3rd report of patient whose NRTI-associated lactic acidosis responded to riboflavin (vitamin B2)
by Harvey S. Bartnof, MD, HIV&hepatitis.com
Lactic acidosis with hepatomegaly (large liver)/steatosis (fatty infiltrates) and/or pancreatitis (inflammation of the pancreas) is an uncommon, but life-threatening complication associated with most drugs in the NRTI (nucleoside reverse transcriptase inhibitor) drug class. The best treatment is early recognition of the condition, discontinuing the NRTI drug(s) and if necessary, hospitalization and supportive care.
Two published cases in the world have implicated riboflavin (vitamin B2) supplements as being helpful in treating the condition. Now, researchers from Wayne State University have reported a third case of NRTI-associated lactic acidosis with hepatic steatosis that appears to have responded to riboflavin supplementation. The report was presented at Digestive Disease Week 2000 held in San Diego, California May 21-24, 2000. The lead author was Prasad M. Kulkarni, MD.
Lactic acidosis is a condition whereby the level of acid in the blood is too high, leading to a life-threatening decrease in ‘pH.’ This condition is a rare complication of most drugs in the NRTI drug class. The first case was reported in 1991 and was linked to monotherapy with zidovudine. Since then, other NRTI drugs have been linked to the condition, particularly d4T, ddI and possibly 3TC. Implicating the newer NRTI drugs (such as abacavir) is more problematic, since most patients are now taking combination HAART for HIV.
In a recent review by the FDA of 106 cases of lactic acidosis associated with NRTI drug therapy, hepatic steatosis was reported in 69% and pancreatitis in 22%. Other risk factors were obesity (high BMI or body mass index, weight divided by height squared) in 80% and female gender. (See below for more about this FDA review study.) Persons prone to or who have pre-existing liver problems, including chronic hepatitis B or C, may be at increased risk. Some of the first reported cases were among those who had co-infection with HIV/HBV (hepatitis B virus) or HIV/HCV (hepatitis C virus).
There is growing evidence that the toxicity is to ‘gamma DNA polymerase’ in mitochondria (energy producing ‘organelles’ in cells). (The DNA in mitochondria is separate from the DNA in the nucleus of cells. The NRTI drugs have a very low ‘affinity’ for the ‘alpha’ and ‘beta’ DNA polymerases in the nucleus.) Adverse events associated with the NRTI drugs appears to be related to mitochondrial damage in several types of cells, leading to myopathy (muscle disease), pancreatitis (** inflammation of the pancreas gland in the abdomen), neuropathy (nerve disease, particularly ‘peripheral’ neuropathy in the feet and hands) and liver disease.
There are two reported cases in the world literature indicating that riboflavin supplementation may help treat lactic acidosis related to NRTI drugs. In the current report of the third reported case, a 67-year-old African-American man with HIV infection was treated with d4T, 3TC and nelfinavir. He had been taking the triple HAART combination for 14 months since first diagnosed with HIV in February 1998. Due to symptoms of loss of appetite, nausea, vomiting and weight loss, he was admitted to the hospital. He had a tender, enlarged liver (below the right front lower rib margin) and was obese (BMI or body mass index was 29). But, he was neither jaundiced (yellowing of skin) nor icteric (yellowing of eyes). His ALT (alanine aminotransferase, liver enzyme) was elevated at 63 units per liter with a normal amylase (pancreas enzyme). His HIV RNA viral load was 3,500 copies per milliliter and CD4 count was 132 cells per microliter. His lactic acid level was abnormally elevated at 7.7 millimoles per liter (mmol/L). Tests for new infections were negative as were other potential causes of lactic acidosis. He was negative for hepatitis B and C.
On admission to the hospital, his anti-HIV medications were stopped due to the possibility of lactic acidosis/hepatomegaly with steatosis associated with NRTI drug toxicity. A liver biopsy did show ‘steatosis’ or fatty infiltration. Yet, his lactic acid level continued to increase to 9 mmol/L and higher. His physicians decided to start riboflavin 50 mg once daily. Two days later, the lactic acid level began to decline from a maximum of 11 mmol/L.
During the next several days, the lactic acid level ‘returned to normal.’ Assuming a ‘normal’ level is less than 2.1 mmol/L, however, a chart of his lactic acid levels shown at the authors’ poster revealed that a level of 2 mmol/L first appeared 30 days after hospitalization. Two weeks after starting riboflavin, the patients symptoms resolved, his ALT improved and he was discharged from the hospital. After that, the patient wanted neither to restart anti-HIV therapy nor have a repeat liver biopsy.
The authors concluded, ‘Treatment with riboflavin is an important advance and deserves further study.’ The difficulty with single case reports like this one is the following. We do not know that this man might have started to show a decline in his lactic acid level at the time that it did without starting riboflavin. This is one reason why controlled studies are designed. However, due to the uncommon rate at which lactic acidosis due to NRTI drugs occurs, a randomized study will never be performed. This reviewer is aware of one patient with the same diagnosis who did not respond to riboflavin supplementation and died.
Another supplement that has been proposed as a potential therapy for lactic acidosis in this setting is carnitine (two naturally occurring amino acids that together are used for normal fat metabolism) and thiamine or vitamin B1.
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 hyperlactatemia (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 diarrhea.’ 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.
In a review of 106 cases of lactic acidosis in patients taking anti-HIV therapy that were 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 dyspnea (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 that was associate with the syndrome, 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).
At the recent 3rd International Workshop on Salvage Therapy for HIV Infection another study addressed the issue of lactic acidosis. It 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 (without symptoms) are associated with several abnormal laboratory (Òpulmonary’ or lung function) test results when exercise testing was performed.
Whether patients taking NRTI drug(s) should also take a daily multiple B vitamin supplement to prevent increases in lactic acid and lactic acidosis is unknown. Most physicians would not be against their patients taking an over-the-counter daily vitamin supplement.
- Boubaker K and others. Hyperlactatemia and antiretroviral therapy in the Swiss HIV Cohort Study. Abstract 57 at the 7th Conference on Retroviruses and OpportunisticInfections; 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.
- Fouty B and others. Riboflavin to treat nucleoside analogue-induced lactic acidosis. Lancet 1998 July 25;352(9124):291-2.
- 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.
- Kulkarni PM and others. Lactic acidosis and hepatic steatosis in HIV seropositive patients treated with nucleoside analogues. Abstract and poster 95 at Digestive Disease Week 2000; May 21-24, 2000; San Diego, California.
- 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.Schramm C and others. Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. European Journal of Anaesthesiology 1999 October;16(10):733-5