclusion in the study. Laboratory and clinical data from controls were those closest to the index date. Chronic hepatitis B virus infection was defined as the presence of a positive surface antigen (HBsAg) result for longer than 6 months whereas chronic hepatitis C infection was defined as antibody positive for hepatitis C virus. For the analysis, peripheral neuropathy, pancreatitis, bone marrow suppression and myopathy were considered as ADRs attributable to mitochondrial dysfunction.
Based on previous data suggesting that stavudine is the strongest risk factor for hyperlactataemia/lactic acidosis , stavudine was taken as the main exposure for the sample size calculation. It was estimated from retrospective data that about 40% of the study population would be exposed to stavudine over the study period. In order to detect an increased risk of hyperlactataemia/lactic acidosis among individuals exposed to stavudine with an odds ratio (OR) of two or more, with 90% power and 5% significance, the required sample size was 135 cases plus 270 controls.
Statistical analysis was performed using STATA version 9.1 (StataCorp LP, College Station, Texas USA). Conditional logistic regression was used to identify risk factors associated with the study outcome, in order to take account of the matching of cases and controls. Significance testing was based on the likelihood ratio test approach. A regression model was built using the stepwise forward approach, including in the process those factors found significant (P < 0.05) in the univariate analysis. Data on ART exposure were analysed based on single NRTI exposure irrespective of other ART each patient was taking simultaneously, as well as the NRTI combinations most frequently taken.
The study involved the use of patients' records and direct contact between researchers and patients was not needed. However, ethical approval was obtained from all relevant ethics committees where required. In the UK, full approval was obtained from the Multicentre Research Ethics Committee of London. Written informed consent was obtained from participants when requested by the relevant ethics committee.
A total of 110 cases (49 with lactic acidosis) and 220 controls from 19 centres in 10 countries were included. Cases were significantly older than controls: median ages 42.4 years [interquartile range (IQR), 36.0–52.5] and 40 years (IQR, 35.0–47.1), respectively (P = 0.011). Table 1 shows the demographic characteristics of the study participants. Three pregnant women (one case) were included in the study. There was a higher proportion of nonwhite patients among cases (41.9%) than among controls (31.2%) (P = 0.032).
The cases (n = 110) had a significantly lower CD4 cell counts than controls (n = 212) at the time of the inclusion: median CD4 cell count 248 cells/μl [95% confidence interval (CI), 136.5–365] and 400 cells/μl (95% CI, 220–551.5), respectively; P < 0.001). There was no difference in the duration of the period from the first positive HIV-1 serology and inclusion between cases (n = 110) and controls (n = 216): 70.1 months (95% CI, 20.6–132.6) and 82.2 months (95% CI, 39.2–130.3), respectively (P = 0.175).
The median blood lactate among cases was 6.8 mol/l (IQR, 5.5–8.1) compared with 1.4 mmol/l (IQR, 1.1–1.9) among the 62/220 (28.2%) controls with available data. Four (6.5%) of the controls had lactate levels higher than 2.2 mmol/l, with a maximum of 3.4 mmol/l. All four were asymptomatic at the time of their inclusion in the study. Controls with available blood lactate results did not differ from controls without lactate results with respect to any of the explanatory variables assessed in the study (data not shown).
In the univariate analysis, cases were more likely than controls to have a concurrent ADR attributable to mitochondrial dysfunction (OR, 5.87; 95% CI, 3.14–10.98). The frequency of hepatitis B and hepatitis C infection was similar in cases and controls. At the time of study inclusion, 5 cases and 21 controls were not taking any NRTI; 73/105 (69.5%) cases were receiving stavudine and 64/105 (61%) were receiving didanosine at the time of the event compared with 79/199 (39.7%) and 55/199 (27.6%) controls, respectively (stavudine: OR, 3.63; 95% CI, 2.10–6.29; didanosine: OR, 6.08; 95% CI, 3.12–11.84). Controls (n = 199) were more likely to be receiving zidovudine or lamivudine (Fig. 1, Table 2).
Table 2 also shows the current exposure to the more common NRTI combinations. Cases were more likely to be taking stavudine/didanosine-based combinations, with or without other NRTI or tenofovir, than controls (OR, 25.31, 95% CI, 7.43–86.23). Similarly, cases were more likely to be receiving stavudine or didanosine alone or in combinations excluding each other than were controls (stavudine: OR, 3.85; 95% CI, 1.34–11.02; didanosine: OR, 6.5; 95% CI, 1.98–21.38). However, as shown in Table 3, the strength of the association with dideoxynucleosides was dependent on duration of current exposure. The OR for exposure to stavudine and didanosine between cases and controls was significantly higher when the current duration of treatment was under 12 months compared with longer than 24 months (Table 3). Furthermore, after adjusting by other variables (age, gender and current CD4 cell count), the trend of reduction in OR values for hyperlactataemia/lactic acidosis over time in those patients taking didanosine remained clear (OR, 9.26, 5.01 and 2.28 for patients exposed for < 12, 12–24 and > 24 months, respectively) whereas the trend with stavudine became less apparent (OR, 3.67, 6.23 and 5.28, respectively).
In a multivariable model adjusting for baseline CD4 cell count, hyperlactataemia/lactic acidosis case status remained significantly associated with age > 40 years (OR, 2.6; 95% CI, 1.08–6.29), female gender (OR, 5.97; 95% CI, 1.92–18.5), low current CD4 cell count and current exposure to stavudine, didanosine or the combination of these two drugs. The effect of a combination of stavudine and didanosine was associated with a higher risk than with either drug alone. The increased risk associated with both didanosine and stavudine appeared to be independent of the exposure to other NRTI or tenofovir (Table 4).
This is the largest study of risk factors for hyperlactataemia/lactic acidosis in patients taking ART performed to date, and the largest case series on hyperlactataemia/lactic acidosis. The sample size targeted was not quite achieved, mainly because strict case definitions were used and two centres were unable to produce data on time for the study. Current exposure to stavudine and didanosine were strongly associated with the development of hyperlactataemia/lactic acidosis. The association with stavudine is well known [3,9,11,12], but the association with didanosine has been less well documented. Table 5 summarizes a number of studies previously published on risk factors for hyperlactataemia or lactic acidosis. Many of these studies are small. The case definitions used in these studies are different and it is difficult to make direct comparisons between them. Only a few of the studies found an association between didanosine exposure and hyperlactataemia [13–15]. Furthermore, it has been suggested that the effect of stavudine exposure on the likelihood of developing hyperlactataemia/lactic acidosis is stronger when stavudine is used in combination with didanosine [14,16]. Our data strongly support this.
The risk of developing hyperlactataemia/lactic acidosis in our study was dependent on duration of exposure. The association between hyperlactataemia/lactic acidosis and dideoxynucleosides became less strong with increasing duration of exposure to these drugs in the univariate analysis. Furthermore, the effect persisted for didanosine even when adjusted for potential confounders. This finding has not previously been reported, and contrasts with in-vitro data . However, in-vivo compensatory mechanisms, which maintain mitochondrial function in the face of mitochondrial DNA depletion, may explain this . It also contrasts with studies suggesting that longer duration of stavudine exposure is associated with a moderate increase in the likelihood of abnormal lactate result , and that duration of NRTI exposure was the only factor associated with mitochondrial DNA depletion . These were both small studies with surrogate biochemical markers of mitochondrial dysfunction rather than clinical mitochondrial impairment. Two studies have suggested that longer exposure to both stavudine and didanosine may be associated with hyperlactataemia/lactic acidosis. In one of these, only 52 out of the 267 patients with hyperlactataemia had a confirmatory abnormal result and none of the five cases with a blood lactate level about 5 mmol/l had any confirmatory test . Carr et al.  have proposed that among patients with abnormal blood lactate (> 2.0 mmol/l), those with longer exposure to NRTI appeared to be at higher risk for peripheral lipoatrophy. These authors found that patients with hyperlactataemia (a single abnormal result) were exposed to stavudine or didanosine for longer than patients with normal lactate values. However, this was a case–control study in which cases were selected on the basis of having lipoatrophy.
Our results are consistent with studies suggesting that mitochondrial toxicity is related to individual susceptibility. Patients with borderline or subclinical mitochondrial impairment may be at higher risk of NRTI-induced clinical manifestations ; for example, an association between late onset Leber's hereditary optic neuropathy and NRTI exposure in HIV-1-infected patients has been suggested [24,25]. In addition, a single-centre cohort study on didanosine monotherapy showed that the incidence of pancreatitis reached a peak within the first 6 months on therapy and showed a sharp decline thereafter .
Furthermore, a study has shown that patients with mitochondrial haplogroup T (common in European populations) are at higher risk of peripheral neuropathy compared with patients with other haplogoups . The effect of haplogroup T was stronger among those randomized to receive stavudine/didanosine, but data on duration of NRTI exposure were not presented. Outside of studies linked to HIV, a small study on ototoxicity attributed to cisplatin showed that patients belonging to the rare European mitochondrial haplogroup J were overrepresented among those with impaired hearing .
It has been suggested that female patients are more likely to develop some ART-related ADR. In one observational study, men were almost 50% less likely than women to discontinue ART because of ADR . Women, particularly those from ethnic minorities living in developed countries, tend to access regular HIV medical care late in the course of their HIV disease compared with men [30–32]. Consequently, it is possible that more advanced immunosuppression may predispose treated female patients to certain toxicities. However, in our study, male and female cases were at very similar degrees of HIV-1 disease progression both at baseline (nadir CD4 cell count < 200 cell/μl was noted in 70% of males and 87% of females) and at the time of the event (CD4 cell count < 200 cells/μl seen in 47% of males and 40% of females).
The majority of our study population was white, including Europeans, Americans and Australians. Cases were significantly more likely to be nonwhite (i.e. black African, American or Caribbean, Asian or Hispanic) than controls. There was a degree of ethnic homogeneity at most participating centres. Because cases and controls were matched by centre, it is likely that there was unintentional matching by ethnic background. This would result in an underestimation of any association between ethnicity and hyperlactataemia/lactic acidosis. Most studies on hyperlactataemia and/or lactic acidosis have not included data on the ethnicity, but all were from centres with relatively homogeneous populations [3,13,14]. A recent cohort study showed that black Africans, and particularly black women, may be at much higher risk of developing severe hyperlactataemia (defined as blood lactate > 5 mmol/l) . There are no conclusive data on the incidence of hyperlactataemia/lactic acidosis in African settings, but preliminary data suggest that it may be more common in African countries than in well-resourced regions .
Interestingly, in this study most nonwhite participants and cases were female (61.2 and 58.3%, respectively). Nevertheless, the association between gender and hyperlactataemia/lactic acidosis was unchanged by adjustment for ethnicity. In addition, there was little evidence of an interaction between gender and ethnicity (P = 0.539).
Advanced HIV disease has been proposed as a risk factor for ART-associated events such as lipoatrophy and peripheral neuropathy [35,36]. Our study showed a strong association between low CD4 cell count at the time of the event and the study outcome. The univariate analysis showed that low nadir CD4 cell count was also associated with hyperlactataemia/lactic acidosis. Similarly, a small case–control study on lactic acidosis found an association with nadir CD4 cell count < 250 cell/μl, but not with CD4 cell count at the time of the event . A report from the Swiss Cohort Study showed that higher CD4 cell count may protect against hyperlactataemia (defined as blood lactate > 2.4 mmol/l) .
Cases were more likely than controls to have a concurrent ADR attributable to mitochondrial dysfunction in the univariate analysis (OR, 5.87; 95% CI, 3.14–10.98). However, it was impossible to elucidate whether or not the concurrent mitochondrial toxicity was part of the clinical presentation of an episode of hyperlactataemia/lactic acidosis. In addition, even if the episode of hyperlactataemia/lactic acidosis was an independent condition, it represented a very severe mitochondrial toxicity and other concurrent (and even recent previous) mitochondria-related ADRs may be steps in the pathogenic pathway to more severe mitochondrial dysfunction. Therefore, it was considered sensible to exclude concurrent mitochondrial dysfunctions from the multivariate analysis. Also dates of previous ADR were not recorded and so it was not possible to know how close in time previous ADRs and the study event were to each other. It was, therefore, decided to exclude previous ADR from the multivariate model.
Like any other retrospective study, ours has limitations. First, it included cases from centres with different policies for monitoring patients on ART and, therefore, not all data were available at each site. Such differences might also have affected the likelihood of case identification, particularly among patients without symptoms. In centres where blood lactate was not routinely monitored (13 out of 19), it is possible that clinicians might have been more likely to preferentially request lactate levels in patients receiving dideoxynucleosides. Finally, two endpoints were combined in a single outcome (hyperlactataemia/lactic acidosis).
In conclusion, exposure to dideoxynucleosides was strongly associated with the likelihood of developing hyperlactataemia/lactic acidosis. The impact of such an adverse effect may be much more important in resource-limited countries, not only because of the frequent use of such drugs but also because other risk factors independently associated with hyperlactataemia/lactic acidosis are also more frequent. Female patients and those with advanced HIV-1-induced immunosuppression are at much higher risk of developing serious NRTI-induced mitochondrial dysfunction. This observation is consistent with the hypothesis of a specific susceptibility to mitochondrial toxicity, where genetic background may or may not lead to subclinical mitochondrial dysfunction and facilitate NRTI-induced mitochondrial damage. If so, relatively short exposure to any mitochondrial toxic drug may be enough to induce clinically evident mitochondrial dysfunction. In reality, ART options are limited in resource-constrained settings, and laboratory support for monitoring of therapy is scanty. Therefore, further work is needed to examine the risk of these severe complications in African populations, to improve our understanding of susceptibility and to make antiretroviral agents with lower toxicity available at affordable prices for individuals at high risk of developing toxicity.
The study group wish to thank Joanna Turner, Claudia Ochoa, Sophie Herbert, Lars Mathiesen, Jan Gerstoft, Mooka Busi, Luuk Gras, Sima Zaheri, Shula Grivell, Teresa García-Benayas, Erika Gremlich, Sundhiya Mandalia, Emma MacFarlane, Anele Waters, Lisa Heald, and Glen Curran for their support in retrieving patients' information.
Members of the writing committee of the Lactic Acidosis International Study Group. Alejandro Arenas-Pinto, Andrew Copas and Ian Weller (Centre for Sexual Health & HIV Research, University College London, UK; Arenas-Pinto also Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela), Alison Grant (Clinical Research Unit, London School of Hygiene and Tropical Medicine, London, UK), David Dunn and Krishnan Bhaskaran (Clinical Trials Unit, Medical Research Council, London, UK), Andrew Carr (St Vincent's Hospital, Sydney, Australia), Peter Reiss (Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands), Simon Edwards (The Mortimer Market Centre, Camden Primary Care NHS Trust, London, UK), Signe Westring Worm (Copenhagen HIV-1 Programme, Hvidovre Hospital, Copenhagen, Denmark), Turner Overton (Washington University, St Louis, USA), Esteban Martinez (Hospital Clinic, Barcelona, Spain), Jennifer Hoy (Alfred Hospital, Melbourne, Australia), Pedro Cahn (Fundación Huesped, Buenos Aires, Argentina), Rainer Weber (University Hospital, Zurich, Switzerland).
Members of the Lactic Acidosis International Study Group. Argentina: Pedro Cahn (Fundación Huesped, Buenos Aires); Australia: Paddy Mallon, Andrew Carr (St Vincent's Hospital, Sydney); Jennifer Hoy (Alfred Hospital, Melbourne); Denmark: Signe Westring Worm, Jens Lundgren (Hvidovre Hospital, Copenhagen); Ireland: Fiona Mulcahy (St James' Hospital, Dublin), William Powderly (University College Dublin); the Netherlands: Peter Reiss (Academic Medical Center, Amsterdam); Spain: Esteban Martínez (Hospital Clinic, Barcelona), Vincent Soriano (Hospital Carlos III, Madrid); Switzerland: Rainer Weber (University Hospital, Zurich); United Kingdom: Alejandro Arenas-Pinto, Ian Weller, Andrew Copas (University College London), Alison Grant, Stephen Evans (London School of Hygiene and Tropical Medicine, London), Simon Edwards (Camden Primary Care NHS Trust), David Dunn, Krishnan Bhaskaran (Medical Research Council, London), Chris Taylor (King's College Hospital, London), Alec Bonington (North Manchester General Hospital, Manchester), Jonathan Ainsworth (North Middlesex Hospital, London), Martin Fisher (Brighton General Hospital, Brighton), Moses Kapembwa (Northwick Hospital, London), Graeme Moyle (Chelsea and Westminster Hospital, London); United States: Turner Overton (Washington University, St Louis); Venezuela: Julio Castro, Alejandro Arenas-Pinto (Universidad Central de Venezuela, Caracas).
Sponsorship: The study was funded by an educational grant from Bristol-Myers Squibb. AAP was partially funded by the Consejo de Desarrollo Científico y Humanístico, Universidad Central de Venezuela.
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HIV; hyperlactataemia; lactic acidosis; mitochondria; nucleoside reverse transcriptase inhibitors; toxicity
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