General Information
Antiretroviral (ARV) drugs are used in combination to treat HIV infection. ARV drugs are designed to prevent HIV replicating and functioning properly. A 3-drug combination from two different drug families fully controls growth of HIV in most patients. They have been very effective in the treatment of HIV over a number of years and are the main reason why people are surviving longer with HIV infection. Over this time, however, it has been noted that some people, treated with HIV drugs for long periods (usually more than 12 months), develop problems with the way that their bodies metabolise glucose (sugar) and fats. This can result in a condition called Lipodystrophy. Lipodystrophy is a fat redistribution syndrome with fat atrophy (loss of fat in the face, the buttocks, the arms and the legs) or as fat hypertrophy (excess growth of fat, typically in the breasts, and abdomen). Although exactly how this happens is unclear there is little doubt that lipodystrophy is a direct result of ARV treatment; the most commonly implicated ARV drugs are zidovudine (also known as AZT) and stavudine (also known as d4T).
Lipoatrophy can be very stigmatising, can lower ART adherence, and there is no proven medical treatment to help this condition. Changes to some ARV drugs, particularly the withdrawal of AZT or d4T, may improve lipoatrophy slightly but do not lead to resolution of lipoatrophy. The strongest evidence from studies to date suggests that ceasing AZT or d4T therapy and being on lopinavir, a protease inhibitor (one type of anti-HIV drug), is associated with improvements in lipoatrophy.
One drug and one dietary supplement were recently found to improve lipoatrophy in separate, small, 12-week studies in patients receiving ARV treatment. These two treatments are pravastatin and uridine.
Pravastatin is a drug commonly used to lower cholesterol in patients who have had heart attacks or strokes or to prevent these illnesses in adults at high risk. Pravastatin, when studied in HIV-infected men in Sydney, resulted in a significant improvement in lipoatrophy: patients on pravastatin gained 700 grams of fat in the limbs over 12 weeks, as compared to patients who were not on pravastatin in this study. This increase of 700 grams compares favourably with the 300-400 gram increase over 12 months seen after stopping d4T or AZT. No side effect of pravastatin was observed.
Uridine is sold in Europe as a dietary supplement named NucleomaxX, which can raise levels of uridine in the body. Uridine is an essential component of normal metabolism and in laboratory experiments can prevent AZT and d4T damage of fat cells. Small studies have shown that uridine supplementation during 12 weeks reversed arm and leg lipoatrophy in people taking stavudine (d4T) or zidovudine (AZT). Patients who were receiving uridine had a 900gram increase in limb fat of over this period. One patient withdrew from the trial because of the poor taste of the uridine containing powder; no other side effect was reported.
However, the above-mentioned studies were small and relatively brief. In addition, the uridine study was performed only in adults receiving AZT or D4T; it is not known whether uridine will have any benefit in those not receiving AZT or d4T. This is an important issue as d4T and AZT are not commonly used now in Australia and so the value of uridine and pravastatin in most Australian HIV-infected adults with lipodystrophy is unknown. We therefore need longer term and more relevant data before routinely using these promising treatments for HIV lipoatrophy.
Purpose of the Study
The aim of this study is to more fully examine the effect of pravastatin and uridine, either alone or in combination, to determine if these two drugs can accelerate recovery of lipoatrophy in HIV-infected adults who have previously ceased AZT and d4T therapy. The main purpose of this study is to assess the safety and efficacy of pravastatin alone, uridine alone, and uridine plus pravastatin in HIV-related lipoatrophy.
The St Vincent’s Hospital Research Ethics Committee has examined and approved this study.
Study Design
You are eligible to participate in this study if you have lipoatrophy on physical examination, are HIV-infected, are aged greater than 18 years, have an undetectable HIV viral load in the blood, have been on stable ARV therapy for the last 3 months that does not include AZT or d4T, and if you do not require cholesterol-lowering treatment with pravastatin or similar drugs. If you have experienced loss of HIV control whilst receiving lopinavir, or if you have an ongoing serious infection or illness, you will not be included in the trial.
Study participants will be assigned to one of 4 groups and these will be compared. We are seeking a total of 40 patients to participate in this study for 28 weeks.
You will need to be on a standardized background HIV therapy so that we will be fully able to compare the effects between each group. You will have ceased AZT or d4T at least 3 months ago. All participants will receive the same protease inhibitor, lopinavir boosted by ritonavir (referred as lopinavir/r, which will be given as 2 tablets two times a day), as the “third drug” in their HIV regimen. Therefore, patients receiving a protease inhibitor will switch this protease inhibitor to lopinavir/r. Patients receiving a non-nucleoside (NNRTI, such as nevirapine or efavirenz) with a protease inhibitor will continue the NNRTI and switch their protease inhibitor to r/LPV. Patients on nevirapine or efavirenz without a protease inhibitor will switch those drugs to lopinavir/r. Patients already on lopinavir/r will commence at week 4 on the study.
If you are eligible to enter the study and agree to participate, at entry into the study you will switch your current protease inhibitor or other third anti-HIV drug to lopinavir/r. If the lopinavir/r is well tolerated, 4 weeks later you will then be randomly (by chance) assigned to one of the following four treatment groups for 24 weeks.
Group 1: pravastatin only (40mg, one tablet at night)
Group 2: uridine only (1 sachet, 3 times daily for 10 consecutive days each month)
Group 3: pravastatin + uridine (dosed as above)
Group 4: delayed arm (no immediate therapy)
Assignment to one of the above 4 groups will be done at random by a computer and your doctor has no influence on the treatment chosen for you. You will have a 25% chance of receiving any one treatment. This is an open-label study (in other words, there are no placebo [sugar] pills) so you will be aware of which treatment you are prescribed.
After 24 weeks in one of the 4 groups (28 weeks overall), you will be offered therapy with both pravastatin and uridine for a further 24 weeks. If you want to access those drugs for the additional 24 weeks, you will be required to come back to the clinic at week 32 for safety blood tests. Additional visits and safety blood tests will be done during your standard visits at week 40 and 52. An additional DEXA Scan will be offered at week 52.
The effectiveness of uridine and pravastatin in improving lipoatrophy will be determined by DEXA and CT scans, which provide data on the amount and distribution of fat in the body. These scans take about 60 minutes in total and require no preparation.
Information on the study provided herein is extracted from the consent form approved by the relevant Ethics Board– potential participants in the study should obtain the approved consent form for their review.
PLEASE SEE ALSO CLINICAL TRIALS OVERVIEW
For more information, or a copy of the Consent Form, please email us at trials@holdsworthhouse.com.au
Or call the trials team on (02) 9331 7228
CLINICAL TRIALS INFORMATION
Clinical Trials Home | Current Clinical Trials | About The Research Unit | Clinical Trials Overview
Benefits |
Questions & Answers | Further Information/Contact
|
