Consumer Project on Technology
Essential Action
Oxfam
Treatment Access Campaign
Health Gap
October 16, 2001
Version 1
Introduction
The following is a comment on two reports being circulated by the pharmaceutical industry regarding the importance of patents in Africa as a barrier to treatment for AIDS. These include an October 17, 2001 paper in JAMA, by Amir Attaran and Lee Gillespie-White (AGW), titled "Do Patents for Antiretroviral Drugs Constrain Access to AIDS Treatment in Africa,"[1] and "Facts and Figures on Patenting and Access in Africa," a report of an August 2001 PhRMA survey on patents in Africa, presented by Tom Bombelles on September 30, 2001, at the American Society of Law, Medicine & Ethics (ASLME) conference on Law and Human Rights.
The assertion in both documents is that patents are not an important barrier for access to antiretroviral drugs in African countries, while poverty and limited public and donor spending on health care are important barriers. These are long time industry talking points.
Poverty is of course a terrible problem in Africa, and without support from donors, it will not be possible to extend treatment to everyone in Africa who so desperately needs it. This however does not mean that there are not actions that can be taken immediately, without donor aid, that would benefit many HIV+ patients. And regardless of the success or failure of donor efforts to address the lack of funding for health care, there is still an urgent need to address the barriers to competition presented by patents on pharmaceutical drugs, particularly since donor aid is expected to fall far short of universal coverage. This comment therefore focuses on the question of patents, as a barrier to access for antiretroviral drugs.
Both AGW and PhRMA present data on patents in various African countries. The AGW paper finds 172 antiretroviral drugs or combinations of drugs protected by patent in 53 countries, and the August 2001 PhRMA survey finds 150 drugs or combinations of drugs under patent in 52 countries. The question is, how important are the patents on thse 150 to 172 drugs or combinations of drugs. According AGW and PhRMA, they are not important. According to NGOs working on the access to medicines campaign, they are important barriers.
Which cocktails are blocked by patents?
A three drug HAART regime consists of two NRTI products, plus a third drug consisting of abacavir, a NNRTI or a protease inhibitor. The best choices based upon toxicity and efficacy for the 2 NRTI drugs are d4T, 3TC, AZT or ddI. Among these d4T and AZT cannot be taken together. D4T and 3TC require the smallest amount of active ingredients (80 and 300 milligrams per day), and are the least expensive drugs to manufacture. Among the NNRTI products nevirapine requires the smallest amount of active ingredient, and is the least expensive product of its class to manufacture. The least expensive generic three drug regime is d4T/3TC/nevirapine.
The most significant omission from both the AGW and PhRMA survey are for patents on Trizivir, an important three-drugs- in-one-pill twice a day product sold by GSK involving AZT+3TC+Abacavir that is reportedly widely patented in Africa. Nor do AGW or PhRMA mention generic three-drugs-in-one-pill versions of d4T+3TC+Nevirapine or AZT+3TC+Nevirapine, which combine products sold by different US or European companies, and which are now only available from Indian generic suppliers.
Only briefly noted in the AGW paper is the issue of patents on improvements on existing drugs. Not noted is that while ritonavir is not patented anywhere in Africa, Lopinavir(80%)+Ritonavir(20%) together, a regime that is easier to take, is patented in South Africa. This of course is what GSK has often done, filing patents on new ways of combining older drugs into easier to use presentations such as Combivir or Trizivir.
In South Africa every three drug ARV cocktail is blocked by patents. In the PhRMA survey 15 of 16 ARV products are protected by patent in South Africa. In the AGW paper 13 of 15 products are protected by patent in South Africa. The South Africa market is important for several reasons. First, there are 4 to 5 million HIV+ persons in South Africa. Second, the South Africa economy has more than 40 percent of the GDP for sub-Saharan Africa, a per capita income of more than $3 thousand and a relatively good health care infrastructure, making ARV treatment feasible, if drug prices are low enough. Third, entry into the South Africa market is necessary for generic suppliers to reach the economies of scale (volume) needed for the most efficient production, particularly for those products with post 1996 patents that are patented in Brazil, such as efavirenz or nelfinavir, and currently lack a significant generic market outside of Africa.
Outside of South Africa there are several combinations that are frequently blocked, and some that are never blocked. AGW argue that countries seeking to provide ARV treatment could simply use the ones that are off patent, or negotiate lower prices for the cocktails that are blocked by a single patent. AGW concedes that cocktails based upon the NRTI combinations of 3TC, AZT or 3TC+AZT are frequently blocked by patents, as are the third drugs of nevirapine, abacavir, amprenavir and nelfinavir. But they suggest countries can substitute cocktails based upon a d4T+ddI NRTI combination, and third drugs such as efavirenz, indinavir or ritonavir which are off patent outside of South Africa. While technically true, this would accept severe limits on the available products, including limits on the least expensive combinations, and also present difficult medical problems.
For example, according to Asia Russell from the Health Gap, ddI's food restrictions make it problematic to take with indinavir and some other protease inhibitors, such as indinavir or ritonavir, and combinations involving ddI and nelfinavir are difficult, as both give diarrhea, and one should be taken on an empty stomach while the other absorbs better with food. Russell makes the point that ddI's often cumbersome requirements and dosing schedule inherently limit the options of a clinician for some patients. On the other hand for other patients in some combinations ddI may be a drug of choice. The important point is to ensure that clinicans have access to as many use drugs as possible, to be used in as many combinations, including twice or single day dosing and single pill formats.
Of particular interest to treatment advocates for first line ARV treatment are three drug cocktails that could be cheaply manufactured in a three-drug-in-one-pill combination with twice daily or less dosing. The most important patents for these products are those that involve d4T, 3TC, AZT, abacavir, nevirapine and efavirenz. These cocktails are highly rated in the UK Treatment guidelines in terms of compliance and toxicity[2], and with generic entry into the South Africa market, could be manufactured for $200 to $500 per year or less in large quantities.
Table 1
Number of countries where
d4T, 3TC, AZT, ATZ+3TC, nevirapine, abacavir or
AZT+3TC+abacavir are protected by patent
Product AGW PhRMA Survey
NRTI
D4T 1 1
3TC 33 27
AZT 17 10
AZT+3TC 37 27
NRTI as third drug
abacavir 15 12
abacavir+AZT+3TC omitted from surveys
NNRTI as third drug
nevirapine 25 24
efavirenz 1 2
Both the AGW and PhRMA surveys lump together large and small countries, and do not examine patent coverage by population, HIV+ patients or measures of income such as GDP. If one does look at these factors, the concentration of patents is clearly focused where the patients and income are. For example, in the PhRMA Survey, the 23 countries in Sub-Saharan Africa that have 4 or more ARV products on patent have 53 percent of the HIV+ patients and 68 percent of the Region GDP. The 20 Sub- Saharan countries that have patents on 6 or more ARV products have 46 percent of the patients and 56 percent of the regions GDP[3].
All of the least expensive generic cocktails -- those that can be currently manufactured for less than $500 per year -- are blocked by patents on 3TC, AZT, AZT+3TC or Nevirapine.[4]
AGW's suggestion that countries can make do with the US and European offers of concessionary prices does not deal realistically with the factors that lead to those price decreases (threats of compulsory licenses, extraordinary and unsustainable NGO and UN pressures, the existence of a competitive market for ARVs created by Brazil), nor does it recognize the substantial price differences that still exist. Merck is selling efavirenz for $500 per year, a *single* NNRTI, which is about double to price quoted for the cheapest *three* drug NNRTI combination by generic producers. The least expensive *two* drug NRTI regime by a branded company, BMS, is $1 per day for ddI and d4T, and this must be used with a more expensive third drug. The BMS 2 drug ddI/d4T combination is more expensive than the price of a *three* drug d4T/3TC/Nevirapine combination by the generic producers, in part because ddI is a more expensive product to manufacture than 3TC, a product that is widely patented in Africa. For the African market, every dollar that can be cut off the price of a cocktail is important. Given the extent of AIDS and poverty in Africa, we cannot afford to pay 50, 100, 300 or 500 percent more than the competitive price for drugs.
Patients also need as many choices as possible, and high prices on any products can create unneeded burdens on a system. In Brazil a single drug (nelfinavir) on patent was costing the government 28 percent of its entire ARV drug budget, until the government used the threat of a compulsory license to drive the price down.
It bears repeating that today's lower prices for ARV drugs in Africa are due to creditable threats of generic entry that have been made possible by the existence of a competitive market for ARV drugs. This competitive market existed because Brazil did not adopt patents on medicines until 1996, and India does not yet issue product patents for pharmaceuticals. This will change. WTO and African Growth and Opportunity Act (AOGA) rules require nearly all African countries to adopt 20 year patents on medicines, and this will affect both new products and improvements of older products. There is no benefit to understating the significance of changes in trade rules. One must also note that both the AGW and PhRMA surveys were timed to appear a few weeks before the WTO Doha meeting, where TRIPS rules will be debated.
Finally, AGW and PhRMA both make the observation that the lower prices in HIV drugs have not by themselves led to substantial treatment opportunities. This is an understatement of the expected impact of the changes in prices, as it will take time to obtain financing for treatment programs, and to overcome registration and patent barriers in many countries. That said, we agree that donor aid is extremely important, and continue our work to advocate for such aid. But it is entirely irrational, and in our opinion, deeply cynical, to pit donor aid against efforts over overcome patent barriers. Everything possible needs to be done. Every barrier for cheaper medicine needs to be removed.
[1] The AGW Jama paper is an update of an earlier survey by Lee Gillespie-White that found fewer ARV patents, "Patent Protection And Access To Hiv/Aids Pharmaceuticals In Sub- Saharan Africa, A Report Prepared For The World Intellectual Property Organization (Wipo)," December 2000. http://www.wipo.int/about-ip/en/studies/pdf/iipi_hiv.pdf.
[2] Three drug cocktails based upon Nevirapine, Abacavir and efavirenz are the highest ratings for adherence and long term toxicity in the UK ARV guidelines.
Table 2-1
Agents to be used in combination with dual NRTI background.
British HIV Association (BHIVA) guidelines for the treatment
of HIV-infected adults with antiretroviral therapy(Accepted:
27 July 2001)
http://www.aidsmap.com/about/bhiva/guidelines.pdf
Potency Adherence Long term
toxicity
Abacavir ++ +++ +
Efavirenz +++ +++ +
Nelfinavir ++ ++ ++
Saquinavir SGC ++ + ++
Indinavir ++ + +++
Lopinavir/ritonavir +++ ++ ++
Ritonavir/indinavir ++ ++ +++
Nevirapine ++ +++ +
Ritonavir/saquinavir ++ ++ ++
NRTI = nucleoside reverse transcriptase inhibitor; SGC =
soft gel capsule.
+ low
++ medium
+++ high
[3]
Table 3-1
Where are the patented AV products?
45 Sub-Saharan Countries*
(Cumulative percentages)
Number of
Patented HIV+
Products Countries Pop Patients GDP Income
15 1 7% 17% 41% 64%
8+ 2 9% 23% 43% 68%
7+ 6 19% 39% 50% 74%
6+ 11 25% 46% 56% 82%
5+ 12 25% 46% 57% 82%
4+ 23 39% 53% 68% 85%
3+ 24 42% 57% 71% 88%
2+ 28 71% 72% 87% 93%
1+ 29 71% 72% 87% 93%
0+ 45 100% 100% 100% 100%
* Based upon August 2001 PhRMA survey, excluding Somalia.
[4] Manufacturing costs are related to the amount of
required active ingredient, and also are influenced by
economies of scale and experience. Drugs with significant
generic markets, including those off patent in Brazil before
the 1996 changes in the Brazil patent law, have competitive
suppliers, and relatively lower prices.
Table 4-1
Typical doses for HAART regimes
nucleoside reverse transcriptase inhibitors (NRTI)
AZT 300 x 2 = 600 mg
d4T 40 x 2 = 80 mg
ddI 200 x 2 = 400 mg
3TC 150 x 2 = 300 mg
abacavir 300 x 2 = 600 mg
non-nucleoside reverse transcriptase inhibitors (NNRTI)
delavirdine 400 x 3 = 1,200 mg
efavirenz 600 x 1 = 600 mg
Nevirapine 200 x 2 = 400 mg
Protease Inhibitors
saquinavir (200 x 6) x 3 times a day = 3,600 mg
norvir 600 mg twice a day = 1,200 mg
indinavir 800 mg three times per day = 2,400 mg
nelfinavir 750 mg three times per day = 2,250 mg
lopinavir 133 mg of ABT 378 and 33 mg of Norvir
in 3 pills twice a day = 996 mg
Table 4-2
Where are Patents on Combivir, 3TC,
AZT, nevirapine and abacavir
Country combivir 3TC AZT nevirapine abacavir total
----------------------------------------------------------
Benin x x x 3
Botswana x x x x x 5
Burkina Faso x x x 3
Cameroon x x x 3
CAR x x x 3
Chad x x x 3
Congo x x x 3
Equatorial Guinea x x 2
Gabon x x x 3
Gambia x x x x x 5
Ghana x x x x 4
Guinea x x x 3
Ivory Coast x x x 3
Kenya x x x x x 5
Lesotho x x x x 4
Madagascar x 1
Malawi x x x x 4
Mali x x x 3
Mauritania x x x 3
Niger x 1
Nigeria x 1
Senegal x x x 3
South Africa x x x x x 5
Swaziland x x x x 4
Togo x x x 3
Uganda x x x x x 5
Zambia x x x x x 5
Zimbabwe x x x x x 5
Northern Africa
Egypt x x 2
Sudan x x x x x 5
Table 4-3
Patents, Population, Patients and Incomes
Patents Country Population HIV+ GDP/Pop
15 South Africa 39,796 4,200,000 3170
8 Zimbabwe 11,509 1,500,000 530
7 Gambia 1,266 13,000 330
7 Kenya 29,507 2,100,000 360
7 Malawi 10,674 800,000 240
7 Uganda 21,209 820,000 320
6 Botswana 1,592 290,000 3240
6 Ghana 19,699 340,000 390
6 Lesotho 2,108 240,000 550
6 Swaziland 981 130,000 1360
6 Zambia 8,974 870,000 330
5 Gabon 1,196 23,000 3300
4 Benin 5,945 70,000 380
4 Burkina Faso 11,633 350,000 240
4 Cameroon 14,704 540,000 600
4 CAR 3,550 240,000 290
4 Chad 7,462 92,000 210
4 Congo 2,867 86,000 550
4 Guinea 7,375 55,000 510
4 Mali 10,900 100,000 240
4 Mauritania 2,602 6,600 390
4 Senegal 9,251 79,000 510
4 Togo 4,515 130,000 310
3 Ivory Coast 14,534 760,000 710
2 DRC (Zaire) 50,407 1,100,000 330
2 Equatorial Guin 442 1,100 1170
2 Niger 10,414 64,000 190
2 Nigeria 108,995 2,700,000 260
1 Guinea Bissau 1,188 14,000 160
0 Angola 12,497 160,000 270
0 Burundi 6,587 360,000 120
0 Comoro Islands 327 400 350
0 Dijbouti 600 37,000 790
0 Eritrea 3,717 49,000 200
0 Ethiopia 61,123 3,000,000 100
0 Madagascar 15,502 11,000 250
0 Mauritius 1,149 500 3550
0 Mozambique 19,222 1,200,000 220
0 Namibia 1,689 160,000 1890
0 Rwanda 7,238 400,000 250
0 Sao Tome 165 - 270
0 Seychelles 79 - 6540
0 Sierra Leon 4,721 68,000 130
0 Tanzania 36,232 1,300,000 260
0 Cape Verde 405 - 1330
Northern Africa and Somalia (not included)
0 Algeria 30,000 11,000 1550
0 Libya 5,400 1,400 no data
0 Morocco 28,200 5,000 1190
0 Somalia 9,718 No data no data
7 Sudan 36,080 140,000 330
0 Tunisia 9,500 2,200 2090
2 Egypt 62,400 8,100 1390