Exercise testing in HIV patients with random increased lactic acid levels: evidence for a reduced anaerobic threshold with a pattern of mitochondrial dysfunction
Harvey S. Bartnof, MD
An uncommon, but life-threatening complication of treatment with drugs in the NRTI (nucleoside reverse transcriptase inhibitor) drug class is lactic acidosis with hepatic steatosis (excess fat in the liver).
When tested, some patients taking anti-HIV therapy have had a mild increase in their lactic acid level in blood, yet without symptoms. It is unknown whether those persons were at increased risk of progressing to ‘full-blown’ lactic acidosis or have other abnormalities.
One of the more interesting presentations at the recent 3rd International Workshop on Salvage Therapy for HIV Infection addressed this issue. The study was presented by Marianne Harris, MD, from the British Columbia Center for Excellence in HIV/AIDS. She discussed the results of a small study indicating that mild increases in lactic acidosis are associated with several abnormal laboratory (‘pulmonary’ or lung function) test results when exercise testing was performed.
Dr. Harris first presented information about the reproducibility of random lactic acid test results among HIV positive persons being followed at her institution. She also discussed predisposing factors for and the rate of increased lactic acid. All patients who had a random venous (from a vein, vessel carrying blood back to the heart) lactic acid level in their chart between August 1999 and January 2000 were included. All must have also been taking anti-HIV therapy.
During the 6-month inclusion period, 331 patients had a random venous lactic acid (LA) test result. Among those, 68 or 21% had an abnormal increase in the LA level (normal is less than or equal to 2.1 millimoles per litre at her institution). A total of 27 patients or 8% had a level that was moderately or severely increased (greater than 3 millimoles per litre).
To measure the reproducibility of the LA test, Dr. Harris analysed those with at least two measurements. Among the 331 patients with at least one LA test result, 149 had at least two measurements. Among those, 138 or 93% had a reproducible result. Specifically, the LA was repeatedly normal in 105 patients and repeatedly abnormal in 33 patients. Those findings were statistically significant.
Dr. Harris performed a statistical analysis to examine factors associated with an abnormal LA test. Each of the following 13 factors was not associated with an abnormal LA measurement: age; gender (sex); CD4 count; time on anti-HIV therapy; time on NRTI drugs; time on protease inhibitor drugs; time on non-NRTI drugs; time on abacavir; time on zidovudine; current abacavir; current zidovudine; and current non-NRTI drug therapy.
In a ‘multivariate analysis,’ each of the following factors was independently and highly statistically associated with an abnormal result (note that ‘associated with’ does not mean ‘causation’): current hydroxyurea, (‘odds ratio’ of 4.1), current d4T, (‘odds ratio’ of 4.1) and time on d4T (‘odds ratio’ of 1.1 per three months of d4T therapy). Note that d4T was and is a very commonly used NRTI drug. Thus, if few patients were taking non-d4T regimens, this might lead to a statistical ‘association’ without necessarily indicating ‘causation.’
Then Dr. Harris presented her findings about exercise testing and abnormal LA levels. She and her colleagues compared the ‘anaerobic threshold’ in 21 patients with at least two abnormal LA test results to eight control patients who were taking anti-HIV therapy, but had a normal LA test. Anaerobic threshold is the point at which during exercise, energy production within cells switches from ‘aerobic’ (energy produced within ‘mitochondria’ part of cells, with the help of oxygen) to ‘anaerobic’ (energy produced within the ‘cytoplasm’ of cells, where there are no other cellular structures, without using oxygen). After the switch to anaerobic energy production, the amount of ‘carbon dioxide’ (CO2) produced increases, which in turn, increases the amount of air that is breathed in and out per minute. (Increased CO2 increases breathing to rid the body of the excess CO2.) Increased breathing also affects peak oxygen consumption, which is measured as a percentage of normal. The ‘anaerobic threshold’ is defined by the percentage of maximum oxygen consumption when the increase in breathing occurs, which is correlated with an increase in LA levels. A normal anaerobic threshold is greater than 40% of the predicted normal level.
A low anaerobic threshold could be due to abnormal function of mitochondria and/or more commonly, poor ‘cardiopulmonary’ fitness, i.e., being ‘out-of-shape’ due to being a ‘couch potato’ and/or ‘mouse potato’ (sitting in front of a computer for extended periods). Dr. Harris defined a reduced anaerobic threshold due to mitochondrial dysfunction using three abnormal results during exercise testing. Those were: an anaerobic threshold less than 40% of the predicted normal level; decreased peak uptake of oxygen that was less than 60% of the predicted normal level; and increased ‘minute ventilation’ (amount of air breathed per minute) at greater than 80 litres of air per minute.
‘Cardiopulmonary’ (heart/lung) exercise testing is performed in a laboratory on a treadmill device whereby the patient has to walk, jog or run as the treadmill belt moves. Nose plugs are used, and a tube is placed in the mouth. This allows for accurate measurements of the amount of air that is breathed in and out per minute. Exhaled (breathed out) CO2 and oxygen also can be measured. A ‘pulse oximeter’ is placed on the skin to measure the oxygen level in the body. In addition, an intravenous (IV) line may be inserted so that blood can be tested during exercise, particularly the acid state of the blood (‘bicarbonate’ level). A catheter may also be placed into an artery to measure levels of oxygen, CO2 and the ‘pH,’ which directly reflects the acid state there. Chest wires also may be placed so that the heart rhythm can be observed, in addition to possible changes on an ‘electrocardiogram’ (ECG or heart wave test) suggesting low oxygen in heart muscle cells.
Among the 21 HIV-positive patients with an increased LA level at least twice who underwent exercise testing, the mean baseline LA in venous blood was 2.9 millimoles per litre (range 2.2-7.4). Among the eight control, HIV-positive patients who underwent exercise testing, the mean baseline LA was 1.3 millimoles per litre (range 0.8-2.1). As stated above, all patients were taking anti-HIV therapy.
The results of the exercise testing showed that a reduced anaerobic threshold was present in 13 of 21 (62%) patients with a high baseline LA, compared to 4 of 8 (50%) of control patients. Yet, those with a reduced anaerobic threshold due to mitochondrial dysfunction was present in 9 of 21 (43%) patients with a high baseline LA, compared to only 1 of 8 (13%) of control patients.
Dr. Harris had four conclusions. First, random venous lactic acid levels are stable among [most] HIV positive individuals taking anti-HIV therapy who have an abnormally high level. Second, ‘random venous lactic acid is frequently elevated in [HIV positive] patients taking antiretroviral therapy.’ Third, ‘high random venous lactic acid is associated with [and not necessarily caused by] time on d4T , current d4T and current hydroxyurea use.’ Lastly, ‘high random venous lactic acid may be associated with physiologic dysfunction.’
There are a few limitations with the study. First, the study was small, particularly the number who underwent exercise testing. Second, the first part (before the exercise testing) of the study was retrospective, which carries less weight than a prospective one. Third, Dr. Harris did not state whether those with a reason for LA testing among the entire cohort, i.e., not random, were specifically excluded from the analysis. A physician ordering a LA test usually would have some reason to do so. This would be due to patient symptoms or other abnormal laboratory tests. Dr. Harris did not indicate whether there was a specific reason for the ‘random’ testing. However, based upon her second conclusion above, there is an assumption that all LA tests included in the analysis were truly random, without a reason for testing. The study might have carried more weight if there were some other mechanism for ‘randomisation.’ That could be all HIV positive patients at their institution taking anti-HIV therapy having a random LA level. Or, 50-100 consecutive patients during one week who are having routine (not urgent or emergent) follow-up could be tested. Also, the random patients in Dr. Harris’ study might have had some symptoms related to increased LA levels. She did not indicate whether such potential symptoms were recorded in the chart near the time of the random test.
Even if the exercise testing results are proven in future studies, the clinical significance would be unknown. Other than a decrease in aerobic exercise capacity for some, the results do not necessarily indicate that those with a random increase in lactic acid are at risk for future development of ‘full-blown’ lactic acidosis/steatosis with clinical symptoms and other abnormal lab tests. Some of them might be at increased risk, but the entire cohort of those with a random increase would need to be followed prospectively to prove that. It has been shown that other co-factors are associated with the development of clinical lactic acidosis with steatosis. Those are female gender and obesity as measured by a high body mass index (BMI, weight divided by height squared).
During a discussion later at the Workshop, William Powderly, MD, from Washington University in St. Louis, Missouri, mentioned an analogous clinical situation. Patients taking didanosine with a mild increase in amylase was not predictive of future progression to clinical pancreatitis. Dr. Powderly said that if the person has a mild increase in lactic acid and has symptoms related to lactic acidosis, then the patient has ‘toxicity.’ However, the symptoms of lactic acidosis, particularly in the early stages, are non-specific. Fatigue and nausea are common symptoms in persons with HIV infection, particularly as a side effect of many anti-HIV medications. Other symptoms of lactic acidosis are somewhat more specific, i.e. weight loss, although that could be due to other causes, possibly an AIDS-related opportunistic condition. However, the symptom of shortness of breath on exertion can occur with lactic acidosis. That symptom might be elicited earlier in a patient’s course with exercise testing. Exertional shortness-of-breath would likely be revealed in association with a reduced anaerobic threshold during exercise testing, as shown in Dr. Harris’ study above.
Lastly, the exercise test results do not resolve the issue of true causality of mild increases in lactic acid. Several of the NRTI drugs have been associated with lactic acidosis/steatosis in the past. Zidovudine was the most common, but it also was the first and only available anti-HIV drug for several years when patients took it as monotherapy. In the current era of combination therapy, it is more difficult to prove cause and effect.
Notwithstanding these limitations, Dr. Harris’ study is quite interesting and provocative. Additional, prospective studies in the future with a larger number of patients will help to determine whether her results are reproducible and have any clinical significance.
There were a few reports about lactic acid levels in HIV positive patients at the recent 7th Conference on Retroviruses and Opportunistic Infections. J.T. Lonergan, MD, Diane Havlir, MD, and colleagues from the University of California at San Diego measured the rate of increased lactic acid in blood in their HIV patient population of 1,285 persons. The rate was 1.4 cases per 1,000 person-months * of NRTI drug therapy. (* The number of patients times the number of months of those patients taking NRTI drugs equals the number of patient-months.) They also found zero cases in 6,376 person-months of non-d4T therapy.
In the Swiss Study Cohort, K. Boubaker, MD, and colleagues from Switzerland concluded that hyperlactataemia (increased lactic acid in blood) was a ‘frequent laboratory abnormality among patients receiving antiretroviral therapy.’ They performed a ‘cross-sectional’ analysis of the 1,300 HIV positive patients in the Swiss Cohort in August 1999 and reported their findings at the 7th Retrovirus Conference. Among the first 272 patients, lactic acid levels were increased in 42 or 15.4% of patients. Among those 42, 33 or 79% had ‘clinical abnormalities, the most frequent being fatigue and diarrhoea.’ They also reported that ‘additional laboratory abnormalities were observed in 25 of 42 [or 60%] patients, the most frequent being elevated urate [uric acid, associated with ‘gout’ arthritis] and alteration of hepatic [liver] tests.
It is interesting to note that the 15% rate in the first 272 patients of the Swiss Cohort Study is somewhat similar to the 21% rate in the random lactic acid testing in the report by Dr. Harris above.
In a review of 106 cases of lactic acidosis reported to the FDA, Drs. D.E. Boxwell and B.A. Styrt reported that the most common symptoms were nausea, vomiting, abdominal pain, malaise (weakness), weight loss and dyspnoea (shortness-of-breath). Note that ‘full-blown’ clinical lactic acidosis is not the same as mere increases in lactic acid, without the full clinical syndrome of acidosis. (Although in the Swiss Cohort above, 79% of those with increased lactic acid had symptoms.) In the most common double NRTI drug combination, d4T plus 3TC, liver steatosis was associated in 69% and pancreatitis in 22%. This report was presented at last year’s ICAAC (39th Conference on Antimicrobial Agents and Chemotherapy).
These studies, though preliminary, suggest that more could be be done routinely in clinic to detect mitochondrial toxicity and lactic acidosis. Further data to validate these measures should be urgently sought.
- Boubaker K and others. Hyperlactatemia and antiretroviral therapy in the Swiss HIV Cohort Study. Abstract 57 at the 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, California.
- Boxwell DI and Styrt BA. Lactic acidosis in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs). Abstract and poster presentation 1284 at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 26-29, 1999; San Francisco, California.
- Harris M and others. Lactic acidosis complicating antiretroviral therapy: frequency and correlates. Abstract and oral presentation 34 at the 3rd International Workshop on Salvage Therapy for HIV Infection; April 12-14, 2000; Chicago; Illinois and Antiviral Therapy 2000; 5 (Suppl. 2): page 31.
- Harris M and others. Physiological disturbance among HIV-positive patients with elevated random venous lactic acid levels on antiretroviral therapy. Abstract and oral presentation 35 at the 3rd International Workshop on Salvage Therapy for HIV Infection; April 12-14, 2000; Chicago; Illinois and Antiviral Therapy 2000; 5 (Suppl. 2): page 31.
- Lonergan LT and others. Hyperlactatemia in 20 patients receiving NRTI combination regimens. Abstract 56 at the 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, California.