Lactic acidosis is a serious side-effect of the nucleoside analogue reverse transcriptase inhibitors (NRTIs), such as AZT (zidovudine, Retrovir) and d4T(stavudine, Zerit). Although rare, when it does occur there is a high chance of death even if it is treated immediately. Lactic acidosis may occur in conjunction with severe hepatomegaly (enlarged liver).

Lactate or lactic acid is an end-product of glucose breakdown by the body. It is produced when the oxygen supply is limited, such as during vigorous exercise. It is produced in the mitochondria, the cellular components where glucose is broken down in the production of energy. Lactic acidosis is the condition caused by over-accumulation of lactate in the body, which the body is unable to clear.

An abnormal accumulation of lactic acid in the blood, also known as hyperlactataemia or lactic acidaemia, develops prior to lactic acidosis. Lactic acidemia may be associated with symptoms such as fatigue, breathlessness, abdominal pain and weight loss.

Lactic acidosis is thought to be caused by damage to mitochondrial DNA caused by NRTIs. Other NRTI-related side effects associated with damage to the mitochondrial DNA include neuropathy, bone marrow suppression, and liver and pancreatic damage.

Studies indicate that between 30 and 60% of people on NRTI therapy have elevated levels of lactate in their blood, although levels are rarely high enough to induce symptoms of lactic acidosis (Vrouenraets 2001; Harris 2000; Garcí¡­Benavas 2000; Desai 2003). A French study reported that 0.8% of patients taking anti-HIV drugs develop symptoms of high lactate each year (Gerard 2000).

Risk factors for lactic acidosis

All NRTIs have been implicated in lactic acidosis, but several reports have linked d4T and ddI (didanosine, Videx / VidexEC) most closely with lactic acidosis (Mokrzycki 2000; Moore 2000; Boubake 2001; Lonergan 2000a; Gerard 2000). Other key findings include:

• A study in 31 patients identified as having hyperlactatemia found that the risk of developing high lactate was higher in those who received d4T compared with those who received AZT and 3TC (lamivudine, Epivir; Lonergan 2000b).

• A study of nine people with lactic acidosis found low creatinine clearance and a CD4 cell count below 250 cells/mm³ prior to commencing therapy were the only significant risk factors for the condition (Bonnet 2003). This suggests a link between lactic acidosis and kidney impairment.

• A study of 14 patients with symptomatic hyperlactataemia found that all had been taking d4T. However, the authors emphasised that this finding did not prove a particular link between d4T and lactic acidosis due to the study design (Gerard 2000). A similar case series from Spain showed that ten of twelve individuals were receiving treatment with d4T (Falco 2002).

• A review of patients at the Chelsea and Westminster Hospital in London found that the rate of hyperlactatemia was greatest in those receiving d4T and ddI together. Only current ddI treatment was associated with an increased risk of hyperlactatemia compared to the control group but there was no significant difference when ddI-based therapy was compared with 3TC-based therapy. Combined use of 3TC with abacavir (Ziagen) or d4T was associated with a reduced risk of hyperlactatemia compared to d4T and ddI (Moyle 2002).

The nucleotide analogue reverse transcriptase inhibitor tenofovir (Viread), combined with ddI or ddI and d4T also seems to increase the risk of lactic acidosis, possibly due to a drug interaction between ddI and tenofovir which leads to higher blood levels of ddI (Yoganathan 2002; Murphy 2003; Rivas 2003).

Duration of exposure to NRTIs may be a factor in the development of lactic acidosis. However, some cases have been reported in people within 20 months of starting antiretroviral therapy, suggesting that lactic acidosis is not always the result of long-term cumulative toxicity (Falco 2002).

Pregnant women taking ddI and d4T may be at increased risk of lactic acidosis, according to the United States Food and Drug Administration and pharmaceutical company Bristol-Myers Squibb. Three pregnant women taking ddI and d4T have died and several others have experienced non-fatal lactic acidosis, according to data collected from clinical trials and post-marketing surveillance.

Other risk factors for lactic acidosis include obesity, severe infection or malnutrition (Brinkman 1999). Concurrent treatment with ribavirin (Copegus / Rebetol / Vorazole) for viral hepatitis and NRTIs may increase the risk of lactic acidosis, although a recent study has suggested that co-infection with hepatitis C virus may be an independent risk factor for elevated lactate levels (Braitstein 2004). This study also found evidence that non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens may also increase the chances of elevated lactate levels. Conflicting data are available on the impact of gender on development of lactic acidosis.

Although it has been suggested that lactic acidosis may be associated with mitochondrial toxicity in muscle tissue, there is no evidence that exercise will worsen lactate levels in HIV-positive people (Bauer 2004). It is believed that elevated lactate levels are probably a consequence of liver dysfunction (Roge 2000).

Lactic acidosis has been linked to body fat and metabolic changes seen among people on highly active antiretroviral therapy (HAART; Carr 2000). However, this link has not been fully established and remains disputed. In one study, elevated lactate levels were associated with elevated cholesterol and triglyceride levels in patients receiving HAART, but not in untreated people (Blanco 2000). In contrast, another study found that high lactate levels are linked to elevations of the liver enzyme alanine aminotransferase (ALT) and blood glucose (Moyle 2002). For more details see Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

Elevated blood lactate levels has also been observed in HIV-negative infants with HIV-positive mothers who were exposed to antiretrovirals during gestation, birth and postnatally. The risk of this was greatest in children exposed to ddI, but the majority of the infants showed regression to normal lactate levels within the first year of life. Symptoms were rare, but included slow psychomotor development (Noguera 2004).

Symptoms

Initial symptoms of high lactate levels include nausea, lack of appetite and malaise, as well as fatigue and difficulty in breathing. Muscle pain and numbness or tingling sensations have also been reported. In lactic acidosis, the liver may become swollen and tender, and liver enzymes may be elevated. Symptoms of acute lactic acidosis include difficulty in breathing and hyperventilation. Diagnosis is usually confirmed with a liver ultrasound.

Fourteen cases of rapidly ascending neuromuscular weakness mimicking Guillain-Barré ³yndrome have been associated with the use of NRTIs. Five of these cases were fatal. In most of these cases, non-specific symptoms and signs associated with lactic acidosis preceded the development of neuromuscular problems.

The long-term consequences of large elevations in lactate levels for those with pre-existing liver damage is unknown.

Monitoring

To date, there are no laboratory tests which clearly predict who is at risk of lactic acidosis. Although measuring lactic acid levels in the blood has been suggested, the usefulness of this measure has not been established.

Although some experts regard monitoring lactate levels in patients on HAART as essential (Gerard 2000), results from other studies have suggested that measuring lactate levels is an imprecise way of identifying risk of lactic acidosis, as measurements are prone to error: excess tourniquet compression when taking the blood sample, failure to store the specimen correctly or delayed processing can all distort the results, with delayed processing particularly likely to lead to falsely elevated readings (Dubé ²001). Inter-laboratory variations are also likely.

A large Swiss study of over 1500 people found that 11% had elevated lactic acid levels. However, only 1% of the participants had very high levels. A Spanish study found that 60% of 127 people on HAART had high lactate levels in blood (Garcí¡­Benavas 2000), which suggests simple monitoring of lactate levels will not give an indication of risk.

In a study of the incidence of lactic acidosis and hyperlactataemia in 1239 patients receiving treatment at the Chelsea and Westminster Hospital, London, 9% had an 'elevated' measurement above 2.5mM, with treated patients having a median of 1.4mM and untreated 1.1mM. Elevated levels of lactate were poorly predictive of a subsequent elevated plasma lactate, leading the reserachers to conclude that screening of lactate is of limited relevance in individuals without symptoms of hyperlactatemia. Nevertheless the Chelsea and Westminster team continue to monitor lactate levels of people taking NRTIs (Moyle 2002).

An analysis of the Western Australia HIV Cohort similarly found that while 65% of patients on NRTIs had at least one lactate measurement above 1.5mM, only 39% had mean elevations above 1.5mM during the 18 month study period, and only less than 1% developed symptomatic hyperlactatemia (John 2001).

Most recently, French researchers have suggested monitoring kidney function in patients who have an acute infection or are taking drugs known to be toxic to the kidneys. This suggestion follows their finding that poor creatinine clearance, a sign of kidney impairment, is a risk factor for lactic acidosis (Bonnet 2003). However, it is not clear what action would follow from a finding of poor creatinine clearance. Dose reductions or monitoring drug levels may be a possibility.

Testing for mitochondrial toxicity

Testing for mitochondrial DNA content of blood cells has also been proposed as a means of detecting lactic acidosis. However, studies examining this hypothesis have produced conflicting results.

A team at the University of British Columbia reported on the use of a mitochondrial DNA assay to assess mtDNA levels in the peripheral blood mononuclear cells from eight patients with high lactate levls and symptoms assumed to be caused by mitochondrial toxicity. The team found that the ratio of mitochondrial to nuclear DNA was nearly 70% lower in the patients with hyperlactatemia when compared with HIV-negative people, and 43% lower when compared with HIV-positive untreated people. Mitochondrial DNA levels improved when NRTI treatment was stopped, and did not deteriorate when NRTI treatment without d4T was resumed, leading the authors to suggest that d4T may have an especially toxic effect on mitochondrial DNA, and that this test could be used to monitor mitochondrial toxicity (Cote 2002).

Despite these findings, another study in patients with lipoatrophy failed to show any association between NRTI treatment and mitochondrial DNA depletion (McComsey 2002).

The key difference between these two studies is that patients in the first were selected on the basis of lactate levels, while those in the second study were selected on the basis of fat wasting. Furthermore, neither study monitored levels of mtDNA over time in a way that proves that depletion of mtDNA over time increases the risk of developing hyperlactataemia.

Lactate elevations and lipodystrophy

The researchers who have linked lactic acidosis to lipodystrophy have suggested that C-peptide, a by-product of the pancreas that is linked to insulin production, and liver function results may be elevated in people with this syndrome. However, given that the relationship between lipodystrophy and lactic acidosis remains theoretical, monitoring C-peptide and liver function should be regarded as experimental.

Elevated lactate levels have been strongly associated with the development of fat wasting in several studies, which have shown that only those patients with elevated lactate and blood sugar levels developed fat wasting. An Australian study also found an association between increased levels of lactate and reduced bone mineral density in the spine (Carr 2001), while another study found that people who developed peripheral neuropathy were significantly more likely to have elevated lactate levels (Brew 2001).

Treatment of lactic acidosis

Treatment for lactic acidosis typically consists of fluid and bicarbonate administration. Patients may also need respiratory support. NRTIs should usually be discontinued until lactate levels have returned to normal, and some researchers have suggested that a combination of protease inhibitors and non-nucleoside reverse transcriptase inhibitors should be used in order to eliminate the risk of further mitochondrial toxicity during the recovery period if antiretroviral therapy remains essential (i.e. at CD4 cell counts below 200 cells/mm³).

At the 2001 Eighth Conference on Retroviruses and Opportunistic Infections, Dr Andrew Carr suggested the following guidelines for management of elevated lactate levels:

• Individuals with lactate levels greater than 10mM should be taken off NRTI treatment immediately. At this level, individuals are likely to have symptoms and a high risk of death if treatment is not discontinued promptly.

• Individuals with lactate levels between 5 and 10mM should be taken off treatment unless other causes of elevated lactate can be identified. However, those without symptoms who have lactate levels above 5mM should be retested, since this measurement may be a testing error.

• Patients with symptoms and lactate levels between 2 and 5mM should be investigated for other causes before discontinuing therapy.

Lactate levels may take some months to return to normal levels, suggesting that abnormal lactate production by damaged mitochondria takes some time to correct. However, a recent study showed that lactate levels can fall within four weeks of stopping therapy, and that there was also evidence of improvement in mitochondrial DNA during that time (Harris 2003).

At present there is little evidence to show whether or not it is safe to resume NRTI therapy after lactate levels have normalised. Spanish researchers have reported that six out of twelve patients who resumed NRTI therapy, excluding d4T, experienced no further problems. Several other groups have reported similar, limited observations (Falco 2002; Cote 2002; John 2001). A case series of twelve patients, predominantly receiving d4T treatment, were able to resume treatment with 3TC and abacavir-containing regimens without a recurrence of hyperlactatemia in all but one case after an average treatment interruption of 123 days (Lonergan 2002).

Riboflavin (vitamin B₂), thiamine (vitamin B₁), and L-carnitine (Carnitor) have been proposed as treatments for lactic acidosis (Dalton 2001; Falco 2002). Although the evidence remains inconclusive, there have been reports of only four of 18 people with lactic acidosis dying after treatment with riboflavin or thiamine. It has also been suggested that vitamins C and E, and co-enzyme Q may protect against damage to the mitochondria, although this remains unproven. Carnitine and vitamins may stabilise lactate levels among people with mild elevations who continue NRTI treatment (Gerard 2000).

Dichloroacetate, which has been used to treat lactic acidosis in burns victims, has been used at the Chelsea and Westminster Hospital in London in four cases of lactic acidosis occurring after NRTI treatment. Resolution of symptoms occurred in three out of four cases, with normalisation of lactate levels after at least two treatments, but one individual subsequently developed acute pancreatitis and died (Davies 2001).

There have also been two case reports documenting the effectiveness of an oral sugar cane supplement called mitocnol (NucleomaxX) in relieving the symptoms of mitochondrial toxicity, including elevated lactate levels. This may work by increasing levels of the naturally-occurring nucleoside uridine (Walker 2004).

Key research into lactic acidosis

Braitstein (2004) recruited 552 HIV / HCV co-infected patients starting a HAART regimen containing two NRTIs plus a protease inhibitor (PI) and an NNRTI. Of 370 patients having lactate levels measured, 146 were elevated lactate measurement (>2.2mM). After adjustment for intravenous drug use, HAART adherence, baseline CD4 cell count, gender, AIDS diagnosis, age, whether HAART was PI or NNRTI-based, NRTIs used and virologic response to HAART, HCV antibody status was associated with elevated lactate (adjusted hazard ratio [AHR]: 2.0, p = 0.002), as was use of NNRTIs (AHR 2.9, p < 0.001).

Noguera (2004) conducted a prospective observational study of 127 HIV-negative infants born to HIV-positive women. 85% of the women received HAART during preagnany and 93% AZT during labour. 96% of the children received AZT alone. 63 children had elevated lactate levels at least once in the first year of life. Lactate levels were higher in children exposed to NRTIs than in controls. In 44 children lactate levels returned to normal within 1 year. 3 infants had a slight delay in pscyhomotor development. Gestational use of ddI was associated with increased risk of elevated lactate.

Bonnet (2003) conducted a case control study of 9 patients diagnosed with lactic acidosis whilst receiving nucleoside analogue therapy has revealed that low creatinine clearance and a CD4 cell count below 250 cells/mm³ prior to commencing therapy were the only significant risk factors for the condition. A trend towards greater incidence was seen in women, and the majority of lactic acidosis cases were coinfected with hepatitis B or C.

Harris (2003) studied a switch from d4T to tenofovir in 75 people who had symptoms such as high lactate, peripheral neuropathy, fat wasting and/or intractable fatigue. Data on 28 people showed that tenofovir had been stopped due to insomnia and elevated creatinine. Four-week follow-up showed viral load below 50 copies/ml in all 26 switchers, and mean corpuscular volume had fallen significantly and median ratio of mitochondrial DNA/nuclear DNA had increased significantly. Among people who switched due to high lactate, average lactate levels fell by about a quarter. Six-month data on 21 people showed 20 had viral load below 50 copies/ml.

Rivas reported a case of fatal lactic acidosis in a 45-year-old woman who swtiched from ddI/d4T/nevirapine to d4T (30mg twice daily), ddI (250mg once daily) and tenofovir (300mg once daily). The woman stopped nevirapine due to elevated liver enzymes. Within days of the switch, the woman developed vomiting, abdominal pain, confusion and reduced alertness, jaundice and elevated liver enzymes and bilirubin. Her lactic acid levels were 16.38 mmol/l (normal range 0.6-1.7, threshold for discontinuing therapy 5mmol/l). Antiretroviral treatment was discontinued immediately and bicarbonate, vitamin K, thiamin and riboflavin were given in order to bring the hyperlactatemia under control. Treatment failed, and the woman died 36 hours later. The lactic acidosis has been attributed to elevated levels of ddI resulting from the drug interaction with tenofovir, despite the reduced ddI dosage.

Murphy (2003) reported the death of a man taking a HAART regimen containing tenofovir and ddI from kidney failure and lactic acidosis. Although the man had pre-existing impaired kidney function, this case adds to the growing body of evidence that tenofovir can be toxic to the kidneys and adds to cautions about the use of tenofovir and ddI together in people with impaired renal function. When his CD4 count fell to 35, the man switched from ddI (400mg once daily), efavirenz, saquinavir and ritonavir to ddI (400mg once daily), tenofovir (300mg once daily), amprenavir and ritonavir. Despite initial evidence that the man was tolerating the regimen, at six weeks he presented to hospital with a four-day history of progressive fatigue, urine retention, muscle pain, and worsening peripheral neuropathy. The man had low blood pressure (90/50mm Hg), and a creatinine level of 7.6mg/dl, and had blood and protein in his urine. Anti-HIV therapy was stopped. On admission to intensive care his lactic acid level was 5.5mM and increased to 16.7mM despite therapy to lower it. No evidence of infection was found and doctors concluded that the mans high lactic levels were due to drug toxicity. Despite further treatment to lower lactic acid levels, the mans condition continued to worsen and intensive care was withdrawn in accordance with the patients wish that he did not receive prolonged aggressive therapy. He subsequently died.

Yoganathan reported four cases of symptomatic high lactate. In two cases the patient were taking d4T/ddI/tenofovir.

Desai (2003) conducted a chart-review of 127 HIV-positive children in the Brooklyn Pediatric AIDS Network to look for evidence of elevated lactic levels. A total of 251 lactic readings were obtained, from the 104 HAART-treated and the 23 treatment-naﶥ children who were aged between one and 17 years. The overwhelming majority of the HAART-treated children, 102 (98%) were taking NRTIs as part of their therapy. The most common regimen was two NRTIs and a protease inhibitor, which was prescribed to 57 (55%) of children. The most commonly prescribed drugs were d4T, which 51 (49%) of children were d4T taking and ritonavir, which was taken by 38 (36.5%) of children. Mean lactate levels were 1.7mmol/l (range 0.6-4.4mmol/l). Almost one third of the children had at least one reading over 2 mmol/l, and of the total of 251 lactate measurements 56 (25.6%) were over 2mmol/l. None of the children in this study had a reading above 4.4mmol/l. Only one patient became ill because of elevated lactic levels, experiencing abdominal pain and nausea and vomiting.

Lichtenstein (2003) analysed a database of 7820 HIV-positive people and found risk of peripheral neuropathy, pancreatitis and lactic acidosis increased as CD4 count decreased. For people with CD4 counts between 0-99, incidence was 16% compared with an incidence of 5% for people with CD4 counts above 500. The incidence of these conditions was significantly greater when CD4 count was above 350.

Moyle (2002) analyzed cross-sectional and longitudinal data from 1239 HIV-infected people who had been taking anti-HIV treatments for more than four months. Most patients were men and the average age was 39 years. Median lactate was 1.4mmol/L among these treated patients, compared with 1.1mmol/L in untreated patients from the same clinic. 8.7% of treated patients had elevated serum lactate (above 2.5mmol/L). 9 patients (0.8%) had lactate levels above 5mmol/L, including 4 with lactic acidosis. 6/9 were taking ddI and d4T and 4/9 were female. Multivariate analysis showed ddI doubled the risk of high lactate while abacavir reduced the risk of abacavir by half. Longitudinal data collected from 750 participants in the study showed that raised lactate is often transient. Despite the limited use of monitoring lactate, the authors continue to monitor lactate levels.

Cô´© (2002) studied the levels of mitochondrial DNA (mtDNA) in the blood cells of 8 people with symptomatic lactic acidemia who were taking antiretroviral therapy, and compared the results with mtDNA in 24 HIV-negative people and 47 HIV-infected people who had never taken treatments. The ratio of mtDNA to nuclear DNA in blood cells was 70% and 43% lower in people with high lactate compared to untreated HIV-infected people and HIV-negative controls, respectively. Levels of mtDNA improved when treatment with nucleoside analogues (NRTIs) was stopped. When therapy without d4T was re-started, no further deterioration was observed.

Gerard (2000) investigated the 964 HIV-infected patients attending the University Unit of Infectious Diseases in Tourcoing, France between Sept. 1997-August 1999. All patients on antiretroviral therapy (n=871) were investigated for symptoms of high lactate levels , and those with possible symptoms had their lactate levels tested. Those with high lactate had functional respiratory tests (FRT), and liver or muscle biopsies were proposed. After 2 years follow-up, 14 patients with symptomatic hyperlactaemia were identified, including one patient who died of lactic acidosis. All 14 had been taking d4T. Incidence per year was 0.8% and 1.2% among those on d4T. Median lactate levels were 1mmol/L in controls and 2.3 mmol/L in the symptomatic hyperlactaemic patients. Symptoms included fatigue, weakness, abdominal pain, weight loss, peripheral neuropathy and difficult or rapid breathing after exercise. FRT showed a deviation towards anaerobiosis with high lactate/pyruvate ratios at rest and during exercise. 4 patients tested for mitochondrial ultrastructural abnormalities all showed these abnormalities. 4/5 patients who underwent muscle biopsies showed signs of mitochondrial dysfunction. Two patients with mild lactate elevations had their conditions stabilise with carnitine and vitamins while five patients who stopped their NRTIs showed improvement.

Falco (2002) reported a case series of 12 people taking antiretrovirals who developed lactic acidosis and conducted a literature review which covered 60 other cases. The death rate was high: death occurred in 33% of 12 and 57% of 60. Only serum lactate above 10mM was associated with greater risk of death. Although numbers are small and data inconclusive, the authors found some evidence that administration of thiamine, riboflavin, L-carnitine, vitamin C and antioxidants may reduce the risk of death in people with lactic acidosis

Vrouenraets (2001) assessed plasma lactate levels in 223 patients, 178 (78%) on NRTIs. 135/173 (78%) of those on NRTI had normal lactate compared to 92% of those not on NRTI treatment. Mild hyperlactemia (between 2.1-5mmol/L) occurred in 21% of people on NRTIs and 8% of untreated patients. Only one individual had very high levels but these normalised within 2 weeks. d4T treatment was significantly associated with mild hyperlactemia (<2.1mmol/L). AZT and abacavir were associated with increased risk of high lactate. There was no relationship between duration of treatment and lactate levels and there was large fluctuations in lactate levels.

John (2001) conducted a retrospective analysis of 349 HIV-infected people in the Western Australia HIV Cohort for 18 months. During this time, two people developed severe fulminant lactic acidosis (lactate above 5mmol/L) and hepatitic steatosis due to nucleoside analogue reverse transcriptase inhibitors (NRTIs). Five others had symptomic lactatemia (nausea or abdominal pain, evidence of hepatic steatosis and lactate levels between 2.8-4.1mmol/L) but change of therapy led to relief of symptoms and a decline in lactate levels. Mildly elevated mean lactate levels between 1.5mmol/L and 2.5mmol/L occurred in 39.8% of participants, while 4.4% had mean levels between 2.5-3.5mmol/L. However, 65% of participants had at least one lactate result over 1.5 mmol/L. Measurements were made approximately 4 times during the study period. Analysis of mean lactate levels by antiretroviral regimen, individual drugs and drug classes found all stavudine-treated patients had higher mean lactate concentrations compared to people on zidovudine-based therapy or no treatment (1.65 vs 1.45 and 1.34mmol/L, p<0.05). There was no significant difference in lactate levels between those on lamivudine- and didanosine-based regimens. Lactate levels rose over time in both treatment groups, with a greater increase in the stavudine group (p<0.01). Statistical analysis found no factors other than stavudine therapy to be significantly associated with elevated lactate, including total duration of NRTI treatment.

Brew (2001) presented a prospective study of 63 patients on HAART of whom 21 developed peripheral neuropathy (PN) during follow-up. PN was attributed to d4T in 15 people, due to improvement on cessation of d4T. 13/15 had high lactate while on d4T which returned to normal upon cessation. Only 1/6 people with HIV-related PN had high lactate and only 3 people had high lactate in the absence of PN.

Garcí¡­Benavas (2000) conducted a cross sectional of 127 people on HAART for more than 6 months. Mean lactate levels were 18.5mg/dL with 60% diagnosed with hyperlactataemia. Factors associated with high lactate levels were: homosexual practice, injecting drug use, duration of HAART (but not NRTIs), elevated lipids and body fat changes. No association was found with CD4 count, and HCV infection.

Ter Hofstede (2000) reported four deaths in HIV-infected adults due to lactic acidosis. Autopsies and muscle biopsies revealed severe damage to the mitochondria and hepatic steatosis (fatty liver). Three of these individuals had been taking d4T/ddI and the fourth individual was also taking d4T.

Lonergan (2000) presented a study of 20 people on d4T who presented with abdominal pain or nausea and high lactate (2.9-19.0mmol/L). d4T was ceased and all individuals improved. Of 19 who restarted NRTI treatment, only one developed high lactate levels.

Lonergan (2001) identified 33 cases of hyperlactatemia between 7/98 and 5/00 in NRTI treated patients. The incidence rate for d4T-containing regimens was 25.6 cases per 1000 person years of d4T treatment vs 1.9 cases per 1000 years of treatment with any other drug. The relative risks of developing hyperlactatemia was assessed for various regimens compared to AZT/3TC: 3TC alone (10.5), d4T/3TC (11.6), d4T/abacavir (15.0); d4T/ddI (36.3); d4T/ddI/abacavir (147.9). Overall incidence was 14.5 per 1000 person years.

Delgado (2001) reported symptomatic lactic acidemia in 5 people taking d4T plus one other NRTI. Symptoms included weight loss and fatigue. Peak lactic acid levels were between 3.1-7.4mmol/L (normal range 0.5-2.1). Symptoms resolved upon cessation of therapy. 4/5 safety restarted treatment with an altered regimen.

Blanco (2000) conducted a cross-sectional analysis of 127 patients with >6 months treatment experience. Hyperlactatemia was present in 60%. Male gender, elevated triglycerides, hypercholesterolemia, body fat changes and time on HAART were all significantly correlated with hyperlactatemia. but individual drugs, CD4 cell count and total NRTI exposure were not correlated.

Boxwell and Styrt (1999) presented results of Federal Drug Administration monitoring of lactic acidosis. 60 cases of lactic acidosis have been associated with nucleoside analogue use, 46 with monotherapy. Onset occurred approximately 9 months into treatment, with a 55% death-rate. Women were over-represented and there was some evidence that over-weight people were at greater risk. Liver dysfunction was mild although LDH were high.

Mokrzycki (2000) reported 5 cases of lactic acidosis associated with d4T monotherapy or d4T plus 3TC or delavirdine. Average time on treatment was 9.4 months and mean peak in lactate level was 10.3mmol/L. Symptoms included vomiting, abdominal pain and liver damage. Two individuals also have other signs of mitochondrial toxicity - pancreatitis and myopathy. Four people improved after d4T was ceased and one person died.

Coghlan (2001) retrospectively analysed records of HIV-infected patients attending an American public hospital between 1995-2000. 12 cases of symptomatic lactic acidosis were identified. All had extensive NRTI exposure and ddI/d4T were commonly taken. 11 presented with abdominal pain, nausea and/or vomiting. 8 had experienced severe weight loss prior to symptoms. 6 had fatty liver. 5 progressed to multi-organ failure and died.

Carr (2000) analysed data on 14 people taking NRTIs with body fat changes, 32 drug-naﶥ patients, 28 NRTI patients without body fat changes, 44 PI recipients without body fat changes and 102 PI recipients with body fat changes. The body fat changes in people on NRTIs were either peripheral fat loss or abdominal weight gain, but in most cases the abdominal weight gain was reported to be hepatomegaly. Although the body fat changes looked very similar to those seen in PI recipients, they were accompanied by elevated lactate, recent onset nausea, fatigue and lower levels of lipids, glucose and insulin.

Tantisiriwat (2001) reported 37 HIV-positive hospital admissions out of 1261 during 1996-98 has elevated lactic acid, but only 6.1% of these cases could be definitively related to antiretroviral therapy.

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