E-DRUG: WHO to reduce stavudine dose from 40 to 30mg?
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CROI: high burden of side-effects from d4T (stavudine) leads to WHO dose reduction
recommendation Wednesday, March 21, 2007
The WHO's HIV treatment guidelines panel has concluded that the recommended
adult dose of d4T should be reduced to 30mg twice daily for adults weighing
more than 60kg. The analysis shows that a 30mg dose is just as effective as
a 40mg dose, but carries less risk of side-effects such as peripheral
neuropathy.
By Keith Alcorn
The World Health Organization¹s HIV treatment guidelines panel has concluded
that the recommended adult dose of d4T (stavudine) should be reduced
to 30mg twice daily for adults weighing more than 60kg, following a review
of a still unpublished meta-analysis of clinical trials. The analysis shows
that a 30mg dose is just as effective as a 40mg dose, but carries less risk
of side-effects such as peripheral neuropathy.
The decision was revealed by Professor Charlie Gilks of WHO¹s HIV Department
during a discussion session at last month's Fourteenth Conference on
Retroviruses and Opportunistic Infections that demonstrated the magnitude of
complications being experienced due to nucleoside analogue antiretrovirals -
especially d4T - in resource-limited settings.
Researchers from the University of Maryland School of Medicine presented one
of the largest-yet analyses of toxicity-related treatment changes to the
conference, reporting on 6,520 patients treated in PEPFAR-funded programmes
in Uganda, Zambia and Kenya.
One thousand one hundred and sixty-four treatment changes were recorded due
to toxicity. Just under a quarter of the 2,149 d4T-exposed patients switched
treatment, compared to 13.2% of the 1,433 AZT (zidovudine)-exposed
patients. Unsurprisingly, peripheral neuropathy was the overwhelming reason
for switching from d4T (279 of the 517 switches), just as anaemia was the
most common reason for switching from AZT (123 of 264 switches). A high
proportion of patients had undocumented reasons for switching.
Of note is the very low switch rate from tenofovir, which was used
as part of the first-line regimen in Uganda.
Anthony Amoroso, presenting, said: ³We think we¹re underestimating the rate
of toxicity because of the long-term nature of the toxicities. Also, where
there's a lack of switching, it's due to a lack of alternatives. Different
sites had different rates of switching - less experienced providers had
lower rates of switching, but there was no country difference in the adverse
event rates.²
Relieving d4T-related toxicity by switching to AZT - is it safe - and
practical?
A second poster presentation, from the US Centers for Disease Control Global
AIDS Program, showed that a switch from d4T to AZT tended to be well
tolerated in a large cohort of patients receiving antiretroviral therapy
(ART) in rural Uganda, with little anaemia.
The study reported outcomes in 261 of 768 d4T-treated patients who switched
to AZT after a median of 7.6 months. After a median of 17 months on AZT six
grade 3 or 4 cases of anaemia had been detected, not significantly different
to the incidence of anaemia in those who remained on d4T, although
leuokocyte counts tended to fall in the AZT-treated patients. Whether the
development of grade 1 or 2 neutropenia in the AZT-treated patients was due
to concomitant treatment with cotrimoxazole remains unknown.
Discussion at the conference noted that initiating treatment with d4T and
then switching to AZT after a few months might minimise the risk of
toxicities associated with both drugs. Immune restoration appears to reduce
the risk of AZT-associated anaemia, so why not switch treatment before the
peripheral neuropathy associated with d4T becomes apparent.
³This is a very important finding,² said Dr Moses Sinkala, director of
health in Lusaka, Zambia. ³We would like to get rid of d4T but we are stuck
with it.²
³We have considered revising our guidelines in Uganda," said another
audience member, "but writing [this approach] into public health guidelines
is not attractive - it adds another layer of complication.²
Professor Ian Weller of University College London added another caution:
³There¹s not a clear window [at the beginning of therapy] in which people
aren¹t going to get mitochondrial toxicities - the attack rate is pretty
constant over time.²
Lipodystrophy an emerging complication
Although peripheral neuropathy is frequently reported as the most common
side effect of d4T treatment in resource-limited settings, a small South
African longitudinal study of metabolic complications showed a high rate of
lipodystrophy in 60 black South African patients after 24 months of
treatment with d4T/3TC (stavudine/lamivudine) and efavirenz. Lipodystrophy was
assessed using measures of skinfold thickness and body mass index, together
with physician and patient perception (George 2007).
Forty-three per cent were judged to have some degree of lipodystrophy, which
generally became apparent after about 18 months of treatment - perhaps
explaining why, to date, the incidence appears to have been low in
resource-limited settings.
Indeed, a larger South African cohort, from the University of Witwatersrand,
which had been followed for a median of 18 months found a much lower rate of
lipodystrophy (8.5%). But it also found a surprisingly high rate of another
toxicity which has been less commonly reported in the developed world -
gynaecomastia (growth of male breast tissue) (8.3%). Although not
life-threatening, this is not a toxicity that is likely to improve the
popularity of antiretroviral therapy in a country beset with misinformation
about HIV treatment.
Severe hyperlactatemia
The most serious toxicity concerns focus on the incidence of severe
hyperlactatemia in d4T-treated patients. Hyperlactatemia occurs when lactic
acid levels become severely elevated as a a result of mitochondrial toxicity
caused by d4T.
At last year¹s CROI, South African researchers reported on an alarmingly
high incidence of hyperlactatatemia in women weighing more than 60kg who had
gained weight rapidly after starting d4T-based antiretroviral therapy.
At this year¹s conference, researchers from Grote Juust hospital and the
University of Cape Town reported on a case control study of 71 incident
cases of severe hyperlactatemia and 142 controls matched according to clinic
and date of treatment initiation.
Hyperlactaemia was defined as a lactate level of 5mmol/L or above.
The study confirmed that female sex, baseline weight above 60kg and a low
nadir CD4 cell count were all strongly associated with an increased risk of
developing hyperlactatemia. In addition, rapid weight gain of at least 6kg
during the first six months of ART, or weight loss of at least 3kg in the
three months prior to the date that hyperlactatemia was diagnosed were
strongly predictive, as were presenting with peripheral neuropathy and new
gastrointestinal symptoms.
The development of severe hyperlactatemia thus seems to be multifactorial,
said Dr Graeme Meintjes of Grote Juust hospital, and its detection requires
clinical vigilance in settings where lactate levels are not routinely
tested, since hyperlactatemia may be rapidly life-threatening if treatment
is not stopped. The Grote Juust study found that 15% of acute cases were
fatal, and that standard bicarbonate below 15mmol/L was the only significant
predictor of mortality in those presenting with severe hyperlactatemia.
Treatment with d4T must not be resumed if an individual stops the drug due
to severe lactate elevations, and there has been considerable caution in the
past about using AZT instead in such patients.
Re-challenge with an AZT-based regimen was well tolerated after
normalisation of lactate levels in those patients with less severe
hyperlactatemia (lactate < 10.4mmol/L) (n=29), but in more severely affected
patients tenofovir-based (n=5) or NRTI-sparing regimens (efavirenz and
lopinavir/ritonavir (Kaletra), n=25) had to be used, with no recurrences (n=30).
South African management guidelines for hyperlactatemia were published last
year, and can be reviewed in a special edition of HIV & AIDS Treatment in
Practice.
References
1. Amoroso A et al. ARV-associated drug toxicities leading to a switch in
medication: experience in Uganda, Kenya and Zambia. Fourteenth Conference on
Retroviruses and Opportunistic Infections, Los Angeles, abstract 789, 2007.
2. Forna F et al. Tolerance to zidovudine after single-drug substitution
from stavudine in a home-based AIDS care program in rural Uganda. Fourteenth
Conference on Retroviruses and Opportunistic Infections, Los Angeles,
abstract 793, 2007.
3. George J et al. Metabolic complications in black South African patients.
Fourteenth Conference on Retroviruses and Opportunistic Infections, Los
Angeles, abstract 796, 2007.
4. Osler M et al. Severe hyperlactatemia complicating ART with stavudine
first-line therapy in South Africa: incidence, risk factors and outcomes.
Fourteenth Conference on Retroviruses and Opportunistic Infections, Los
Angeles, abstract 792, 2007
SOURCE: NAM
http://www.aidsmap.com/en/news/99BDC190-703D-455E-ADF1-78B76…
Sharonann Lynch
MSF Lesotho
Mobile: +266 5842 0614
Office: +266 2236 0713
Email: sharonann.lynch@gmail.com