[Ip-health] U.S. 's Misguided and Bad-Faith Attack on the WHO's 3-by-5 Plan

[B.Baker@neu.edu]

U.S.'s Misguided and Bad-Faith Attack on the WHO's 3-by-5 Plan
   Brook K. Baker, Northeastern University School of Law and Health GAP
                             December 18, 2003

As the U.S. government plods slowly towards expanded funding for its
largely bilateral global AIDS initiative (President's Emergency Plan for
AIDS Relief) and as it sends successive waves of teary-eyed politicians on
fact-finding tours to AIDS orphanages in Africa, it has been working hard
behind the scenes to undercut multilateral AIDS initiatives including the
Global Fund to Fight AIDS, TB, and Malaria and the WHO 3-by-5 plan (three
million people on antiretroviral therapy by the end of 2005).  The U.S.
systematic under-funding of the Global Fund and its persistent suppression
of donor and recipient expectations has been well documented.  The
"highlight" of the Administration's campaign for the planned failure of the
Global Fund is its scale-back of annual donations to the Global Fund, now
set at only $200 million annually for the next five years.  That will keep
the Fund's executive structure going while Richard Feachem (Executive
Director) and Tommy Thompson (Chairperson of the Board and U.S. Secretary
of Health and Human Services) supervise the gradual dissipation of all
forward motion on a unique plan to provide a coordinated global response to
the worst pandemics of modern time.

Having succeeded in engineering a downward slope in grant applications at
the Global Fund, the U.S. has recently turned its attention on the WHO and
its ambitious plan to provide antiretroviral therapy to 3 million people
living with AIDS by the end of 2005, roughly one-third of those in need of
AIDS medication to prevent their premature deaths within the following two
years.  Jealous of the WHO's leadership role, desirous of unilateral
credit, and eager to tout the gentle flip side of its brutal War on Terror,
the Bush Administration has embarked on a subtle disinformation campaign,
coordinated with its business ally, Big Pharma, to try to undermine the
role of low cost, standard quality generic medicines in the battle against
AIDS and to discredit efforts to rapidly increase capacity to deliver
antiretroviral therapy by relying less on medical experts and more on
community-based health workers.

In mounting its attack on the WHO's historic enterprise, the U.S. has
wrapped itself in the mantle of medical ethics and questioned key
components of the WHO plan including:  (1) "overly simplistic"
recommendations for simplified and standardized front-line combination
therapies, including fixed-dose combination medicines; (2) reliance on the
WHO's pre-qualification program to identify presumptively safe and
efficacious AIDS medicines, particularly Cipla's Triomune; (3) advocacy for
free treatment rather than co-payments; and (4) reliance on a new corps of
community health workers for much of the direct care delivery.  In essence
the U.S. government is saying that it has a unique vision for a
platinum-standard program of AIDS treatment and that anything less is
third-rate and violates medical ethics.  Coincidentally, the U.S. bemoans
that African countries have minimal capacity to deliver such high quality
care and thus the U.S. is justified in its go-slow approach to
appropriations and planning.

There is a deep and abiding irony in the U.S.'s hypocritical attack on the
ethics of the WHO's 3-by-5 plan whereby it seeks to ride the high horse of
exaggerated concern for highest quality treatment.  This is the same
government that has inspired and enforced structural adjustment policies at
the World Bank and the International Monetary Fund and in its own bilateral
programs that have decimated the already weak, but theretofore improving
public health systems of sub-Saharan Africa during much of the 1980's and
90's.  This is the same government that dramatically reduced development
spending in Africa and the rest of the world at the end of the Cold War
because it no longer needed to prop up corrupt post-colonial allies in the
struggle against the Soviet Union.  This is the same government that has
pursued neo-liberal economic policies and unfair trade policies that have
undermined rural economies and prompted much of the migration that fuels
the spread of HIV/AIDS.  And, most significantly, this is the same
government that sat on the sidelines and flat-funded international funding
for AIDS during the 1990's as the pandemic exploded exponentially on an
unprepared continent.

Moral exhortations from a recently converted perpetrator are always a bit
hard to swallow, but the hypocrisy of the U.S. position is not just that it
denies its past but that it is using the discourse of medical ethics to
mask its underlying pursuit of pharmaceutical interests.  There is an
extraordinary match between the talking points pursued by Administration
spokespersons at the WHO and the well-worn talking point of PhRMA and other
industry mouthpieces.  Big Pharma has consistently slandered the quality of
"pirated" generic products to preserve the illusion of the superiority of
their patent-protected and monopoly-priced medicines.  It has tried to
impose higher-than-necessary regulatory standards on drug registration
authorities in developing countries through harmonization schemes and
otherwise.   And, it has relentlessly pursued heightened intellectual
property protections in multilateral, regional, and bilateral trade
agreements ? protections that would limit compulsory license and parallel
importation rights, extend patent terms, deny access to clinical trial
data, and undermine exportation of generic medicines to countries that
can't make them on their own.

Certainly it is appropriate for health officials and experts to question
the WHO's 3-by-5 plan in good faith.  Though the U.S. attacks are
undoubtedly advanced in bad faith, it makes sense to review the merits of
the expressed concerns, always weighing in the background the reality of
8000 deaths a day.

Fixed-dose combinations

There are two central and interrelated benefits that arise from the use of
FDCs in the administration of Highly Active Antiretroviral Therapy (HAART)
in developing countries.  The first is a lower overall pill count that
predictably increases adherence to treatment regimes.  The second is that
FDCs have been shown to increase compliance because patients can take all
their required medicines on a regular and fixed schedule rather than having
to cope with a more complicated schedule of multiple pills on differing
time schedules.  The impact of reduced pill count and of simplified dosing
schedules is to decrease the incidence of resistance of the AIDS virus to
ARV treatment.

The World Health Organization has emphasized the importance of developing
innovative strategies for enhancing adherence to antiretroviral therapy
because it is a life-long therapy.[1]  It is widely accepted, including by
surveys by pharmaceutical manufacturers, that a main obstacle to patient
compliance with HAART is too many pills and complicated dosing schedules.
[2]  Thus, the WHO has recommended that medical providers utilize
strategies to increase adherence to treatment regimes that "include
minimizing pill counts and dosage frequencies by preferentially using
combination pills on a once-daily or twice-daily basis."[3]  According to
the WHO, "[w]hen available, fixed-dose combinations are advantageous with
respect to the simplification of regimens and consequent improved
adherence."[4]

In addition to referencing the benefits of fixed-dose combinations produced
by major pharmaceutical manufacturers,[5]  the WHO acknowledges that
fixed-dose formulations have been produced by generic manufacturers, "which
[formulations] may facilitate simplified regimens, decrease cost and
promote adherence if they can be legally used and their quality and
bioequivalence has been demonstrated."[6]

The theoretical importance of FDCs has been confirmed by recent research on
twice-daily regimens.  "[R]ecent work on simplification of HAART regimens,
reported at the latest Glasgow conference on HIV treatment, could have a
major impact on compliance-related treatment failure in both resource-rich
and resource-poor countries. ? It is well documented that adherence rises
as the complexity of a HAART regimen declines, a point emphasized by a
recent comparison of the fixed-dose combination of zidovudine and and 3TC
(Combivir) with the 2 drugs given separately."[7] Of course, the long-term
goal is to reach a goal of a once-daily regimen that "provides patients
with a regimen that can fit more easily into their established routines,
thereby increasing treatment adherence."[8]

Medical experts have emphasized that patient compliance is dependent on a
reduced pill burden and simplified dosing schedules, but fixed-dose
combinations have other advantages in terms of ensuring that patients take
triple as opposed to mono or dual therapy.  Triple therapy is essential to
counteract HIV's extraordinary mutation rate, which leads to an accelerated
incidence of drug-resistance in mono or dual therapy regimes.[9]  Providing
HAART through three-drug FDCs reduces the possibility that patients will be
treated with a substandard number of drugs, which is still unfortunately
common in African countries.[10]

Administering HAART through fixed-dose combination pills might also reduce,
though not eliminate, the risk that the patient would split therapies with
others.  Although there has been little research on pill splitting in
resource poor settings, especially since there has so little ARV therapy
provided, there is reason to believe that patients are sometimes coerced to
share pills or do so out of concern for others, especially within family
settings.[11] This is one reason why treatment providers have begun to
encourage voluntary counseling and testing with both partners and why
mother-to-child-prevention-plus programs[12] extend ARV therapy to an
entire family group, since HIV infection is likely to be intra-familial.

The clinical benefit of increased adherence resulting from the use of
fixed-dose combinations is the decreased incidence of resistance of the
AIDS virus to individual medicines and to entire classes of medicines.
According to the WHO, adherence to HAART must be at a very high level to
achieve lasting viral suppression because of the rapid replication and
mutation rates of HIV.[13]  The advantage of triple-therapy is that it
attacks HIV in three ways at the same time, meaning that a mutation that is
resistant to one medicine is unlikely to be simultaneously resistant to the
other two.

Why the U.S. Picks on Cipla's Triomune

Cipla of India has twice ruptured the complacency of Big Pharma with
respect to its patent monopolies on AIDS medicines, first on February 7,
2001, when it announced a price heard round the world ? a standard package
of ARVs for as little as $350/year to NGOs and $600/year to governments in
Africa[14] and a second time on August 7, 2001, when it announced the
formulation of a new three-in-one antiretroviral tablet, Triomune,
combining stavudine, lamivudine, and nevirapine.[15]  The public
announcement of these breakthrough emphasized the cost and therapeutic
advantages of the new fixed-dose combination medicine, only slightly more
than a $1 a day ? a fifth or sixth of the cost of the then cheapest
treatment with brand-name drugs that extra pills and more complex dosing
schedules.  Since Cipla's historic announcement, other Indian companies
have begun to produce fixed-dose combination ARVs,[16] as have companies in
Thailand,[17] and China,[18] and prices of these treatments have continued
to decreased over time.[19] This fall, a new benchmark price has been
established by four generic producers, three Indian and one South African ?
less than $140 per year for WHO preferred fixed-dose combination medicines.
[20]  Accordingly, standard quality FDC generics are now available for a
penny on the dollar of what the major pharmaceutical companies charge in
rich markets.

Given the therapeutic importance of FDCs, it is important to understand why
so few proprietary pharmaceutical manufacturers have produced combination
ARVs and, more to the point, why none of them have done so with a
competitor's product.  In this context, it is important to remember that
HIV medicines are individually patented and that patent-holders have a
perverse economic interest in avoiding the creation of FDCs and in delaying
product improvements.[21] Let's take the Cipla example.  Britain's
GlaxoSmithKline holds the patent for lamivudine, Germany's Boehringer
Igelheim the patent on nevirapine and the US's Bristol-Myers Squibb the
patent on stavudine.  Nothing in principle prohibits these three companies
from entering into voluntary cross-licensing agreements to produce a
three-in-one fixed-dose ARV tablet, especially since this combination is
both efficacious and inexpensive; indeed, the WHO recommends it as a
first-line combination for resource poor settings.[22]  However, in
practice, the proprietary manufacturers have not wanted to dilute
individual brand recognition, nor have they wanted to indirectly promote
the products of a competitor.  Although GlaxoSmithKline will combine its
own HIV products, e.g. Combivir (AZT+3TC) and Trizivir (AZT+3TC+ABC),
neither it nor its competitors have yet combined ARVs with other
manufacturers.  As a consequence, in countries where generics are excluded
because of patent status, doctors and patients are left with the unwieldy
task of prescribing and taking multiple tablets, multiple times a day, and
then monitoring compliance with overly complicated treatment regimes.

The logic of single-medicine pills makes sense in the twisted world of
global pharmaceuticals, where maximizing profit, maintaining competitive
advantage, and promoting brand recognition prevail, but it does not make
sense in the actual lives of AIDS patients in developing countries where
simpler regimes are crucially important to survival.  FDC medicines can be
distributed more easily and reliably; they can ease patient compliance; and
they can reduce risks of resale of drugs by desperately poor patients who
might otherwise be tempted to resell part of their treatment regime in the
hope that one out of three medicines might be enough.  One three-in-one
pill twice a day will also be easier for health aids to monitor if directly
observed therapy is instituted on a broad scale.

There are rumors that major drug companies recognize the comparative
therapeutic advantages of Cipla's FDC Triomune (and Ranbaxy's and Aspen's
as well) and that two companies, GlaxoSmithKline and Bristol Myers Squibb
are engaged in discussions about exclusive cross-licensing agreements to
produce fixed-dose combinations of their joint products.   This exclusive
deal would not increase competition, but the combined product would
undoubtedly offer therapeutic advantages.  In addition to this still
unrealized option, drug companies are urging the WHO to endorse blister
packs containing products from several patent holders (with a.m. and p.m.
doses), arguing that this solution offers greater treatment flexibilities.
Again, this kind of packaging does offer some therapeutic advantages, but
it does not reverse the even great therapeutic value of low-cost, generic
FDCs.

WHO Pre-Qualification Project

The U.S. delegation and Big Pharma could not mount a credible all out
assault on the concept of fixed-dose combination medicines and on the idea
of Cipla's Triomune, so instead they are attacking the WHO
Pre-Qualification Project, at least to the extent that it "improperly"
pre-qualified Triomune.  By punishing Cipla and subtly undermining WHO
pre-qualification standards, the U.S./Big-Pharma team continue to hype the
superior quality of proprietary, patented drugs and to freeze its most
loathed generic competitor out of the rapidly expanding global market for
ARVs.

Because poor quality medicines can have serious health consequence, all
treatment advocates and program designers must be concerned that there are
exacting quality standards during both the production and distribution
process.  If medicines do not contain the correct active ingredients in
correct quantities, if medicines contain harmful substances, or if quality
and efficacy deteriorate because of improper handling or expiration,
patients will be exposed to substandard or even dangerous therapies that
can lead to treatment failure, drug resistance, and even death.  The issue
of drug quality is particularly important in AIDS therapy because the
therapeutic range of most ARVs is quite narrow and because on the
life-threatening consequences of non-therapeutic dosing.

The WHO has just released a study documenting the growing problem of
substandard and counterfeit medicines estimating that up to 25% of
medicines consumed in poor countries are deficient and that the
deficiencies are particularly problematic for high-markup products treating
HIV/AIDS, tuberculosis, and malaria.[23]  "Trade in substandard and
counterfeit medicines is most prevalent in countries with weak drug
regulation control and enforcement, scarcity and/or erratic supply of basic
medicines, unregulated markets and unaffordable prices," according to the
WHO press release.  To redress these recurrent problems, the WHO
recommended legislative reform to strengthen enforcement powers in drug
regulatory authorities, strategies to reduce corruption and criminal
activity, and international cooperation.

Because of the importance of product safety and efficacy and because the
documented risks of substandard and counterfeit medicines, pharmaceutical
products procured with multilateral and bilateral resources in pursuit of
the 3-by-5 goal should certainly be authorized by the relevant national
drug regulatory authority (NDRA) in the country in which they will be used.
However, in addition, they should be separately evaluated for safety,
quality, and efficacy, if the relevant NDRA does not have the capacity to
enforce appropriate standards.  In this respect, the WHO Pre-Qualification
Project can play an important role in identifying AIDS medicines which are
bio-equivalent to standard products and which are produced according to
Good Manufacturing Processes.[24] Of course, an alternative route to
quality assurance is to require registration by a stringent NDRA, one that
is a member of the Pharmaceutical Inspection Convention/Scheme and/or the
International Conference of Harmonisation.[25]

The essence of the U.S. attack on Triomune's pre-qualification at the WHO
is that the WHO pre-qualification project cut too many corners and, more
subtly, that registration should instead, if possible, be based on
registration at a strict NDRA, like the FDA.  In particular, the U.S. is
"concerned" that the pre-qualification project has just pre-qualified
Cipla's generic fixed-dose combination ARVs despite the lack of underlying
evidence on bio-availability and despite clinical trials comparing the
efficacy and safety of fixed-dose combinations versus treatment regimes
that using proprietary products.  The U.S. presumably cites the risk that
co-formulation of medicines can affect potency and rates of absorption of
individual components (bio-availability) and that care must be exercised to
combine drugs that are complementary in action and, have similar
half-lives, and present non-cumulative side effects.  Fortunately, this is
a technological problem that can often be solved if detected early in the
production process.[26]

In an ideal world, drug companies would have cross-licensed their medicines
to each other (rather than merely protect their patent kingdoms), conducted
relevant clinical trials, and thereby produced fully satisfactory evidence
on the superiority of fixed-dose combinations, particularly when one takes
into account patient compliance.  There would be Pharmacopoeia monographs
and standards available by which to evaluated generic equivalents.
However, in the imperfect world we live in, the WHO was left to a slightly
less optimal alternative ? it had to establish pharmacokentic
bio-equivalence of generic fixed-dose combinations against evidence derived
from the individual products,[27] a procedure that had previously been
allowed even in the U.S. with respect to GlaxoSmithKline's combo drug
Trizivir.  This kind of pragmatic flexibility, while still pursuing high
standards, is the correct response to an AIDS pandemic where the world
doesn't have an extra five years to conduct double-blind clinical studies
of the most promising, pro-adherence product.

The U.S. makes it sound like the WHO pre-qualification project used a big
rubber stamp in a back office to approve Triomune, but, of course, the
truth is far different.  Where pre-existing evidence of a comparable
product is lacking, the WHO appoints experts who perform a rigorous and
comprehensive evaluation of products to confirm compliance with
international standards.  In this regard, investigators perform dossier
evaluations and conduct site inspections of manufacturing facilities.
Dossiers are evaluated for compliance with WHO recommendations and
guidelines regarding the assessment of multi-source products.[28]
Assessment teams included three specialists on quality issues and two on
bio-availability/bio-equivalence.  In addition, inspections are performed
for individual products at individual manufacturing sites to assess
compliance with Good Manufacturing Practices as recommended by the World
Health Organization.[29] The team of inspectors includes a leader inspector
from countries that are members of the Pharmaceutical Inspection
Co-operation Scheme, a WHO expert from its Quality Assurance and Safety:
Medicines team, and an inspector for the local NDRA.  Only after this
rigorous process did the WHO pre-qualify multiple generic ARVs including
fixed-dose combinations.[30]

Free treatment vs. user fees and cost recovery

One would have thought that the neo-liberal ideology of cost-recovery and
user fees, brought to an art form by the World Bank and the IMF, would have
been sufficiently discredited that no one would seriously propose that poor
people living with HIV/AIDS would have choose drugs over food, shelter, and
schooling.  Evidence that co-payments had reduced use of family planning
and SDI clinics prompted Congress to adopt legislation ordering the
Executive to oppose user fees for health and schooling at the World Bank
and IMF.  The wisdom of that ban was confirmed by a recent study showing
that financial constraints, including though not limited to the
out-of-pocket cost of antiretrovirals, have been reported as the most
significant barrier to antiretroviral adherence in patients living with
HIV/AIDS in Botswana prior to the introduction of free treatment.[31]  Even
with the costs of medicines going down to $140 a year, the costs of
treatment are likely to be overwhelming for the vast majority of patients
in sub-Saharan Africa who earn less than $2 a day.  What portion of their
meager salary should destitute Africans pay to source life-saving
medicines?  What child should they keep home from school, which daily meals
should they skip?

The WHO has undoubtedly selected the correct standard in urging that
antiretroviral therapy be offered free as part of a rich package of public
health services in developing countries.  Where medical aid schemes cover
the costs of treatment and drug purchases, certainly some cost recovery
will occur.  But what you don't want to do, in the middle of an escalating
pandemic, is impose fees that deter treatment for a life-long condition.
Hopefully, some sound minds in Washington will realize the absurdity of
imposing failed user fees and co-payments on poor people in developing
countries.

Community health workers

The last U.S. attack on the WHO 3-by-5 plan involves a critique of
excessive reliance sub-physician health workers and on 40,000-60,000 new
community health workers, workers to be recruited, trained, and deployed as
part of the WHO's 3-by-5 plan.  Presumably, the U.S., blinded by the
culture of increasing medical specialization and the medicalization of all
public health initiatives, thinks that it is better to wait for a decade of
intensive medical training for physicians before you start to dose the AIDS
pandemic.  As much as it is desirable to have more HIV/AIDS specialists in
developing countries, wishing won't make it happen ? it won't necessarily
prompt long-term commitments by First World health specialists (though many
are heroically offering their services) and it certainly won't magically
improve primary, secondary, tertiary, and medical education in Africa to
train 50 times the number of doctors that there are now.

Instead of waiting on strategies to retain existing physicians and nurses
who are being recruited to Northern health sectors in record numbers and to
recruit a greatly expanded corps of highly trained AIDS physicians, the WHO
has adopted a two-part strategy for using non-physician health care
workers.  Key decisions concerning when to start therapy, whether to
substitute drugs because of adverse side effect, whether to switch regimens
because of treatment failure and drug resistance, and when to stop therapy
will be made nurse practitioners or physician's assistants working under
the supervision of doctors; harder cases will be referred to physicians in
district hospitals.  Reliance on non-physician resources even for these
important decisions will be aids by WHO's adoption of standardized and
simplified treatment regimes and by wholesale training of existing health
sector workers.

As the frontline eyes and ears of the program and as culturally competent
community health practitioners the WHO advocates "urgently training tens of
thousands of community health workers to support the delivery and
monitoring of HIV/AIDS treatment.  An intensive training programme would
enable these health workers to evaluate and monitor patients, and make sure
they receive and are taking their medicines."[32] The value of community
health workers is that they can aid community mobilization, initiate
treatment preparedness, accelerate prevention efforts through VCT and
otherwise, and help ensure adherence to medical regimens.

Conclusion

Although it is important to respond to each of the U.S. attacks against the
WHO 3-by-5 plan on the merits, it is equally important to understand the
politics behind this attack.  In essence, at the behest of it
pharmaceutical masters, the U.S. is arguing that brand-name, patent
medicines preferentially be used to fight global AIDS.  At the alter of
neo-liberal orthodoxy, it insists that user-fees should be imposed, that
poor consumers will appreciate what they are forced to pay for, even though
study after study has shown that user fees, on the ground, impede rather
than enhance access to treatment.  And, at the behest of conservative
elements of the medical establishment, it argues that scale-up should be
scaled back ? that it is better to go slow than to practice less than ideal
care, even though ideal care is decades away.  The WHO 3-by-5 plan will
certainly need to be fine-tuned and improved over time.  Excessive
compromises on quality should not be made at the alter of expediency and
operational deficiencies should be quickly corrected.  But the WHO has
launched an initiative where few have dared tread below ? it is replacing
rhetoric and hallow, platitudinous expressions of concern with a pragmatic
and bold plan for action.  Rather than stand by and watch millions die
needlessly every year, the WHO has overcome its own historical lethargy and
is finally beginning to meet its mandate as a global public health
institution.  We can not let the U.S. succeed in undermining this new
commitment with its nit-picking and bad faith concerns.

____________________________________
[1] World Health Organization, Scaling Up Antiretroviral Therapy in
Resource-Limited Settings:  Guidelines for a Public Health Approach, 16
(June 2002) [WHO Scaling Up]; World Health Organization, Adherence for
Long-Term Therapies:  Evidence for Action, 95-106 (2003) [WHO Adherence for
Long-Term Therapies] (noting that the large number of medications,
complicated dosing requirement, and sub-optimal tolerability make adherence
difficult).
[2] See, e.g., HIV-Positive Patients Find Medications Hard to Take,
GlaxoSmithKline Survey Finds, Kaiser Daily HIV/AIDS Report (March 19, 2001)
http://www.kaisernetwork.org/daily_reports/print_report.cfm?DR_ID=3495&dr_cat=1
; Protease Inhibitors:  Drug Companies Seek Treatments to Reduce Pill
Intake, Kaiser Daily Reports (February 3, 2000) (reporting a small study by
Bristol-Myers Squibb and multiple quotes from medical experts about the
desirability of reducing the pill burden)
http://www.kaisernetwork.org/aids/2000/02/kh000203.3.htm.
[3] WHO Scaling Up at 16.  The WHO notes that, "[a] number of fixed-dose
combination products containing two or three ARV drugs, current on the
market, can be used twice a day."  Id.  "There is evidence that simplified
regimens that require fewer pills and lower dose frequencies improve
adherence."  WHO Adherence for Long-Term Therapies at 97.  See, Panel on
Clinical Practices for Treatment of HIV, Guidelines for the use of
antiretroviral agents in HIV-infected adults and adolescents (NIH 2002)
(recommending, if possible, to reduce dose frequency and number of pills).
[4] WHO Scaling Up at 31.
[5] WHO Scaling Up at 31, including GlaxoSmithKline's Combivir and Trizivir
(now a disfavored combination).
[6] WHO Scaling Up at 31 (referring presumably to fixed-dose combinations
like Trimune from Cipla Ltd.).
[7] Jeffrey Laurence, M.D., Simplifying HIV Therapeutics, and the Global
Treatment of AIDS, AIDS Read 13(1): 5-6 (2003)(citing J. Jordan, T. Delea,
B. Sherrill, et al., Impact of fixed-dose combination
zidovudine/lamivudines on adherence to antiretroviral therapy:  a
retrospective claims-based cohort study, in:  Program and abstracts of the
6th International Congress on Drug therapy in HIV Infection; November
17-21, 2002; Glasgow, U.K., Abstract P97) (accessed July 1, 2003
www.medscape.com/viewarticle/449706_print).
[8] Richard B. Pollard, M.D., Management Trends:  Can HIV Infection Be
Treated Successfully With a Once-Daily Regimen?, AIDS read 12(11): 489-500
(2002) (accessed July 1, 2003 www.medscape.com/viewarticle/444894_print).
"HAART typically involves a complex intermingling of medications, dosing
schedules, and side effects that often place a heavy burden on patients.
Once-daily doxsing is the least confusing schedule and is the one preferred
by patients, as is a regimen with fewer pills that can be taken without
dietary restrictions.  Although drug research has not quite met all of
these conditions, achievement of this objective is coming closer. ? The
potential advantages of once-daily dosing include better under standing of
the regimen by the patient and, hence, increased adherence."  Id.
[9] Scaling Up at 24.
[10] Scaling Up at 29 (noting that "it is recognized that many HIV-infected
individuals in the developing world are being treated with dual [nucleoside
analogue reverse transcriptase inhibitor] combinations because potent
three-drug and four-drug combinations are not affordable").
[11] Julian Meldrum, Success and failure in HIV treatment:  contrasting
lessons from South Africa, AIDSMAP (August 25, 2003)
http://www.aidsmap.com/news/newsdisplay2.asp?newsId=2264.
[12] "The MTCT-Plus Initiative is a new HIV/AIDS treatment program
coordinated by the Mailman School of Public Health at Columbia University
in response t the UN Secretary General's Call to Action.  The MTCT-Plus
Initiative will support the provision of HIV-specific care, including
access to a number of standardized antiretroviral option when clinically
indicated, to HIV-infected women and children identified in pMTCT programs,
and to their HIV-infected family members as appropriate.  The MTCT-Plus
Initiative aims to decrease morbility and mortality, further reduce
mother-to-child transmission of HIV, lessen orphanage, promote VCT, and

strengthen local health care capacity.  It is hoped that this Initiative
can provide an important first step towards greater access to HIV care in
resource-limited settings."  http://www.mtctplus.org/index.html.
[13] WHO Adherence for Long-Term Therapies at 96.
[14] Donald G. McNeil Jr., Indian Company Offers to Supply AIDS Drugs at
Low Cost in Africa, New York Times, Feb. 7,
2001<http://www.nytimes.com/2001/02/07/health/07AIDS.html>.
[15] Cipla Releases Three-in-One Drug Combination of Stavudine, Lamivudine
and Nevirapine, Kaisernetwork.org:  daily reports (August 7, 2001).
[16] See MSF Untangling the web at 13.
[17] Thai Government to Sell AIDS Drug Combination Pill for Less Than $1
Per Day, Kaisernetwork.org:  daily reports (March 25, 2002).
[18] Chinese Pharmaceutical Firm Begins Distribution of Generic
Antiretroviral Drugs, Kaisernetwork.org:  daily reports (January 30, 2003).
[19] MSF Untangling the web.
[20] Mark Schoofs, Clinton Program Would Help Poor Nations Get AIDS Drugs,
Wall Street Journal (October 23, 2003).
[21] In the search for simpler treatment regimes, it is also important to
emphasize the goal of developing once-a-day, time-released pills and
medicine formulations that reduce the side effects of ARVs, such as nausea.
Once again, the perverse financial interests of patent-holders often stand
in the way of early introduction of truly effective treatment protocols.
Why?  Because patent-holders like to hold reformulations of their already
patented medicines in reserve so that they can extend their patents through
a process called evergreening.  For example, Bristol Myers Squibbs waited
until 2000 to file a patent application on a once a day enteric-coated ddI,
the third generation of this drug.  ddI is the second oldest AIDS drug and
one developed at public expense to the degree that the U.S. Department of
Health and Human Services holds the first patent.  Why did Bristol-Myers
wait over ten years to announce an enteric-coating?  Did it lack such
"technology" in 1990?  Of course not, it delayed an improved formulation so
that it could "evergreen" and extend its pricing monopoly with a "new"
patent on this minor but important reformulation.
[22] WHO Scaling Up at 30, Table 3.
[23] WHO, Substandard and counterfeit medicines, Fact Sheet no. 275 (Nov.
2003).
[24] WHO pre-qualification should not replace the requirement of in-country
registration, but it should help fill a capacity gap in low-income
countries that have difficulty independently assessing quality of medicines
and manufacturers' adherence to Good Manufacturing Practice.  See
<http://www.who.int/medicines/organization/gsm/activities/pilotproc/pilotprocmain.shtml>.

[25]  The ICH brings together the regulatory authorities from the United
States, the European Union and Japan.  See <http://www.ich.org>.   The
IPC/S is comprised of Australia, Austria, Belgium, Canada, Czech Republic,
Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland,
Italy, Liechtenstein, Malaysia, Netherlands, Norway, Portugal, Romania,
Singapore, Slovak Republic, Spain, Sweden, Switzerland, United Kingdom. See
<http://www.picscheme.org/overview/picsauth.htm>.
[26]  Email from Richard Laing to Pharm-policy list, Aug 13, 2001,
http://lists.essential.org/pipermail/pharm-policy/2001-August/001356.html.
[27]  "Triomune, produced pharmacokinetics similar to those produced by the
3  drugs  when  they  were  given  individually."   Jeffrey Laurence, M.D.,
Simplifying  HIV  Therapeutics, and the Global Treatment of AIDS, AIDS Read
13(1):  5-6  (2003)(citing  J.  A. Gogtay, V. Manek, V. G. Nayak, et al., A
pharmacokenetic  evaluation  of lamivudine, stavudine, and nevirapine given
as  a fixed dose combination pill versus the same drugs given separately in
health   human   volunteers,   in:    Program  and  abstracts  of  the  6th
International  Congress  on  Drug therapy in HIV Infection; November 17-21,
2002; Glasgow, U.K., Abstract PL8.4).
[28]  WHO,  Marketing Authorization of Pharmaceutical Products with Special
Reference   to  Multisource  (Generic)  Products:   A  Manual  for  a  Drug
Regulatory Authority, (WHO/DMP/RGS/98.5) and Bio-equivalence Data (Annex 9,
WHO  Technical  Report  Series  No. 863).  In some instances the evaluators
used ICH guidelines to complement WHO guidelines.
[29] WHO, Quality Assurance of Pharmaceuticals.  A Compendium of Guidelines
and   Related   Materials,  Volume  2,  Good  Manufacturing  Practices  and
Inspections.
[30] See WHO Procurement, Quality and Sourcing Project:  Access to HIV/AIDS
Drugs  and  Diagnostics of Acceptable Quality:  Manufacturers and Suppliers
whose  HIV-Related  Medicines  have  been Found Acceptable in Principle for
Procurement by UN Agencies (Eleventh edition, December 1, 2003).
[31]  Weiser  S  et  al.  Barriers to antiretroviral adherence for patients
living  with  HIV  infection  and  AIDS  in Botswana. J Acquir Immune Defic
Syndr, 34:281?288, 2003.
[32] WHO, World Health Organization and UNAIDS Unveil Plan to get 3 million
AIDS     Patients     on    Treatment    by    2005    (Dec.    1,    2003)
<http://www.who.int/mediacentre/releases/2003/pr89/en/print.html>.