Healthy Skepticism Library item: 1545

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Publication type: news

Baker B.
U.S.'s Misguided and Bad-Faith Attack on the WHO's 3-by-5 Plan
IP-Health 2003 Dec 18

Full text:

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 programs¹² 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 Africa¹⁴ 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.

[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

. 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 .

[26] Email from Richard Laing to Pharm-policy list, Aug 13, 2001,

http://lists.essential.org/pipermail/pharm-policy/2001-August/00135

6.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.

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