Simon Collins, HIV i-Base
Increases in the level of lactic acid have been recognised in both HIV-positive adults and children and is linked to all nucleoside analogues as well as in people not using ARV treatment [1, 2].
More seriously, lactic acidosis (LA) can be fatal in over half the reported cases. Attention was focused on this with the recent FDA requirement for a new emphasis on this in product information summaries and advertising for abacavir, d4T and ddI. Two posters on lactic acid were presented at the Lipodystrophy workshop.
Kees Brinkman presented a poster on a protocol for treatment of LA  based on incomplete case reports (using riboflavin, L-carnitine and co-enzymeQ ). This involves:
- Stopping NRTI treatment immediately
- Start treatment with viramin B complex forte 4 ml (i.v.) BID (per 2 ml ampulle: 50 mg thiamine, 10mg riboflavine, 100mg nicotinamide, 10 mg pyridoxine, 10mg dexpanthenol)
- L-carnitine 1000mg (i.v.) BID
Treatment should be continued until lactate levels fall below 3 mmol/l. Oral continuation of treatment can be considered.
Six patients were treated using this protocol in the Netherlands between November 1999-June 2000. Background NTRI therapy was ddI/d4T/HU in three patients (duration 9, 9 and 17 months), d4T/3TC in one (11 mo), d4T/ddI (>12mo) in one and DDI/HU/3TC/abacavir (11.5mo) in one. Clinical syndrome included nausea, vomiting, abdominal complaints, liver failure, pancreatitis; lactate >5 mmol/l, bicarbonate <20 mmol/l.
All patients recovered, although one elected to stop all treatment after 6 days (with lactate 4.4 mmol/l) and died 3 days later. Normalisation to <3 mmol/l occurred from 4-over 20 days – the 20-day resolution being in a patient that used oral B1, B2 complex rather than i.v. administration.
While not all cases of LA prove fatal, and early recognition of symptoms and discontinuation of NRTIs alone may have been responsible for the favourable outcome, this non-toxic intervention would seem to be a simple and prudent measure for patients presenting with lactic acidosis. Dr Brinkman commented that although prospective randomised trials would be useful they are hardly imaginable in this setting.
Early diagnosis is clearly critical, and Y Gerard from the Infectious Diseases Dept, University Tourcoing, France presented a poster recommending routine measurement of anion gap (AG) to allow for early recognition of symptoms . A similar study from Johns Hopkins was also presented at the Retrovirus conference earlier this year .
AG was routinely measured every two months since March 2000 in a prospective study involving the whole cohort at this clinic (2065 AG measurements in 806 patients). AG was calculated as ([Na+K]-Cl+CO2]) and defined as high when >20. Twelve patients developed AG>20 (1.5%) all of whom were using HAART. A statistically significant difference was found between use of background NRTIs with 10/374 patients using d4T (2.7%) and 1/326 using AZT (0.3%). Three of these patients were then found to have lactic acidosis, however, AG was elevated in only half the patients who presented with high lactate levels.
One case of lactic acidosis was diagnosed with a high AG of 30.3 (lactate 9 mmol/l) which resolved following discontinuation of ARVs and administration of carnitine, riboflavin, vitamin C, E and co-enzyme Q. Treatment was also interrupted in another with AG of 25.8 (lactate 4.2 mmol/l). Three patients also normalised AG in whom elevated lactate was detected while continuing on the same treatment.
- Montaner, J et al – Screening for Nucleoside-Associated Lactic Acidosis. Abstract TuPpB1233. XIII World AIDS Conference, Durban, 2000.
- Church, J et al – Near-Fatal Metabolic Acidosis, Liver Failure in Mitochondrial DNA Depletion in an HIV-infected Child Treated with Combination ARV Therapy.Abstract 58. 7th CROI, 2000. http://www.retroconference.org/2000/abstracts/58.htm
- Brinkman, K et al – Treatment of Lactic Acidosis. Abstract P15. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
- Riboflavin: Fouty et al (Lancet 1998) and Luzatti et al (Lancet, 1999). L-carnitine: Cloosens et al (AIDS, 2000). Co-enzyme Q: Lenzo et al (AIDS 1997) and John S (AIDS, 2000).
- Gazzard, Y et al – Early Diagnosis of Lactic Acidosis in HIV-infected Adults Receiving ARVs: Anion Gap Measurement. Abstract P19. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
- Moore, R et al – Differences in Anion Gap with Different NRTI Combinations. Abstract 55. 7th CROI, 2000.