A new study to be conducted in South Africa, Uganda and India has sparked a heated debate in the HIV activist and research community.
The debate demonstrates a divide in strategy at the start of the fourth decade of the epidemic.
The debate has sprung from a clinical trial that aims to see whether low-dose stavudine, or d4T, is as effective as tenofovir, or TDF, one of the antiretrovirals (ARVs) currently recommended for first-line HIV treatment by the World Health Organisation (WHO). d4T was long used as the primary first-line therapy but harsh side effects, including neuropathy (nerve damage) and lipodystrophy (abnormal, sometimes disfiguring, fat distribution), led the WHO to recommend against its use in 2011. It suggested that TDF or zidovudine (AZT) be used instead. But both drugs are relatively expensive: according to the health advocacy organisation, Médecins Sans Frontières (MSF), d4T is available for as little as $20 (R204) a patient a year, compared with $75 (R764) a patient a year for AZT and $57 (R581) a patient a year for TDF.
And the change in guidelines comes with a global cash crunch: although HIV funding increased dramatically throughout the 2000s, it dipped in 2010 and has remained at a steady low since then.
Citing pragmatism, researchers want to see whether reducing the d4T dose from 30mg to 20mg will reduce side effects and still successfully suppress HIV, which would lower treatment costs. Globally, 26-million people need ARVs, a number that recently increased from 17-million due to a change in WHO guidelines. It is now recommended that people should start treatment earlier when their CD4 count, a measure of immune response, is at 500 – a change from the previous recommendation to start treatment at CD4 count of 350. Worldwide 10-million people are on treatment, with 34-million infected.
Francois Venter of the University of the Witwatersrand, who is the lead clinical researcher for the South African leg of the trial, says that countries such as relatively wealthy South Africa may be able to provide TDF, which has been recommended for first-line treatment in the country since 2010. But “in a country like Malawi, let’s say they use TDF for a year and then don’t have the money and the alternative is d4T [at 30mg] and we do not have the data for the 20mg dosage, the reality is that, in many countries, if this study fails or shuts down, people are going to [continue to] be on 30mg d4T, rather than a safer dose of d4T”.
Making poor use d4T “unethical”
Although most countries have changed their guidelines to move away from d4T, as of 2011 1.2-million people were on the drug, with 40% of South Africa’s patients taking d4T. The study has received ethics approval and is currently recruiting patients.
But doctors and activists say advocating that a bad drug should continue to be used by the world’s poorer patients is unethical. Writing in the March 2012 issue of the Southern African Journal of HIV Medicine, the authors from the HIV-advocacy group Treatment Action Campaign, MSF, and other organisations say that the WHO’s suggestion to move towards tenofovir-based treatment is “an important step towards bringing treatment in poor countries in line with rich ones [save for rare exceptions, d4T is no longer used in the United States and Europe, with the US removing it from the preferred list of first-line therapies in 2004]”.
“As the WHO and all countries are phasing out stavudine, this study will send a confusing message, and it may slow down this transition while countries wait for the results.”
Disagreements over the trial come against a background discussion about the sustainability of HIV treatment programmes. Without an immediate cure in sight, donors are wary about whether they will be willing and able to continue footing the bill for lifelong HIV treatment. The US President’s Emergency Plan for Aids Relief is increasingly moving away from funding government treatment programmes towards “technical assistance”.
The programme was cut by $380-million for the 2013 fiscal year and the Global Fund to Fight Aids, TB and Malaria, the largest multilateral donor, is short of $1.3-billion for the 2011-2013 period.
African activists are increasingly looking to their own governments to set aside more for health, calling for them to fulfil a commitment made in Abuja in 2001 to spend 15% of their budgets on health.
UNAids, the agency responsible for fighting the epidemic, states that in 2011, although “56 of 99 middle-income countries …[funded] more than half their HIV response”, countries such as Malawi and Mozambique still rely almost entirely on foreign funding for their HIV programmes.
Given the new WHO treatment guidelines, the organisation estimates that 10% more than the currently estimated $22-million to $24-million required each year is needed. UNAids says funding programmes are increasingly focused on making the “greatest impact and in the most efficient way”, an aim that falls in line with the priorities of the d4T study.
Venter says: “It’s not an easy debate and not a study I wish I was doing. But I think it’s still the most important study we can do given programme realities and resource constraints.”
But criticism of the d4T trial goes beyond global equity. The March 2012 article from the Southern African Journal of HIV Medicine says the trial won’t yield the results necessary to see whether 20mg of d4T is safer than the 30mg dose because it is a virological outcome study. This means that the main indicator is whether 20mg of d4T is as effective in suppressing HIV as 30mg of TDF, the current recommended dose for first-line treatment. Also, the two-year d4T treatment period makes it impossible to follow long-term side effects in patients, a key shortcoming as most people suffer from side effects if they continue d4T treatment for several years. The authors also note that, although previous trials of 20mg of d4T showed lower side effects, the rate was still “unacceptably high”.
The article’s authors say TDF is a better drug when used for patients infected with, or at risk of hepatitis B and/or tuberculosis, a reality for many in Southern Africa, and that placing patients on the best first-line therapy, even if it’s more expensive, means they don’t have to undergo expensive second-line treatments as quickly due to treatment failure.
Trial may be “superfluous”
Finally, the authors say that, by the time the d4T study results are known, they may be superfluous as there are other clinical trials taking place that attempt to lower the amount of the active pharmaceutical ingredient in TDF, thus potentially lowering the price of the drug.
“If current price trends continue, it is likely the anticipated cost savings associated with stavudine could be overtaken by expected further price reductions for tenofovir and other components of the first-line regimen by the time stavudine 20mg would be ready for use,” the authors write.
Venter says surrogate markers for some side effects will be considered during the trial and researchers are hoping to extend the study to consider long-term side effects. He says that lower-dose tenofovir is not likely to come on to the market for several years and its price is not known.
But, Venter says, d4T is likely to be here to stay, even if for only a select few, and, therefore, finding the correct dose is essential.
“There are some awkward situations where you want d4T, such as if someone becomes resistant to another drug,” he says. Running out of drug stocks, which is not infrequent in African countries, means that d4T may have to be used in some cases, even if AZT or TDF are considered the treatment of choice. (When South Africa experienced a shortage of TDF in 2012, patients were given d4T instead.)
“We want the drug to be used as safely as possible. This is about options, and it’s about providing the best possible treatment at the lowest possible cost.”
Mara Kardas-Nelson is a journalist at the M&G Health Journalism Centre. Her stories are produced with the support of the Open Society Foundation but are editorially independent of any sponsorship