low-dose.html
DEBATE
LOW-DOSE STAVUDINE TRIALS: A PUBLIC HEALTH PRIORITY FOR DEVELOPING COUNTRIES
W D Francois Venter,
MB BCh, FCP (SA), Dip HIV Man (SA), DTM&H (SA), MMed
Wits Reproductive Health and HIV Institute (WRHI),
Department of Medicine, University of the Witwatersrand and Charlotte
Maxeke Johannesburg Academic Hospital, Johannesburg
Steve Innes,
MB BCh, MRCPCH, MPhil
Mark Cotton,
MB ChB, MMed, FCPaed, DTM&H, DCH (SA), PhD
Children’s Infectious Diseases Clinical
Research Unit (KID-CRU), Tygerberg Children’s Hospital and
Stellenbosch University, W Cape
The debate around relooking at stavudine dosing, both in terms of
the adult low-dose stavudine study and more broadly, is welcome. The
study being proposed to evaluate low-dose stavudine v. tenofovir is a
fairly standard placebo-controlled non-inferiority study. The study
design is not controversial; however, the choice of study drug has
attracted critical attention. We have previously discussed the issue of
stavudine use, cost and access, and the significant implications of
stavudine in developing countries, in detail in a recent article.1
We continue to believe that low-dose stavudine clinical trials, in both
adults and children, are a priority for developing countries. These
studies are being proposed simply because tenofovir is very expensive,
and the only available cheaper alternative is stavudine. With
recession, unertainty about donor commitments, the compromise of
several treatment projects by lack of money, and the plain fact that
many developing countries are unable to take ownership of the
antiretroviral programme within their budgets, this and similar studies
are urgent and necessary for our region to continue to expand access to
antiretroviral therapy.
Stavudine was chosen because it is very cheap, easily co-formulated,
very well tolerated initially, and requires no laboratory toxicity
monitoring in routine clinical practice. Tenofovir was chosen as the
comparator for the trial as it is currently the ‘gold
standard’ in many guidelines, and the alternatives (zidovudine
(AZT) and abacavir) are now more expensive than tenofovir. Abacavir
would be regarded as the equivalent gold standard for paediatric care.
As clinicians involved with antiretroviral (ARV) programmes for the
last few years, and having used stavudine in large numbers of both
adults and children in the past decade, we identify with the
instinctive discomfort of many critics. However, we feel that there is
a very strong case for studying stavudine further, and many of the
arguments against further trials are not consistent with how we study
other antiretrovirals, or indeed medication efficacy in general.
Tenofovir certainly has benefits over stavudine: it is dosed daily, and
has anti-hepatitis B activity; counter-arguments could be that
hepatitis B is easily screened for, and that renal toxicity
increasingly recognised with tenofovir has potentially serious
consequences in developing countries, where monitoring and access to
renal care, dialysis and transplantation are almost non-existent.2
These arguments, however, are likely to be irrelevant when the cost of
medication is considered. Broadly, other more substantial arguments
fall into the following categories.
STAVUDINE TOXICITY
This is the most serious disagreement. Critics maintain that
stavudine is too toxic to be used, that it is not possible to monitor
toxicity safely, and that the trial duration is only 2 years, hence
limiting the usefulness of the data.
Toxicity concerns are exclusively based on data around high dosages
of stavudine, largely the (now historic) adult 40 mg twice a day (bd)
dosage, for which there are extensive toxicity data, including from our
own centres. More limited data suggest that 30 mg bd is significantly
safer, at least in the medium term, but still carries significant
toxicity. We do not contest this – stavudine causes often
irreversible and stigmatising lipo-atrophy, as well as peripheral
neuropathy and other mitochondrial toxicity in adults. However, all
drugs are toxic in sufficient dosages. AZT was originally dosed at far
higher levels than currently; toxicity forced the testing of lower
doses that were far better tolerated with equal virological suppression
levels, and AZT became the standard of first-line care for almost a
decade. However, AZT still has some toxicity at this lower dose, and
even lower doses are being tried.3
The original dose-finding
studies of stavudine (d4T) were a complex affair, and the originator
company did not complete what we consider to have been the natural next
phase of study, largely as it was clear that the significant investment
on another large clinical trial was unlikely to be recouped, as well as
a probable internal assessment that the drug had a significant public
relations problem related to lipo-atrophy in developed countries, where
profits are made. There is some evidence that dosing at 20 mg bd is
safer and gives equivalent virological efficacy, but these data have
not been tested in a rigorous manner.5
This study plans to repeat those done for drugs such as AZT and many
others – optimising the dosage of stavudine so as to minimise
toxicity, while maintaining virological efficacy. It also responds to
observer calls for more research on stavudine using high-quality trials.3
,
5
,
10
Critics have maintained that stavudine toxicity is impossible to
monitor safely. Safety and toxicity monitoring in the proposed study
has been extensively examined by many experts, and we are confident
that we can pursue the study safely. Ethics committees are currently
examining the proposed toxicity monitoring schedules. The doctors
involved in the study have plenty of experience in the early
recognition of stavudine toxicity.
We agree with critics that the study will not give us evidence on
long-term toxicity. Our study is currently funded to run for 2 years,
like most registration ARV studies. For many countries, providing 2
years of safe therapy at reduced cost is of significant importance.
However, we have extensive lipo-atrophy pre-clinical toxicity
monitoring built into the study; if no additional toxicity in the
stavudine arm using DEXA scans is demonstrated, it is plausible that
the drug could be used for longer, and we therefore intend motivating
to extend the study.
Finally, it is contended that this study would never be run in a
developed country. We see absolutely no scientific and ethical reasons
why not. However, the urgency remains in our region. Rationing has
already begun in many programmes, and universal access, with the
attendant benefits of HIV prevention suggested by the HPTN 052 trial,
is unlikely to be more than a public health dream unless we lower the
cost of safe treatment. Even developed countries have had to make
rationing decisions, cf. the recent decision to restrict access to
first-line tenofovir in the UK; rationing was made easier by having
good data to base these decisions on.
TENOFOVIR COST
It is asserted that the price of tenofovir is still dropping and
will approach that of stavudine. We have consulted extensively over
this with the Clinton Health Access Initiative (CHAI) as well as
generic companies, and it seems that price equivalence will not be
possible, simply because the daily milligram dosage (a daily 300 mg v.
the proposed 40 mg) is so different, as raw chemicals drive the generic
manufacturing costs. Furthermore, the incremental drops in the price of
tenofovir (the latest announced by the CHAI in January 2012) are
unlikely to be as significant as previous ones, as manufacturing
efficiencies have largely been realised.
NEW DRUG AVAILABILITY
The next assertion is that new drugs are in the offing and will be
available by the time this study has results, making the results
irrelevant. We believe that confidence in a new drug that will
cost-effectively and timeously replace tenofovir is a huge act of
faith. Many new medications are indeed being tested, and a small number
may show efficacy when this study is completed. However, most drugs
fail, even in phase 3 studies, so even this is uncertain. Also, the
drugs may not be tested with backbones conventionally used in our
context (e.g. raltegravir may be used instead of efavirenz), which may
limit agreement on whether we can use the drug safely with available
backbone drugs.
Furthermore, the registration process, local regulatory approval,
negotiations with generic manufacturers and acceptance into national
guidelines mean that it takes many years to go from clinical trial
success to broad availability. Tenofovir took over 5 years for
registration in South Africa. Prolonged registration is the rule rather
than the exception in many developing countries. We may need several
more years for adequate costing, price reductions and agreement on
priorities for access to this treatment.
We believe that it is responsible to study alternatives to tenofovir and other expensive first-line medications.
OTHER ISSUES
In paediatric care, abacavir is the current preferred first-line
drug owing to concerns about tenofovir toxicity and also to to preserve
AZT for a second-line NRTI backbone. Abacavir is very expensive.
Stavudine remains the most widely used ARV for HIV-infected children in
sub-Saharan Africa. Apart from cost, abacavir has
other real problems. Although the incidence of abacavir
hypersensitivity reactions is probably low, there is no confirmatory
test widely available in
the public sector. The HLA-B5701 gene test is simply not available
outside large tertiary centres, and the gene appears to be a largely
Caucasian one anyway. Nonspecific fever and rash are common in
childhood, especially during immune reconstitution, and many children
are likely to receive the label ‘possible previous abacavir
hypersensitivity reaction’, which eliminates the option of ever
re-introducing abacavir in their regimen. Once abacavir is eliminated,
the remaining options in sub-Saharan Africa are zidovudine or stavudine.
The danger of zidovudine-related bone marrow suppression (a common
problem with varying degrees of severity) is significant and requires
some laboratory monitoring. Stavudine offers almost toxicity-free
short-term efficacy. For unknown reasons, thymidine-related peripheral
neuropathy has not been documented in pre-pubertal children, and
symptomatic lactic acidosis appears remarkably less common than in adults. The
incidence of lipo-atrophy is concerning but is strongly dose-related.
We think that its frequency and severity will be significantly reduced
with the use of low-dose stavudine. In addition, stigmatising
lipo-atrophy is avoidable if reasonable awareness is maintained and
appropriate drug switches made before lipo-atrophy becomes obvious.9
,
11
,
12
An unrecognised benefit of using children’s regimens similar to
adults’ is that it makes children less susceptible to supply-line
problems, a huge problem in developing countries. Getting the dose of
stavudine right in children is as compelling as it is in adults, and
these studies should be prioritised by funders.
In the end, we desperately need alternatives to tenofovir for
adults and to abacavir in children in poorer countries. The only
current alternative is conventionally dosed stavudine, as AZT and
abacavir are more expensive than tenofovir. A minister of health or
donor faced with the decision to treat two people with a moderately
toxic drug or one with a relatively safe regimen, with the other person
definitely dying of AIDS, faces very little choice. Making stavudine
safer is an urgent public health issue. We think that doing it safely,
efficiently and ethically is possible and should be everyone’s
priority.
REFERENCES
1. Innes S, Cotton M, Venter F. Why should we still care about
the stavudine dose? Southern African Journal of HIV Medicine
2011;12(4):14-15.
1. Innes S, Cotton M, Venter F. Why should we still care about
the stavudine dose? Southern African Journal of HIV Medicine
2011;12(4):14-15.
2. Scherzer R, Estrella M, Li Y, Deeks SG, Grunfeld C, Shlipak
MG. Association of tenofovir exposure with kidney disease risk in HIV
infection. AIDS 2012 [Epub ahead of print, 4 Feb].
2. Scherzer R, Estrella M, Li Y, Deeks SG, Grunfeld C, Shlipak
MG. Association of tenofovir exposure with kidney disease risk in HIV
infection. AIDS 2012 [Epub ahead of print, 4 Feb].
3. Makinson A, Moing VL, Kouanfack C, Laurent C, Delaporte E.
Safety of stavudine in the treatment of HIV infection with a special
focus on resource-limited settings. Expert Opin Drug Saf
2008;7(3):283-293.
3. Makinson A, Moing VL, Kouanfack C, Laurent C, Delaporte E.
Safety of stavudine in the treatment of HIV infection with a special
focus on resource-limited settings. Expert Opin Drug Saf
2008;7(3):283-293.
4. Pujades-Rodríguez M, Dantony E, Pinoges L, et al.
AIDS Working Group of Médecins Sans Frontières. Toxicity
associated with stavudine dose reduction from 40 to 30 mg in first-line
antiretroviral therapy. PLoS One 2011;6(11):e28112 [Epub 21 Nov 2011].
4. Pujades-Rodríguez M, Dantony E, Pinoges L, et al.
AIDS Working Group of Médecins Sans Frontières. Toxicity
associated with stavudine dose reduction from 40 to 30 mg in first-line
antiretroviral therapy. PLoS One 2011;6(11):e28112 [Epub 21 Nov 2011].
5. Hill A. d4T: keep it or abandon it? Asian Biomedicine 2010;4(4):541-546.
5. Hill A. d4T: keep it or abandon it? Asian Biomedicine 2010;4(4):541-546.
6. Boulle A, Orrell C, Kaplan R, et al. Substitution due to
antiretroviral toxicity or contraindication in the first 3 years of
antiretroviral therapy in a large South African cohort. Antivir Ther
2007;12:753-760.
6. Boulle A, Orrell C, Kaplan R, et al. Substitution due to
antiretroviral toxicity or contraindication in the first 3 years of
antiretroviral therapy in a large South African cohort. Antivir Ther
2007;12:753-760.
7. George JA, Venter WD, Van Deventer HE, Crowther NJ. A
longitudinal study of the changes in body fat and metabolic parameters
in a South African population of HIV-positive patients receiving an
antiretroviral therapeutic regimen containing stavudine. AIDS Res Hum
Retroviruses 2009;25(8):771-781.
7. George JA, Venter WD, Van Deventer HE, Crowther NJ. A
longitudinal study of the changes in body fat and metabolic parameters
in a South African population of HIV-positive patients receiving an
antiretroviral therapeutic regimen containing stavudine. AIDS Res Hum
Retroviruses 2009;25(8):771-781.
8. Innes S, Levin L, Cotton M. Lipodystrophy syndrome in
HIV-infected children on HAART. South African Journal of HIV Medicine
2009;10(4):76-80.
8. Innes S, Levin L, Cotton M. Lipodystrophy syndrome in
HIV-infected children on HAART. South African Journal of HIV Medicine
2009;10(4):76-80.
9. Bobat R, Kindra G, Kiepiela P, et al. Use of abacavir in 30
HIV-infected children from Durban, South Africa: report from a pilot
study. Pediatr Infect Dis J 2010;29(9):890.
9. Bobat R, Kindra G, Kiepiela P, et al. Use of abacavir in 30
HIV-infected children from Durban, South Africa: report from a pilot
study. Pediatr Infect Dis J 2010;29(9):890.
10. Spaulding A, Rutherford GW, Siegfried N. Stavudine or
zidovudine in three-drug combination therapy for initial treatment of
HIV infection in antiretroviral-naïve individuals. Cochrane
Database Syst Rev 2010 Aug 4;(8):CD008651.
10. Spaulding A, Rutherford GW, Siegfried N. Stavudine or
zidovudine in three-drug combination therapy for initial treatment of
HIV infection in antiretroviral-naïve individuals. Cochrane
Database Syst Rev 2010 Aug 4;(8):CD008651.
11. Eley B. Metabolic complications of antiretroviral therapy
in HIV-infected children. Expert Opin Drug Metab Toxicol
2008;4(1):37-49.
11. Eley B. Metabolic complications of antiretroviral therapy
in HIV-infected children. Expert Opin Drug Metab Toxicol
2008;4(1):37-49.
12. Rabie H, Henning KL, Schoeman P, De Villiers N, Pretorius
GHJ, Cotton M. Abacavir: its use and hypersensitivity. Southern African
Journal of HIV Medicine 2009;10(4):81-84.
12. Rabie H, Henning KL, Schoeman P, De Villiers N, Pretorius
GHJ, Cotton M. Abacavir: its use and hypersensitivity. Southern African
Journal of HIV Medicine 2009;10(4):81-84.