AIDS Clinical Trials Group (ACTG) study A5129 was a prospective multicenter study to explore the efficacy of B-vitamin administration in preventing progression of asymptomatic or minimally symptomatic venous hyperlactatemia. The study was designed to be conducted in 2 steps: step I, screening for sustained hyperlactatemia, and step II, vitamin B therapy for subjects with sustained hyperlactatemia. Eligible subjects were enrolled between February 2002 and September 2002 at 3 sites: Beth Israel Medical Center in New York, Case Western Reserve University in Ohio, and the University of North Carolina in North Carolina.
HIV-infected subjects ≥13 years of age on NRTI-containing ART for at least 4 weeks with indications for lactate measurement but without symptoms associated with rapidly progressive hyperlactatemia were eligible to enroll into step I. Subjects must have had at least one of the following indications for lactate measurement: a history of venous or arterial lactate level >1 but <4 times the upper limit of normal (ULN); an anion gap >15 mmol/L within 3 months before entry, serum carbon dioxide (CO2) or bicarbonate (HCO3) <20 mmol/L, creatine kinase (CK) >2 times the ULN, alanine aminotransferase (ALT) >1 and <5 times the ULN, or lactic dehydrogenase (LDH) >2 times the ULN; current use of d4T-containing therapy for at least 6 months; nausea of grade 2 (DAIDS Toxicity Grading Scale), mild abdominal pain or other vague abdominal complaints that do not limit daily activities (grade 1), mild fatigue or weakness (grade 1), anorexia associated with reported loss of <3% total body weight, or mild to moderate peripheral neuropathy (grade 1 or 2) all within 30 days prior to entry; current lipoatrophy; or a clinical diagnosis of osteopenia, osteoporosis, or spontaneous fracture.
During step I, all subjects had venous lactate levels drawn in strict accordance with the AACTG Guidelines for Lactate Collection and Processing. 28 These guidelines specify that venous lactate specimens must be collected without the aid of fist-clenching or use of a tourniquet. If a tourniquet is necessary, it is applied lightly and the lactate level is drawn first. Additionally, subjects are asked to refrain from exercise and alcohol consumption for 24 hours prior to the blood draw. Blood is collected in the appropriate chilled tube and processed within 30 minutes of the draw. At 2 of the study sites, venous lactate specimens were collected in tubes containing sodium fluoride–potassium oxalate (gray top). At the other site (University of North Carolina), tubes containing sodium heparin (green top) were used. For the purpose of this study, sustained hyperlactatemia was defined as 2 consecutive elevated nonexercise venous lactate levels ≥1.5 and ≤4 times the ULN, the second of which must be fasting and measured no more than 30 days after the first. The ULN of venous lactate was 2.4 mmol/L at 1 site and 2.2 mmol/L at the other 2 sites.
The first 34 subjects enrolled had nonfasting venous lactate levels obtained at entry (week 0) and then fasting venous lactate levels collected again within 14 days (week 2). To facilitate enrollment, the protocol was amended in May 2002 to eliminate the second venous lactate collection in cases in which the week 0 lactate was <1.5 or >4 times the ULN. Therefore, the remaining subjects only had a week 2 lactate level obtained if their week 0 level was between 1.5 and 4 times the ULN.
Based on the results of step I of the study, step II was not initiated.
Descriptive statistics are used to describe the study sample. Categoric variables are summarized by frequency counts and percentages. Continuous variables are summarized by displaying descriptive statistics. Confidence intervals are used to estimate population parameters, and graphic methods are used to display lactate data.
From February 2002 to August 2002, 83 subjects were enrolled. Baseline characteristics of the subjects are listed in Table 1. Most of the subjects were male (86%) and nonwhite (65%). All subjects were receiving NRTI antiretroviral agents at baseline and, as expected given the inclusion criteria, most (71%) were receiving d4T at entry or for the 6 months just prior to entry (74%). At study entry, 43 (52%) were taking 3TC, 18 (22%) were taking ddI, and 14 (17%) were taking abacavir; 52 (63%) were receiving a protease inhibitor; and 31 (37%) were receiving a non-NRTI.
Two thirds (67%) of study participants had 2 or more risk factors or signs associated with hyperlactatemia, and 10 (11%) had 4 or more factors. In addition to d4T exposure, risk factors experienced by at least 10% of the cohort included anorexia during the previous 30 days (100%), LDH >2 times the ULN within the 3 months prior to entry (78%), an anion gap >15 mmol/L in the previous 3 months (63%), an ALT level between 1 and 5 times the ULN during the 3 months prior to study entry (17%), lipoatrophy (14%), fatigue (13%), peripheral neuropathy (11%), and mild abdominal pain (10%).
At baseline, the median nonfasting and nonexercise venous lactate level of the cohort obtained using strict adherence to standardized venous lactate collection techniques was 1.2 mmol/L (range: 0.7–5.1 mmol/L). A repeat venous lactate level performed in a nonexercise and fasted state was collected from 34 subjects at week 2; the median lactate value at this time point was 1.1 mmol/L (range: 0.5–4.6 mmol/L). As demonstrated in Figure 1, only 1 subject had a venous lactate level >1.5 times the ULN at baseline, with a value 2.1 times the ULN (5.1 mmol/L). On repeat testing at week 2, the venous lactate level of this subject was 1.2 times the ULN (2.9 mmol/L), although no intervention had been performed. This subject was receiving d4T, efavirenz, and indinavir at study entry, and d4T exposure was the only reported risk factor for hyperlactatemia. Another subject prescribed d4T, abacavir, and lopinavir/ritonavir had a lactate level at entry of 1.4 times the ULN and then 1.9 times the ULN at the week 2 visit. This subject entered the study with >6 months of d4T exposure, fatigue, elevated anion gap, and lipoatrophy. Two other subjects had a single venous lactate measurement of between 1.0 and 1.5 times the ULN. One was taking d4T, ddI, and indinavir, and the other was taking d4T, ddI, nevirapine, and lopinavir/ritonavir. Both had >6 months of d4T therapy prior to study entry, and at baseline, the latter subject reported a history of fatigue, lipoatrophy, and peripheral neuropathy. None of these subjects reported new symptoms associated with hyperlactatemia during the study.
There were no episodes of symptomatic hyperlactatemia or lactic acidosis during the study. Given our data (0 of 83), a 95% confidence interval for the prevalence of hyperlactatemia is (0 [3.54%]). In other words, the true prevalence of hyperlactatemia as defined by this study is likely to be less than 3.54%.
Nevertheless, the subject whose lactate increased from 1.4 to 1.9 times the ULN from entry to week 2 was diagnosed with symptomatic lactic acidosis within 3 weeks of the week 2 final study visit. A review of the medical records of the remaining subjects was conducted at the 3 study sites. No other cases of symptomatic hyperlactatemia or lactic acidosis were detected within the 24 weeks following study discontinuation.
In this study, sustained elevations of blood lactate above 1.5 times the ULN in a cohort of antiretroviral-treated HIV-infected persons with multiple putative risk factors and/or signs of hyperlactatemia were not observed.
Only 2 subjects had a lactate value above 1.5 times the ULN at 1 of the on-study determinations. In 1 case, the entry lactate level of 2.1 times the ULN declined on subsequent testing to 1.2 times the ULN. In the other case, the lactate level was observed to rise from a baseline of 1.4 to 1.9 times the ULN at week 2 in the absence of symptoms. Shortly thereafter, however, the subject became symptomatic with lactic acidosis. This improved on withdrawal of ART and later recurred with reintroduction of therapy. This subject, without symptoms of elevated blood lactate during the 2-week study period, appears to have had evolving hyperlactatemia that progressed to symptomatic lactic acidosis in the 3-week period after the study. A search of the medical records of the remaining subjects failed to document any other cases of symptomatic hyperlactatemia or lactic acidosis within 6 months of subject study discontinuation.
These results suggest that hyperlactatemia, especially sustained hyperlactatemia, is rarer than previously reported even among subjects with risk factors previously associated with lactate elevation. Hyperlactatemia identified in previous studies and in practice may be a result of falsely elevated lactate measurements influenced by the methods and conditions of specimen collection. In this study, we believe that strict adherence to guidelines for the collection and processing of these specimens likely reduced the possibility of such falsely elevated lactate results.
There are potential limitations to our investigation; foremost is the potential for type II error given the size of the cohort studied. If the prevalence of hyperlactatemia above 1.5 times the ULN is at least 5%, however, as suggested in previous cross-sectional studies, there would be greater than a 98% probability that our study should have detected at least a single case. Furthermore, our inclusion criteria were based on published data regarding factors associated with elevated lactate in the setting of antiretroviral exposure and therefore should have led to enrichment of the cohort with cases of hyperlactatemia and an increase in the prevalence beyond that found in nonselected populations. Another possible limitation of our study is the definition of hyperlactatemia that we employed. The defining of hyperlactatemia as 1.5 times the ULN rather than as any level above the ULN was designed to eliminate from the case definition lactate levels that were higher than the laboratory reference ranges but of little or no clinical significance. In this study, only 4 subjects had a venous lactate level above the ULN, the 2 subjects described previously and 2 with single lactate values between 1 and 1.5 times the ULN. Even when applying a stringent definition of hyperlactatemia as any value above the ULN, the prevalence of asymptomatic hyperlactatemia that we observed was lower than those reported in previous cross-sectional studies of populations not selected for risk factors for elevated lactate. 14–16 One study conducted at 1 of the sites participating in this study did find a similar prevalence of elevations of lactate above the ULN with strict adherence to lactate collection guidelines. 17 As with the other previous investigations, this study, unlike our investigation, enrolled subjects without known risk factors for hyperlactatemia. Lastly, although the rigorous blood collection and processing techniques used reduce spurious results, venous lactate collection remains subject to increased variability compared with arterial lactate collection, on which reference ranges are based. Importantly, only 4 subjects had a lactate level less than the ULN, and in 2, the levels were within 0.3 mmol/L of the ULN.
These results indicate that sustained asymptomatic hyperlactatemia is rare when lactate levels are carefully collected. In addition, we conclude that routine screening of lactate levels in asymptomatic ART-receiving patients is not justified.
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