Pitt, J

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KEY PRACTICE POINTJennifer Pin, MB ChB~ Dip ObsterClinical Research Urn'l, Somerset Hospital and University ofCape TownTHE SOUTHERN AmlCAN JOURNAL OF HIV MEDICINECONCLUSIONREFERENCESThe XIVth International AIDS Conference will beremembered as the meeting that emphasised the need forboth prevention and treatment of HIV/AIDS. It will also beremembered for the presentation of the first reports ofpilot HAART projects that demonstrated the feasibility andeffectiveness of such interventions in developing countries.1. Marseille E, Hofmann PS, Kahn lG. HN preventioll before HAART in sub·SaharanAfrica. Lancet 2002; 359: 1851-1856.2. Cr~ A, Royd K. Alban A, Guinness LCost-effectiveness of HIV{AJOS interventionsin Africa: a systematic review of the evidenc~ Lancer 2002; 359: 1635-1643.3. Farmer P, leandre F, MLlkherj~ 15. er al. Communjty-ba~ approach~ to HIVtreatmmt in (~urce-poor settings. Lancer 2001; 358: 404-409.4. Weidk Pl, Ma'amba S. Mwebaze R. tl al. Assessment of a pilot antiretroviral drugtherapy programme in Uganda: patients' response. survival, and drug resist;;nce.Lancer 2002; 360: 34-40.LactateThe inhibition of DNA polymerase-y impairs the synthesisof mitochondrial enzymes and leads to the dysfunction ofthe respiratory chain and the accumulation of acetyl-CoAwithin the mitochondria. This build-up of acetyl-CoA shiftsthe balance of pyruvate metabolism towards lactatereduction. The result is the accumulation of lactate in theblood (Fig. 2).'-'Fig. 1. Aerobic oxidative phosphorylation.the doors to a competitive market in generic drugs in thedeveloping world as a way to deal with the epidemic in asustainable manner. He noted that pilot HAART projectsusing generic drugs that combine prevention andtreatment, such as the one conducted by Medecins SansFrontieres in Khayelitsha (Abstracts 1095 and 36851. haveproved that HAART can be feasible in limited-resourcesettings and should be expanded. Achmat lives with HIVand has free access to antiretrovirais, yet he declared hewould not take the lifesaving drugs until the South Africangovernment agreed to an action plan to provide HAART inthe public hospitals in South Africa.Reprinted with permission, Or Jean Nachega, JohnsHopkins HIVReport, 2002.NRTI-ASSOCIATED HYPERLACTATAEMIAAND LACTIC ACIDOSISBACKGROUNDSince the advent of highly active antiretroviral therapy(HAARl]. the prognosis of patients with HIV infection hasimproved dramatically - as evidenced by the decrease inmortality and morbidity rates.' However, this increase inlife expectancy carries the risk of significant drugtoxicities, such as the nucleoside reverse transcriptaseinhibitor (NRTI]-associated mitochondrial toxicity.Mitochondria are organelles which are present in all cellsexcept erythrocytes. They generate cellular energy in theform of adenosine triphosphate (ATP) by aerobic oxidativephosphorylation (Fig. 1). This process is dependent on DNApolymerase-y, an enzyme that replicates the majorcomponents of mitochondrial DNA2.3HBRUARY 2003 -----------CASE 1: ASYMPTOMATIC HYPERLACTATAEMIATHE SOUTHtRN AFRICAN JOURNAL Of HIV MEOICINEFig. 3. Changes over time ofbiochemical parameters in case 1.Ther.:lnv channedIr'\/ \./,- '\ ----./ \~" ~ '1l' ~ ~ ~-+-ALTx 10-1iiJ iiJ iiJ iiJ iiJ iiJ ....... LDHxl0-2~Qj~0 ~Qj ~Qj ~Qj ~Qj LactateCASE 2: SYMPTOMATIC LACTIC ACIDOSIS WITHRECOVERYShe presented at week 32 with a 2-week history of nausea,vomiting and epigastric pain. She was treated forgastroenteritis. Liver function tests showed a mildtransaminitis and an elevated LDH level. She returned atweek 33 with ongoing gastrointestinal (Gin symptoms anda worsening of the biochemical abnormalities [Fig. 4).She has been clinically well since then. Her lactate levelshave remained normal on continued therapy.A 34-year-old woman (height 163 cm, weight 87 kg,BMI 33) was commenced on therapy with a proteaseinhibitor/d4T 4D mg twice a day/3TC 150 mg twice a day.The baseline viral load was 54 600 copies/ml and thebaseline CD4 count 145M"1210~ 8~ 6•2oThe patient was admitted at week 34 with ongoing GITsymptoms. dyspnoea and paraesthesiae. Her lactate levelwas 9.1 mmol/l and arterial blood gas measurementrevealed a metabolic acidosis: pH 7.3/partial pressurecarbon dioxide (pCO,) 1.5 kPa/partial pressure oxygen (pO,)8.4 kPa/standard bicarbonate (SB) 5.9 mmol/1. She wasdiagnosed with lactic acidosis. She had stopped her HMRTon admission. Her symptoms settled by week 35 and shewas discharged.Fig. 4. Changes over time ofbiochemical parameters in case 2.As she was asymptomatic. her lactate levels weremonitored over the next 6 weeks. This demonstrated alinear increase in lactate (Fig. 3). Based on the rate of rise.it was predicted that her lactate levels would soon reach 10mmol/1. As the mortality rate associated with a lactate level>10 mmol/l is 800/a, she was changed to a non-d4T-NRTIregimen at week 59. The biochemical abnormalities settledon the new therapy.levels. This biochemical picture raised suspicions of anincrease in lactate. Her lactate level was measured at week52 and found to be elevated at 2.4 mmol/l [upper limit ofnormal (ULN) 2.0 mmol/l}.----------- HHRUARY 200311... RespiratoryrjF;> chainAcetyl-CoAMitochondriaThem~_I.I ~,..--/'-.. ~\,. J '. .~'O / \... • \ r ," I.........-.- ALTx 10-1N ~ ~ ~~ 0 ~ ~ N ~~ ~N M ~ '" '" '" '" ........... LDH x 10 - 2• • ~ ~ ~ ~ ~ ~ ~ ~• • • • • • • • • •• • • • • 0 0 • • • Lactate• • • • • • • •Lactate PyruvateCytoplasm1816,.12~ 10E 86•2oAt week 48, she was noted to have an asymptomaticincrease in transaminase and lactate dehydrogenase (LDH)The resultant mitochondrial dysfunction may manifestbiochemically as hyperlactataemia and lactic acidosis orclinically as hepatic steatosis, pancreatitis, peripheralneuropathy and myopathy.Fig. 2. Inhibition of DNA polymerase-v and shift to lactatepraduction.A 29-year-old woman (height 169 cm, weight 106 kg, bodymass index (BMI) 37) was commenced on therapy with aprotease inhibitor/ddl 4D0 mg 4 times a day/d4T 4D mgtwice a day. The baseline viral load was 26 000 copies/mland the baseline CD4 count 279MThe toxicity of NRTls is related to their antiretroviralmechanism of action: the selective inhibition of viral DNAreplication. If the selectivity of the NRTI is not absolute,cellular targets such as mitochondrial DNA polymerase-vwill be affected.'"All currently available NRTls inhibit human mitochondrialDNA polymerase-v to some degree. The relative potency ofinhibition of DNA polymerase-v by NRTls is as follows:zalcitabine > didanosine > stavudine > lamivudine >zidovudine > abacavir.~' Abacavir has avery low affinity formitochondrial DNA polymerase-v.' The risk for developingNRTI-related mitochondrial toxicity increases with lengthof time on therapy.'The following three cases illustrate the spectrum ofhyperlactataemia.FEBRUARY 2003 -----------CASE 3: SYMPTOMATIC LACTIC ACIDOSISRESULTING IN PATIENT DEATHA 34-year-old woman (height 158 cm, weight 75 kg, BMI30) was commenced on nelfinavir 1250 mg twice aday/ddl400 mg 4 times a day / d4T 40 mg twice a day.The baseline viral load was 547 152 copies/ml and thebaseline CD4 count 125MThe initial regimen failed virologically and the patient waschanged to indinavir 800 mg twice a day/RN 100 mg twicea day/ddl 400 mg 4 times a day/d4T 40 mg twice a day,based on viral genotyping.She was fully suppressed (viral load < 50 copies/m I) andclinically well after 24 weeks of therapy.She presented at week 32 with a 2-day history of nausea,vomiting and epigastric pain. She had suffered an episodeof diarrhoea during the previous week. She was admittedwith suspected acute pancreatitis. She had stopped takingher HAART before admission.Arterial blood gas measurement revealed a partiallycompensated metabolic acidosis: pH 7.29/pO, 16.23 kPa/pCO,1.98 kPa/SB 7.3 mmol/I. Her lactate level was reported as21.6 mmol/I. She was diagnosed with lactic acidosis andadmitted to the ICU. Aggressive supportive therapy -including intravenous rehydration, intravenous sodiumbicarbonate and parenteral vitamin B, including riboflavin- was instituted. She did not respond to these measuresand died 2 days later due to lactic acidosis.CLINICAL SYNDROMESHyperlactataemia or lactic acidosis can be manifestationsof NRTI-induced mitochondrial toxicity.HYPERLACTATAEMIA: CASE 1This elevation in serum lactate (venous lactate> 2.0 mmol/I) in the absence of metabolic acidosis (arterialpH < 7.3) can be asymptomatic or symptomatic.The symptoms may include fatigue, asthenia, malaise, GITsymptoms (loss of appetite, loss of weight, nausea,vomiting, abdominal pain, dyspepsia ± bloating), dyspnoeaand neurological symptoms (paraesthesiae, muscleweakness). An elevated LDH level, mild transaminitis and adecrease in bicarbonate often precede the onset ofsymptoms."The reported incidence of asymptomatic hyperlactataemiain NRTI-treated patients ranges from 8% to 21''10, whilethat for symptomatic hyperlactataemia is only 1 - 2%."·"At present we are unable IQ predict which patients withasymptomatic hyperlactataemia will go on to develop lacticacidosis." However, recent literature reviews have reportedan increased risk in female patients" and patients with anincreased BMI.'·" This trend is supported by our three cases.Deficiencies in ribofiavin and thiamine, cofactors requiredfor oxidative phosphorylation, may further predisposepatients to the development of hyperlactataemia';LACTIC ACIDOSIS: CASES 2 AND 3This symptomatic elevation in serum lactate accompaniedby metabolic acidosis is often associated with a mildtransaminitis and a rise in LDH" Liver biopsy revealshepatic steatosis.The reported rate of lactic acidosis varies from 0.85 casesper 1 000 patient-years of treatment" to 8.4 cases/l 000patient-years," with an even higher rate reported amongpatients taking only stavudine and didanosine." There aresome indications that the rate may be even higher in SouthAfrican patients." Although development of lactic acidosisis not a frequent event, it is important because of theassociated high mortality rate, which approaches 80% inpatients with a serum lactate level> 10 mmol/I.'MANAGEMENTRoutine monitoring of lactate levels is not recommendedfor all patients receiving NRTls.' However, Adda et al."propose a diagnostic index for monitoring patients ontherapy and predicting the occurrence of hyperlactataemia.This index includes an elevated LDH level (> 2 x ULN)together with elevated transaminases (aspartateaminotransferase (ASn and/or alanine aminotransferase[ALn > 2 x ULN) and the presence of nausea and/orvomiting. This index showed WOOfo sensitivity, 98%specificity, 100% negative predictive value and 50%positive predictive value for hyperlactataemia.Patients who manifest persistent symptoms, signs orlaboratory abnormalities (transaminitis/raised LDH)suggestive of hyperlactataemia should be evaluated withvenous lactate sampling.Further management depends on the absolute lactate leveland the relationship of the abnormality to the underlyingsymptom(s). The strategy outlined in Table I has beenproposedHBefore attributing hyperlactataemia or lactic acidosis solelyto the use of NRTls, other causes of metabolic acidosis needto be ruled out, including sepsis/uraemia/diabeticketoacidosis/thyrotoxicosis/lymphoma."Once the diagnosis of NRTI-related mitochondrial toxicityis made, NRTI therapy should be stopped. Cessation oftreatment should lead to the resolution of symptoms."""THE SOUTHtllN AFRICAN JOURNAL OF HIV MEDICINETHE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINETABLE I. PROPOSED STRATEGY FOR INTERPRETING LACTATELEVELSAs HAART becomes more affordable and accessible, soNRTI-associated mitochondrial toxicity will probablybecome more prevalent It therefore becomes increasinglyffHRUARY 20031. Mocroh A, Vt. a S, Benficld n. 1:. aL Changing parrerns of mortality ao:ross Europe:in patients infected w:tn HIV-l. Lon~t 1998; 352: 1725-1729.2. Khouri S, Cushing H. tactic acidosis secondary ,0 nudeoside ana og antireil'oviralther.;P'{. fnf~rM~2OCKl; 17: 5-47-554.3. Landovitz ,Sax PE. NRn-associatfd mitochondrial toxicity. AIDS Din COft 2001:13: 343-349.4. Brinkman K. Adverse effects of reverse uanscr:prase irr:Mors: mitochondrialtoxicity as common pamwa~ AIDS 1998; 12: 1735-1744.5. Chm CH, Vazquu-FcdJa M, Cherg YC Effect of anti-human immunodeficiercyvirus nucleoside ana ogs on mitochondria DNA and its implication for de.a~toxicity. Mol Pharm 1991; 39: 625-628.6. Martin Jl, Brown C£. Ma,,,h~'N5-Davis N. Rmdon JE. Effem of antiviral nudeosid~ana'ogs on hJ'1lan DNA pdvm~ses and mitochondrial DNA syr:rnesis. AnomicrobAgml:SChmlorh~r 1994; 38: 2743-2749.7. Daluge SM, Good Ss. P.ilitlo MB, er of. 1592U89. a novel carbocydic nudeosid~analog with potent, selectiv~ anti-hutl"an immunode"'icieJ"CY virus activity.AnomictobAgt'nl:SChemom~ 1997; 41: 1082-1093.8. uhla! T. Chen MS. Ircorporation 0; se ec~ed nJdeoside phosphor"a:es ard arti-human immunodeficiency virus nudeotidt ana!oques into DNA by human DNApoJvmerases a, ~ and y. Antiviral Chem Chemorher 1997; 8: 187-195.9. Boubaker K, Aepp M. Sudre p. t:taL Hvperlarntem'a and antirettoviral therapy: TheSwiss HIV Cohort Srudy. ain Infect Dis 2001; 33: 1931-1937.10. Adda N, Palloa S, Wakeford C, Kargl D, Rousseau. lactic addem:a in HIV infectedpatients tecriving triple combination therapy: Predictive factors and dinicalfeatures. 39th Congress of the Infectious Disease Society 0; America, San Francisco,25 - 28 Oct 2001 (Abstract 201669).11. Carr A, Miller J, law M, Cooper DA. Asyndrome of lipoatrophv, lactic acidemia andliver dysfunction associated with HIV nucleoside analogue therapv contribution toprOlease inhibitor-related JipodystrOphv syndrome. AIDS 2000; 14: F25-F32.12. Boubaker K, Aepp M, Sudre P, er al. Hvperlactatemia and antiretroviral therapy inthe Swiss HIV Cohort Study (SHCS). 7th Conference on Retroviru5e!o andOpportunistic Infections, San Francisco, Ftb 2000 (Abstract 57).13. Vrouenraets SM. Hyperlactatemia in HIV-infected patients: The role of NRntreatment 8th Conference on Retroviru~ and Opportunistic Infections, Chicago,5-8 Ftb 2001 (Abstract 6251.14. Falco V, Rodrigua 0, Ribera E, et al. Severe nucleoside-associated lactiC acidosis inhuman immunodeficiency virus-infected patieot3: report of 12 castS and review ofthe literature. ain Infret Dis 2002; 34: 838·846.IS, Fouty B, Frerman F, Reeves R. Riboflavin to tr~t nucleoside analogue induced lacticacidosis. /.onert 1998; 352: 291-29216. Getard Y, Maulin L. Yazdanpanah Y. et aL Symptomatic hyperlactatemia; anemerging complication of antitetroviral therapy. AiDS 2000; 14: 2723-2730.17. Cart A Lactic acidffllia and bone di~se in HlV disease. 8th Confttener onRetrovirustS and Opportunistic Infections, Chicago,S· 8 FrlI 2001 (Abstract l121.18, Chma G, Arieff Al. Cummings C. Th:erney lM. !lictic acidosis comp'icating theacquired Immunooe"'iciency syndrome. Ann InremMtd 1993; 118: 37-39.19. l.onergan JT, Hav ir 0, Bdrbe:r E, Matnews Wc. Incidenct and Outcome ofhyper1artiitffllia associated with dinical manifemtions in HlV·jnfected adultsrecei 'og NRn·containirg rt9;tl"ens. 8th Can;erence on RerrovirustS anaOpportunistic In~ot1s, Chicago,S - 8 Fto 2001 (Abstract 624).20, Mo-.rzycki MH, Hams C. MaV H, LaJt J, PaJTIisano llacoc acidosis associated witllsravudine administration: a rrport of 5 cases. Oin Infrcr Dis 2000; 30: 198-200.21. DaJton SO, Rahimi AR. Emerging ro e of riboflavin in the treatment of nuckosideafl4:ogJe-induced type Blamc acidosis. AiDS Patienr Cere 5TDs 2001; 15: 611-614.22. Posteraro AF, Mauridlo M, Winter SM. Riboflavin treatment of annrtUcMfdlinductd lactic acidosis and nepatic steatosis.. Conn Ikd 2001; 65: 387-390.21 Ariti C, Teba!di Po., Ouinzan GP, Maggiolo F. Ripomonti O. Suter F. Severe lacticaodosis and thia!T1JJ'le administration in an HlV-in'ected patient on HAARllnt)STDAlDS2001; 12:407-409.24. Brinkman K, Vroueruaets S, Kaufmann R, Wiegel H, FriS5el'l 1 Treatmera or laetkacidosis. 2nd International Workshop on k1verse Drug Reactions and lipooystrophyin HlV, Toronto, 12 - is Sep 2(0) (Abstract P151.25. Mill~ KO, Carreron M, Wood lV, Dalakas MC, Kavacs !A. lactic acidosis ara hepa .steatosis associat~ with use of sravudine: report or ~r cases. Ann Intern~2(0); 133: 192-196.26. l.enzo NP, Gar...s SA. French MA Hepatic sttatosis and tactic acidosis associatedwith stavudine treatment in an HlV patient: a case rrport AIDS 1997; 11: 1294-1296.27. John M, Moore CB, lames IR. rtal. Chronic hyperlactHemia in HIV-infected pati~ntstaking antireuoviral therapv. AIDS 2001; 15: 717-723.REFERENCESimportant for clinicians to be aware of these rare butpotentially life-threatening drug toxicities and the need todiagnose them early and intervene appropriately.ActionNo interventionInvestigate other causesObserveExclude other causesConsiderdiscontinuation of NRTIObserveDiscontinue NRTIExclude other causesDiscontinue NRTIExclude other causesSymptomsNoYesNoYesNoYesAny'-"etale5 - 10 mmol/l2 - 5 mmol!1>10 mmol!1< 2 mmol!1Further treatment is largely supportive. Hyperlactataemiacan be managed on an outpatient basis, but patients withlactic acidosis require hospitalisation with aggressiveintravenous rehydration and alkalinisation with high-dosebicarbonate infusions'Brinkman et al." propose twice-daily vitamin supple-mentation for the treatment of lactic acidosis, including 50mg thiamine/lO mg riboflavin/lOO mg nicotinamide/la mgpyridoxine/lO mg dexpanthenol/100 mg intravenousl-carnitine. The regimen is continued until serum lactatelevels fall below 3 mmol/1.On recovery from hyperlactataemia or lactic acidosis,rechallenge with NRTI-sparing regimens is preferred."However, in cases of moderate hyperlactataemia there havebeen reports of rechallenge with non-d4T NRTI-containingregimens, which were not associated with relapse.""" Inboth situations, careful monitoring of clinical andbiochemical status is required.A recent case series has shown that specific therapy usingthe cofactors of oxidative phosphorylation (thiamine,riboflavin, l-carnitine, prostaglandin E and coenzyme Q)are associated with a lower mortality rate." This supportsprevious anecdotal information of patients with lacticacidosis who responded dramatically to administration ofessential cofactors: high-dose riboflavin 50 mg once daily,thiamine 100 mg by intravenous infusion, or l-carnitine50 mg/kg daily respectively."·"

NRTI-Associated hyperlactataemia and lactic acidosis

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NRTI-Associated hyperlactataemia and lactic acidosis

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