Eshun-Wilson, Ingrid

Soentjens, Patrick

Taljaard, Jantjies

Zeier, Michele

South African Medical Journal (SAMJ)

SAMJ FORUM929December 2005, Vol. 95, No. 12  SAMJThe prognosis of patients infected with HIV type 1 hasimproved markedly since the advent of potent antiretroviraltherapies (ARTs). ARTs have enabled sustained suppression ofHIV replication, recovery of the immune system and asubstantial decrease in the frequency of opportunisticinfections. Antiretrovirals may, however, cause life-threateningcomplications which include lactic acidosis, pancreatitis,hypersensitivity reactions, liver toxicity and severe immunereconstitution inflammatory syndrome.A subgroup of patients being treated with nucleoside reversetranscriptase inhibitors (NRTIs) will develop symptomatichyperlactataemia and lactic acidosis, a manifestation ofmitochondrial toxicity. Using mechanisms similar to those used to inhibit viralreplication, NRTIs also inhibit human mitochondrial DNApolymerase gamma.1 This inhibition leads to a depletion ofmitochondrial DNA and an alteration in the synthesis ofmitochondrial proteins. Subsequently there is an accumulationof mutations within mitochondrial DNA; this may lead toclinical toxicities such as skeletal myopathy, cardiomyopathy,neuropathy, HIV-associated neuromuscular weaknesssyndrome, pancreatitis, hepatic steatosis and lactic acidosis.2Some NRTIs have a greater affinity for DNA polymerasegamma and therefore cause lactic acidosis more commonly.Stavudine (d4T) and didanosine (ddI) have the greatest affinity,and tenofovir (TDF) and abacavir (ABC) the least (ddI > d4T >AZT > 3TC = ABC = TDF).  The use of stavudine is the mostfrequently identified risk factor.3Lactic acidosis and symptomatic hyperlactataemia can occurfrom 1 month to 20 months after commencing NRTIs.4 Patientsmay be asymptomatic, have nonspecific symptoms or becritically ill. Typical initial symptoms may develop over 1 - 6weeks5 and include dyspnoea, abdominal complaints(vomiting, pain and distension), myalgia, fatigue and weightloss. There may also be associated lipodystrophy and axonalneuropathy. The development of these conditions will dependon the patient’s adherence, duration of treatment, the specificNRTIs used and also the number of NRTIs in the regimen. Several factors may predispose a patient to the developmentof lactic acidosis/hyperlactataemia.  These include female sex,excellent compliance, duration of treatment of more than 6months, chronic muscle or kidney disease, chronic hepatitis Bor C infection, and the combination of d4T and ddI, especiallyin pregnancy.5-7 The correlation between women with anincreased body mass index (BMI) and lactic acidosis remainsunproven.  Conditions unrelated to NRTI administration mayalso cause lactic acidosis (Table I) and this differential mustalways be considered in all patients who present with raisedserum lactate levels.There is no consensus on criteria or definitions with regard toraised serum lactate concentrations. Hyperlactataemia iscommonly referred to as one of three clinical and biochemicalentities. 1. Asymptomatic hyperlactataemia (subclinicalhyperlactataemia). Here the lactate level is mildly ormoderately raised (2.5 - 5 mmol/l, depending on preferredcriteria) and the patient is asymptomatic.8 Up to 25% or moreof patients treated with NRTIs will have an elevated lactateconcentration during their course of treatment, but most (85%)Ingrid Eshun-Wilson completed her medical studies at the Universityof Cape Town, worked as a medical officer at the Tygerberg AcademicHospital HIV Family Clinic, and obtained her Diploma in HIVManagement in 2004.  She is currently a registrar in urology atTygerberg Hospital and Stellenbosch University.Patrick Soentjens qualified as a physician at the University ofLeuven, Belgium, and worked at the Tygerberg Hospital HIV FamilyClinic for 18 months as part of his training as a specialist in infectiousdiseases.Michele Zeier is principal medical officer at the Tygerberg HospitalHIV Family Clinic and director of the Adult HIV Research Unit.Jantjie Taljaard is a physician in the Department of InternalMedicine at Tygerberg Academic Hospital and Stellenbosch Universityand heads the Adult Infectious Diseases Unit.Symptomatic hyperlactataemia and lactic acidosis in the eraof highly active antiretroviral therapyIngrid Eshun-Wilson, Patrick Soentjens, Michele Zeier, Jantjie TaljaardCLINICAL PRACTICETable I. Conditions causing raised serum lactate in theabsence of NRTI use6,7,9Increased energy levels Exogenous intoxicationExercise SalicylatesInfection (sepsis) BiguanidesDecreased lactate clearance IsoniazidKidney disease CyanideLiver disease MethanolMalignancy Shock/hyperperfusion statesCorresponding author: J Taljaard (jjt@sun.ac.za)Pg 929-930  22/11/05  7:52 pm  Page 929December 2005, Vol. 95, No. 12  SAMJSAMJ FORUM930remain symptom free.9 Hyperlactataemia may be transient orprolonged and has not been found to predict the onset ofsymptomatic or severe lactic acidosis.10 Therefore screeningasymptomatic patients on NRTIs is not considered beneficial.8The variability in lactate measurements may reflect differencesin venous sampling techniques.92. Symptomatic hyperlactataemia. In this category patientshave moderately elevated lactate levels (2.5 - 5 mmol/l), noacidosis, but are symptomatic.10 The prevalence of thiscondition is approximately 8 - 14.5 per 1 000 patient-years.9This may be an early manifestation before the onset of acutesevere lactic acidosis. Withdrawal of ARTs at this stage usuallyleads to good clinical recovery indicating the significance of anearly diagnosis.93. Lactic acidosis. The criteria used to diagnose lactic acidosisinclude serum lactate > 5 mmol/l, bicarbonate level < 20mmol/l, arterial pH < 7.34 and anion gap > 12. The incidencevaries from centre to centre but is thought to be in the region of1 - 5 per 1 000 patient-years.7 These patients are usuallysymptomatic and the mortality rate is high. A serum lactateconcentration of > 10 mmol/l is considered an independentpredictor of mortality and a level > 15 mmol/l is associatedwith > 60% mortality.4For an accurate lactate measurement the specimen must becollected from an uncuffed arm, in a fluoride tube, put on iceimmediately and sent to the laboratory within 4 hours. Asecond specimen should be taken to confirm an elevatedlactate.  The patient should be well hydrated and should notexercise for 24 hours before sampling.11In resource-poor settings where this is not possiblecalculating the anion gap will be helpful as this may alert oneto the presence of a raised serum lactate (anion gap = (Na + K)– (HCO3 + Cl)).1 A normal anion gap ranges from 6 to 12mmol/l.On admission, arterial blood gases, urea and electrolytes andsurrogate markers should be monitored.  Surrogate markersinclude lactate dehydrogenase (LDH), creatinine kinase (CK),amylase, lipase and transaminases.11 The patient should beassessed for other signs of mitochondrial toxicity includingperipheral neuropathy and lipoatrophy. An abdominalultrasound and/or computed tomography (CT) scan should beperformed if pancreatitis is suspected and a liver biopsy shouldbe considered to confirm a diagnosis of possible hepaticsteatosis.In those patients with symptomatic hyperlactataemia or lacticacidosis all antiretroviral medication must be discontinued.9The need for hospital admission depends on the severity ofsymptoms, presence of acidosis and lactate levels. Owing to thelong half-life of mitochondria (4.5 - 8 weeks) the time requiredfor clinical recovery ranges from 4 to 28 weeks.11Management is predominantly supportive, namelyintravenous fluid rehydration, dialysis and respiratory support.There is little evidence to support or negate the administrationof sodium bicarbonate. Administration of essential co-factorssuch as thiamine, riboflavin, L-carnitine, vitamin C andantioxidants have been used anecdotally.4,12 Several publishedcase reports describing the use of different co-factors atdifferent dosages suggest they may induce recovery from lacticacidosis.4 The experience with riboflavin seems the mostextensive.11 However, no adequate controlled trials exist tosupport this.Although the safest treatment option for patients when readyto be re-challenged with ARTs would be a NRTI-sparingregimen, i.e. the combination of a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor, switching to anotherNRTI after recovery may be justified.  NRTIs such as TDF,ABC, 3TC and AZT have a lower affinity for DNA polymerasegamma and have been used safely.3,11 This may be an optionwhere fewer antiretroviral drugs are available (public sector) orin those patients with limited treatment options.  In theseselected cases NRTIs with a lower affinity may be initiatedonce lactate measurements have been found to be within thenormal range for 2 - 3 months. Subsequent close monitoring oflactate levels will be necessary.In South Africa, as ARTs become more utilised and d4T-containing regimens remain the first line of treatment, theprevalence of NRTI-related mitochondrial toxicity can beexpected to increase significantly.  The clinician must be awareof the risk factors and have a high index of suspicion for thesesyndromes in every patient on NRTI therapy. Policy makerswill have to seriously consider the swift registration of newerand safer antiretroviral drugs available on the internationalmarket and it will become necessary for drug companies tofind innovative ways to make these drugs available tocommunities with limited financial resources. 1. Arenas-Pinto A, Grant AD, Edwards S, et al.  Lactic acidosis in HIV infected patients: asystematic review of published cases.  Sex Transm Infect 2003; 79: 340-343.2. McComsey G, Lonergan JT.  Mitochondrial dysfunction:  Patient monitoring and toxicitymanagement. J Aquir Immune Defic Syndr Hum Retrovirol 2004; 37: S30-S35.3. Lonergan JT, Barber E, Mathews WC.  Safety and efficacy of switching to alternativenucleoside analogues following symptomatic hyperlactatemia and lactic acidosis.  AIDS2003; 17: 2495-2499.4. Falco V, Rodriguez D, Ribera E, et al.  Severe nucleoside-associated lactic acidosis in humanimmunodefeciency virus-infected patients:  Report of 12 cases and review of the literature.Clin Infect Dis 2002; 34: 838-846.5. National Institute of Health.  Safety and toxicity of individual antiretroviral agents inpregnancy.  Supplement. Safety and Toxicity 2004; 23: 1-7.6. Bonnet F, Bonarek M, Morlat P, et al.  Risk factors for lactic acidosis in HIV- infected patientstreated with nucleoside reverse-transcriptase inhibitors: A case-control study.  Clin Infect Dis2003; 36: 1324-1328.7. Cossarizza A, Moyle G.  Antiretroviral nucleoside and nucleotide analogues andmitochondria. AIDS 2004; 18: 137-151.8. Moyle GJ, Datta D, Mandalia S, et al.  Hyperlactataemia and lactic acidosis duringantiretroviral therapy:  relevance, reproducibility and possible risk factors.  AIDS 2002; 16:1341-1349.9. Ogedegbe AE, Thomas DL, Diehl AM.  Hyperlactataemia syndromes associated with HIVtherapy. Lancet Infect Dis 2003; 3: 329-37.10. John M, Moore CB, James IR, et al.  Chronic hyperlactatemia in HIV-infected patients takingantiretroviral therapy.  AIDS 2001; 15: 717-723.11. Bartlett JG. Medical Management of HIV Infection. Baltimore: Johns Hopkins University Schoolof Medicine, 2004: 91-93.12. Manfredi R, Motta R, Patrono D, et al.  Frequency, risk factors and features ofhyperlactatemia in a large number of patients undergoing antiretroviral therapy. AIDS 2003;17: 2131-2133.Pg 929-930  22/11/05  7:52 pm  Page 930

Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy

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Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy

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