Antiretrovirals

HIV infection is characterised by intense and persistent viral replication that leads to a gradual depletion of white blood cells. These cells (of which T cells are an important part, as they are responsible for antibody production) normally orchestrate the body's immune response, signalling other cells in the system to perform their special function. HIV's preferred target are cells that have a docking molecule called cluster designation 4 (CD4) on them (they are also called helper T cells).

The primary goal of antiretroviral therapy is to keep viral replication as low as possible and maintain it that way for as long as possible. The lower the 'viral load' the lower the progress of infection.

There are three classes of antiretroviral drugs (based on information from UNAIDS). Their function is to target two key enzymes that HIV requires to replicate: protease and reverse transcriptase.

Nucleoside Reverse Transcriptase Inhibitors (NRTI): these drugs include Zidovudine (also known as AZT), Stavudine, Lamivudine, Didanosine and Zalcitabine (all manufactured and available in Guyana).

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI): these drugs perform the same function as NRTIs, but differ slightly in chemical composition. They are: Nevirapine, Efavirenz (manufactured and available in Guyana) and Delavirdine.

Protease Inhibitors (PI): these drugs include Indinavir, Nelfinavir (manufactured and available in Guyana) and Ritonavir, Saquinavir and Amprenavir.

Currently, New GPC is planning to expand the range of nine drugs to twelve, according to reports from Dr Leslie Ramsammy, Minister of Health. Though each AIDS patient would only require three drugs (hence, the triple drug therapy) at one time, it is necessary to have a large stable of different drugs, as treatment has to be varied.

Treatment usually begins with a combination of two NRTIs and one NNRTI, moving up to two NRTIs and one PI. Key monitoring devices in gauging the success of antiretroviral therapy are the CD4 and Viral Load tests, which test the degree of immunodeficiency and amount of virus present. What is necessary is testing at least two times per year (as per WHO guidelines), in order to be able to change the antiretroviral drug combination, as soon as it appears that HIV is developing resistance to the therapy.

However, the cost of the CD4 and Viral Load tests exceed US$150 together, and furthermore, cannot be performed anywhere in Guyana at the moment. So far, according to Dr Ali, Acting Director of the Genito-Urinary Medicine (GUM) Clinic in Georgetown, no tests have been ordered for the patients under treatment. Ramsammy is investigating the possibilities of transferring technology from Brazil, where indigenous technology allows the tests to be done at a cost of approximately US$ 25. Ali stresses that it is important that testing begin as soon as possible.

Why go local?

So far, the entire financial burden of antiretroviral drug treatment is being borne by the Government of Guyana, at a cost of about US$400 per person, per year. Since the drugs were introduced in April, approximately 80 AIDS patients have been administered the treatment.

Dr Ramroop, Executive Chairman, New GPC is keen to stress that the production of antiretroviral drugs was taken up entirely as a "public service initiative," and the price at which the drugs are being sold to the government, supports his point. His company has invested in an upgradation of facilities, as well as incurred expense on research and consultation. While he plans to break even on his costs, he is not actively sourcing export markets, or planning production for other countries. However, if the Ministry of Health were to request the New GPC to produce - say - for the CARICOM market, he would be willing to oblige them.

The options open to the Guyanese government, at the time of deciding an agenda of antiretroviral therapy, were:

- To import drugs from a country like India, which has a private sector industry manufacturing generics (companies like Ranbaxy and Cipla) and has an established tradition of supplying to South Africa and Brazil, among others;

- To import drugs and/or technological skills from neighbouring Brazil, which has a joint public-private partnership for antiretroviral drug production;

- To join a CARICOM lobbying initiative to pressure Western pharmaceutical companies to reduce prices;

- To indigenously manufacture generics.

Ramsammy states that there were two problems with importing drugs from a country like India. One, that while Cipla advertised a price of US$350 for MSF, it later extended a US$ 600 offer to governments of other countries. A "humanitarian" price around the MSF offer was yet being considered, as to when, and whom, it could be offered to. Two, that when the offer was made in 2001, the Government of Guyana was unsure about its commitment to provide these drugs free of cost to the public. Cipla's offer was only for non-profit, public distribution.

Ramsammy has negotiated with Cipla before, and while the rationale he offers holds, it would seem that there might be some cost benefits worth pursuing in the current framework, where the government is capable of, and committed to publicly funding antiretroviral treatment. Ranbaxy, another Indian pharmaceutical company, was offering its triple therapy drugs at much higher prices, around US$700.

Brazil, he states, was an option that was actively explored. While Brazil's AIDS programme has been widely touted as a model for developing countries, for having halved its HIV+ population in the last decade (and offers plenty for Guyana to learn from, in terms of strategy), he says that the price of drugs there, is still a great deal higher than US$400, due to its initiative being a public-private partnership. Ranbaxy, for one, has a manufacturing facility in Brazil, having been contracted to produce Lamivudine for the government AIDS programme.

Further, Ramsammy states, the Brazilian government (which was earlier under some fire for producing generics) was disallowed from exporting the drugs. While no specific statute preventing Brazil from doing this could be found, it is true that Brazil's indigenous manufacture of antiretroviral drugs has created a flutter at the WTO.

The infamous United States Trade Representative's annual Section 301 report, reiterated its concern over Article 68 of Brazil's Industrial Property Law, a pending measure that imposes local production of a patented invention as a condition for enjoying exclusive patent rights over it. The report called the provision "a protectionist measure intended to create jobs for Brazilian nationals."

Brazil was later able to successfully negotiate itself out of the WTO/TRIPS agreement framework, with a continued pledge to discuss the IP issue through diplomatic channels. AIDS activists saw this, along with South Africa's legislation (which allows international patent rights to be circumvented in the case of public health crises), as a move forward in the developing world's fight against the pharmaceutical regime. However, in the absence of actually importing drugs, Ramsammy states that he is actively exploring the possibility of transferring the technology for cheaper CD4 and Viral Load tests, an issue which is of now of pressing importance.

Within the Caribbean, Ramsammy states that the regional lobbying initiative is recent. Thus far, each country has negotiated its own (discounted) prices on antiretroviral therapy. Thus, prices may range from US$3000 in the Bahamas, to US$2000 in Jamaica and Trinidad and Tobago. There has never been any significant price advantage in allying with our Caribbean neighbours, he states.

"I figured Guyana would never be given the drugs at a cheaper price than Africa," says Ramsammy, "and that price was already too high to begin with." Within these parameters, the decision to go it alone was reached.

The issues at hand

One issue that immediately comes up in the wake of developing countries manufacturing generic drugs locally, is the Agreement on TRIPS (Trade Related Intellectual Property Rights). On December 1, 2001, after a round of WTO meetings in Doha, Qatar, developing countries won a major victory in the fight to produce generic versions of drugs patented in the USA and Western Europe.

As a Z magazine (www.znet.org) essay puts it - "The clause is simple enough: it states that the set of WTO rules covering patents on drugs, the Agreement on Trade-Related Intellectual Property Rights (TRIPS), 'can and should be interpreted and implemented in a manner supportive of WTO Members' right to protect public health and, in particular, to promote access to medicines for all.'

But this little paragraph was the site of a long, bitter battle between the United States, acting for the big pharmaceutical companies, and Brazil, India and Africa, acting for the majority of the 36 million people with HIV/AIDS who are too poor to afford expensive, patented anti-HIV medicines."

Thus, countries that now produce generic drugs can still 'conform' to the norms of the WTO, and can proceed (unlike earlier) without the daunting fear of attracting trade sanctions from the US. Yet, in countries such as South Africa, Kenya and Zimbabwe, according to Africa Review journal, prices for the triple therapy antiretroviral cocktail have only dropped to about US$600-800, still significantly below Cipla's offer price of US$350, or even Guyana's.

Quality is a concern that frequently comes up from local groups in civil society, especially those who work directly with people who are HIV+. The point being made by this section of the concerned public is - how are antiretroviral drugs being tested and where are they being certified?

Ramroop states emphatically that the New GPC is a company with a long history of generic drug production. Other than the company history, which has seen drugs of a complex nature manufactured in Guyana and sold within the Caribbean, Ramroop says that there are adequate quality control (QC) processes and checks in place. Further, as a safety measure, he has sent batches of the drugs to be tested by a unit of the French laboratory, SGS, in India, where the chemicals are sourced.

Ramroop quotes several factors in the production of these drugs that are vital to a larger public's understanding and trust of antiretroviral medicine. Firstly, the 'raw material' - in this case, chemicals - are imported from a company in Hyderabad, India, called Matrix Laboratories. Matrix supplies the same materials to pharmaceutical companies in the US, as well as to Ranbaxy and Cipla. Secondly, a large Indian pharmaceutical company (he is willing to name it privately but not publicly) that has a proven track record in the production of antiretroviral medicine has provided technical know-how to the New GPC through a consultative agreement.

Ramroop states that the reasons for keeping New GPC's consulting agreements under wraps are nothing to be suspicious about; the Indian pharma company in question has provided help that is beyond the normal call of duty, more out of humanitarian than profit-based motives. Publicly alluding to it could possibly distort that company's business relationships with other countries in Latin America, where the financial arrangements are different.

The current norms for testing are evidently inadequate. Ramsammy explains that the Food and Drug Analyst Department in Guyana does not currently have the expertise to certify the antiretroviral drugs. Yet, he hopes that certification from the Caribbean Regional Drug Testing Laboratory (CRDTL)in Jamaica, will be forthcoming. This would allow a greater degree of state control and authority over the quality and standard of locally produced pharmaceutical products. It would also provide for independent testing and certification of drugs that are now only passed through internal, corporate QC.

Ali of the GUM Clinic in Georgetown speaks of the treatment as proceeding smoothly, and going well. He has not observed any adverse effects to the treatment in his patients, at least not any that go against conventional expectations in managing the medical treatment of AIDS through antiretrovirals. He is one of the four doctors trained overseas by the government in this area; the others were Dr Ramnaraine, Dr Morris Edwards and Dr Persaud.

The issues at hand, Ali says, are the introduction of testing techniques and an expansion of the AIDS medical infrastructure itself. At present, only a small proportion of the HIV+ population has full blown AIDS. According to the Ministry of Health, there are approximately 1500 HIV+ Guyanese registered with the public health system. UNAIDS and local statistics put the estimated total HIV+ population at about 20,000 (in 2001), based on a prevalence rate of about 3%, while the Health Ministry estimates a current prevalence rate of about 5% (which would move the figure up to 30,000).

Clearly, statistics show there are still a large number of AIDS patients who remain untreated. The problem is distance, and the inability of people to move easily. One thinks of the distances on the coast, but how much more impossible it may be to come into Georgetown from parts of the interior, say - for instance - from a mining camp or an Amerindian settlement.

Ali is hopeful that the public medical system will see some more decentralisation. At the moment, a patient needs to visit the GUM clinic in Georgetown at least once every month, if just to pick up medication. Ali states that there is a possibility that the network might be expanded to include Mercy Hosiptal, also in Georgetown. Initially, in diagnosing the stage of the disease, more consultations are necessary. Even within this framework, he stresses that decentralisation must happen if antiretroviral therapy is required to reach every AIDS patient in Guyana.

Ramsammy concedes that most of the medical work being done around AIDS patients has been - and still is - the treatment and management of 'opportunistic infection.' These are infections that the body is prone to after its internal defence system is weakened by the virus. Signs and evidence of this infection are also used, within the public health system in Guyana, and in many developing countries, as indications of a patient's general health.

Thus, though Guyana might not yet have the CD4 and Viral Load tests available, doctors gauge a patient's recovery (and response to antiretroviral treatment) by his state of general health. Tuberculosis, pneumonia, fungal infections, diarrhoea and herpes are some of the common infections that are manifested in the case of people living with AIDS.

One benefit of generics over western-patented antiretrovirals is the ease of compliance. In regions such as the Caribbean, without vast health infrastructure, the compliance of an AIDS patient - taking the dosage of pills regularly, in the format specified - is key to the process. If, for example a patient in the US needs to take 2 NRTIs and 1 PI, he would be likely to take three distinct pills, as they would be manufactured by different companies. Generic production however, since it is all inclusive, can physically combine some of the prescribed antiretroviral courses, thus considerably easing the strain.

Why is the Caribbean not buying?

A point echoed by both Ramroop and Ramsammy is that Guyana being a small country in the Caribbean, and further, a poor country, it is possible to get away with more than what a large, visibly populated nation like Brazil or India could. Guyana - and even, by extension, the Caribbean - is not a conventionally attractive market (in terms of income or population).

The cooperation extended to New GPC, as well as to the Health Ministry (by governments of countries we have friendly relations with) has been tremendous; the help has often extended to low-cost consulting agreements, even from the international private sector.

Ramsammy states that Guyana has the capacity to manufacture for the Caribbean market, but possibly not any more than that. The initiative, to bring down costs within the Caribbean as a whole, is not seen as a profit-making, export-oriented strategy, rather, a humanitarian gesture. Ramsammy states that even if New GPC were to continue supplying antiretrovirals to just Guyana alone, it is possible that costs would come down at a future period, when the volume of patients being treated is higher.

In a recent report (Associated Press, July 2002) Caricom announced a settlement reached with six major pharmaceutical companies (Hoffman La-Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Abbott and GlaxoSmithKline). The Caribbean delegation, led by Denzil Douglas, the Prime Minister of St Kitts and Nevis, successfully negotiated a markdown of "up to 90 per cent" off US drug prices for antiretrovirals.

However, given current US prices, that places the average cost of triple drug therapy, per person, per year, at anywhere between US$ 1200 and US$ 1800 (as not all drugs will be sold at the 90% markdown). While it is a settlement that recognises the need for cheaper drugs in the Caribbean, its negotiated prices do not match (or even come close to) those currently prevailing in Africa, neither the prices on offer in Brazil, South Africa and India. Further, these prices are 4 times the cost in Guyana.

In fact, Ramsammy sees this recent settlement as being important mainly because it has allowed the Caribbean to lobby as a region, rather than as previously, which saw individual nations striking their own deals. Ramsammy concludes that these just-negotiated prices, especially when compared to the Guyanese prices on offer, just don't match up.

The current situation, namely, a local production capability for antiretrovirals in Guyana is something of a breakthrough. Combined with the already low (and promise of a lower) price, the issue seems almost moot, especially as New GPC has clarified that they have the capacity to produce for the region.

Dr. James St. Catherine, Programme Manager, Health Sector Development, CARICOM, says that negotiations with western pharmaceutical companies had begun one year ago, before Guyana's production facility was planned. Yet, he says that the price factor is essential, and he is keen on exploring the offer of local production.

What would be absolutely necessary, he emphasises, is certification from CRDTL in Jamaica.

He notes that there could be other problems: the possible need for a local in-country enactment that ratifies the WTO's post-Doha amendments to TRIPS on public health crises and the possibility that some country loans (perhaps from the World Bank) are linked to preconditions on who to buy antiretroviral drugs from.

Yet, he says that none of these would - or should - be roadblocks. The negotiations with western pharmaceutical companies have not been concluded.

He says that when, and if, certification from the CRDTL is achieved, CARICOM would be willing to seriously consider the prospect of buying the cheaper Guyanese antiretrovirals.