mitochondrial toxicity and hiv therapy · mitochondrial toxicity and hiv therapy alex j white...

Review

Mitochondrial toxicity and HIV therapy

Alex J White

Nucleoside reverse transcriptase inhibitors (NRTIs) remain the cornerstone of highly activeantiretroviral therapy (HAART) combination regimens. However, it has been known for sometime that these agents have the potential to cause varied side eVects, many of which are thoughtto be due to their eVects on mitochondria. Mitochondria, the key energy generating organelles inthe cell, are unique in having their own DNA, a double stranded circular genome of about 16 000bases. There is a separate enzyme present inside the cell that replicates mitochondrial DNA,polymerase gamma. NRTIs can aVect the function of this enzyme and this may lead to depletionof mitochondrial DNA or qualitative changes. The study of inherited mitochondrial diseases hasled to further understanding of the consequences of mutations or depletion in mitochondrialDNA. Key among these is the realisation that there may be substantial heteroplasmy amongmitochondria within a given cell, and among cells in a particular tissue. The unpredictable natureof mitochondrial segregation during cellular replication makes it diYcult to predict the likelihoodof dysfunction in a given tissue. In addition, there is a threshold eVect for the expression of mito-chondrial dysfunction, both at the mitochondrial and cellular level. Various clinical and in vitrostudies have suggested that NRTIs are associated with mitochondrial dysfunction in diVerent tis-sues, although the weight of evidence is limited in many cases. The heterogeneity in the tissuesaVected by the diVerent drugs raises interesting questions, and possible explanations include dif-ferential distribution or activation of these agents. This article reviews the major recognised tox-icities associated with NRTI therapy and evidence for mitochondrial dysfunction in these com-plications. Data were identified through searching of online databases including Medline andCurrent Contents for relevant articles, along with abstracts and posters from recent conferencesin the HIV and mitochondrial fields.(Sex Transm Inf 2001;77:158–173)

Keywords: mitochondrial toxicity; HIV therapy

IntroductionCurrent guidelines for the management of HIVinfected individuals recommend the use ofcombinations including at least three agents—highly active antiretroviral therapy (HAART).This term was coined because of the magni-tude of the eVects seen in the early clinicalstudies of regimens combining the new HIVprotease inhibitors (PIs) with the establishednucleoside reverse transcriptase inhibitors(NRTIs). In addition to profound eVects onviral load and CD4 cell count, these regimenswere shown to significantly delay diseaseprogression and death. Analyses of populationdata have also shown reductions in morbidityand mortality associated with increased use ofHAART. The initial enthusiasm for PI regi-mens has waned somewhat with the realisationthat these agents may be associated with longterm toxicity in the form of a metabolicsyndrome that has become known as HIVassociated lipodystrophy.1 This, coupled withthe development of cross resistance betweencurrently available agents in the PI class, hasled to a search for other regimens that may beemployed either before or after PI therapy.Other triple regimens that have been studiedhave replaced the PI by either a non-nucleosidereverse transcriptase inhibitor (NNRTI) oranother NRTI. These “PI sparing” regimenshave shown comparable eYcacy on surrogatemarkers of HIV disease in clinical trials. How-ever, whatever drug is chosen as the third

agent, HAART combinations invariably con-tain two NRTIs as the backbone of theregimen. While there are some toxicitiescommon to all NRTIs, such as the raresyndrome of acute lactic acidosis, there are alsoa wide variety of tissue specific toxicities witheach agent, the precise pathophysiology ofwhich is frequently unclear. In vitro studieshave shown that NRTIs may inhibit thereplication of mitochondrial DNA2 and thus itis believed that some clinical toxicities of theseagents may be the result of impaired mitochon-drial function or replication, as reviewedrecently by Brinkman and colleagues.3–5 Thisarticle will review the evidence for NRTIinduced mitochondrial dysfunction in the con-text of our current understanding of mitochon-drial biology and possible managementstrategies that may be employed to minimisethe clinical eVects of these toxicities in the HIVinfected individual, with a particular focus onrecently identified toxicity.

Mitochondrial biologySTRUCTURE

The identification of filaments (mito) andgrains (chondria) under the light microscopeby scientists in the 19th century provided earlyclues, but it was only the advent of electronmicroscopy that led to the widespread visuali-sation of mitochondria as the sausage-shapedorganelles as shown in figure 1 and familiar tostudents of medicine and biology the worldover.6 While this classic picture has been

Sex Transm Inf 2001;77:158–173158

Anti-InfectivesClinical Developmentand Product Strategy,GlaxoSmithKlineResearch andDevelopment,Greenford Road,Greenford, Middlesex,UB6 0HE, UKA White

Correspondence to:[email protected]

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accepted for a number of years, recent studieshave shown it to be an oversimplification.Rather than always being present as discreteorganelles, mitochondria have also been shownto form a highly integrated network, and toundergo what appears to be a frequent processof fusion and fission. In addition, depletion inmitochondrial DNA has been shown to causemorphological changes in mitochondria fromcultured human cells, and a high energydemand or oxidative stress will induce prolif-eration of the mitochondrial network to satisfythe cell’s energy needs.

FUNCTION

The main function of mitochondria is toproduce energy for the cell in the form ofadenosine triphosphate (ATP), via the processof oxidative phosphorylation (fig 2). Acetyl-CoA is generated either via glycolysis in thecytosol or â oxidation of fatty acids in themitochondria. The passage of acetyl-CoA

through the tricarboxylic acid cycle generatesNADH and FADH2, which are powerfulreducing agents. Oxidative phosphorylationtakes electrons from these reducing agents andpasses them down the electron transport chain,eventually reducing oxygen to water. Thetransport of electrons down the diVerent com-ponents of the electron transport chain alsoleads to the pumping of protons out of themitochondria. This creates an electrochemicalgradient leading to the return of protons intothe mitochondria via specific channels. As pro-tons pass through this channel, an integralcomponent catalyses the synthesis of ATP. TheATP is then exchanged with ADP from thecytosol by a specific carrier, the ADP/ATPtranslocator. In addition, while consideringmitochondrial function it is important toacknowledge that mitochondria are known toparticipate in other cellular processes, particu-larly apoptosis. Thus, it can be seen that mito-chondria are not only essential for energy gen-eration within the cell but also function as keyregulators of cellular survival.

GENOME AND REPLICATION

Uniquely among organelles, it was recognisedback in the 1960s that mitochondria have theirown DNA distinct from that of the cell. Mito-chondrial DNA is a circular, double strandedDNA molecule of about 16 000 bases, codingfor 13 polypeptides, 22 transfer RNAs(tRNAs), and two ribosomal RNAs (rRNAs).7

The gene products of mitochondrial DNA arequite limited, and the bulk of the organelle isactually encoded for by nuclear DNA (nDNA).Considering mitochondrial genetics, there arecertain features that are highly significant.8

Firstly, mitochondrial DNA is maternallyinherited. Paternal mtDNA copy number insperm cells is low in number by comparison

Figure 1 Mitochondria and the cell.

Figure 2 Energy generation in mitochondria. Mitochondria generate energy by oxidative phosphorylation. If this isimpaired, energy may be generated by anaerobic metabolism where pyruvate is converted to lactate, possibly leading to lacticacidosis.

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with the large number of mtDNA molecules inthe oocyte. In addition, it appears that althoughpaternal mtDNA is transferred during fertilisa-tion, it is lost early in embryogenesis. One ofthe most important observations of mitochon-drial genetics is that diVerent mtDNA variantsmay coexist in a single cell, the state of hetero-plasmy. It has also been noted that there is agenetic bottleneck in mitochondrial DNA atsome point between oogenesis and develop-ment of the embryo. This means that althoughthere may be a large degree of heteroplasmy inthe mother, the restriction and amplificationthat occurs during the bottleneck results in avery small number of mtDNA variants ulti-mately populating the embryo. Considering theeVects of heteroplasmy at a cellular and tissuelevel, we encounter two further features ofmitochondrial genetics, replicative segregationand the threshold eVect. Replicative segrega-tion refers to the distribution of heteroplasmicmitochondria during cell division (fig 3),although it is now known that mitochondria dohave some interaction with cytoskeletal com-ponents and thus this process is unlikely to becompletely random. The threshold eVect canalso be seen in figure 3, since it is only when thepopulation of mitochondria with altered mito-chondrial DNA exceeds a certain threshold(usually quite high, >80%) that the cell showsevidence of mitochondrial dysfunction.9

MITOCHONDRIAL DNA POLYMERASE

There are at least nine polymerases involved inthe replication and maintenance of cellularDNA; however, only one, DNA polymerasegamma, is responsible for mitochondrial DNAreplication. Human mitochondrial DNA

polymerase is a family A DNA polymerase andwas cloned and characterised by Ropp andCopeland in 1996.10 It has been shown thatpolymerase gamma is expressed and translatedin cells which have been depleted of mitochon-drial DNA.11 The process of mitochondrialDNA replication has recently been reviewed12

and will not be described here. Polymerasegamma has to perform both replication andrepair for mtDNA although for some time itwas believed that repair activity was absent.However, polymerase gamma has been shownto participate in base excision repair, and otherrepair proteins have also been shown to bepresent in mitochondria; thus the once com-mon view that mitochondria had little or nocapacity for DNA repair should be reconsid-ered.13

Mitochondrial diseaseMitochondrial disease can result from muta-tions or rearrangements in both mitochon-drial14 and nuclear DNA,15 and generallyinvolves post-mitotic tissues. The clinical pres-entation includes organs such as the centraland peripheral nervous system, the bonemarrow, skeletal and cardiac muscle, thegastrointestinal tract, the kidneys, the pan-creas, and the liver. An important feature thatrelates to the heteroplasmy and thresholdeVects discussed above is the heterogeneity ofthe clinical presentation of many of theseinherited defects.16 This is thought to relate tothe mutation load in particular tissues ofdiVerent individuals. For example, Kearns-Sayre syndrome, an encephalomyopathy, andPearson syndrome, a disease of the pancreasand bone marrow, both result from the same

Figure 3 Although homoplasty is the normal state, diVerent populations of mitochondria may coexist in a cell, the state ofheteroplasmy. Since segregation of mitochondria during cellular replication is almost random, daughter cells may havediVerent ratios of normal to dysfunctional mitochondria to the parent cell. If the population of mutant mitochondria reachesa certain threshold (70% in this example, but this can be as high as 95% in some tissues), then the cell exhibitsdysfunction.9

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deletion of nearly 5000 base pairs in mitochon-drial DNA. A further example is the mutationin a tRNA gene at position 3243, which whenpresent at high levels is associated with theMELAS syndrome (mitochondrial encephalo-myopathy with lactic acidosis and stroke-likeepisodes), but with maternally inheriteddiabetes and deafness when present at lowlevels. The critical significance of the level ofmutant mitochondrial DNA in determiningthe clinical presentation has naturally led to afocus on the patterns and maintenance of het-eroplasmy. There has been some controversyover whether mutant or normal mitochondriahave a selection advantage, since results usingcybrid cells have not been consistent. A recentmodel suggests that although damaged mito-chondria may replicate as quickly as normalmitochondria, they are degraded more slowlyand thus persist in post-mitotic cells, butmitotically active tissues may be able to rejuve-nate the population.

NRTIs and mitochondrial DNAAfter HIV has entered the cell, it is required tointegrate with the host cell genome. To do this,it needs to convert single stranded viral RNAinto double stranded DNA and this task is per-formed by the enzyme reverse transcriptase.The NRTIs resemble the natural nucleosidesbut do not have a free 3' hydroxyl group, andthus once they are added to the growing DNAchain, termination occurs. Many NRTIs havebeen investigated for anti-HIV activity, andsome knowledge of the structure-activity rela-tion of these agents has been established. Sincethese drugs resemble natural nucleosides, thepotential for inhibition of DNA polymerasesexists, although there are suYcient diVerencesbetween the enzymes to enable selectiveinhibition to occur.

IN VITRO STUDIES WITH NRTIS

Early studies of NRTIs demonstrated minimaleVect on DNA polymerase alpha, the mainenzyme responsible for nuclear DNA replica-tion, but polymerase beta and gamma wereaVected to some degree.17 The clinical signifi-cance of the inhibition of DNA polymerasebeta is unknown, this enzyme synthesises shortsections of DNA as part of a group of enzymesinvolved in repair. Recently it has been shownthat Tat, a gene product of HIV, induces theexpression of DNA polymerase beta.18 TheeVects of NRTIs on polymerase gamma havebeen studied and it appears logical that inhibi-tion of this enzyme and chain terminationwould lead to mitochondrial DNA depletion,which upon falling below the critical thresholdwould lead to insuYcient energy generationand subsequent cellular dysfunction.2 Initial invitro studies with NRTIs examined the toxicityof these agents in murine bone marrowprogenitor cells, since the first NRTI licensedfor the treatment of HIV, zidovudine, was asso-ciated with anaemia and neutropenia in theclinic. These studies showed that zidovudineexhibited toxicity in these models, appearing toconfirm what was observed in patients.19 Laterstudies in neuronal cell models showed that the

ddC, ddI, and d4T caused toxicity, whereasAZT and 3TC did not, again reflecting whatwas seen in clinical practice.20 The recognitionthat NRTIs may interfere with mitochondrialDNA synthesis led to many studies evaluatingthese eVects in vitro, recently reviewed byKakuda.21 These studies suggested a ranking ofddC > ddI > d4T > 3TC > ZDV > ABC foreVects on mitochondrial polymerase gamma.Martin and colleagues examined both the inhi-bition of polymerase gamma and the inhibitionof mitochondrial DNA synthesis, since somecorrelation was expected.22 Although a similarranking of the NRTIs for eVects on mitochon-drial DNA synthesis was noted, there was noclear correlation with the potency of mitochon-drial DNA inhibition. For example, one agentstudied (935U83) was a highly potent inhibitorof polymerase gamma and yet showed no eVectof mitochondrial DNA synthesis.22

Considering all in vitro experiments, it isimportant to note that these studies can onlyprovide information on the eVect of a drug in aparticular cell type under given experimentalconditions. Sensitivity to drugs varies betweencell types and there are many other factorsinvolved. One that has obvious implications ifthe mechanism of NRTI toxicity is indeedincorporation into mitochondrial DNA, isremoval by exonuclease activity. Gray and col-leagues demonstrated that lamivudine (3TC)is a substrate for the exonuclease activity ofpolymerase gamma, thus it can be excised ifincorporated.23 Studies with other NRTIs haveshown that they are substrates for cytosolicexonucleases, but the exonuclease activity maybe inhibited by high levels of the NRTI mono-phosphate.24

ACTIVATION OF THE NRTIS

Another important factor to consider is theanabolism of the NRTIs, since these agentsneed to be phosphorylated three times beforethey can be added to the growing DNA chainby HIV reverse transcriptase or other polymer-ases. This process is known to vary with theactivation state of the cell, with stavudine(d4T) and zidovudine (ZDV) being moreactive in activated cells and other NRTIs beingmore active in resting cells. In addition,intermediary anabolites may be implicated intoxicity of NRTIs, as has been shown for ZDVmonophosphate in a study of CEM cells.25

Considering the mitochondrial eVects ofNRTIs, it is important to note that many cellu-lar kinases exist in both mitochondrial andcytosolic forms. In addition to their subcellularlocalisation, these kinases frequently diVer intheir substrate specificity and regulationthrough the cell cycle. Early studies of zalcit-abine (ddC) suggested that the drug was phos-phorylated in the cytosol and then transportedinto the mitochondria. In the neuronal cellmodel referred to above, it was noted that ddCwas only phosphorylated to the monophos-phate in mitochondria, compared with themonophosphate, diphosphate, and triphos-phate in the cytosol.20 Other investigators havereported similar results, and transport activityfor both dCTP26 and ddCDP-choline27 has


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recently been described, suggesting that mito-chondrial toxicity due to ddC is the result oftransport of anabolites into the mitochondria,rather than phosphorylation therein.

Although less relevant for ddC, studies withother NRTIs demonstrate that mitochondrialphosphorylation can be a factor in determiningdrug toxicity. Fialuridine (FIAU) was investi-gated for the treatment of hepatitis B butunfortunately led to profound liver toxicity inmost patients exposed to the drug for longerthan 10 weeks.28 The liver toxicity was a conse-quence of severe mitochondrial dysfunctionand in vitro experiments showed that FIAUwas a much better substrate for mitochondrialthymidine kinase (TK-2) than the cytosolicform (TK-1), although the fact that FIAU isnot a chain terminator like other NRTIs andmay be incorporated also played a significantpart.29 The NRTIs zidovudine and stavudineare also activated by thymidine kinase, and ini-tial studies suggested that they could inhibitboth TK-1 and TK-2, although d4T was notshown to act as substrate for either of theseenzymes.30 Subsequently it has been recognisedthat d4T is relatively poorly phosphorylatedcompared with thymidine and ZDV,31 and laterstudies have shown that d4T is indeed asubstrate for these enzymes.32 In the neuronalcell model referred to above, d4T was shown tobe phosphorylated to the triphosphate withinthe mitochondria.20 Considering other nucle-osides, while the formation of ddA-monophosphate from didanosine (ddI) occursthrough a slightly diVerent enzymatic mech-anism than other NRTIs, the second phospho-rylation step is catalysed by adenylate kinase.This enzyme also exists as cytosolic (AK-1)and mitochondrial forms (AK-2), and thus thepotential for diVerential inhibition exists. Ourunderstanding of kinases involved in theactivation of guanosine analogues, such asabacavir and DAPD, is not as far advanced interms of a link between activation and toxicity,although studies with nucleosides used in can-cer therapy have shown a direct relationbetween mitochondrial deoxyguanosine kinaseactivity and cytotoxicity.33

NRTI TRANSPORT

The entry of NRTIs into cells has beenobserved to occur at diVerent rates, and thereare many transport systems available for nucle-osides. Since the phosphorylation of NRTIsmay diVer between subcellular compartments,it follows that movement of the drugs and theiranabolites between the cytosolic and mito-chondrial compartments is of considerableinterest.34 Early studies with lamivudine (3TC)showed synergistic or additive activity againstHIV in vitro, and also protection against thedelayed mitochondrial toxicity associated withd4T, ZDV, ddC, and ddI.35 The protectionconferred by 3TC in this study was thought tobe due to interference with the uptake of theother agents into mitochondria. Subsequentexperiments have shown that other “unnatu-ral” NRTIs in the same class, such asL(−)Fd4C, also show similar properties.36

Considering NRTI transport into mitochon-dria, the studies discussed above with 3TC andL(−)Fd4C suggest that this process may beinhibited, although whether NRTI anabolitescan be exported from mitochondria remainsunclear. Further understanding of the activa-tion and transport of the NRTIs within diVer-ent subcellular compartments may lead tomolecules or strategies in which eYcacy can beenhanced and toxicity reduced.

HIV AND MITOCHONDRIA

It is known that many of the toxicitiesassociated with NRTI therapy may also berelated to HIV infection itself, but it is not oftenappreciated that there is also known to be adirect interaction between HIV and mitochon-dria. Early studies showed that HIV RNAcould be found in mitochondria of infectedcells, and that there were mitochondrial altera-tions in patients with the acute HIV syndromeand stable infection. More recent work hasshown that the HIV TAT protein may promotemitochondrially induced apoptosis,37 consist-ent with our knowledge of the importance ofthis process in the immune cell destructioncaused by the virus. A specific interactionbetween the HIV viral protein R and the mito-chondrial permeability transition pore complex(PTPC) has recently been demonstrated byJacotot and colleagues,38 and with the recog-nised involvement of the PTPC in apoptosis itseems likely that HIV aVects the immunesystem at least in part by interacting with mito-chondria leading to programmed cell death.Such viral eVects are not uncommon; indeedthe hepatitis B virus protein X has also beenshown to interact with a component of thePTPC.

Clinical toxicity of the NRTIsNRTIs are associated with a wide spectrum oftoxicities, many also caused or exacerbated byHIV itself. Since the tissue involvement andclinical presentation often resembles aspects ofinherited mitochondrial disease, and it isknown that NRTIs may aVect mitochondrialfunction, many authors have proposed thatmitochondrial toxicity of the NRTIs is theunderlying pathophysiology behind most ofthese toxicities.3 Lewis and Dalakas putforward the “polymerase gamma hypothesis”in their review,39 suggesting that the manifesta-tions of NRTI toxicity relate to the combinedeVects of four principal factors. Firstly, the tis-sue must have some dependence on oxidativephosphorylation; secondly, the NRTI mustpass into the tissue itself; thirdly, the NRTImust be phosphorylated by cellular kinases;and, finally, it must inhibit polymerase gammaactivity by competing with the natural sub-strate or by chain termination.39 The datareviewed earlier identify some refinements thatmay be made to this hypothesis such as the roleof phosphorylation in diVerent subcellularcompartments, particularly the mitochondrionitself. More fundamental is the lack of correla-tion between polymerase gamma inhibitionand mitochondrial DNA depletion as identi-fied by Martin and colleagues.22 In addition,

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the neuronal cell model showed that theneurotoxic eVect of d4T did not correlate withmitochondrial DNA depletion, whereas therewas a correlation between the eVect of ddC andmitochondrial DNA levels.20 A full reappraisalof the polymerase gamma hypothesis is beyondthe scope of this review, although our extendedunderstanding of the many processes involvedin NRTI toxicity warrants some expansion ofthe initial ideas. The major toxicities associatedwith NRTI therapy will now be reviewed andevidence for a mitochondrial pathophysiologydiscussed.

HAEMATOLOGICAL TOXICITY

HIV infection and AIDS are known to be asso-ciated with significant haematological toxicity,including anaemia, neutropenia, and thrombo-cytopenia.40 In addition, studies with zidovu-dine have shown that this drug may compoundthe haematological toxicity of HIV and lead tothe independent development of anaemia andneutropenia.41 Consistent with these observa-tions, the incidence of anaemia or neutropeniain mildly or asymptomatic adults treated withzidovudine was between 1.1% and 9.7%,whereas in adults with AIDS or AIDS relatedcomplex it ranged from 15% to as high as61%.41 This toxicity is generally reversible andmay be managed by dose reduction or drugwithdrawal. Other interventions also appear toconfer varying degrees of benefit, includinggrowth factors for neutropenia,42 and recom-binant haemoglobin43 or erythropoietin44 foranaemia. In vitro studies also confirm the hae-matological toxicity of HIV and zidovudine,19

although the mechanism of this toxicity isunclear. One study suggested that permeationof the drugs into canine bone marrow progeni-tor cells might be an indicator of drug specifictoxicity, since although ZDV permeation wasitself slow, ddI was even slower and ddC didnot permeate at all.45 Törnevik and colleaguessuggested that the cytotoxic eVect correlateswith ZDV monophosphate levels,25 Faraj andcolleagues confirmed these findings and didnot demonstrate a correlation between toxicityand mitochondrial DNA inhibition,46 suggest-ing that this eVect may occur through someother mechanism. Although it is known thatmitochondrial dysfunction may result in hae-matological toxicity, it seems possible thatzidovudine associated haematological toxicitymay result from alternative eVects, perhaps onhaem metabolism or gene expression. Bothzidovudine and stavudine treatment are knownto be associated with macrocytosis, althoughthe mechanism and clinical significance isunclear.47 HIV infection is also known to beassociated with thrombocytopenia,48 possiblythrough the action of specific viral strains in thebone marrow, and this has been shown toimprove with zidovudine treatment.49

MYOPATHY

HIV infection may be associated with myopa-thy at all stages of the disease.50 It was alsonoted that zidovudine therapy may be associ-ated with myopathy in the early studies withthis agent,51 although distinguishing the disease

and drug related myopathies has proveddiYcult.52 Simpson and colleagues analyseddata from a placebo controlled study ofzidovudine,53 and conducted a prospectivemyopathy substudy in a large trial of combina-tion therapy.54 In the first study, ACTG 016,five out of 279 (1.8%) zidovudine treatedpatients had a composite myopathy diagnosis,compared with none in the placebo group.ACTG 016 examined a dose of 200 mgzidovudine every 4 hours (1200 mg/day), andthree instances of dose reduction in the fivepatients with a composite myopathy diagnosisled to improvements in creatine kinase levels,but no improvement in strength. However, CKlevels were also observed to improve independ-ent of dose reduction, and in these instancesimprovement in strength was noted on oneoccasion.53 The second study, ACTG 175, wasa placebo controlled comparison of ZDV orddI monotherapy and ZDV/ddC or ZDV/ddIdual therapy in 2467 patients with HIVinfection. A myopathy substudy was alsoconducted in the 1067 antiretroviral naive par-ticipants in this trial. No significant diVerenceswere observed between the treatment arms foradverse events related to myopathy, althoughthe ZDV/ddC group had a reduced incidenceof myalgia compared with the other groups.Although site diagnoses in this study weremade without predefined criteria, it is notewor-thy that only six cases of myopathy were identi-fied, four on ddI monotherapy, one each onZDV/ddI and ZDV/ddC dual therapy, andnone on ZDV monotherapy.54 The lack of anassociation between ZDV therapy and myopa-thy in this study may in part relate to the doseadministered, since the dose of ZDV used inthis study was half that in ACTG 016 (600mg/day v 1200 mg/day).

The data reviewed above illustrate that drugrelated myopathy is quite rare, particularly withcurrently used doses, and a number of studieshave attempted to explain the pathophysiologyof this disorder. Benbrik and colleagues studiedthe eVects of ddI, ddC, and ZDV on culturedhuman muscle cells and showed that althoughZDV was the most potent inhibitor of cell pro-liferation, ddC and ddI were the most potentinhibitors of mitochondrial function.55 Deple-tion of mitochondrial DNA has been reportedin patients with zidovudine related myopathy,and this has been shown to be reversible ondrug withdrawal.56 The histopathological as-sessment of myopathy has proved somewhatcontroversial, particularly with regard to thepresence of “red ragged fibres” and abnormali-ties in mitochondrial morphology. Since thereis frequently little correlation between theseobservations and the presence of myopathy,their use in isolation is not recommended.57

Chariot and colleagues have shown that thehistological assessment of zidovudine myopa-thy may be improved by looking cytochrome coxidase activity,58 and studies in rats havereported similar observations. Many inheritedmitochondrial diseases are known to be associ-ated with myopathy,59 and the changes ob-served in mitochondrial DNA levels in clinicaland laboratory studies of zidovudine myopathy


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strongly support a mitochondrial pathophysiol-ogy for this eVect, although it should beacknowledged that there are data suggestingother mechanisms.60 Finally, it is worth notingthat HIV infection may rarely be associatedwith rhabdomyolysis, and with the increasinguse of cholesterol lowering drugs in patientswith HIV infection, the potential myotoxicityof the HMG CoA reductase inhibitors shouldbe noted since cases of rhabdomyolysis associ-ated with these agents in HIV patients havebeen reported.61

CARDIOMYOPATHY

Abnormal cardiac pathology was identified inpostmortem studies of AIDS patients in themid 1980s, and subsequent studies have shownthat cardiac involvement in HIV infection is byno means uncommon.62 The spectrum ofcardiac disease in HIV infection has beenreviewed elsewhere and will not be consideredfurther here.63 It is known that mitochondrialdysfunction may frequently be associated withheart disease.64 In vitro studies have identifiedthat cardiac mitochondrial DNA polymerasemay be inhibited by zidovudine,65 and studiesin rats have shown that the drug may alsoinduce ultrastructural changes in cardiac myo-cytes.66 A recent study by Lewis and colleaguesdemonstrated that zidovudine and HIV infec-tion led to the independent development ofcardiomyopathic changes in a transgenicmouse model,67 although the dose of zidovu-dine used in this study was significantly higherthan that used clinically in HIV infectedpatients (∼200 mg/kg v 8 mg/kg). Lipshultz andcolleagues studied cardiac structure and func-tion in HIV infected children and found noassociation between any changes and treatmentwith zidovudine.68 In a more recent study, thesame group studied infants exposed to zidovu-dine perinatally and again noted an absence ofcardiac dysfunction.69 Others have reported anassociation between cardiomyopathy andtherapy with ZDV, ddC or ddI,70 but the majorpart appears to be played by HIV disease orother as yet unidentified factors.71

NEUROPATHY

Peripheral neuropathy has long been recog-nised as a complication of HIV infection, theincidence of which increases with the degree ofimmunosuppression.72 Three of the currentlylicensed NRTIs, ddC, ddI and d4T, have alsobeen associated with the development of distalsymmetrical polyneuropathy in clinical stud-ies.73 It is diYcult to distinguish HIV and drugrelated neuropathy, although drug related neu-ropathy is more likely to be painful, have anabrupt onset, and rapid progression.74 Thediagnosis of neuropathy should follow acomprehensive neurological history and exam-ination, including assessment of other risk fac-tors such as concomitant neurotoxic medi-cation or nutritional deficiency.73 In theneuromuscular substudy of ACTG 175 dis-cussed above, only half of the site diagnoseswere confirmed as drug related by a reviewusing defined criteria.54 The incidence of drugrelated neuropathy was significantly greater in

the ZDV/ddC arm, but not diVerent in the ddI,ZDV, or ZDV/ddI arms.54 The duration oftreatment with the neurotoxic NRTIs increasesthe likelihood of the development of drugrelated neuropathy, with 25% of ddC treatedpatients developing this complication after >9months of therapy.74 Studies with ddI haveshown that this agent is associated with thedevelopment of neuropathy but at lowerfrequency than ddC or d4T, and the reportedrates have been similar to non-neurotoxicagents in some studies.74 In the large paralleltrack study of d4T, neuropathy was reported in17% of patients receiving d4T 40 mg/day com-pared with 23% of patients receiving 80mg/day.74 Although there is limited informationon the risk associated with combinations ofneurotoxic NRTIs, Moore and colleagues haverecently reported an analysis in 1116 patientson the Johns Hopkins HIV database. Thisstudy showed that the risk of peripheralneuropathy in patients treated with ddI andd4T was 3.5-fold greater than for patientstreated with ddI alone in a multivariate modeladjusted for other factors.75 Hydroxyurea wasshown to increase the risk of peripheralneuropathy still further, since patients takingddI/d4T hydroxyurea were shown to have a7.8-fold greater risk than ddI alone,75 findingsthat have also been confirmed by othergroups.76 Since studies have shown that thedevelopment of neuropathy with ddC, ddI, andd4T is dose related, management by dosereduction or discontinuation is normally rec-ommended.74 In addition to treatment withanalgesics, tricyclic antidepressants, and topi-cal anaesthetics specific interventions havebeen examined. Although recent studies ofrecombinant human nerve growth factor77 andvibratory stimuli78 have not shown significanteYcacy, a pilot study of lamotrigine reportedsome improvements in symptoms.79 Famularoand colleagues noted that 12 HIV infectedpatients with peripheral neuropathy on regi-mens including ddC, ddI, or d4T had acetylcarnitine deficiency compared with controlswith no disease or non-drug related neuropa-thies.80 Subsequent to this, Hart and colleaguesrecently reported a small, uncontrolled investi-gation into the use of L-acetyl-carnitine (1500mg twice daily) for the treatment of drugrelated neuropathy and showed improvementsin symptoms and evidence of peripheral nerveregeneration in the four patients studied.81

Carnitine and its derivatives are importantintermediaries in the transport and utilisationof fatty acids by mitochondria. More recently,Cergnul and colleagues reported a small, shortterm, placebo controlled study of topical aspi-rin in diethyl ether, during which the patientstreated with this solution reported improve-ments in pain relief.82

In vitro studies have confirmed the neuro-toxic potential of ddC and ddI, and correla-tions with mitochondrial DNA depletion wereobserved.20 However, although d4T exhibitedneurotoxicity in the same study, there was nocorrelation with mitochondrial DNA deple-tion. A study in rabbits showed mitochondrial

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alterations in peripheral nerves after ddC treat-ment,83 but similar studies with ddI and d4Tshowed no neurotoxic eVect in the samespecies,84 although ddI has been shown tocause neurotoxicity in rats given very highdoses. The well described neuropathies associ-ated with inherited mitochondrial diseases85

and the evidence discussed above do suggest arole for mitochondrial dysfunction in thepathogenesis of drug related neuropathy butinconsistencies do exist. The benefit ofL-acetyl-carnitine supplementation also sup-ports this mechanism but it is clear that larger,well controlled studies are needed before it canbe widely recommended, and other therapiesfor the management of neuropathy are urgentlyrequired.

PANCREATITIS

Individuals with HIV infection are at greaterrisk for the development of pancreatitis as aresult of immunodeficiency and exposure to avariety of pancreatotoxic agents.86 These in-clude drugs used to treat opportunistic infec-tions, such as pentamidine, and drugs to treatthe HIV infection itself, principally didanosine.The reported incidence of pancreatitis withdidanosine varies. Maxson and colleagues sug-gested it was relatively common with clinicalpancreatitis present in 23.5% of their patientsand asymptomatic elevations of amylase andlipase in an additional 39.2%.87 However, itshould be noted that most of the patients in thisstudy were taking both pentamidine and dida-nosine, thus additive or synergistic toxicitywould be predicted to account for the higherrates observed.87 Other studies suggest an inci-dence ranging from 4%–7% at currentlyrecommended doses, with rates increasing athigher doses of ddI.86 Fatal cases of pancreati-tis have been reported,88 and mortality rangesfrom 6% at current doses to 17% at higherdoses. The ACTG 5025 study examinedintensification of d4T/ddI/IDV with hydroxy-urea and reported that two of the patients inthe hydroxyurea arm developed fatal pancrea-titis, two other cases in the non-hydroxyureaarm survived.89 More recently, Moore and col-leagues reported a fourfold increased risk forpancreatitis when hydroxyurea was used withddI or ddI and d4T. They also reported asimilar incidence associated with either ddI ord4T alone and an increased risk of pancreatitisif these two agents were used together.90

Asymptomatic elevations in serum pancreaticenzymes occur more frequently than clinical

pancreatitis, and these should be monitored,particularly if other risk factors are present. Ifpancreatitis has developed in the past, perma-nent discontinuation of ddI is suggested sincerechallenge often results in recurrent disease.86

There are limited data suggesting an associ-ation with other NRTIs, the incidence withddC therapy appears to be <1%,91 andalthough early paediatric studies describedcases in children receiving 3TC, many of thesechildren had a previous history of pancreatitisor were receiving concurrent pancreatotoxicmedication.86 A recent comparative study ofZDV/3TC and ddI monotherapy in 471 paedi-atric HIV patients reported no cases ofpancreatitis in the ZDV/3TC arm and four inthe ddI arm,92 and pancreatitis has rarely beenreported in adults treated with 3TC.93 Cases ofpancreatitis associated with severe lactic acido-sis have been reported,94 and mitochondrialdysfunction is known to be associated withpancreatic abnormalities,95 but the evidencesupporting a mitochondrial pathophysiologyfor ddI associated pancreatitis is limited atpresent. Early studies in a rat model ofpancreatitis demonstrated no changes even atextremely high doses of ddI,96 although a morerecent study of a pancreatic cell line suggesteda dose dependent mitochondrial toxicity of ddIin this system.97 Since it has been observed thatthe protease inhibitors may lead to significantincreases in plasma triglyceride levels and it isalso known that raised triglyceride levels are arisk factor for pancreatitis, these parametersshould be monitored since cases of pancreatitishave been reported under these circum-stances.98

LACTIC ACIDOSIS

Severe liver toxicity, manifesting as acute lacticacidosis with evidence of hepatic steatosis isprobably the most worrisome toxicity of theNRTIs, since it can often be fatal and progres-sion may be rapid. It was first identified in theera of NRTI monotherapy but cases have con-tinued to be reported with dual and triplecombination therapy. Brinkman and colleagueshave recently reviewed this area4 and otherreviews have been published previously99 so thissection will concentrate on recent data.

When a cell is unable to generate enoughenergy through oxidative phosphorylation,anaerobic respiration occurs via the conversionof pyruvate to lactate in the cytoplasm. Thisalso results in excess production of hydrogenions, which if uncontrolled, may lead to a

Table 1 Cohort studies of raised lactate levels or anion gap

Study No Hyperlactataemia prevalence Analysis Factors associated with hyperlactataemia

Harris et al106 331 68/331 (21%) >2.1 mmol/l, 27/331 (8%) > 3.0 mmol/l Multivariate logistic regression Current d4T, time on d4T, currenthydroxyurea

John et al107 349 224/349 (64%) >1.5 mmol/l, 83/349 (24%) >2.5–5 mmol/l,5/349 (1%) >5 mmol/l

Cox proportional hazards,multivariate linear regression

d4T therapy, fat wasting

Boubaker et al108 988 107/988 (11%) > 2 mmol/l, 14/988 (1%) > 4 mmol/l Multivariate logistic regression d4T or ddI therapy, fat wasting,hypertriglyceridaemia

Vrouenraets et al109 223 No ARV treatment, 4/49 (8%) 2–5 mmol/lNRTI treatment, 38/174 (22%) 2–5 mmol/l

Multivariate analysis NRTI treatment, d4T therapy

Moore et al110 628 Anion gap > 16 mEq/l, 7% to 14% depending on NRTIcombination

Multivariate logistic regression d4T/3TC 2.3-fold greater risk thanZDV/3TC (p=0.02)

Gerard et al111 806 Anion gap > 20 mEq/l, 0 to 3.3% depending on NRTIcombination

Paired comparisons D4T/3TC greater anion gap thanZDV/3TC (p<0.001)


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cellular and subsequently metabolic acidosis.Clearance is normally performed by the liverand kidneys but if the production is excessiveor these organs are damaged, accumulation oflactate and hydrogen ions may occur andsevere lactic acidosis may result. Lactic acidosisis a known feature of many mitochondrial dis-orders9 and steatosis results from inhibition offatty acid oxidation, leading to the accumula-tion of lipid droplets. In vitro studies and recentreports showing evidence of mitochondrialdysfunction after detailed clinical and labora-tory investigations in patients with lactic acido-sis associated with d4T and ddI100 or ZDV101

confirm a mitochondrial pathophysiology.Cases of severe lactic acidosis have beenreported with all NRTIs, and the incidence ofthe acute syndrome is fortunately quite rare,around 1.3 per 1000 person years, although itshould be noted that the initial data from whichthis rate was calculated were probably inad-equate.4

Recently a number of groups have studiedthe prevalence of symptomatic hyperlactatae-mia and others have surveyed large cohorts forthe prevalence of lactate levels above the upperlimit of normal. Before reviewing these data, itis worth mentioning that lactate measurementis fraught with problems and care needs to betaken over sampling and handling to avoidmisleading values.102 In an extended follow upof their earlier paper,103 Lonergan and col-leagues have described 33 patients with de-compensated or symptomatic hyperlactataemiaassociated with NRTI treatment in a largecohort.104 The clinical presentation and lactateelevations were milder than in other studies ofacute lactic acidosis. Symptoms includedabdominal pain, nausea, and distension, andonly one patient required hospitalisation.Antiretroviral therapy was discontinued inthese patients until lactate levels normalised(median time 49 days).The incidence of thissyndrome was observed to be about 13-foldgreater than that quoted for acute lactic acido-sis, and it was also noted to be particularlyassociated with d4T containing regimens, with31/33 cases on d4T containing therapies. Sev-enteen patients have restarted therapy, 16replacing d4T with ABC (n=10), ZDV (n=4),or both (n=2). All patients taking 3TCrestarted this drug in their new regimen, andthere have been no recurrences of the syn-drome to date.104 Gerard and colleaguesdescribed 14 cases of decompensated hyperlac-tataemia in a cohort of 871 patients; theincidence was 0.8% per year which rose to1.2% per year if only patients on d4T contain-ing regimens were included.105 The clinicalpresentation was similar to that described byLonergan and colleagues, muscle biopsies fromfour of five patients showed ultrastructural andbiochemical evidence of mitochondrial dys-function. These data suggest that patients mayexperience a milder form of decompensatedlactic acidosis more frequently than the acutesyndrome described previously. Hence, signsand symptoms should be monitored since thissyndrome may also be associated with signifi-cant morbidity. Regarding the association with

d4T containing regimens, it is important tointerpret such data with caution since theremay be confounding biases which have notbeen identified in such studies and the numberof cases are too small to draw definitiveconclusions. Many other large studies have alsoinvestigated the prevalence of hyperlactatae-mia; however, it is important to distinguishthese studies from those of Lonergan and Ger-ard, since these larger studies have reportedany patients with raised lactate levels, not justthose with symptoms. Across these studies,there is a higher incidence of hyperlactataemiaon d4T containing therapies (table 1).106–111 Inaddition, some studies primarily focused onlipodystrophy have also noted an associationbetween d4T therapy and hyperlactataemia.112

Saint Marc and colleagues noted that patientsswitched from d4T to either ZDV or ABC hadsignificant reductions in their plasma lactatelevels, which were elevated on d4Ttherapy.113 114

While it remains clear that acute lacticacidosis, decompensated hyperlactataemia,and compensated hyperlactataemia may beassociated with all NRTIs the data reviewedabove suggest a greater risk associated withd4T therapy. Prospective studies of prevalenceand resolution will be required to confirm theseobservations, although the evidence from mul-tivariate analyses of large cohorts appears con-sistent. The OZCOMBO I study, a randomisedcomparison of ZDV/3TC, d4T/3TC, andd4T/ddI with indinavir described significantlyincreased lactate levels with d4T/ddI armcompared with the other two arms, although itshould be noted that the level of follow up inthis analysis was poor.115 A key question thatremains to be answered is whether the presenceof asymptomatic hyperlactataemia is an indica-tor of a predisposition to develop symptomaticlactic acidosis, or whether it reflects the currentlevel of interest in this parameter and thusmore frequent monitoring and reporting. Thecomparative rarity of decompensated lacticacidosis compared with the high frequency ofpatients with lactate elevation but no symp-toms suggests that routine lactate monitoring isunlikely to be helpful in this regard. A highdegree of awareness of related symptomswould appear to be the best approach atpresent. Treatment of lactic acidosis has beenreviewed by Brinkman,4 and generally involvesthe administration of what might be termedmitochondrial supportive therapy such as thia-mine, riboflavin, ubiquinone, and acetyl-carnitine in addition to cessation of antiretrovi-ral therapy and intensive support. Doses andeYcacy are unclear and since it is likely thatcessation of NRTI therapy is the mostsignificant factor contributing to observedimprovements controlled studies are required.Brinkman and colleagues have suggested aprotocol in the absence of standardised recom-mendations.116 Dichloroacetate (DCA) hasbeen studied for the treatment of lactic acidosisand was found to have no benefit it terms ofdecreased mortality in one large study.117 How-ever, through its action on pyruvate dehydroge-nase, DCA directly reduces lactate production

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and more recent case reports have suggestedthat this agent may be useful in NRTIassociated lactic acidosis.118

LIPODYSTROPHY

Reports of metabolic and body habitus changesin HIV patients led to the description of whathas become known as HIV associated lipodys-trophy. Initial studies associated this syndromewith the protease inhibitors although subse-quently it has become clear that the NRTIs,particularly d4T, also play a part. A detaileddiscussion of lipodystrophy is beyond the scopeof this article; recent reviews of lipodystrophy119

and HIV associated lipodystrophy1 have beenpublished. This section will describe the stud-ies associating NRTI therapy with lipodystro-phy, since Brinkman and colleagues120 andKakuda and colleagues121 have proposed thatthis may be related to mitochondrial toxicity.Before reviewing the data it is worth noting thata consensus definition for lipodystrophy is stillunder development and there are many otherfactors that may influence the development ofmetabolic or body habitus changes in anindividual. Therefore, it must be rememberedthat lipodystrophy is undoubtedly a syndromewith a multifactorial aetiology. Table 2 presentsthe findings from both cohort studies and ran-domised, controlled trials that have examinedthe association of NRTIs with lipodys-trophy.115 122–140 167 It can be seen that overallduration of NRTI therapy and d4T therapy inparticular are associated with the developmentof lipodystrophy. Since time on therapy hasbeen identified as a risk factor the associationwith d4T could simply be because it was themost recently used nucleoside. However, mostof the studies conducted rigorous multivariateanalyses to control for confounding factorssuch as time on therapy, and the independent

eVect of d4T remained significant. Further-more, the evidence from cohort studies (fig 4)is consistent with that from randomisedcontrolled trials in therapy naive patients—forexample, the ALBI study. In this study,d4T/ddI was associated with a significantlygreater risk of lipodystrophy than ZDV/3TC inboth analyses, whether of all patients asrandomised at the start of the study (54% v20%, p=0.001), or those patients who re-mained on NRTIs alone (52% v 10%,p=0.02).138 Some authors have examinedswitching patients from d4T to other NRTIs toimprove lipodystrophy. In an extended followup of an earlier study,113 Saint-Marc et alreported 59 patients with subcutaneous fatwasting on d4T therapy (18 on NRTI therapyand 41 on PI therapy), where d4T was replacedby either ZDV or ABC. This was shown toresult in major improvements in peripheral fatwasting in most patients independent ofconcomitant PI use (83% in the NRTI groupand 71% in the PI group) after 12 months. Fatwasting was assessed by objective measure-ment (abdominal and mid-thigh CT scan) andreductions in serum lactate levels were alsoobserved.114 Polo and colleagues also observedimprovements in fat wasting and metabolicparameters in 10 patients switched fromd4T/ddI to ZDV/3TC while maintaining indi-navir.141 A more recent report describedimprovements in facial fat wasting in 11patients who discontinued d4T, nine switchedto ZDV or ABC.142 The data reviewed abovestrongly support a significant role of d4Tamong the NRTIs in the development ofsubcutaneous fat wasting, and provide encour-aging early evidence with regard to reversibilityon switching to other NRTIs; however, theresults of ongoing randomised studies areawaited to confirm these findings.

Figure 4 Cohort studies have shown that d4T (stavudine) is associated with a greater risk of lipodystrophy, primarilysubcutaneous fat wasting, compared with ZDV (zidovudine). This figure shows the relative risk for D4T versus ZDV fromstudies where this information was given or could be calculated. It should be noted that the multivariate analyses denoted byan asterisk are the most reliable indicators, since they have controlled for possible confounding variables such as previoustherapy duration Note: % refers to LD prevalence.

Boufassa et al (n = 595)

Gervasoni et al (n = 306)

Multivariate analysis

10Increased risk with ZDV Increased risk with d4T0 1

34%

33%33%

17%62%

10%10%

44%49%

34%53%

11%52%

53%16%

57%28%Bernasconi et al SHCS (n = 1355)

Galli et al (n = 188)

Saint Marc et al (n = 139)

Carr et al (n = 220)

Wolf et al (n = 93)

Mauss et al (n = 221)

HOPS et al (n = 1077)

Mallal et al (n = 277)

Carmena et al (n = 232)

Galli et al LipoICONA (n = 704)

Chene et al APROCO (n = 321)ˆ

Mallolas et al (n = 506)

Galli et al LIMS (n = 2258)

Schwenk et al (n = 278)

Bogner et al (n = 115)


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Tabl

e2

Coh

ort

stud

ies

and

rand

omis

edco

ntro

lled

tria

lsof

lipod

ystr

ophy

with

NR

TIs

Stu

dyN

oR

xL

Das

sess

men

tO

vera

llL

Dpr

eval

ence

Ana

lysi

sF

acto

rsas

soci

ated

with

incr

ease

dri

skof

LD

Coh

orts

tudi

esB

ern

asco

niet

al12

2S

wis

sH

IVco

hort

1359

NR

TI

PI

Phy

sici

anan

dpa

tien

tas

sess

men

tA

nyL

D:5

78/1

359

(43%

),F

atlo

ss(F

L):

382/

1359

(28%

),F

atac

c(F

A):

412/

1359

(30%

)M

ulti

vari

ate

logi

stic

regr

essi

onF

atlo

ss—

age,

grea

ter

NR

TI

expo

sure

,d4T

,AB

C,

elev

ated

lact

ate

Fat

gain

—ag

eG

ouja

rdet

al12

3L

ipos

ud

646

NR

TI

PI

Phy

sici

anas

sess

men

tA

nyL

D:3

74/6

46(5

8%),

LD

(PI

grou

p):3

16/4

98(6

4%),

LD

(NR

TI

grou

p):5

8/14

8(3

9%)

Un

adju

sted

com

pari

son

ofL

D+

wit

hL

D−

Dur

atio

nof

trea

tmen

tov

eral

l,du

rati

onof

PI

trea

tmen

t,d4

Tth

erap

yG

alli

etal

124

188

Onl

yN

RT

IP

hysi

cian

and

pati

ent

asse

ssm

ent

Any

LD

:31/

188

(16%

),A

nyL

D(F

emal

e):2

5/96

(26%

),A

nyL

D(M

ale)

:6/9

2(7

%)

Mul

tiva

riat

ean

alys

isF

emal

ese

x,d4

T

Sai

ntM

arc

etal

125

LIP

OC

Ost

ud

y15

4N

RT

IP

IP

hysi

cian

asse

ssm

ent,

BIA

,CT

Any

LD

:82/

154

(53%

),F

L(P

Igr

oup)

:58/

100

(58%

),F

L(N

RT

Igr

oup)

:15/

39(3

8%),

FA

(PI

grou

p):4

5/10

0(4

5%),

FA

(NR

TI

grou

p):3

/39

(8%

)

Mul

tiva

riat

elo

gist

icre

gres

sion

d4T

ther

apy

Car

ret

al12

622

0N

RT

IP

IP

hysi

cian

and

pati

ent

asse

ssm

ent,

DE

XA

,CT

NA

—ca

se-c

ontr

olst

udy,

116

LD

case

s,10

4co

ntro

lsM

ulti

vari

ate

anal

ysis

FL

:age

,gre

ater

NR

TI

expo

sure

,d4T

ther

apy,

elev

ated

lact

ate

FA

:age

,PI

dura

tion

,3T

CG

erva

son

ieta

l127

306

NR

TI

PI

Phy

sici

anas

sess

men

t,D

EX

AA

nyL

D:3

2/30

6(1

1%),

LD

(NR

TI

grou

p):1

2/16

2(7

%)

Mul

tiva

rate

logi

stic

regr

essi

onD

urat

ion

ofA

RT

,vir

allo

ad>

1000

0co

pies

Wol

fet

al12

893

NR

TI

PI

Phy

sici

anas

sess

men

tA

nyL

D:4

9/93

(53%

)M

ulti

vari

ate

logi

stic

regr

essi

onE

leva

ted

oest

radi

ol,t

rigl

ycer

ide

>50

0m

g/dl

,d4T

Mau

sset

al12

9L

ipA

RT

221

NR

TI

PI

Phy

sici

anan

dpa

tien

tas

sess

men

tat

3ye

ars

Any

LD

:76/

221

(34%

)M

ulti

vari

ate

anal

ysis

CD

4na

dir

<20

0ce

lls,d

4Ttr

eatm

ent

Lic

hten

stei

net

al13

0H

OP

S10

77N

RT

IP

IP

hysi

cian

and

pati

ent

asse

ssm

ent

Any

LD

:529

/107

7(4

9%),

Mod

erat

e/se

vere

LD

:18

%M

ulti

vari

ate

logi

stic

regr

essi

onA

ge,w

hite

race

,cha

nge

inB

MI,

nad

irC

D4,

stud

ysi

te,d

4T,i

ndin

avir

Mal

lale

tal13

1W

Aus

tral

iaco

hort

277

NR

TI

PI

Phy

sici

anas

sess

men

t,lo

ngit

udin

alD

EX

AO

vera

llF

L:1

21/2

77(4

4%),

FL

(PI

grou

p):1

12/2

01(5

4%),

FL

(NR

TI

gp.)

:9/7

1(1

3%)

Cox

prop

orti

onal

haza

rds,

mul

tiva

riat

elin

ear

regr

essi

onF

L—

age,

whi

tera

ce,d

ualN

RT

Ith

erap

ydu

rati

on,

d4T

du

rati

on,P

Id

ura

tion

Car

men

aet

al13

223

2N

RT

IP

IP

hysi

cian

asse

ssm

ent

Ove

rall

LD

:24/

232

(10%

)M

ulti

vari

ate

logi

stic

regr

essi

onU

ndet

ecta

ble

vira

lloa

d,d4

Tth

erap

yG

alli

etal

133

Lip

oIC

ON

A70

4N

RT

IP

IP

hysi

cian

asse

ssm

ent

FL

:43/

704

(10%

),F

A:6

2/70

4(1

1%),

Mix

ed:

29/7

04(6

%)

Cox

prop

orti

onal

haza

rds

mod

elF

L:d

4T,H

CV

neg

ativ

eF

A:w

eigh

t,M

ixed

:Fem

ale

sex,

indi

navi

rS

aves

etal

134

AP

RO

CO

670

All

NR

TI

+P

IP

hysi

cian

and

pati

ent

asse

ssm

ent

Any

LD

12m

onth

s:18

8/30

4(6

2%),

Any

LD

20m

onth

s:21

2/33

6(6

3%)

Mul

tiva

riat

ean

alys

isA

ge,B

MI,

dura

tion

ofA

RT

befo

rein

itia

tion

ofP

I

Mar

tine

zet

al13

550

6A

llN

RT

I+

PI

Phy

sici

anan

dpa

tien

tas

sess

men

tA

nyL

D:8

2/50

6(1

7%),

FL

alon

e:25

/506

(31%

),B

oth

FL

+F

A:4

2/50

6(8

%)

Mul

tiva

riat

ere

gres

sion

Age

,sex

ualt

rans

mis

sion

ofH

IV,d

4Tth

erap

y

Gal

liet

al13

6L

IMS

2258

NR

TI

PI

Phy

sici

anan

dpa

tien

tas

sess

men

tA

nyL

D:7

50/2

258

(33%

),F

A:4

35/2

258

(19%

)M

ult

ivar

iate

anal

ysis

Age

,AR

Td

ura

tion

and

no

ofd

rugs

.Fem

ale

sex

Sch

wen

ket

al16

727

8H

AA

RT

Phy

sici

anan

dpa

tien

tas

sess

men

tA

nyL

D:8

8/27

8(3

2%),

FL

18/2

78(2

1%),

FA

10/2

78(1

1%),

Mix

ed:5

9/27

8(6

7%)

Mul

tiva

riat

elo

gist

icre

gres

sion

Age

,PI

dura

tion

,low

CD

4

Bog

ner

etal

137

115

HA

AR

TP

hysi

cian

and

pati

ent

asse

ssm

ent

FL

:39/

115

(34%

),F

A:3

3/11

5(2

9%)

Bac

kwar

dlo

gist

icre

gres

sion

All:

HA

AR

Tdu

rati

on,w

hite

race

.FL

:age

and

vira

llo

ad

Stu

dyN

oR

xL

Das

sess

men

tF

indi

ngs

Ran

dom

ised

,con

trol

led

tria

lsM

olin

aet

al13

8A

LB

Ist

ud

y15

1Z

DV

/3T

Cv

d4T

/dd

Iv

d4T

/dd

Ifo

r3

mon

ths

then

ZD

V/3

TC

Phy

sici

anas

sess

men

tat

30m

onth

s(1

20/1

51)

Ove

rall

LD

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Brinkman and colleagues proposed thatNRTI associated lipodystrophy may be relatedto mitochondrial toxicity partly due to thesimilarities between Madelung’s disease andsome of the clinical features of the lipodystro-phy syndrome.120 While Saint-Marc and col-leagues noted a reduction in plasma lactatelevels as lipodystrophy improved114 and Carrand colleagues described a syndrome of lacticacidaemia and peripheral fat wasting,112 both ofthese observations also related to the presenceor absence of d4T therapy, which is known tobe associated with a higher risk for thedevelopment of both hyperlactataemia andperipheral fat wasting. More recently, Walker etal143 and Shikuma et al144 have demonstratedthat fat biopsies from patients with lipodystro-phy show depletion of mtDNA compared withcontrols, and Mallal and colleagues have dem-onstrated ultrastructural abnormalities of mi-tochondria in similar tissue.145 The mean loss ofmtDNA reported by Walker and colleagueswas 44%, below what might normally beconsidered a threshold for expression ofdysfunction. However, it is important to recog-nise that the threshold eVect applies toindividual cells within a tissue; since a biopsy islikely to include both normal and abnormalcells (fig 3) this lower average level of depletionsupports rather than discounts some mito-chondrial eVect. Paulik and colleagues havedescribed an association between metaboliccomplications associated with NRTIs andchanges in the expression of genes and markersof oxidative stress in animal models and cellculture.146 They also reported that antioxidantssuch as ascorbate and tocopherol amelioratedthese adverse eVects, suggesting future studiesof these agents may be warranted.

RENAL TOXICITY

Adefovir, a nucleotide analogue, was shown toinduce nephrotoxicity in a significant pro-portion of patients after longer than 6 months’exposure.147 Recent experiments have demon-strated that adefovir is a substrate for thehuman renal organic anion transporter 1, andis thus concentrated in the cells of the proximaltubule.148 This has been shown to result inincreased cytotoxicity in vitro, although themechanism of this cytotoxicity is unclear.148

The clinical presentation of renal involvementin inherited mitochondrial disease is similar tothat noted for adefovir toxicity,149 and adefoviris known to inhibit mitochondrial DNApolymerase,150 but it is currently unknownwhether the nephrotoxicity of adefovir is mito-chondrial in nature. Adefovir is no longer beingpursued for the treatment of HIV, althoughlower doses are being studied for the treatmentof hepatitis B infection. No particular associ-ation with other nucleoside analogues has beenreported, although a case of nephrotoxicitywith ddI was reported some years ago151 andone with d4T/3TC more recently,152 althoughthe latter may have been associated withdecompensated hyperlactataemia.

NRTIs AND PERINATAL TRANSMISSION

Zidovudine therapy has been widely used forthe prevention of mother to child transmissionand significant reductions have been observedin the number of new infections as a result ofthis and other interventions. Blanche andcolleagues recently reported eight cases ofmitochondrial dysfunction in uninfected chil-dren exposed to zidovudine and lamivudine ina clinical study for the prevention of perinataltransmission.153 The evidence for mitochon-drial dysfunction in these children was notcomprehensive, only two had evidence ofhistological or histochemical features of mito-chondrial disease and mitochondrial DNA lev-els were normal in the three children for whomdata were available. In a more recent report, thesame authors have described 16 cases stronglysuspected of mitochondrial dysfunction.154

Since the initial reports, there have been exten-sive eVorts among other groups to look forsimilar cases, however various analyses havefailed to identify any deaths similar to thosereported by Blanche and colleagues.155–158

Nevertheless, this study raised important ques-tions around the risk-benefit ratio of theprevention of perinatal transmission usingantiretrovirals. Further research and follow upmust continue, particularly considering the useof other NRTIs for this indication and toinform clinical management, since elevatedlactate levels in infants are common and maybe associated with a variety of causes but couldalso indicate mitochondrial dysfunction in thepresence of other findings. Taking these data incontext, the clear public health benefits associ-ated with reductions in perinatal transmissionhave meant current recommendations forantiretroviral use remain unchanged, althoughcontinued vigilance is warranted.159

Management of mitochondrial toxicitySince NRTI associated mitochondrial toxicityis acquired during NRTI treatment, cessationof the oVending agent or dose reduction maybe suYcient to limit the toxicity as has beendiscussed when these clinical toxicities havebeen reviewed above. There are a variety ofstrategies that may be employed to treat mito-chondrial disease,160 but they are generallypoorly studied and are frequently used on thebasis of a theoretical rationale alone. Brinkmanhas reviewed the evidence supporting the useof supplements such as thiamine, riboflavin,ubiquinone, and acetyl-carnitine,4 and it wouldcertainly appear reasonable to employ theseagents in patients with severe mitochondrialdisease, such as lactic acidosis. However,whether they might be used concomitantlywith antiretroviral therapy to delay the onset ofmitochondrial toxicity, if that is indeed thepathophysiological mechanism for the toxicityconcerned, remains to be answered by prospec-tive studies.

Mitochondrial toxicity of new agentsWith the inexorable development of resistanceto all agents used to treat HIV, new agents arecontinually being investigated. With the knownpotential for mitochondrial toxicity with


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NRTIs, detailed studies are required althoughthe inconsistencies discussed previously withvarious in vitro and animal models make com-prehensive evaluation diYcult. Fialuridine(FIAU) was an investigational nucleoside ana-logue for the treatment of hepatitis B, andalthough initially well tolerated, after 12–14weeks many patients experienced severe multi-organ mitochondrial toxicity and died, despitereceiving emergency liver transplants.28 Studiesin dogs and monkeys had failed to predict thistoxicity, although later studies in woodchucksconfirmed the profound mitochondrial toxicityof this agent.161 The withdrawal of adefovir dis-cussed earlier and the recent suspension in thedevelopment of F-ddA illustrate the diYcultiesin developing new NRTIs for the treatment ofHIV. Didanosine (ddI) is actually converted toddA as it is anabolised, and lodenosine(F-ddA) is a fluorinated version of thismolecule with better bioavailability and en-hanced potency against HIV in vitro. In vitrostudies did not identify appreciable eVects onmitochondrial DNA levels or lactate produc-tion,162 but a phase II study of F-ddA in combi-nation with d4T and indinavir was stoppedwhen one patient died and others showed evi-dence of liver or kidney problems.163 As hasbeen discussed earlier, the use of hydroxyureato boost the eYcacy of NRTIs has been shownto be associated with an increased risk ofperipheral neuropathy and pancreatitis.75 76 89

Since hydroxyurea leads to a reduction in theintracellular levels of natural nucleosides,NRTIs are more likely to be incorporated byreverse transcriptase, thus their eYcacy may beenhanced. However, the clinical evidencesuggests that hydroxyurea also increases thelikelihood of NRTI incorporation into mito-chondrial DNA, thus the possible increase ineYcacy must be balanced with an increasedrisk of toxicity.

Considering licensed agents, the most recentnucleoside analogue to be approved for thetreatment of HIV infection, abacavir, showedminimal potential for mitochondrial toxicity inlaboratory studies.164 This has subsequentlybeen confirmed in clinical studies of over25 000 patients which have yet to identify anassociation between the drug and significantlong term toxicity.165 166 However, abacavir isassociated with a hypersensitivity reaction inapproximately 4% of patients which may be lifethreatening on rechallenge.166 The improve-ments in lipodystrophy and lactate levelsdescribed previously when patients wereswitched from d4T to either ZDV or ABC sug-gest the drug may have utility in such circum-stances.

SummaryNucleoside reverse transcriptase inhibitors(NRTIs) remain the cornerstone of highlyactive antiretroviral therapy (HAART) combi-nation regimens. However, it has been knownfor some time that these agents have the poten-tial to cause varied side eVects, many of whichare thought to be due to their eVects on mito-chondria.

Mitochondrial toxicity does appear to be therelated to many of the adverse eVects associ-ated with treatment with these agents. How-ever, we should be careful not to assume that allNRTI toxicities are due to this particularmechanism. In considering the evidence re-viewed previously, while lactic acidosis andmyopathy seem clearly mitochondrial in na-ture, we start to encounter diYculties inassociating neuropathy with this pathophysiol-ogy owing to the diVerent responses of theneurotoxic agents in various studies. Anaemiaand neutropenia seem more likely to be a directeVect of zidovudine or one of its anabolites,and we only have one in vitro study to suggestddI associated pancreatitis might be mitochon-drial in nature. Perhaps unsurprisingly, al-though lipodystrophy is clearly associated withNRTIs and particularly stavudine, we are stillin the process of describing the many diVerentpathways that may be involved hence it is pre-mature to assign one particular mechanism.

Considering management of toxicity, whiledose reduction or discontinuation of thecausative agent may lead to improvements orresolution of the side eVects associated withthat particular drug, this may not always be anoption. Supplements such as acetyl-carnitine,riboflavin, thiamine, and coenzyme-Q all havea theoretical rationale for use in these situationsand have been shown in studies to have somebenefit, although their prospective use is notyet justified.

Continued research into the pathogenesis ofNRTI associated toxicity, coupled with the sig-nificant advances being made in mitochondrialresearch, should lead to improved understand-ing which will facilitate interventions tomanage these toxicities, and aid the develop-ment of newer agents for which these toxicitiesare absent or minimised.

I would like to thank David Nolan, Simon Mallal, and DominicPaes for their valuable comments during the preparation of thismanuscript.

Conflict of interest: AJW is employed by GlaxoSmithKlineResearch and Development, part of GlaxoSmithKline Plc, whomanufacture and market many currently licensed treatments forHIV infection.

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