[Ip-health] Letter to Gates Foundation on clinical trial on comparing stavudine at 20 mg to tenofovir

Katy Athersuch katy.athersuch at googlemail.com
Wed Dec 21 04:59:47 PST 2011

Please find below and at the link, a joint letter from people with HIV and
community activists to the Gates Foundations on concerns over a proposed
clinical trial comparing stavudine at 20 mg to tenofovir.


Bill and Melinda Gates
Bill & Melinda Gates Foundation
PO Box 23350
Seattle, WA 98102
14 December 2011

Dear Mr and Mrs Gates,

We write as people with HIV and community activists with serious and
unresolved concerns about the proposed clinical trial comparing stavudine
at 20 mg to tenofovir.1 Although we are broadly very supportive of dose
optimisation strategies, we do not support this trial; we do not think that
the Bill and Melinda Gates Foundation should support it; nor do we think it
should proceed. Several of us have discussed this with your representatives
both formally and informally over the past months. Those of us who met with
your representatives on 19 July 2011 at the International AIDS Society
conference in Rome received no response to the concerns we raised. We
summarise our objections as follows:

1. Stavudine is more toxic than tenofovir, and for this reason, it is an
inferior 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 treatment (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 three years.

For good reason, tenofovir has become the gold standard for today’s
first-line antiretroviral therapy. Its introduction in developing countries
is an important step to slowly bringing treatment in poor countries in line
with rich ones. As 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.

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 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 at 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, health
workers and from an operational standpoint.

3. Stavudine's side effects cut into stavudine's savings on cost. A study
just published by MSF shows that inpatient care and essential drug costs
were higher for people on stavudine than 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
QALYs 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 ($97 ppy 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 thus 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 virologic endpoint study (although
Bristol-Myers Squibb studied and rejected 20 mg BID). 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. Your representatives have agreed that this important
question about longer-term toxicity will not be answered in the trial, thus
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
BID is as good as tenofovir QD in first-line ART regimens for use in public
health programmes in resource-limited settings.

6. Stavudine must be taken twice a day, compared to tenofovir’s once-daily
dosing. A twice-daily dosing regimen (as with stavudine 20 mg) does not
have the simplicity of a oncedaily 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

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 prior to initiation of ART in most resourcelimited settings, yet
HBV is endemic. For example in South Africa, an estimated 5% of HIVpositive
people are HBV co-infected9. Giving a stavudine/lamivudine-based regimen to
HIV/HBV co-infected people will create lamivudine resistant HBV in this
population (90% at four years)10. Continuing lamivudine in the context of
HBV drug resistance may lead to hepatitis flares; these flares can cause
serious liver damage, and are potentially lifethreatening. 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

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.11 Because the stavudine 20mg
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
five-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 thus likely to take nine years from now for there to be enough
evidence that 20mg 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 will be overtaken by expected further price reductions for
tenofovir, by the time stavudine 20mg were 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 of what stavudinebased 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 an FDC 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.12 Chimerix Inc. also has a promising tenofovir
pro-drug in development, CMX-157.

Furthermore, your organisation is also investing in the reformulation of
the existing tenofovir, with the goal of increasing bioavailability, hence
reducing the required API and in turn the cost.

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.

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 rich countries.

Yours sincerely,

Isabelle Andrieux-Meyer, Médecins Sans Frontières
Polly Clayden, HIV i-Base
Lei Chou, Treatment Action Group
Simon Collins, HIV i-Base
Lihle Dlamini, Treatment Action Campaign
Vuyiseka Dubula, Treatment Action Campaign
Nathan Geffen, Treatment Action Campaign
Eric Goemaere, Médecins Sans Frontières
Mark Harrington, Treatment Action Group
Matthew Kavanagh, Health GAP
Nonkosi Khumalo, Treatment Action Campaign
Sharonann Lynch, Médecins Sans Frontières
Tido von Schoen-Angerer, Médecins Sans Frontières
Tracy Swan, Treatment Action Group
Wim Vandevelde, European AIDS Treatment Group

*Please address all correspondence to:*
sharonann.lynch at msf.org
polly.clayden at i-base.org.uk
nathangeffen at gmail.com
markhar at gmail.com

1 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 early 2012.
2 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults
and Adolescents. 29 October 2004.
3 WHO Rapid Advice: Antiretroviral therapy for HIV infection in adults and
adolescents. November 2009.
http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf, page 10
4 EMA 17 February 2011. EMA/127094/2011. EMEA/H/C/000110/R/79. Questions
and answers on the review of Zerit
(stavudine): Outcome of a renewal procedure:
5 Adjusted hazard ratio: 5.43, 95% confidence interval: 3.31 to 8.91.
Bygrave H et al. 2011. Implementing a tenofovir-based firstline
regimen in rural Lesotho: clinical outcomes and toxicities after two years.
J Acquir Immune Defic Syndr. 2011 Mar
1;56(3):e75-8. http://www.ncbi.nlm.nih.gov/pubmed/21164354
6 Menezes et al. A longitudinal study of stavudine-associated toxicities in
a large cohort of South African HIV infected subjects.
BMC Infectious Diseases 2011, 11:244 doi:10.1186/1471-2334-11-244
7 Anderson R et al. Design and implementation of the stavudine parallel
track programme. Comparison of safety and efficacy of
two doses of stavudine in a simple trial in the US parallel track
programme. J Inf Dis. 1995; 171:118-22.
8 Jouquet 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. JAIDS Publish Ahead of Print. DOI: 10.1097/QAI.
9 Communication Dr Mark Sonderup, Division of Hepatology, University of
Cape Town.
10Benhamou Y et al. Long-term incidence of hepatitis B virus resistance to
lamivudine in human immunodeficiency virusinfected
patients. Hepatology. 1999;30:1302-1306.
11 Untangling the Web of Antiretroviral Price Reductions, 14th Edition.
July 2011. Médecins Sans Frontières Campaign for Access to Essential
12 FOSTER CITY, Calif., Nov 15, 2011 (BUSINESS WIRE). Gilead Sciences
Finalizes Agreement with Tibotec
Pharmaceuticals to Develop and Commercialize a Single-Tablet Regimen of
Prezista(R) with Emtriva(R), GS 7340 and

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