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Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study

Hulgan, Todda,b; Haas, David Wa,c,d; Haines, Jonathan Lc; Ritchie, Marylyn Dc,e; Robbins, Gregory Kf; Shafer, Robert Wg; Clifford, David Bh; Kallianpur, Asha Rb,i; Summar, Marshallc; Canter, Jeffrey Ac,e

doi: 10.1097/01.aids.0000180786.02930.a1

Objective: HIV nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups.

Design: Case–control study of Adult AIDS Clinical Trials Group (ACTG) study 384 and ACTG Human DNA Repository participants.

Methods: ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression.

Results: A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddI plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4–25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddI plus d4T, older age, and mitochondrial haplogroup T.

Conclusions: A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.

From the aDivision of Infectious Diseases, Department of Medicine

bCenter for Health Services Research

cCenter for Human Genetics Research

dDepartment of Microbiology and Immunology

eDepartment of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

fDepartment of Medicine, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA

gDepartment of Medicine-Infectious Diseases, Stanford University, Stanford, California, USA

hDepartment of Neurology and Neurological Surgery, Washington University School of Medicine, St. Louis, Misouri, USA

iDivision of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Received 21 April, 2005

Revised 3 June, 2005

Accepted 14 June, 2005

Correspondence to T. Hulgan, Division of Infectious Diseases, Vanderbilt University School of Medicine, 345 24th Ave N; Suite 105, Nashville, TN 37203, USA. Tel: +1 615 467 0154 extn 105; fax: +1 615 467 0158; e-mail:

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The availability of potent antiretroviral therapy has reduced morbidity and mortality due to AIDS [1,2]. Preferred initial therapies for HIV-1 infection include two nucleoside reverse transcriptase inhibitors (NRTI) plus either an HIV protease inhibitor or a non-nucleoside reverse transcriptase inhibitor [3]. Active intracellular anabolites of approved NRTI block viral replication by competing with endogenous cellular nucleotides for incorporation into proviral DNA, and are relatively specific for HIV reverse transcriptase. However, their ability to inhibit human mitochondrial DNA polymerase-γ [4] has been associated with toxicities that include peripheral neuropathy, lipoatrophy, hepatic steatosis and lactic acidosis [5].

Up to 15% of HIV-infected individuals may develop peripheral neuropathy that is characterized by distal, symmetric anesthesia and/or painful dysesthesia [6]. Although peripheral neuropathy can complicate untreated HIV infection [7], most cases since the availability of antiretroviral therapy have resulted from exposure to NRTI, particularly the dideoxynucleosides didanosine (ddI) and stavudine (d4T) [8,9]. There is considerable evidence that mitochondrial injury underlies NRTI-associated peripheral neuropathy [10,11]. Despite similarities between the clinical manifestations of inborn (genetic) errors of mitochondrial function and NRTI toxicities [12,13], genetic factors that predict NRTI-associated peripheral neuropathy have not been described.

The human mitochondrial genome consists of a circular, double-stranded DNA molecule that encodes ribosomal RNA, transfer RNA, and 13 polypeptides that are essential for oxidative phosphorylation [14]. Stable single nucleotide polymorphisms in the mitochondrial genome have emerged over the past 150 000 years, and combinations of these polymorphisms define mitochondrial haplogroups [15]. The phylogeny of mitochondrial haplogroups differs between continents and populations, and has been used to map prehistoric human migrations [15,16]. For example, haplogroup H is present in approximately 40% of individuals of Europeans ancestry but is rare among Africans and Asians [15]. Recent studies suggest possible functional differences between some haplogroups. European mitochondrial haplogroup J has been associated with longevity in northern Italians [17] and Finns [18], relative protection against Parkinson disease [19], and expression of Leber hereditary optic neuropathy, a rare cause of adult-onset blindness [20].

We hypothesized that stable polymorphisms within the mitochondrial genome might influence susceptibility to NRTI-associated peripheral neuropathy. To test this hypothesis we characterized European mitochondrial haplogroups in HIV-infected individuals who had previously participated in a prospective, randomized clinical trial of antiretroviral therapy. Many of these individuals developed peripheral neuropathy during the study.

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Study subjects

This retrospective exploratory analysis included participants from Adult AIDS Clinical Trials Group (ACTG) study 384, a multicenter randomized trial that enrolled volunteers in the US and Italy between October 1998 and November 1999 [21,22]. Eligibility criteria for ACTG 384 included having at least 500 HIV RNA copies/ml plasma and fewer than 7 days of prior antiretroviral therapy. Participants were randomized to three- or four-drug therapy with ddI plus d4T or zidovudine (ZDV) plus lamivudine (3TC) in combination with efavirenz (EFV), nelfinavir (NFV), or both. Clinical assessments were obtained at screening, entry, weeks 4, 8, 12, 16, 20, and 24, and every 8 weeks thereafter. Regimen failure was defined according to virologic and toxicity-related criteria, and the primary endpoint was time to failure of the second regimen or discontinuation of all study medications for any reason. The most frequent self-identified race/ethnicity categories of ACTG 384 participants were ‘white, non-Hispanic’, ‘black, non-Hispanic’, and ‘Hispanic’. We hereafter refer to these groups as white, black, and Hispanic, respectively. Human DNA was obtained under ACTG protocol A5128 [23]. These studies were approved by institutional review boards for each site, and participants provided written informed consent. The Vanderbilt Committee for the Protection of Human Subjects and the ACTG approved the use of DNA.

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Study medications

Nucleoside reverse transcriptase inhibitors were open-labeled: ddI (400 mg or 250 mg daily based on weight; enteric-coated tablets were available during the final year of study); d4T (40 mg or 30 mg twice daily based on weight); and ZDV (300 mg) and 3TC (150 mg) administered as a fixed-dose combination twice daily. Efavirenz (600 mg once daily) and nelfinavir (1250 mg twice daily) were double-blinded with matching placebos. Two on-study NRTI substitutions (d4T for ZDV or 3TC for ddI) were allowed for intolerance without the regimen being considered to have failed.

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Case definition

Participants in ACTG 384 were asked to report all symptoms at each study visit, and new signs, symptoms, or diagnoses were recorded. Cases were participants who developed peripheral neuropathy of at least grade 1 during participation in ACTG 384. Controls were ACTG 384 participants who did not develop peripheral neuropathy. Participants with documented peripheral neuropathy prior to randomization were excluded from analyses. Peripheral neuropathy was graded according to the Division of AIDS (National Institutes of Health, Bethesda, Maryland, USA) Table for Severity of Adult Adverse Experiences as follows: Grade 1, mild paresthesia not requiring therapy, or mild neurosensory impairment such as decreased vibratory, pinprick, or hot/cold sensation in the great toes in a focal area or symmetrical distribution; Grade 2, moderate paresthesia requiring non-narcotic analgesia, or moderate neurosensory impairment such as decreased vibratory, pinprick, or hot/cold sensation to the ankle, or decreased position sense or mild impairment that is not asymmetrical; Grade 3, severe discomfort, discomfort requiring narcotic analgesia for symptomatic improvement, or severe neurosensory impairment; Grade 4, incapacitating discomfort, discomfort not responsive to narcotics, or sensory impairment involving the limbs and trunk to the knees or wrists, or loss of sensation of at least moderate degree in multiple different body areas such as the upper and lower extremities.

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Study design

This case–control study included only those persons who had participated in ACTG 384 and also contributed DNA to the ACTG Human DNA Repository (Vanderbilt Center for Human Genetics Research, Nashville, Tennessee, USA) under ACTG protocol A5128 as described elsewhere [23]. Because protocol A5128 did not open to accrual until 2002, nearly 4 years after ACTG study 384 began, many ACTG 384 participants were not available to enroll A5128. In addition, ACTG 384 participants in Italy did not enroll into A5128. To assess for selection bias based on protocol A5128 participation, data from ACTG 384 participants who did not enroll in A5128 were also analyzed.

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DNA sequencing and mitochondrial haplogroup determination

DNA was isolated from whole blood using PUREGENE (Gentra Systems Inc., Minneapolis, Minnesota, USA). Genotyping was performed with the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems Inc., Foster City, California, USA) using the 5′ nuclease allelic discrimination Taqman assay. Based on the work of Torroni et al. [16], we characterized single nucleoside polymorphisms at positions 1719, 4580, 7028, 8251, 9055, 10398, 12308, 13368, 13708, and 16391. Probes and primers were based on previously reported sequences [19]. Genotypic data were analyzed using ABI Sequence Detection System version 2.0 software and confirmed by visual inspection of the plots.

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Statistical analysis

Simple proportions were used to describe demographic and genetic data. Fisher's exact and Wilcoxon rank-sum (Mann–Whitney U) tests were used for comparisons of peripheral neuropathy with categorical and continuous covariates, respectively. Univariate and multivariate logistic regression were used to determine odds ratios (OR) and 95% confidence intervals (CI) for haplogroup associations with peripheral neuropathy. Because some haplogroups included few subjects, exact odds ratios are reported. Due to the exploratory nature of this genetic study, analyses were not corrected for multiple comparisons. Stata version 8.2 (Stata Corp., College Station, Texas, USA) was used for data management and analyses, and SAS version 9.1 (SAS Institute, Cary, North Carolina, USA) was used for exact logistic regression.

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A total of 980 persons in the US and Italy participated in ACTG 384, of whom 526 (54%) had DNA available for analysis. Seventeen (3.2%) of these participants had symptoms, signs, and/or a diagnosis of peripheral neuropathy prior to randomization and were excluded from subsequent analyses. Results presented hereafter reflect the 509 persons in the US who had no evidence of peripheral neuropathy prior to randomization and underwent genetic analyses. The disposition of all ACTG 384 study participants is shown in Fig. 1. Somewhat more subjects who underwent genetic analyses were randomized to ddI plus d4T arms (P = 0.03) compared to other ACTG 384 participants (Table 1), but otherwise the groups were similar. The median age of genetic study participants was 36 years, 49% were white, and 17% were female.

Fig. 1

Fig. 1

Table 1

Table 1

Peripheral neuropathy of any grade was reported in 147 (29%) genetic study participants during ACTG 384, 108 (73%) of whom had been randomized to receive ddI plus d4T, and 39 (27%) to receive ZDV plus 3TC (P < 0.001). Sixty-one participants (42%) developed at least grade 2 peripheral neuropathy. Participants who developed peripheral neuropathy had lower baseline CD4 T-cell counts (P = 0.003), higher baseline plasma HIV-1 RNA concentrations (P = 0.004), and were older at study entry (P = 0.0001) than those who did not develop peripheral neuropathy (Table 1). The proportion of study participants who developed peripheral neuropathy did not differ by race or sex (P > 0.3 for each). Among white participants, those who developed peripheral neuropathy were older (P = 0.01) and more likely to have been randomized to a d4T plus ddI treatment arm (P = 0.007) than those who did not. They also tended to have higher baseline HIV RNA and lower CD4 T-cell counts, but these comparisons were not significant (P > 0.1 for both).

We attempted to characterize the polymorphisms that define nine European mitochondrial haplogroups in all study participants. Because mitochondrial haplogroups for African–Americans are not well characterized, we focused on haplogroups that have been described among Caucasians in Europe and North America [16,19]. Approximately 95% of whites could be assigned to known European haplogroups (Table 2). Six (2.3%) did not have a polymorphism pattern characteristic of any of these groups, and one or more polymorphic sites were unresolved in seven (2.7%). Haplogroup frequencies among whites were similar to those previously reported [19], with the signature polymorphism for haplogroup T present in 10%.

Table 2

Table 2

Of the nine European mitochondrial haplogroups, only haplogroup T was seen with greater frequency in participants with peripheral neuropathy (Table 2). Among white participants, 17.1% of those who developed peripheral neuropathy belonged to haplogroup T compared to 6.7% of those who did not develop peripheral neuropathy (OR, 2.8; 95% CI, 1.1–7.1; P = 0.03; Fig. 2a). This relationship was strongest among the 137 whites randomized to receive ddI plus d4T. In this subgroup, 10 of 48 (20.8%) who developed peripheral neuropathy belonged to haplogroup T, while four of 89 (4.5%) who did not develop peripheral neuropathy belonged to this haplogroup (OR, 5.4; 95% CI, 1.4–25.1; P = 0.009; Fig. 2b). We used an intent-to-treat analysis, but some participants had switched from the initially randomized NRTI prior to documented peripheral neuropathy. Results were similar when this analysis was repeated based on NRTI prescribed at the time closest to documented peripheral neuropathy (data not shown).

Fig. 2

Fig. 2

To identify independent predictors of peripheral neuropathy in white study participants, we used a multivariate logistic regression model that included age, sex, randomization arm (ddI plus d4T or ZDV plus 3TC, as well as blinded EFV, NFV, or both), baseline CD4 T-cell count, baseline plasma HIV RNA concentration, and mitochondrial haplogroup T (Table 3). Factors significantly associated with development of peripheral neuropathy in this model were randomization to receive ddI plus d4T (OR, 2.57 versus ZDV plus 3TC; 95% CI, 1.37–4.83; P = 0.003), older age at randomization (OR, 1.05 per year; 95% CI, 1.02–1.09; P = 0.005), and mitochondrial haplogroup T (OR, 2.89; 95% CI, 1.17–7.13; P = 0.02).

Table 3

Table 3

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In this study, we observed that white ACTG 384 participants who belonged to mitochondrial haplogroup T were at increased risk of developing peripheral neuropathy during antiretroviral therapy, particularly if they had been randomized to receive ddI plus d4T. By multivariate analysis, randomization to receive ddI plus d4T, older age, and belonging to mitochondrial haplogroup T were independent predictors of peripheral neuropathy. To our knowledge, this is the first study to identify a possible genetic predictor of peripheral neuropathy during antiretroviral therapy, and the first to characterize mitochondrial haplogroups among HIV-infected individuals.

There is considerable evidence that peripheral neuropathy and other NRTI toxicities involve inhibition of mitochondrial DNA polymerase-γ, ultimately leading to mitochondrial dysfunction, impaired oxidative phosphorylation, and tissue injury [4,24,25]. Incubation of T-lymphoblastoid cell lines with NRTI results in mitochondrial DNA depletion, morphologic changes of mitochondria, and increased lactic acid production [26–29]. In a rabbit model of drug-induced peripheral neuropathy, mitochondria in neuronal cells from animals exposed to the dideoxynucleoside zalcitabine (ddC) exhibited structural changes [30]. Among HIV-infected individuals with ddC-induced peripheral neuropathy, mitochondria in peripheral nerves were morphologically abnormal, and mitochondrial DNA content was decreased [11]. Importantly, the tendency of NRTI to cause peripheral neuropathy and other putative mitochondrial toxicities approximates their in vitro affinities for mitochondrial DNA polymerase-γ (ddC > ddI and d4T > other NRTI) [24]. In addition, there are in vitro and animal data supporting effects of NRTI on mitochondria independent of mitochondrial DNA polymerase-γ [31,32]. Clinical manifestations of some inherited disorders of mitochondrial function and oxidative phosphorylation resemble NRTI-associated toxicities, and can include neuropathies and other neurodegenerative phenotypes [12,13]. These observations provide rationale for a link between mitochondrial genetics and NRTI-induced peripheral neuropathy.

Mitochondrial DNA is maternally inherited and undergoes sequence evolution approximately 10–17 times faster than nuclear genes [15]. Mitochondrial mutations that emerged at various times over the past 150 000 years have reached polymorphism frequencies and are maintained within populations through genetic drift and selection [33,34]. The greatest diversity of mitochondrial DNA is found in Africa, where at least 157 polymorphisms define more than 100 mitochondrial haplotypes [35]. Based on phylogenetic analyses, multiple haplotypes are assigned to larger, more coherent haplogroups. For example, most African mitochondria belong to macro-haplogroup L, which is further divided into numerous haplogroups and sub-haplogroups [15]. European haplogroups are much less diverse in comparison. Approximately 10–15% of persons of European descent belong to haplogroup T, which is distinguished by a signature pattern of three polymorphisms at nucleotide base positions 7028, 10398, and 13368 [15,16,19]. The position 13368 polymorphism is unique to haplogroup T, whereas position 7028 and 10398 polymorphisms are shared with haplogroups U, V, W, and X [16].

Mitochondrial haplogroups have been most extensively used to understand prehistoric human migrations [15]. Only recently has the potential relevance of functional differences between mitochondrial haplogroups to human health and disease been appreciated. Studies in northern Italy [17] and Finland [18] have identified greater longevity among persons belonging to mitochondrial haplogroup J. In a recent age- and sex-matched case–control study involving persons of European ancestry, Parkinson disease was significantly less frequent among persons belonging to haplogroups J or K [19]. A similar observation has been reported in a Finnish population [36]. Parkinson disease is believed to result, at least in part, from mitochondrial impairment, free radical-induced oxidant injury, and neurodegeneration [37], similar to NRTI-associated peripheral neuropathy. Molecular mechanisms underlying functional differences between haplogroups are unknown.

The polymorphisms that define mitochondrial haplogroups are homoplasmic, and their functional implications are likely to be subtle, contributing to susceptibility to additional genetic or epigenetic factors, such as drugs or environmental toxins. These differ from somatic mutations that accumulate in mitochondrial DNA during the lifetime of an individual, resulting in heteroplasmic mixtures of mutant and wild-type DNA that are present in variable proportions of mitochondria and are often tissue specific [38]. Heteroplasmy can also directly affect expression of rare mitochondrial diseases in which the proportion of mutant mitochondrial DNA in a given tissue can determine the clinical phenotype [39].

There are possible explanations for a relationship between mitochondrial haplogroup T and peripheral neuropathy. Although aberrations in mitochondrial DNA can impair energy production [34], haplogroup T has not been previously associated with mitochondrial dysfunction or disease. In addition, the signature haplogroup T polymorphism at position 13368, located in the ND5 region of the mitochondrial gene encoding complex I respiratory chain subunits, does not change an amino acid is therefore unlikely to directly alter mitochondrial function. However, polymorphisms that change amino acids have been described in other mitochondrial diseases and are reported in persons belonging to the T haplogroup [40]. Such polymorphisms may affect the efficiency of oxidative phosphorylation to an extent that is not apparent under basal conditions, but is unmasked by exposure to additional stressors, such as NRTI. Importantly, mitochondrial polymorphisms that influence susceptibility to toxic exposures could plausibly explain variations in clinical phenotypes resulting from both mitochondrial DNA polymerase-γ dependent and independent mechanisms.

There are limited previous data to support an association between mitochondrial haplogroups, NRTI, and susceptibility to drug neurotoxicity. There are reports of HIV-infected persons with Leber hereditary optic neuropathy, a rare cause of inherited blindness that typically occurs in the third decade of life and is associated with one of three mitochondrial DNA mutations in a majority of cases [41]. Not all persons with one of these mutations lose vision, however, suggesting that additional genetic or epigenetic factors are necessary for disease expression. In all six cases of Leber hereditary optic neuropathy reported in HIV-infected persons, the atypically late onset of visual loss occurred during NRTI therapy [41–45]. With respect to associations between mitochondrial haplogroups and drug toxicity in general, one study suggested that cisplatin-induced mitochondrial ototoxicity may be more frequent among persons belonging to European haplogroup J [46]. These reports support the concept that exposure to drugs, and NRTI in particular, can precipitate clinical mitochondrial dysfunction in genetically predisposed individuals.

The relationship between mitochondrial haplogroup T and peripheral neuropathy must be validated in independent cohorts. In addition, because African–American haplogroups have not been well defined, our ability to identify potential genetic effects in this study was limited to whites. Similar analyses must be extended to African–American and other non-European haplogroups. Peripheral neuropathy is a complex phenotype, and it is possible that this outcome was misclassified in some subjects. However, if a diagnosis of NRTI-associated peripheral neuropathy was assigned when it was not present, or not recorded when present, this should have biased our results toward finding no effect. Peripheral neuropathy caused by HIV infection rather than NRTI exposure was unlikely in this study, since study participants received potent antiretroviral therapy and most had excellent virologic responses [6]. The sample size was too small to assess haplogroup differences based on severity of peripheral neuropathy.

Current guidelines recommend avoiding combined use of ddI and d4T because of increased toxicity [3], but these and other NRTI are still widely prescribed. Because of its ease of generic production and co-formulation with other antiretroviral drugs, d4T is a particularly important antiretroviral agent in resource limited settings [47]. As the AIDS epidemic has increasingly affected persons of non-European ancestry, it is critical to define relationships between mitochondrial haplogroups, peripheral neuropathy, and other NRTI toxicities in these populations. At present, there are no reliable clinical predictors of NRTI-associated peripheral neuropathy, and available therapies are of limited efficacy [48]. Identifying individuals at greatest risk could further influence prescribing practices to avoid this complication. In addition, the results of the present study may guide biochemical investigations to elucidate functional mechanisms that underlie the relationship between mitochondrial haplogroup T and NRTI-associated peripheral neuropathy.

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The authors gratefully acknowledge the many HIV-infected patients who volunteered for ACTG 384 and protocol A5128. We also acknowledge Laura Smeaton, MS, for invaluable assistance in obtaining clinical data from ACTG 384 and for helpful discussions, and Gema Barkanic, MS, for statistical assistance.

Sponsorship: Supported by the National Institutes of Health Mentored Career Development Award AT002508 (TH), and a Developmental Core Award from the Vanderbilt-Meharry Center for AIDS Research AI54999 (JC), and in part by the Adult AIDS Clinical Trials Group, funded by the National Institute of Allergy and Infectious Diseases (grant AI38858). Other grant support included AI46339 (DWH), NS32228, AI25903 (DBC), U54RRO19453 (MLS), and AI54999 (DWH).

These data were presented at the Twelfth Conference on Retroviruses and Opportunistic Infections. Boston, MA, February 2005 [abstract 43].

Conflict of interest: DC and RWSR received research grants and honoraria from GlaxoSmithKline and Bristol Myers Squibb.

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Other members of the ACTG 384 team were M. Fischl (Miami University), M. Dube (Indiana University), C. Pettinelli (National Institutes of Health), R. Delapenha (Howard University), B. Putnam (University of Colorado), M. Klebert (Washington University), M. Testa (Harvard School of Public Health), A. Chiesi, C. Tomino (Istituto Superiore de Sanita), S. Deeks (University of California, San Francisco), T. Nevin (Social & Scientific Systems), J. Levin, V. French, O. Fennell (Adult AIDS Clinical Trials Group Community Constituency Group), M. Stevens, R. Grosso, B. Dusak, S. Hodder (Bristol-Myers Squibb), J. Tolson, C. Brothers (GlaxoSmithKline), R. Leavitt (Merck), D. Manion, N. Ruiz, K. Morrissey (DuPont Pharmaceuticals), M. Becker, B. Quart (Agouron), C. Jennings (Northwestern University), L. Gedeon, S. Dascomb, M. Cooper, M. Murphy, K. Blakelock (Frontier Science and Technology Foundation), A. Doolan (Massachusetts General Hospital).

48. Luciano CA, Pardo CA, McArthur JC. Recent developments in the HIV neuropathies. Curr Opin Neurol 2003; 16:403–409.

HIV; reverse transcriptase inhibitors; peripheral neuropathies; drug toxicity; mitochondrial DNA; pharmacogenetics

© 2005 Lippincott Williams & Wilkins, Inc.