Uridine supplement reverses thymidine-induced lipoatrophy
Simon Collins, HIV i-Base
Two years ago at the Lipodystrophy Workshop, Ulrich Walker presented in vitro data that supported uridine supplementation to reduce or reverse lipoatrophy induced by thymidine analogue associated mitochondrial toxicity. Last years Workshop saw further in vitro data [1, 2]. There was therefore considerable interest in the first in vivo results, presented in by Sutinen and colleagues from the same research group, in an oral presentation at this years workshop. 
Twenty patients who were taking d4T- or AZT-containing HAART for >18 months, were randomised in 1:1 ratio to receive either three cycles of NucelomaxX (a dietary supplement given at a dose of 36g, three times daily, for the first ten days of each month, for three months) or a taste-matched placebo. Body composition was measured by DEXA and MRI and liver fat was quantified by proton spectroscopy on day 90.
Patients in the NucleomaxX arm gained statistically significant increases in limb fat after 3 months (range 400g 1500g) compared to both baseline and placebo patients (both P<0.05). Total body fat and intra-abdominal fat also increased. The proportion of limb fat to total fat increased from 19% to 25% in the uridine arm. This change was not clinically noticeable by patients. No significant changes occurred in the placebo group. One patient receiving placebo died from myocardial infarction during the study, and one patient discontinued due to its bad taste.
HDL (good) cholesterol fell from 1.24 to 1.15 mmol/L in the uridine group but there was no effect on triglycerides, lactates, or insulin resistance. CD4 counts remained stable and no patients experienced viral rebound. PK confirmed that the supplement provided increased levels of urdine in plasma.
A second study using NucelomaxX was presented as a poster by McComsey and colleagues from Case Western Reserve University, Ohio.  Sixteen patients on d4T-containing HAART were given 36g NucleomaxX three times a day, every other day, for 16 weeks, with follow-up at 32 weeks after 16 weeks off-uridine. As this study only recorded patient and doctor perceptions about improvements in lipoatrophy (both groups reported benefits) rather than a physical measure, it is difficult to comments on the results.
Uridine is not a potential treatment for lipoatrophy in itself it only reverses fat loss in people who are using lipoatrophy-causing treatment. Nevertheless, it is very interesting to know that a protective agent is available for people who are dependent on either d4T or AZT. The highest needs for such a treatment however is in resource-limited countries where d4T is still a cornerstone of treatment, and the cost of NucleomaxX, at 84 euros for three days (nine 36g sachets, approximately 240 euros/month) may be higher than the discounted price for tenofovir or abacavir, the switch treatments of choice. Optimal dosing may also not have been established, given the different design of the two studies above.
Taken together these two studies suggest that uridine supplements maybe a new treatment tool in managing lipoatrophy. Their use beyond persons receiving pyrimidine NRTIs (and specifically thymidine analogs) has not been evaluated. Furthermore, it is important to note that the studies reported involved small numbers of individuals and did not use endpoints that could be considered standard or part of the established lipodystrophy case definition approach. In particular, self-report of lipoatrophy is widely thought by physicians working in this area to be of limited value. Larger placebo-controlled studies using established objective endpoints such as DEXA scanning are now required.
In addition, limited safety data have been reported with this supplement and details of possible drug interactions with life-saving antiretroviral medications have not been evaluated.
A number of supplements, notably garlic supplements and St Johns Wort, are known to have important interactions with some HIV medications. Before individuals rush to buy expensive uridine supplements over the Internet, they should consider that evaluation of potential risks, or establishment of potential benefits, i.e. not to standards normally used by regulatory agencies.
It is unclear why NucleomaxX should be so expensive. Raw materials are cheap and the production process likely to be of low complexity. In addition, the lack of having to submit to clinical trial and regulatory approval means the development process is also low cost. Someone is making an extortionate profit margin here.
There are other strategies to raise plasma uridine levels: 10mL of regular beer contains 0.5mg or uridine – this includes low, or non-alcoholic beers – and drinking 10mL of beer per kilo of body weight was found to raise uridine plasma concentrations by 1.8 fold. Administering uridine itself also raises plasma uridine levels at a cost of about £1.50 a gram. Lastly, another supplement, citicoline (Cytidinediphosphocholine), has also been found to be an efficient agent in raising uridine plasma levels and can be purchased for less than £1.40 per gram.
The Mitocnol Research Society
- Blanchard P. Uridine as a potential treatment for NRTI related mitochondrial toxicity. HIV Treatment Bulletin, Vol 4 No7, August 2003.
- Potential for uridine to treat mitochondrial toxicity: still only in vitro data. HIV Treatment Bulletin, Vol 6 no 1, January 2005.
- Sutinen J, Walker K et al. Uridine supplementation increases subcutaneous fat in patients with HAART-associated lipodystrophy: a randomized placebo controlled trial. 7th Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 13-16 November 2005, Dublin. Abstract 7.