“AIDS can be treat” was the slightly off-beat message embroidered on a T-shirt in the exhibition at the Home and Community Care conference in Chiang Mai, Thailand, which has just ended.
The message running through the conference was that treatments do matter, that everyone should have an equal right to them, but they do not remove the need for other forms of care and support. This report focuses on two presentations and one organisation present in the conference exhibition, which relate to practical issues in making treatments accessible in Thailand.
Overcoming the cost barrier
Dr Praphan Phanuphak of the Thai Red Cross Society is one of Thailand’s leading AIDS researchers with an international reputation. TheHIV-NAT project he leads is named for the collaboration with colleagues in the Netherlands and Australia. (This link is to a description of the project published in pdf format by UNAIDS as an example of best practice in clinical research in a developing country.)
At a session on Wednesday on access to antiretrovirals, Dr Phanuphak set out the arguments for provision and then dealt with some of the problems. First among these is the cost of treatment, and so he set out a number of ways to bring down drug prices.
Differential pricing of drugs - charging higher prices where people can afford them, and lower prices elsewhere - exists and can be taken further. He observed that cinema prices in Bangkok and the USA are very different, even though the movies are the same!
Bulk purchasing could help (and had been operating within Thailand), but it meant hospitals giving up some perks and benefits from having individual relationships with suppliers.
Import tax exemptions could cut costs in some countries.
Pharmacies could cut their profit margins on antiretrovirals. Many hospitals in Thailand, which charge patients for drugs, have cut their margins to 3 per cent.
Local production of generic drugs is happening in Thailand, within the law, for AZT, ddI, d4T, 3TC, nevirapine and, in the near future, saquinavir.
Importation of cheaper (generic) drugs from other countries – restricted in Thailand by patent law.
Adopting cheaper regimens. This, he observed, would not feature in any WHO guidelines but he considered that if there was clinical equivalence between different initial regimens, it made complete sense to give priority to the cheapest.
Reducing doses cut costs. AZT at 200mg twice a day, 3TC 150mg once daily, indinavir/ritonavir 400-600:100mg twice daily or 1200:200mg once daily were being used in Thailand, as was saquinavir/ritonavir 1600:100mg once daily.
Fixed dose combinations had advantages in keeping treatments simple and some were available in generic formulations, such as AZT/3TC from the Thai GPO (see below).
The idea of structured intermittent therapy, with a week on/week off system once viral load was below 50 was being researched by NIH in the USA and also in Thailand, by HIV-NAT, although their experience was still limited and this could not be recommended until there were results from larger and longer-term trials.
(Some people dismiss this approach as overly dependent on high-tech laboratory support and too demanding in terms of training for health workers and patients alike, although blister packs could doubtless be developed, including dummy pills for the “off” weeks, modelled on oral contraceptive packaging.)
In Thailand, there is a “magic price range”. When treatments go under US $50 a month, then 80 per cent of Thai patients could afford them. 20 per cent would still need government subsidy, and imposing a means test could be a challenge.
Reducing the cost of monitoring tests
Both CD4 counts and viral load monitoring remained expensive. As with drugs, differential pricing could help, along with bulk purchasing and import tax exemption. Lower technology equipment and home-made reagents (generic monoclonal antibodies and primer sets for viral load) would also help. Procedures could be modified to use less reagents (for example, using half the size of blood sample); some services could be centralised or at least shared between different centres; and profit margins could be cut. The critical and selective use of tests also helped. For example, if viral load does not influence when to start treatment, don’t use it until after someone is being treated.
Flow cytometers could be replaced by microscopy-based systems using either fluorescent microscopes or light microscopes – although manual counting makes it very hard to maintain a quality service on the scale that becomes necessary as treatment access widens. (An individual technician couldn’t and shouldn’t spend more than two to three hours a day looking through a microscope; and what kind of a job is that for anyone?)
Total lymphocyte counts were probably not sensitive enough for monitoring treatment. Some had nonetheless proposed TLC
Semi-quantitative viral load tests were being developed which should reduce costs greatly from the US $68 each which they currently cost the Thai Red Cross Society in their laboratory.
Choosing a first regimen
What to start with: any of 3 NRTIs (with abacavir), 2 NRTIs and an NNRTI, or 2 NRTIs and a boosted protease inhibitor. All had side effects, were comparably potent. He would select the cheapest that was convenient, tolerable and salvageable.
If triple therapy is really impossible to provide, and some antiretroviral treatment will have a major impact on a person’s life, then he would still see a role for double nucleoside analogues, preferably AZT/ddI or AZT/3TC. He gave the example of someone with the beginnings of CMV retinitis, whose eyesight might be preserved. (He would avoid d4T/ddI for fear of cross-resistant mutations ruling out any chance of future benefit from AZT.)
Who pays?
Finally, he asked, who should pay? He personally favoured co-payment, where patients contributed something to the cost, partly to save public funds for the more expensive treatments that would be needed in salvage therapy. For the poorest countries, international funding would be essential, but he thought that even for middle-income countries some international support would be appropriate.
Rationing issues emerge in District Hospitals
David Wilson from Medecins sans Frontieres (MSF, Thailand) spoke on their experience of providing antiretroviral treatment in two District Hospitals, one in a Bangkok suburb and the other in an impoverished fishing town.
There was a major challenge in providing education to health care staff and people living with HIV and AIDS, and in strengthening systems, such as the management of drug supplies to ensure continuity.
Some of the most challenging issues concern the reality that it isn’t possible to provide enough treatment, for some time, to meet the needs of everyone. So how do you choose who gets it? Users and staff were very concerned that the process should be seen to be fair, as it could otherwise get the hospital a bad reputation and generate a great deal of conflict.
If part of the rationale for providing treatment was to reinforce prevention activities by encouraging people at risk to get tested, then it was especially important that treatment should not be rationed on any kind of social, behavioural or “moral” grounds in ways that could be seen as excluding people at higher risk.
On balance, users tended to favour a lottery to allocate treatment places, once clinical criteria were met.
(This principle, however, would seem to be at odds with the aim of giving treatment to parents in order to reduce the social harm of children being orphaned, which is another argument that has been put forwards for expanding access to antiretrovirals.)
After describing initial experience in implementing the MSF programme, which had been encouraging, he focussed on the issue of managing side effects.
People needed a simple and understandable framework for side effects, and he proposed that this should focus on distinguishing between:
Distressing side effects that should be tolerated and managed, and which will go away: patients needed to be warned of these and supported in coping. Examples were nausea, vomiting, headaches, bad dreams (with efavirenz).
Medically serious early side effects, which might lead to cessation of all antiviral treatment, e.g. pancreatitis with ddI (or d4T) skin rashes or liver toxicity with NNRTIs, severe neuropathy with d4T (or ddI).
Longer term side effects, such as lipodystrophy or mitochondrial toxicity.
Having such a framework helped greatly in demystifying the issue and enabling people to feel they could cope with it.
Making the drugs
One agency, more than any other, has enabled Thailand to decide in favour of including payment for antiretrovirals in the scope of its emerging national health insurance scheme. It’s a division of the Thai Ministry of Public Health which produces generic versions of some 300 drugs and biological products (such as vaccines), mostly from the country’s Essential Drugs List. It’s called the Government Pharmaceutical Organization, or GPO for short, and it currently employs 2,200 people with sales of about US $100 million in Thailand.
The GPO makes generic versions of a range of drugs used for AIDS and TB treatment, from fluconazole and cotrimoxazole through rifampicin to the antiretrovirals AZT, 3TC, ddI, d4T, nevirapine and a combined AZT/3TC pill. It is still extending its product range, always within the limits set by Thai patents and patent law, and is also in the process of transferring its know-how to several African countries, including Zimbabwe, Ghana and Nigeria.
GPO often uses the same suppliers for active ingredients as the main international drug companies do – with a testing programme to check on the quality of those supplies. They also carry out their own bio-equivalence studies to make sure their own products deliver the same effective dose of the active ingredients as the internationally licensed versions. They claim that international companies have helped them in sourcing their materials - which suggests a more complex and public-spirited strategy on their part than is generally assumed. The big difference is that GPO can price their tablets and capsules at one fifth to one tenth of what is charged by the main international license-holders.
GP0 launched flavoured versions of buffered ddI before Bristol-Myers did; their buffered ddI is provided as packets of powder to dissolve in water, rather than as tablets. They are currently working on their own version of an enteric coated ddI. They also offer liquid formulations of AZT and 3TC (mainly for children).
The agency avoids wet processes in making up their capsules and tablets. This has made some of their products larger than they would like. Their concern, however, is that if a wet process is used, as appears to be the case for Cipla’s three-in-one nevirapine/3TC/AZT product, then the stability of each of the active ingredients – especially the 3TC – cannot be taken for granted and needs to be double-checked. They claim that when dissolved in water, 3TC can switch from one version to another, potentially reducing its activity and generating unwanted effects.