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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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
HIV; hyperlactataemia; lactic acidosis; mitochondria; nucleoside reverse transcriptase inhibitors; toxicity