Robert Fieldhouse nreports from the 7th International Workshop
on Adverse
Drug Reactions and Lipodystrophy in HIV, 13-16 November 2005, Dublin, Ireland
Uridine increases arm and leg fat
Use
of the dietary supplement NucleomaxX (uridine) by people with treatment-associated
fat loss can increase arm and leg fat in people who still take AZT or d4T.
In test tubes, uridine has prevented and reversed mitochondrial toxicity caused
by nucleoside analogues like d4T or AZT that are associated with fat loss.
Nine people with HIV taking d4T or AZT for an average of 18 months were randomised
to receive 36g of NucleomaxX three-times a day for ten days each month for
36 weeks while 11 received a placebo. After three months the group receiving
NucleomaxX had gained around 900g of subcutaneous limb fat. To put this into
perspective, people who switched from AZT or d4T to abacavir or tenofovir
in the RAVE study gained between 300 and 400g of limb fat over 48 weeks. People
treated with NucleomaxX also gained 200g of intra-abdominal fat. At the end
of the trial, five of the nine individuals taking it reported improvements
in their physical appearance. Whether NucleomaxX will facilitate continued
fat restoration remains to be seen and it may not be appropriate for people
who have switched away from AZT or d4T in an attempt to regain lost fat.
NucleomaxX is available from online pharmacies for around £600 for a
three-month course. However, self-medication is not recommended. Further studies
are planned.
Antiviral Therapy 10: L7, 2005
Pravastatin boosts fat with PI therapy
A study has shown that the lipid-lowering drug pravastatin can significantly
increase limb fat in people with fat loss who are still using protease inhibitors
(PIs).The 16-week study of pravastatin was designed to monitor lipid changes,
so the gains in limb fat came as a welcome surprise.
Only 16 people received pravastatin (40mg daily) and 17 got a placebo, so
a larger randomised study will be needed to draw firm conclusions about the
benefits. While all participants were taking protease inhibitors, only two
were using the thymidine analogues AZT or d4T which have been strongly associated
with fat loss.
At the start, total average cholesterol measured 7.6mmol/l in both groups
which is above average (see lipids feature, Heart of the Matter, page 42,
for explanation of terms). For the first four weeks, people made dietary changes
following consultation with a dietitian. Treatment with pravastatin began
in the fourth week and continued for the next 12. There was a significant
difference in total cholesterol decline between weeks four and 16 of 0.82mmol/l
in those treated with pravastatin and 0.34mmol/L with the placebo.Non-HDL
cholesterol fell by 1.02mmol/l compared to 0.4mmol/l in the placebo group.
At 16 weeks, limb fat increased by 0.72kg in the pravastatin group, compared
to an increase of only 0.19kg among people treated with placebo.
Antiviral Therapy 10: L5, 2005
Depression common among lipo patients
People
with facial fat loss show extremely high rates of depression and anxiety.
That’s the conclusion of researchers from Barts and the London Trust.
They looked at 40 patients living with HIV (38 men and two women) who completed
a series of questionnaires about their facial appearance and rated their depression
and anxiety.
All felt that fat loss affected their confidence; three quarters reported
borderline anxiety, almost half depression, while 85 per cent felt stigmatised,
reporting their appearance was a marker of their HIV status.
Participants were keen to have polylactic acid (New-Fill) treatment but half
were concerned that the effects would not last. Antiviral Therapy 10: L34,
2005
Creatine does not improve strength
New
research suggests use of the dietary supplement creatine by men with HIV increases
lean body mass more significantly than just working out. However, it does
not further improve strength gained from regular weight training. Creatine
is widely used to enhance the response to resistance exercise training as
it is thought to raise intracellular phosphocreatine, a major energy source
during high-intensity exercise.
Dr Giorgos Sakkas, a clinical exercise physiologist from the University of
Thessaly in Greece, reported findings from the study. The study included 40
men with HIV randomised to receive creatine at a loading dose of 20g each
day for five days followed by a maintenance dose of 4.8g a day in six-week
cycles or placebo. The men were in their mid-40s and had been using antiretroviral
therapy for an average of 10 years. Between 35 and 40 per cent of them were
taking protease inhibitors and around 30 per cent were currently using NNRTIs.
After the first two weeks, all participants began a 12-week programme of supervised
resistance training, three times a week.
In total, 33 of the 40 men completed the 14-week study (17 on creatine, 16
placebo). Lean body mass increased in both groups but the gains were greater
in the men who received creatine (2.3kg in 14 weeks compared to 1.3kg with
exercise alone). However, much of the gain in weight was likely to be due
to increased fluid retention in the muscles. Strength increased similarly
in both groups of men, regardless of whether they received creatine or not
(44 per cent vs 42 per cent). Longer-term creatine use may also cause kidney
damage, particularly
if people take higher than recommended doses and have pre-existing kidney
abnormalities.
Antiviral Therapy 10: L6, 2005
Niacin safe for people with raised lipids
Doses of up to 2,000mg of the dietary supplement niacin are safe and well-tolerated
by people on HAART, a new study suggests.The study involved 37 people on antiretrovirals
with lipid abnormalities such as high triglycerides, high non-HDL cholesterol,
or low HDL ‘good’ cholesterol. Four weeks after receiving dietary
and exercise counselling, all participants were given niacin and aspirin.
The dose of niacin was modified by 500mg each four-six weeks to a maximum
tolerated dose of 2,000mg daily. Twenty-three people (70 per cent) reached
the full 2,000mg dose, while eight reached 1,500mg. Total cholesterol fell
by an average of 0.4mmol/l at week 48, non-HDL cholesterol fell by an average
of 1mmol/l, and triglycerides dropped by an average of 8mmol/l. ‘Good’
HDL cholesterol rose by an average of 0.27mmol/l.Three people developed changes
in liver function which caused one person to drop out of the study. Some participants
developed insulin resistance but none developed a reading greater than 11mmol/l
which suggests the onset of diabetes.
Antiviral Therapy 10: L12, 2005
Nucleoside-sparing combo fails on potency
Researchers
have halted a trial investigating HIV therapy without use of nucleoside analogues
(nukes) after seeing higher rates of treatment failure in those not using
them.
The Hippocampe ‘seahorse’ trial was designed to see if people
faired well starting HIV therapy with a combination of a non-nuke (NNRTI)
and a boosted protease inhibitor (PI) instead.
Nukes are a class which include commonly prescribed drugs like AZT, 3TC and
FTC. A nuke-free combo is potentially desirable as it may avoid nuke side
effects such as fat loss.
But researchers were forced to pull the plug on the non-nuke/PI arm of the
trial after 48 weeks. Only 62 per cent of those on that combo were found to
have viral loads below 50 copies compared with 79 per cent of those taking
a nuke with an NNRTI or PI. This means that for the time being, nucleoside
analogues are likely to remain the backbone of HIV therapy. In total, 117
people tested one of three different approaches to HIV therapy; half took
a boosted PI with an NNRTI, a quarter took an NNRTI with nucleoside analogues
while the remaining quarter took nucleoside analogues with a boosted PI.The
study used the NNRTIs efavirenz and nevirapine and the ritonavir-boosted PIs,
lopinavir and indinavir. All currently available nucleosides were allowed
except d4T and ddC.
Resistance testing was not undertaken before the study began so it’s
possible some individuals assigned to the NNRTI-PI combo had resistant virus
which compromised their response. Treatment adherence rates were also slightly
higher among people taking nucleoside analogues.
PS1/3
STOP PRESS Major treatment interruption trial
halted
A major clinical trial comparing continuous therapy with periodic treatment
has been stopped after an excessive number of Aids-defining illnesses occurred
among people taking intermittent therapy.
The SMART study was two years into recruitment and should have run for nine
years. People who are currently on a break from therapy in the trial will
be advised to restart therapy.
When designing the trial, the researchers anticipated a greater number of
Aids-defining events among those who took an interruption. It could be that
the rate seen in the past two years is greater than researchers
consider acceptable. It may be that the study design is at fault, rather than
that treatment interruptions are always unsafe. If you are currently taking
a treatment interruption, discuss the findings with your doctor.
Doctors underestimate wish to inject T-20
Only
ten per cent of eligible patients are being prescribed the self-injectable
fusion inhibitor T-20 (enfuvirtide), despite it being licensed two years ago.
T-20 is often used by patients that are running out of treatment options.
Researchers from the University of Brighton interviewed 499 doctors and 603
treatment-experienced individuals in Europe and the US. They found people
living with HIV are more willing to consider taking self-injected therapies
than many of their doctors anticipate. Despite three-quarters of patients
being willing to inject, only one quarter had discussed options such as T-20
with their doctor. Doctors who prescribed T-20 less frequently were more likely
to believe that their patients would be reluctant to use a self-injected therapy
out of a belief that its drawbacks outweighed its benefits. Dr Mike Youle
(right), director of HIV clinical research at London’s Royal Free Hospital
said: “With the increasing choice of injectable biotech drugs, these
findings potentially have far-reaching implications across a whole range of
therapeutic areas.”
PE7.3/24, 2005
Drug resistance on the increase in UK
The UK has one of the highest rates of antiretroviral drug resistance and
its prevalence appears to be increasing. And resistance does not seem to be
confined to specific subgroups of the HIV population.
Analysing results of the drug resistance tests of 2,357 people who had not
yet started antiretroviral therapy, Dr Deenan Pillay, from University College
London and colleagues from the Health Protection Agency, found that 335 (14
per cent) already had resistance to one or more drugs. By looking at all
resistance tests carried out in untreated individuals between February 1996
and May 2003, the researchers could track if there were changes to resistance
patterns over time.
While most people with resistant virus carried HIV mutations that made the
virus less susceptible to only one class of antiretrovirals, 13 per cent had
virus resistant to two classes and 10 per cent had virus resistant to nucleoside
analogues, NNRTIs and protease inhibitors.Dr Pillay predicted the spread of
resistant virus from people who have been previously treated and developed
treatment failure to people who have never received treatment through unprotected
sex: “There is the potential that this phenomenon will compromise the
great benefits of treatment that have been seen to date.”
British Medical Journal online, 18 November 2005
Tipranavir most superior boosted PI
Two
global trials have shown that newly licensed tipranavir remains the virologically
superior boosted protease inhibitor (PI) when used by people with PI-resistant
HIV.
The 48-week studies compared ritonavir-boosted protease inhibitor tipranavir
against other boosted PIs. Adding the fusion inhibitor T-20 (Enfuvirtide)
to tipranavir/ ritonavir further improves treatment response.
The study enrolled 1,483 people with detectable virus on failing therapy.
The comparator PIs used were lopinavir, indinavir, saquinavir and amprenavir.
At 48 weeks, 34 per cent of those taking tipranavir had at least a 1 log10
drop in their virus, the equivalent of a tenfold decline in virus, say from
1,000 to 100 copies. This compared to 15 per cent of people treated with one
of the comparator PIs.
People treated with tipranavir also had greater increases in their CD4 counts
(45 vs 21 cells over 48 weeks.) Fifty-two per cent who combined tipranavir
with T-20 achieved a viral load below 400 copies. This compared to 20 per
cent of people who combined T-20 with one of the comparator PIs.
People who took tipranavir reported higher rates of cholesterol, triglyceride
and liver function elevations. Those taking it need to take a higher dose
of ritonavir (200mg vs 100mg), which may account for these abnormalities.
LBPS3/8
New potent non-nuke on the horizon
An investigational non-nuke that remains active in the face of emerging resistance
to other currently available non-nukes appears well-tolerated, potent and
safe, according to makers Tibotec.
The latest data on TMC-125, Tibotec’s non-nucleoside reverse transcriptase
inhibitor (NNRTI) brings the possibility of sequencing NNRTIs a step closer.
People who had taken at least one drug from the nucleoside analogue, protease
inhibitor and NNRTI classes for three months, and had a viral load above 1,000
copies, tested one of three twice-daily doses of TMC-125 alongside an optimised
background regimen of at least two drugs selected by resistance testing. A
comparison group took a placebo plus optimised background therapy.
Side effects of TMC-125 were similar to those reported by patients taking
placebo: diarrhoea (25 vs 38 per cent), headache (19 vs 17 per cent), rash
(17 vs 11 per cent) and nausea (17 vs 23 per cent). A second study compared
the antiviral efficacy of 400mg and 800mg twice-daily doses of TMC-125 in
people with NNRTI resistance and three or more protease inhibitor resistance
mutations. In total, 199 people received one of the two doses plus other antiretrovirals
chosen by resistance testing. This was compared to the best available combination
(referred to as ‘active control’), again guided by resistance
testing but excluding TMC-125. After 24 weeks the average viral load decrease
among patients treated with either 400mg or 800mg TMC-125 twice-daily was
significant, greater than 1 log10, compared to 0.19 log10 in people receiving
active control. CD4 cells increased by around 50 in people on TMC-125 compared
to around ten cells in people on active control.
LBPS3/7B, LBPS3/7A, 2005
medical notes
Abdominal fat transfer for facial lipo a success
Improvement in facial fat following surgery that grafts fat from the abdomen
to the face can last for up to one year, early findings from a study suggests.But
Italian researchers found that one in five still required a ‘top-up’
with a facial filler such as New-Fill after autologous fat transfer, to optimise
the results.
The findings were based on data from the first 41 of 151 study patients to
be followed up after a year. Participants had been on HAART for at least six
months, almost half were female and the average age was 44. The average lowest
ever CD4 count was 186 but CD4s were high (629 on average) at the time of
surgery. Patients reported improved satisfaction with their face and body
image following the fat transfer. Antiviral Therapy 10: L46, 2005
Liver function may predict insulin resistance
Liver function results may be a useful clinical indicator for insulin resistance
in people with HIV and body fat changes, new research suggests.
Seventeen people between the ages of 26 and 60 with evidence of body fat changes
were given a complete history and physical examination. Two thirds presented
with evidence of both fat loss and central fat accumulation, while 16 per
cent had either one or the other. Hepatitis B and C coinfection were associated
with insulin and glucose abnormalities.Researchers concluded that fat redistribution
may further add to liver damage and place people with HIV with lipo or hepatitis
coinfection at a particularly high risk of developing insulin resistance.
Antiviral Therapy 10: L48, 2005
Women with lipo opt for silicone implants
Eight women with HIV in Spain have received silicone buttock and/or hip implants
following long-term antiretroviral treatment which resulted in fat loss. All
women reported being very satisfied with the result, but some remained worried
by the contrast between the newly treated area and the extreme thinness of
their legs and thighs.
Antiviral Therapy 10:
L41, 2005
Tenofovir ‘no worse for bone density’
Switching to tenofovir for up to 48 weeks is no worse for bone mineral density
than other ARVs. Thirty-eight
people switched to tenofovir while 34 continued with other nucleoside analogues.
DEXA scans at 48 weeks showed no significant changes in spine bone mineral
density.
But both groups reported significant decreases in bone mineral density in
the neck of the femur.
Antiviral Therapy 10: L90, 2005
Sexual dysfunction high in positive men
Psychological and social factors may contribute to high rates of sexual dysfunction
in men living with HIV, new research suggests.Just over half of the 167 men
who took part in the study reported erectile dysfunction. One in five said
it was moderate or severe. Just under half were unsatisfied with their sex
life. Seventy-seven per cent experiencing erectile dysfunction had perceived
fat loss.
Participants’ most frequently cited fear of infecting a partner and
condom use as obstacles to sexual functioning. A quarter reported having had
unprotected sex in the last month. Antiviral Therapy 10: L97, 2005
New class of HIV drugs at risk of failure…
A single case of liver toxicity during treatment with the investigational
CCR5 antagonist,
maraviroc, was reported by drug manufacturer Pfizer. The news came during
a
talk in which a GlaxoSmithKline researcher described the cases of liver toxicity
with its own CCR5 antagonist, aplaviroc, which has now been discontinued.…
but another new class fairs better
An investigational integrase inhibitor has been shown to significantly decrease
viral load. In a ten-day single drug study in people who have never taken
HAART before, the drug MK-0518 reduced viral load by an average of 2 log10,
the equivalent of a decline from 10,000 to 100 copies of HIV.
Thirty-five people received one of four twice-daily doses of the integrase
inhibitor or placebo. CD4 counts did not change. No patient discontinued therapy
due to side effects, and there were no serious adverse events. Six out of
ten reported dizziness, fatigue and headache, though this did not appear to
differ much from the placebo group. LBPS1/6
Strong seven-year results for lopinavir-ritonavir
Two-thirds of people who start therapy with the ritonavir-boosted protease
inhibitor (PI) lopinavir remain undetectable below 400 copies after seven
years of therapy. The average CD4 increase over the period was 501, irrespective
of how low a person’s CD4 count had been prior to beginning therapy.
No primary PI resistance mutations emerged during the study in people whose
viral load increased above 500 copies. The most reported side effects were
nausea, gastro intestinal and elevated lipids. PE7.9/3
High CD4 signals similar mortality to HIV negative population
French researchers have concluded that people whose CD4 counts rise and stay
over 500 on ARVs have the same risk of dying as the general population.
They found that five years after starting therapy, women, people with hepatitis
C coinfection and those who inject drugs had a greater chance of dying than
the general population.
However, if measures were undertaken, such as increasing adherence, prescribing
better tolerated drugs and treating depression in order to reach sustained
high CD4 counts, everyone with HIV could enjoy the same likelihood of a long
and healthy life. PE18.4/8
Drug resistance in Ireland up in those untreated
Rates of antiretroviral drug resistance among people yet to begin therapy
in Ireland is on the increase. Between March 2003 and January 2005, drug resistance
in newly diagnosed untreated individuals increased from 5.3 to
8.3 per cent. While no multi-drug resistance was observed, researchers concluded
drug resistance testing before
starting therapy should remain standard. PE31/3
Efavirenz works just as well at low CD4 counts
People who begin HIV therapy with CD4 counts below 100 cells with the NNRTI
efavirenz (Sustiva) do better over two years than people taking ritonavir-boosted
indinavir. In
total, 65 people took either efavirenz or indinavir-ritonavir with AZT/3TC.
CD4 increases were better with efavirenz (264 vs 165 cells) and a higher proportion
got a viral load below 200 copies (61 per cent vs 42 per cent). PE 7.9/3
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