Routine lactate monitoring warranted only in those at risk, concludes Swiss study

Routine monitoring for elevated lactate levels is not cost-effective and does not adequately predict lactic acidosis, according to an observational study from the Swiss HIV Cohort Study Group published in the September 1^st issue of the journal Clinical Infectious Diseases. However, the investigators were surprised to find that efavirenz (Sustiva) almost trebled the risk of severe hyperlactataemia, and were unable to adequately explain this finding.

Although lactate levels are routinely monitored in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in well-resourced countries, its usefulness as a predictive tool for lactic acidosis has recently been called into question. In particular, the relationship between mildly elevated lactate levels and risk of lactic acidosis is unknown, as are the clinical long-term consequences of elevated lactate levels.

Consequently, researchers from University Hospital Zurich in Switzerland sought to investigate whether monitoring for lactate levels is worthwhile by assessing the prevalence of, risk factors for, and clinical outcome of elevated lactate levels and lactic acidosis among members of the Swiss HIV Cohort.

Lactate is produced in the mitochondria, an end-product of glucose breakdown. During certain metabolic processes, lactate becomes lactic acid, and when levels of lactic acid are extremely elevated this is known as lactic acidosis. Symptoms include fatigue, breathlessness, abdominal pain and weight loss, and it may be fatal.

It has been known for some time that treatment with nucleoside analogues, specifically ddI (didanosine, Videx/Videx EC) and d4T (stavudine, Zerit), is associated with elevated lactate levels, defined as values above 2.4 mmol/L. Severe hyperlactataemia is defined as lactate levels above 5 mmol/L. This can sometimes, but not always, lead to lactic acidosis, defined in this study as an arterial pH of 7.35 or greater.

A total of 1566 individuals attending the hospital's HIV outpatients' clinic as of August 1^st 1999, with at least two measurements of serum lactate levels, were included in the analysis; there were 4788 person-years of follow-up including over 22,000 lactate measurements. At the start of the study,1178 individuals were already receiving antiretroviral therapy, 214 began HAART after August 1^st 1999, and another 174 remained treatment-naive throughout the observation period, which ended on February 29^th 2004.

During the observation period, 662 (42.3%) study participants had at least one elevated lactate level measurement, 290 (18.5%) had elevated lactate levels on at least two consecutive occasions (of whom 98% were receiving antiretrovirals), and 41 (3.1%, of whom 100% were receiving antiretrovirals, and 96.8% were on HAART) developed severe hyperlactataemia. The positive predictive value for having an elevated lactate level on two consecutive occasions was low (43.8% of all participants: 44.8% on antiretrovirals and 21.1% of treatment-naive), whereas the negative predictive value for having a low lactate level was high (93.68% of all participants: 93.3% on antiretrovirals and 97.7% of treatment-naive).

Between 1999 and 2004, the proportion of individuals receiving ddI- or d4T-containing HAART regimens declined, and those receiving efavirenz increased. During this period, total incidences of elevated lactate levels and severe hyperlactataemia decreased significantly. Between August 1999 and December 2000 there were 172 (95% CI, 147-200) cases of elevated lactate levels on at least two consecutive occasions per 1000 person-years of follow-up. In contrast, between January 2003 and February 2004 there were 22 (95% CI, 15-33) similar cases per 1000 person-years of follow-up.

Univariable Cox proportional hazard analysis found the following factors identified as a significant risk for developing elevated lactate levels amongst the 1392 individuals receiving antiretrovirals: older age, increased waist-hip ratio, high CD4 cell count, liver dysfunction in hepatitis C-negative individuals, and various antiretroviral regimens, including those that contained d4T with or without ddI, boosted and double PI regimens, and efavirenz.

Antiretrovirals that remained significantly associated with elevated lactate levels in multivariable analysis included d4T alone (HR 1.47; 95% CI, 1.18-1.84); d4T plus ddI (HR 3.34; 95% CI, 2.65-4.19); boosted PIs (HR 1.4; 95% CI, 1.01-1.92), double PIs (HR 1.64; 95% CI, 1.15-2.34) and efavirenz (HR 1.46; 95% CI, 1.15-1.87).

Further multivariable analysis, adjusting for sex, age, waist-hip ratio, CD4 cell count, liver function status, and HCV infection status, examined different frequently-used HAART regimens, other than those that included ddI and/or d4T. Only a three class regimen without ddI or d4T remained a significant risk (HR 1.96; 95% CI, 1.18-3.26) and efavirenz in a two-class regimen with two NRTIs (excluding ddI and d4T) was a borderline significant risk (HR 1.34; 95% CI 0.80-2.27).

However, efavirenz remained a significantly increased risk for developing severe hyperlactataemia, one of only two antiretroviral variables to do so in multivariable analysis: d4T plus ddI (Hazard Ratio 6.65; 95% CI, 2.70-16.3) and efavirenz (HR 2.85, 95% CI 1.31-6.21). Two previous studies have found associations between NNRTIs and/or efavirenz and elevated lactate levels, but neither found efavirenz to be a significant risk for developing severe hyperlactataemia. Moyle and colleagues at the Chelsea and Westminster Hospital, London, reported a borderline significant risk of elevated lactate on efavirenz (HR 1.45; 95% CI, 0.97-2.16) in 1239 patients on antiretrovirals. Braitstein and colleagues at the BC Centre for Excellence in Vancouver found evidence that NNRTI-containing regimens increase the risk of elevated lactate (HR 2.9, p < 0.001) in 552 HIV / HCV co-infected patients. This study's authors admit that the "specific mechanism of this association is unknown," but point to recent work by Hadri et al, which suggests that efavirenz may increase lactate levels by suppressing the lipogenic pathway.

Of the 41 individuals with severe hyperlactataemia, four developed lactic acidosis, but none died. On average these four individuals had been receiving antiretroviral therapy (containing both ddI and d4T plus either a PI or an NNRTI) for a mean of 9.7 (range 2.8-16.1) months. Only two had lactate levels available prior to onset of acidosis, however, which ranged from 2.4-5.8 mmol/L in one patient, and 3.8-8.7 mmol/L in the other patient, in the previous six months. Of the remaining 37 individuals, 26 were asymptomatic at the time of their severe hyperlactataemia, and 19 (51.4%) were receiving regimens that contained ddI and d4T.

The investigators also analysed the cost-effectiveness of lactate monitoring. They assessed the cost for each sample at approximately US$20. Since a total of 22,678 samples were analysed to diagnose 41 episodes of severe hyperlactataemia, they calculated that the total cost was US$462,007, and US$11,268 was spent to detect each severe hyperlactataemic episode. "On the basis of our findings," they write, "one might suggest that routine lactate assessment is too expensive and that [it] is not sufficiently predictive for severe adverse events, including lactic acidosis."

Although they concede that life-threatening lactic acidosis can be prevented by lactate monitoring, they conclude by recommending that it may be sufficient to monitor only those with an elevated risk of lactic acidosis in routine clinical practice, whom they identify as "elderly persons, persons with altered liver function, persons receiving didanosine or stavudine, and persons receiving concomitant therapy for HIV and HCV coinfection."