why it's time.html
DEBATE
WHY IT’S TIME TO SAY GOODBYE TO STAVUDINE ... EVERYWHERE
Isabelle Andrieux-Meyer,
1
MD
Polly Clayden
2
Simon Collins
2
Nathan Geffen
3
Eric Goemaere,4
MD, DTMH, PhD
Mark Harrington5
Sharonann Lynch1
Tido von Schoen-Angerer,
1
MD, MSc
Tracy Swan5
1 Médecins Sans Frontières Access Campaign
2 HIV i-Base
3 Treatment Action Campaign
4 Médecins Sans Frontières, South Africa
5 Treatment Action Group
Editor’s note: The previous issue of the SAJHIV
(December 2011) carried an Opinion piece by Innes, Cotton and Venter
regarding the potential value of low-dose of stavudine (20 mg
twice a day). They suggested that reduced dosing of stavudine
may lead to levels of viral suppression comparable with those achieved
with stavudine 30 mg bd but with a lower risk of toxicity and
side-effects, and at a fraction of the cost of tenofovir. The
Opinion was related to a larger proposal, led by Venter, to conduct a
head-to-head trial comparing low-dose stavudine with tenofovir (both in
a regimen including lamivudine and efavirenz) on viral suppression
and other treatment outcomes over 24 months. There has been
considerable debate regarding the advantages and
disadvantages of low-dose stavudine, and in turn the value of any
such trial. Here the debate continues with a commentary by Isabelle
Andrieux-Meyer et al. and a rebuttal by Venter and colleagues.
We read with interest an opinion piece by Innes et al.1 in
the previous issue of the journal, regarding the potential value of
low-dose stavudine (20 mg twice daily). The article focused on
stavudine use in paediatrics (where there are fewer approved
antiretrovirals compared with adults, although there will be greater
choice in the near future, as the US Food and Drug Administration (FDA)
has recently approved tenofovir for 2 - 12-year-olds, and other
regulatory agencies are expected to follow suit). In the article, the
authors used the situation with children to argue for a proposal, led
by Venter, to conduct a head-to-head non-inferiority study in adults
comparing low-dose stavudine with tenofovir (both in a regimen
including lamivudine and efavirenz) with a 48-week virological endpoint
and other treatment outcomes over 96 weeks.* We have serious concerns
about this proposed trial, for the following reasons:
1. Stavudine is more toxic than tenofovir, and for this reason it is an inferior treatment option.
The proposed trial aims to establish virological non-inferiority, which
is a moot point, given the severe adverse events associated with
stavudine. Considerable evidence supports the use of tenofovir over
stavudine; regulatory bodies and the World Health Organization (WHO)
have turned away from the drug. In 2004, stavudine was removed from the
list of preferred first-line antiretroviral drugs recommended by the US
Department of Health and Human Services (DHHS).2
Starting in 2006, the WHO recommended that countries start moving away
from stavudine, and in 2009 recommended that the drug be phased out in
first-line antiretroviral therapy (ART) programmes.3 Earlier
this year, the European Medicines Agency (EMA) revised the indication
for stavudine, noting that ‘… the use of the medicine
should be severely restricted in both adults and children ...
Prescribers are reminded of the severe side effects seen with Zerit
[stavudine] and should only use the medicine when other appropriate
treatments are not available. Patients being treated with Zerit should
be assessed frequently and switched to appropriate alternatives as soon
as possible.’4
Médecins Sans Frontières (MSF)/Doctors Without Borders
have provided further compelling evidence of stavudine’s toxicity
in an operational setting. In a Lesotho cohort, the authors found that
‘… for patients on stavudine, the risk of a
toxicity-driven regimen switch was almost six times higher than
tenofovir’.5 The high
incidence of adverse events among patients on stavudine-containing
first-line regimens has also been documented in a larger prospective
study in South Africa.6 In that study 30% of patients had to switch from stavudine-based to non-stavudine-based regimens within 3 years.
For good reasons, tenofovir has become the gold standard for
today’s first-line antiretroviral therapy. Its introduction in
developing countries is an important step towards bringing treatment in
poor countries in line with rich ones. As the WHO and all countries are
phasing out stavudine, this study will send a confusing message, and it
may slow down this transition while countries wait for the results.
*A
randomised, double-blind study to demonstrate non-inferiority of
stavudine (20 mg BID) compared with tenofovir (300 mg QD)
co-administered with lamivudine and efavirenz in antiretroviral-naive
patients over 96 weeks. If funded and approved, the trial is
anticipated to start in 2012.
There is no prospect that stavudine 20 mg is a better option than
tenofovir. The stavudine parallel track programme, in which over 10 000
patients were randomised to receive 40 (30) mg or 20 (15) mg between
October 1992 and February 1994, showed a higher
incidence of neuropathy in the high-dose arm (21%). Nonetheless, the
incidence of neuropathy observed in the lower-dose arm was also
unacceptably high (15%).7
Of particular importance in low- to middle-income countries –
where tuberculosis (TB) is prevalent among HIV-positive people, who are
also
receiving
stavudine-containing regimens – a South African study looked at
the risk of stavudine substitution for toxicities in 7 066 patients
receiving ongoing TB treatment at ART initiation; concurrent initiation
of TB treatment and ART and incident TB treatment after ART initiation.
The study found people receiving ongoing and concurrent TB treatment to
be at increased risk of toxicity leading to stavudine substitution, irrespective of stavudine dose
(30
and 40 mg). For ongoing TB treatment, adjusted hazard ratio (aHR) was
3.18 (95% confidence interval (CI) 1.82 - 5.56) in the first 2 months
of ART; for concurrent TB treatment, aHR was 6.60 (95% CI 3.03 - 14.37)
in the first 2 months of ART.
The stavudine 20 mg study is not being proposed in any developed
country. Instead it is planned to include only middle- and lower-income
developing countries. Patients enrolling in this trial risk being
randomised to receive treatment that may be less effective and is more
toxic than the current standard of care. There is therefore no good
reason why a properly informed patient should want to enrol in this
study.
2. The poor tolerability of stavudine limits therapeutic durability. A
person has the best chance of successful treatment with their
first-line regimen, making it critical that the medicines are as
tolerable as possible. A tolerable first-line regimen enhances
therapeutic durability by helping people adhere to treatment, and
delays their need to switch to more costly second-line regimens, which
are complicated for patients, for health workers and from an
operational standpoint.
3. Stavudine’s side-effects cut into stavudine’s savings on cost. A
study published by MSF shows that inpatient care and essential drug
costs were higher for people on stavudine than for those on tenofovir
in a cohort in rural Lesotho. According to MSF’s
cost-effectiveness study of switching from stavudine or zidovudine- to
tenofovir-based first-line regimens in Lesotho, the
tenofovir-containing regimen generated higher life years and
quality-adjusted life years than zidovudine or stavudine-based
treatment.8 As the costs of
tenofovir and especially efavirenz drop, the cost benefit to patients
and to health systems will become clearer. Since the study was
completed, the global best price of efavirenz – which partly
drives tenofovir costs – has almost halved (US$97 per patient
year in 2009 to $52 today).
4. Stavudine can compromise second-line options.
When someone does fail their first-line regimen, the longer they remain
on stavudine – which is likely in a context with limited access
to viral load monitoring – the more their second-line options are
compromised. Unlike stavudine, tenofovir does not confer thymidine
analogue mutations (TAMs); people taking tenofovir can stay on a
failing regimen much longer without compromising efficacy of zidovudine
and therefore second-line therapy.
5. Stavudine’s long-term toxicity question will not be answered by this trial.
The proposed 20 mg stavudine dose might be acceptable in a short-term
48- or even 96-week virological endpoint study (although Bristol-Myers
Squibb studied and rejected 20 mg bd). But, because mitrochondrial
toxicity is both dose and time dependent, many of stavudine’s
most serious side-effects (such as peripheral neuropathy and
lipoatrophy) would not necessarily emerge until after such a study was
completed. This study does not include monitoring of surrogate markers
for mitochondrial toxicity, so it cannot shed light on the incidence of
this serious adverse event.
Recently published longer-term Cambodian data on rates of severe
stavudine-associated toxicity show 7% of people to have neuropathy
within the first year; by year 3 the cumulative incidence was 16.6%,
and it rose to 19.0% at year 6. The cumulative incidence of lipoatrophy
was 56% by year 3 and 72% by year 6. Stavudine use significantly
increased the risk for lactic acidosis among people on concurrent TB
treatment; the aHR was 8.6 (95% CI 2.7 - 27.5).10
The investigators have agreed that this important question about
longer-term toxicity will not be answered in the trial, raising the
serious issue that the trial will not be able to answer the primary
policy question which drives it –
whether long-term 20 mg stavudine twice daily is as good as once-daily
tenofovir in first-line ART regimens for use in public health
programmes in resource-limited settings.
6. Stavudine must be taken twice a day, compared with tenofovir’s once-daily dosing.
A twice-daily dosing regimen (as with stavudine 20 mg) does not have
the simplicity of a once-daily fixed-dose combination (as with
tenofovir). People are more likely to adhere to simpler regimens and
therefore are more likely to have better treatment outcomes, as well as
stave off resistance that requires more complex and expensive
second-line regimens.
7. A tenofovir-based regimen is
recommended for HIV/hepatitis B (HBV) coinfection, because stavudine
has no activity against HBV and resistance to lamivudine is inevitable.
While HIV/HBV co-infection is an exclusion criterion for this
trial, it may encourage persistent use of a suboptimal regimen for
HIV/HBV co-infected people. Screening for HBV is not routinely
performed before initiation of ART in most resource-limited settings,
yet HBV is endemic. For example, in South Africa an estimated 5% of
HIV-positive people are HBV co-infected (Dr Mark Sonderup, personal
communication). Giving a stavudine/lamivudine-based regimen to HIV/HBV
co-infected people will create lamivudine-resistant HBV in this
population (90% at 4 years).9
Continuing lamivudine in the context of HBV drug resistance may lead to
hepatitis flares; these flares can cause serious liver damage, and are
potentially life-threatening. Researchers are also concerned about the
transmission of drug-resistant HBV that may not be preventable by
currently available HBV vaccines, a potential public health
catastrophe.
8. Stavudine-related cost savings may become irrelevant by the trial’s end.
The rationale for this trial is to lower treatment costs, as stavudine
is currently cheaper than its alternatives. However, the price of
alternatives, notably tenofovir, has come down dramatically in the last
several years, and is expected to decrease further as demand increases.
According to MSF’s annual ARV pricing report, tenofovir is now
cheaper than zidovudine, with the price of single-drug tenofovir having
decreased by 52% from 2008 to 2011, and the price of the triple
fixed-dose combination of tenofovir, lamivudine and efavirenz having
decreased by 53% to US$173 per person per year over that same time
period.10 The price of the double FDC TDF/3TC co-packed with EFV is $143 per person per year. Furthermore,
the Clinton Health Access Initiative (CHAI) is currently working on the
in the reformulation of tenofovir, with the goal of increasing
bioavailability, hence reducing the required active pharmaceutical
ingredient and in turn the cost.
Because the stavudine 20 mg 96-week efficacy trial is expected to be
completed at the earliest by 2014 - 2015, and would need to be followed
by a larger, longer (perhaps 5-year) field effectiveness trial to
determine longer-term tolerability, the drug may not be available for
use at the new dose until possibly even 2020. It is therefore likely to
take 9 years from now for there to be enough evidence that 20 mg
stavudine is safe and non-inferior to tenofovir, and could be used to
replace tenofovir in first-line regimens.
If current price trends continue, it is likely the anticipated cost
savings associated with stavudine could be overtaken by expected
further price reductions for tenofovir and other components of the
first-line regimen, by the time stavudine 20 mg would be ready for use.
It is worth noting that a three-drug one-pill-once-a-day regimen
containing efavirenz and tenofovir is now priced at roughly half what
stavudine-based Triomune cost when it was first introduced a decade ago.
Further, even greater potential savings could
be achieved if the tenofovir prodrug GS 7340, now in phase II by Gilead
Sciences, is approved at a low milligram dose. Results will be
available within a similar time frame to those from the 96-week
stavudine 20 mg trial. A recent announcement by Gilead of an
agreement with Tibotec to develop a fixed-dose combination of
darunavir, emtricitabine, GS 7340 and cobicistat with ‘less than
one tenth of the amount of the 300 mg of tenofovir disoproxil fumarate
contained in Viread and Truvada’ suggests that this is feasible.11 Chimerix Inc. also has a promising tenofovir pro-drug in development, CMX-157.
Other drugs in late-stage development such as the integrase
inhibitor dolutegravir (50 mg once daily) also offer potential savings
on manufacturing and could end up being cheaper than stavudine 20 mg by
the time it would become available.
9. Stavudine has low acceptability in the community. Finally, and most importantly, the
continued use of stavudine and the proposed trial has raised opposition
from people directly affected by its continued use. As an example, the
Malawi Network of People Living with HIV/AIDS (MANET+) recently held a
press briefing, as the slow pace for phasing out current use of this
drug in their country concerns them. Despite the funding crisis, the
Malawi government has a priority for this to be completed by June 2012.12
It is unclear why the Bill and Melinda Gates Foundation – who
are in discussion with the investigators about funding the proposal
– consider this study to be a priority. It seems an aberration in
an otherwise carefully considered strategy for supporting research into
the optimisation of ART for resource-limited settings. This includes
the ENCORE 1 study of low-dose efavirenz, the reformulation of
tenofovir to increase its bioavailability (working with CHAI), and the
development of innovative potentially long-acting formulations.
For the reasons outlined above, research and the resources it
requires, as well as activist pressure, should focus on increasing
access to safer cost-saving alternatives to stavudine, not on seeking a
comeback for a drug virtually abandoned in wealthy countries.
Please address all correspondence to:
sharonann.lynch@msf.org
polly.clayden@i-base.org.uk
nathangeffen@gmail.com
markhar@gmail.com
REFERENCES
1. Innes S, Cotton M, Venter F. Why should we still care about the
stavudine dose? Southern African Journal of HIV Medicine
201;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
201;12(4):14-15.
2. Panel on Clinical Practices for Treatment of HIV Infection.
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services (DHHS),
2004.
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL10292004002.pdf
(accessed 20 February 2012).
2. Panel on Clinical Practices for Treatment of HIV Infection.
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services (DHHS),
2004.
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL10292004002.pdf
(accessed 20 February 2012).
3. World Health Organization. WHO Rapid Advice: Antiretroviral therapy
for HIV infection in adults and adolescents. WHO, 2009.
http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf (accessed 20
February 2012).
3. World Health Organization. WHO Rapid Advice: Antiretroviral therapy
for HIV infection in adults and adolescents. WHO, 2009.
http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf (accessed 20
February 2012).
4. European Medicines Agency. Questions and answers on the review of
Zerit (stavudine): Outcome of a renewal procedure. European Medicines
Agency, 17 February 2011.
http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000110/WC500102227.pdf
(accessed 20 February 2012).
4. European Medicines Agency. Questions and answers on the review of
Zerit (stavudine): Outcome of a renewal procedure. European Medicines
Agency, 17 February 2011.
http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000110/WC500102227.pdf
(accessed 20 February 2012).
5. Bygrave H, Ford N, van Cutsem G, et al. Implementing a
tenofovir-based first-line regimen in rural Lesotho: clinical outcomes
and toxicities after two years. J Acquir Immune Defic Syndr
2011;56(3):e75-78 [http://dx.doi.org/10.1097/QAI.0b013e3182097505].
5. Bygrave H, Ford N, van Cutsem G, et al. Implementing a
tenofovir-based first-line regimen in rural Lesotho: clinical outcomes
and toxicities after two years. J Acquir Immune Defic Syndr
2011;56(3):e75-78 [http://dx.doi.org/10.1097/QAI.0b013e3182097505].
6. Menezes C, Maskew M, Sanne I, Crowther N, Raal F. A longitudinal
study of stavudine-associated toxicities in a large cohort of South
African HIV infected subjects. BMC Infect Dis 2011;11:244
[http://dx.doi.org/10.1186/1471-2334-11-244].
6. Menezes C, Maskew M, Sanne I, Crowther N, Raal F. A longitudinal
study of stavudine-associated toxicities in a large cohort of South
African HIV infected subjects. BMC Infect Dis 2011;11:244
[http://dx.doi.org/10.1186/1471-2334-11-244].
7. Anderson R, Dunkle L, Smaldone L, et al. Design and implementation
of the stavudine parallel track programme. J Infect Dis
1995;171:118-122.
[http://dx.doi.org/10.1093/infdis/171.Supplement_2.S118].
7. Anderson R, Dunkle L, Smaldone L, et al. Design and implementation
of the stavudine parallel track programme. J Infect Dis
1995;171:118-122.
[http://dx.doi.org/10.1093/infdis/171.Supplement_2.S118].
8. Jouquet G, Bygrave H, Kranzer K, et al. Cost and cost-effectiveness
of switching from d4T or AZT to a TDF-based first-line regimen in a
resource limited setting in rural Lesotho. J Acquir Immune Defic Syndr
2011;58:e68-e74 [http://dx.doi.org/10.1097/QAI.0b013e31822a9f8d].
8. Jouquet G, Bygrave H, Kranzer K, et al. Cost and cost-effectiveness
of switching from d4T or AZT to a TDF-based first-line regimen in a
resource limited setting in rural Lesotho. J Acquir Immune Defic Syndr
2011;58:e68-e74 [http://dx.doi.org/10.1097/QAI.0b013e31822a9f8d].
9. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of
hepatitis B virus resistance to lamivudine in human immunodeficiency
virus-infected patients. Hepatology 1999;30:1302-1306.
[http://dx.doi.org/10.1002/hep.510300525].
9. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of
hepatitis B virus resistance to lamivudine in human immunodeficiency
virus-infected patients. Hepatology 1999;30:1302-1306.
[http://dx.doi.org/10.1002/hep.510300525].
10. Médecins Sans Frontières. Untangling the Web of
Antiretroviral Price Reductions. 14th ed. Médecins Sans
Frontières Campaign for Access to Essential Medicines, July
2011.
http://www.doctorswithoutborders.org/publications/article.cfm?id=5448&cat=special-report
(accessed 20 February 2012).
10. Médecins Sans Frontières. Untangling the Web of
Antiretroviral Price Reductions. 14th ed. Médecins Sans
Frontières Campaign for Access to Essential Medicines, July
2011.
http://www.doctorswithoutborders.org/publications/article.cfm?id=5448&cat=special-report
(accessed 20 February 2012).
11. Gilead. Gilead Sciences Finalizes Agreement with Tibotec
Pharmaceuticals to Develop and Commercialize a Single-Tablet Regimen of
Prezista(R) with Emtriva(R), GS 7340 and Cobicistat. Gilead Press
Release. http://www.gilead.com/pr_1630785 (accessed 20 February 2012).
11. Gilead. Gilead Sciences Finalizes Agreement with Tibotec
Pharmaceuticals to Develop and Commercialize a Single-Tablet Regimen of
Prezista(R) with Emtriva(R), GS 7340 and Cobicistat. Gilead Press
Release. http://www.gilead.com/pr_1630785 (accessed 20 February 2012).
12. Nkhoma P. Manet+ wants ARV d4T phased out. The Daily Times, Malawi,
30 January 2012.
http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou
(accessed 20 February 2012).
12. Nkhoma P. Manet+ wants ARV d4T phased out. The Daily Times, Malawi,
30 January 2012.
http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou
(accessed 20 February 2012).