© Jonathan Heyer/MSF
“The number of people needing HIV treatment will rise over the next two decades and so will the cost of treatment. This is because better, more effective treatments have come on the market and should be offered to patients, and also because, over time, more people will move from first to second (and later) line regimens, which are more expensive.”
-- The Treatment Timebomb -- Report of the Enquiry of the UK All Party Parliamentary Group on AIDS4
There is a growing disconnect between the AIDS treatment available to people in developed countries and to their counterparts in developing countries. In wealthy countries, AIDS now resembles a chronic disease, much like heart disease or diabetes, and patients generally have access to an increasing variety of treatment options once they inevitably develop drug resistance. 5
In contrast, people living with HIV/AIDS in developing countries largely have access to only one combination of medicines that causes significant side effects, with few or no alternatives for when their treatment fails. And the youngest people living with AIDS continue to be an afterthought – paediatric treatment still lags behind that for adults, as does the development of appropriate ARVs for children.
If people living with HIV/AIDS are to be given the same prospects for survival whether they live in developing countries or in wealthy countries, urgent action must be undertaken to ensure access:
- to a less toxic first-line regimen;
- to second- and third-line treatment options as patients develop resistance;
- better and timely detection of treatment failure through increased access to viral load testing, and
- to paediatric AIDS treatment options, which must be prioritised together with the prevention of mother-to-child transmission of the virus.
A) Move to a less-toxic and more robust first-line regimen
The first line of defence to help slow the pace at which patients need to switch to newer, more expensive ARV treatment regimens is a robust first-line drug combination with few side effects.
Today, the majority of people on their first-line of ARVs in low- and middle-income countries receive the combination of lamivudine/stavudine/ nevirapine (3TC/d4T/NVP).6 Thanks to generic competition, this regimen now costs US$ 67 per patient per year (ppy) – 99% less than 10 years ago. This dramatic price drop was possible because of competition among multiple generic manufacturers in countries where these drugs were not patented, such as Brazil, Thailand and India (see graph 1).
Notwithstanding the dramatic price drop over the past decade, using this standard combination comes at a high medical cost. The drug stavudine (d4T) causes serious side effects, some intolerable, such as peripheral neuropathy. It can also lead to lactic acidosis, which in rare cases can lead to death. It also causes stigmatisation because over long-term treatment, patients develop easily recognisable facial wasting.
Stavudine is virtually no longer used in wealthy countries (in 2006, for example, fewer than 2% of patients in Switzerland were taking the drug7). Patients in these countries are offered better-tolerated alternatives, such as tenofovir (TDF) or zidovudine (AZT). Since 2006, WHO has recommended in its HIV/AIDS treatment guidelines that treatment providers begin moving away from stavudine-based regimens because of their long-term irreversible side effects, towards tenofovir or zidovudine-containing regimens.8
This call was repeated in the latest recommendations released by WHO in December 2009 for ART for HIV in adults and adolescents, advising countries to develop a plan to move towards tenofovir or zidovudine-based first-line regimens.9
But until now, the significantly higher costs of these alternatives have largely prevented this switch in many developing countries. Better, less-toxic first-line regimens are still at best nearly double the price of the stavudine-based first-line regimen.
However, there has been a noteworthy downward trend in the prices of less-toxic first-line combinations. The price of tenofovir has come down significantly over the past few years, by almost 77%. This means that TDF-based combinations are now nearly the same price as those containing zidovudine (see graph 2). Fixed-dose combinations containing zidovudine (AZT/3TC/NVP) and those containing tenofovir (TDF/3TC/EFV) have both fallen, by 17% and 59% respectively in the past three years.
It is thanks to generic competition that these prices are steadily coming down, and they can be expected to fall further as demand increases. In countries where the drugs are not under patent or where patents owners permit such competition, the one-pill-once-a-day generic triple combination containing tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) is now available for $176 ppy (see graph 2). But in some lower middle-income countries, patent owners do not permit access to generic products, meaning that countries have to rely on the ‘discounted’ price offered by originator companies. For tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), this means a price almost six times more expensive, at $1,033 ppy.
The price of treatment is clearly a critical concern. But the long-term benefits of patients being able to tolerate and stay on their first ARV combination longer can outweigh the costs. A study in Lesotho showed that using a generic tenofovir-based regimen results in better quality of life for patients as compared to a stavudine-based regimen.10 And while shifting treatment programmes to a new first-line regimen brings with it clear logistical challenges on top of cost concerns, it is critical that treatment providers begin moving away from stavudine as has been done for example in Zambia, Lesotho, Guyana, South Africa and Botswana.
Design HIV drugs with developing countries needs in mind
© P.K. Lee/MSF
With 95% of people with HIV/AIDS living in developing countries, it is urgent that research and development take into account the particular needs of these populations. Such considerations must be systematically integrated into the early stages of the drug development process.
Over the last three years, there have been significant advances in HIV medicine, which have led to a number of new drugs from older classes, as well as entirely new therapeutic classes being approved for use. The new drug classes have different mechanisms of action to target the HIV virus, providing people living with HIV/AIDS with additional treatment options.
However, since ARVs are developed primarily for developed country markets, data relevant to address the specific needs of populations in developing countries, such as pregnant women or people who also need to take drugs for tuberculosis due to co-infection, is not obtained in clinical trials. A further example is the lack of knowledge about the interactions between antimalarials and antiretrovirals,12 even though 80% of people living with HIV live in regions where malaria is endemic.13
Further, there is currently no safety and efficacy data for children for the new drugs etravirine, maraviroc, or raltegravir. For other drugs there are limited data: for efavirenz (no data for children under three years), atazanavir and darunavir (no data for children under six years). This despite the fact that the U.S. Food and Drug Administration (FDA) has included incentives and obligations to encourage submission of data for paediatric use since 199714 and the European Medicines Agency (EMA) followed suit in January 2007.15
The need for high-tech monitoring can also affect the availability of antiretrovirals. For instance, the entry inhibitor maraviroc requires a complicated diagnostic test costing more than US$ 1,900 – a factor making its use impracticable and unaffordable in developing country contexts where even simple laboratory monitoring is rarely available.
B) Secure access to second- and third–line regimens
Lifelong AIDS treatment requires constant access to newer and more potent drug regimens when patients develop side effects or resistance to their medicines over time. Although resistance is an inevitable element of long-term treatment, it can be delayed by using drug combinations with fewer side effects to facilitate adherence, and can be limited by changing treatment soon after viral suppression begins to wane. New WHO guidelines on second-line further simplify and prioritise the choice of regimens.
Demand for newer AIDS drugs is growing fast. In one of MSF’s longest running AIDS treatment programmes, in Khayelitsha, South Africa, 14% of patients on treatment for five years needed to switch to a second-line drug combination because of virological failure.24 And 25% of those patients who switched again developed virological failure to their second-line regimen a further two years later.188
“Seeing a patient that you have been treating since 2003, now failing on her second combination, you feel, as a nurse, you are a failure. We are feeling like our hands are tied.”
-- Mpumi Mantangana, MSF nurse in Khayelitsha, South Africa
MSF’s Khayelitsha data provides a window into the growing need for access to newer AIDS drug regimens across the developing world in the coming years. As some patients in developing countries have already developed resistance to their second-line regimen, it is crucial to secure further treatment options essential to long-term survival. However, the price of newer regimens remains a major barrier to access. The most affordable second-line regimen recommended by new WHO guidelines is today priced at $465 (see graph 3). This is more than three times the most affordable of the improved first-line regimens recommended by WHO.
- At the time of going to press, there is no TDF/3TC + ATV+r co-pack. The Clinton Foundation-negotiated price of the individual components of this package comes to $465. CF expects the co-pack to be available by the end of 2010. At that stage its price is expected to drop to $425.
Death at the doorstep: Thembisa’s story
© Global Health TV
“I’m so worried now because I don’t know what is going to happen to me,” says Thembisa Mkhosana, a mother of two who lives in Khayelitsha, South Africa. Thembisa discovered she was HIV-positive in 2001 and began receiving ART through MSF’s clinic two years later. She responded well to treatment and was able to return to work and take care of her children.
But after showing signs of treatment failure because of drug resistance, Thembisa was switched to a second set of ARVs. Again she developed resistance. Thembisa now needs a third set of ARVs to keep her alive but those newer drugs are unaffordable. “If there’s no such thing that can help me, I know that I’m going to die,” says Thembisa. “And then who is going to look after my children?”
Thembisa is but one of many patients who now need access to newer and more potent, but unaffordable ARV regimens.
“What we are seeing in Khayelitsha is what we will soon see throughout Africa if there is not a focused push for urgent change,” says Dr. Eric Goemaere, Medical Coordinator for MSF in South Africa.
In December 2009, WHO released new recommendations which for the first time raises the need for treatment options after failure of second-line therapy. Many studies are ongoing, and the drugs likely to have anti-HIV activity in third-line regimens are darunavir (boosted with ritonavir), etravirine and raltegravir.9
Because of patent barriers, generic competition on these medicines is severely hampered. Unlike with the first generation of AIDS drugs, patents in key producing countries such as India prevent the production of much more affordable generic versions: many of the newer ARVs will likely be under patent in India, and several such as raltegravir, maraviroc or etravirine already are. The lack of competition among generic manufacturers means that prices cannot be expected to come down the way they did for the first generation of ARVs.
There is no generic version of etravirine, for example. Its manufacturer, Tibotec, has just announced a ‘discounted’ price for Sub-Saharan Africa and least-developed countries, at $913 ppy. A potential thirdline regimen could thus be available for developing countries at the prohibitive price of $3,204 ppy (at best, as this price applies to only Africa and least-developed countries).
There is no room for complacency about these prices. For most people who are failing on their second-line combination already, this unaffordable price will mean they almost certainly once again face death.
It is imperative that governments undertake measures to ensure that people in need of newer and more potent ARVs are not denied access because of patent barriers. This includes, but is not limited to, the routine use of compulsory licensing and other public health safeguards set out in the TRIPS Agreement (Trade-Related Aspects of Intellectual Property Rights). The planned Medicines Patent Pool for antiretrovirals is an important additional mechanism to ensure future availability of affordable essential medicines (see box).
C) Put an end to the neglect of children living with HIV/AIDS
While there has been important progress in scaling-up paediatric AIDS treatment over the past year, children continue to be an afterthought when it comes to treatment and developing appropriate and adapted medicines to meet their needs. Furthermore, much more effort needs to be placed on prevention of mother-to-child transmission (PMTCT) of the virus in order to eliminate these entirely avoidable infections in the first place.
The vast majority of children with HIV/AIDS are infected through transmission from the mother during pregnancy, childbirth or breastfeeding. PMTCT has been so successful in wealthy countries that nearly no children are newly infected with AIDS. But in developing countries, nearly 430,000 new child infections occurred in 2008 – a testament to the failure to effectively implement simplified and efficient PMTCT strategies that could dramatically reduce the number of child infections.16 In the latest WHO guideline on PMTCT and infant feeding, more options have been recommended including the provision of triple ART to all HIV-positive pregnant women and introducing ways to protect the child throughout the breastfeeding period.76 This would lessen the need for paediatric treatment, as has been seen in wealthy countries.
Because there are so few children with HIV/AIDS in wealthy countries, there is very limited investment by the pharmaceutical industry into developing appropriate and adapted paediatric ARVs.
It is noteworthy that the available paediatric FDC tablets that come in doses for various child sizes are produced mainly by generic companies.
The price of the paediatric FDC d4T/ 3TC/NVP, at $53 ppy, is finally lower than that for adults. But the fact that the first WHO prequalified paediatric ARV FDC became available only in 2006, while the adult equivalent has been available since 2001, reflects the way in which children with AIDS lag behind.
Develop simple diagnostic and monitoring tools for adults and children
It is vitally important to be able to detect when a patient is no longer responding to ART. Switching someone to a newer drug combination too late or too soon can compromise the treatment’s effectiveness.
A technology used to detect the level of the AIDS virus in patients’ blood – called ‘viral load’ testing – is the gold standard. However, it requires access to laboratories with sophisticated equipment, trained staff and the transport of blood samples, all of which can be complicated or even impossible in remote settings of poor countries.
There is an urgent need for simple and easy-to-use monitoring tests that can be used on the spot, overcoming these practical barriers. Without access to such tests, many patients are being switched too early or too late, only when they appear to be getting sick again once the virus has taken hold anew.
Furthermore, HIV/AIDS diagnosis in infants is extremely difficult. In babies under 18 months it can only be conducted with the use of a complex DNA-based diagnostic test that is expensive to conduct, also requiring trained personnel and access to sophisticated laboratory equipment. Only 15% of children born to mothers living with HIV in low and middle income countries were tested for HIV within the first two months of life.6 There is a desperate need to develop a simple diagnostic test that can be used to detect the virus in younger infants on the spot, so that treatment can be initiated as early as necessary. Early infant diagnosis is key because without treatment, half the children will die before the age of two.
Until new tools exist, however, it is urgent for donors and treatment providers to ensure that the existing diagnostic technologies are implemented as widely as possible.
Furthermore, of the 22 ARVs approved by the U.S. FDA for adults, five are not approved for use in children and six do not come in any paediatric formulations.18 When paediatric formulations do exist, the majority of them continue to be ill-adapted for use in resource-poor settings. This means they either come in powder or syrup form, with some having a bitter taste, or needing to be mixed with clean water or requiring refrigeration, both of which can be difficult to come by in many developing country contexts.
In April 2008, WHO revised its paediatric ARV treatment guidelines, recommending the use of the protease inhibitor lopinavir/ritonavir (LPV/r) for infants that have been exposed to nevirapine (NVP) directly or through their mothers.130 This recommendation, however justified, means taking a regimen including an LPV/r syrup, which is nearly 60% more expensive than a liquid nevirapine-based regimen and also requires refrigeration.
At the same time, there is no alternative regimen once the child fails this regimen. There is thus an urgent need for the development of child friendly doses of heat-stable protease inhibitors for the youngest patients. Paediatric dosing studies for the newer, more potent drugs must urgently be conducted.
© Espen Rasmussen
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