A proposed trial of low-dose stavudine (also known as d4T) sparked a heated debate between South African researchers and activists at the opening of the first Southern African HIV Clinicians' Society Conference held in Cape Town last month.
Professor Francois Venter of the Wits Reproductive Health and HIV Institute (WHRI), who is running the study, argued that it is “the most important clinical trial right now”. Dr Eric Goemaere of Médecins Sans Frontières (MSF) South Africa argued against the study, saying that the study “will create a double standard”.
Stavudine was licensed at a dose of 40mg twice daily, but a subsequent meta-analysis showed no difference in efficacy between doses of 40mg and 30mg or 20mg, but with a trend towards a lower frequency of side-effects at a lower dose. On the basis of these data the World Health Organization revised its recommendation on d4T dosing in 2007, urging countries to switch to a 30mg dose, but in 2010 WHO issued new guidelines recommending that the use of d4T be phased out in favour of tenofovir due to unacceptable levels of toxicity.
The side-effects that have led to the phase-out of d4T include peripheral neuropathy and lipodystrophy, which can severely affect quality of life. However, due to its low price, the drug is still widely used in the developing world in fixed-dose antiretroviral combinations.
Peripheral neuropathy occurs when the nerves responsible for sensation, including pain, pressure, heat sensation, movement and automatic bodily functions such as breathing, heartbeat, sweating and emptying of the stomach become damaged. It can range from mild numbness or pain to debilitating pain. Other symptoms include increased sensitivity to touch, diminished reflexes and weakness.
Lipodystrophy is a syndrome characterised by abnormal fat distribution and metabolic disturbances in the way the body processes fats (lipids) and glucose. Lipodystrophy can increase risk of diabetes and cardiovascular disease in severe cases. It includes a loss of fat in the face, legs and stomach, or fat accumulation with increased intra-abdominal (visceral) fat, formation of a dorsocervical fat pad ('buffalo hump'), or accumulation of fat in the neck, breasts, or other areas.
Very few people in Europe begin treatment on d4T because the European Medicines Agency says that serious side-effects of d4T mean that the use of the medicine should be severely restricted in both adults and children, and should only be used when other appropriate treatments are not available.
The study now recruiting is a randomised, double‑blind trial designed to demonstrate non‑inferiority of d4T given at 20 mg twice a day compared with tenofovir at 300 mg once a day, coadministered with lamivudine (3TC) and efavirenz (EFV) in antiretroviral‑naive patients over 96 weeks. The study will be run in South Africa, Uganda and India. A total of 1068 male and female antiretroviral-naive HIV-positive people will be randomised in a 1:1 ratio (approximately 534 patients per treatment group). The study has recruited approximately 200 participants thus far.
One of Dr Goemaere’s main arguments against the trial was that it won't answer questions about the drug's long-term toxicity because it will only run for 96 weeks. Many of d4T’s most serious side-effects would not necessarily occur during the study period. Mitrochondrial toxicity, the changes or mutations which can occur in the mithocondria (the cell’s ‘power plants’ involved in the formation of protein and processing of fat), is both time- and dose-dependent. The study also does not include monitoring of surrogate markers for mitochondrial toxicity.
Rates of severe d4T-associated toxicity in longer-term users in a Cambodian study showed that 7% of people developed neuropathy within the first year, but by the third year the cumulative incidence was 16.6%, and it rose to 19% by the sixth year. The cumulative incidence of lipodystrophy was 56% by the third year and 72% by the sixth year. The risk for lactic acidosis among people on concurrent TB treatment and d4T was 8.6 times higher than those not on d4T (aHR=8.6, 95% CI 2.7 - 27.5).
Two hundred Treatment Action Campaign (TAC) activists demonstrated outside the debate, before participating in it. They were wearing T-shirts with “No d4T. Phase it out now!” written across the back. The Secretary-General of TAC, Vuyiseka Dubula, who was also a panellist at the debate said, “We have raised this issue as people living with HIV. If tenofovir is the WHO-recommended regimen and that which is supplied in the South African public sector, why should I leave the best treatment that is available in the world to take part in a study of a drug regimen with high toxicity?”
Dubula also discussed the issues of adherence (d4T is taken twice a day, as opposed to tenofovir which is taken once a day) and the stigma that people faced when they experienced lipodystrophy. “This pill does not only do something to our blood, it also does something to your body…You can ask anyone if they would prefer tenofovir or d4T and they would want take the better drug – tenofovir.“
One of the main reasons for studying the non-inferiority of a lower dose of d4T, for Venter, is because of its lower cost, in the context of dwindling funding for HIV, and widespread tenofovir stock-outs.
“Can you assure me as a clinician on the ground, that in six years we will not be in a position where we have to use 30mg d4T if the tenofovir supply messes up or if there is not enough funding for tenofovir globally?” Prof. Venter asked. “This is why we need this study so that it will be possible to give a lower dose of d4T and see what the side-effects and the outcomes are.”
South Africa has been experiencing tenofovir stockouts this year. “The truth is that patients are more likely to receive tenofovir if they enrol in this study than they are in the public sector. In terms of countries where they have changed to tenofovir, when you go to the clinics everyone is on d4T on 30mg. This is what programmes do when they cannot afford d4T or if there are stockouts,” said Venter.
Generic tenofovir costs six times more per month than d4T, while tenofovir co-formulated with emtricitabine costs four times more than a month’s supply of d4T and lamivudine combined. “Taking the costs of toxicity management into account, the cost-effectiveness ratio (measured in cost per year of life saved) of tenofovir is double that of d4T (when ART is initiated at 350 CD4 cells/ml),” according to Venter.
The need to treat side-effects of d4T reduces the amount of money that might be saved by prescribing it, as shown by a study conducted by MSF in a cohort in rural Lesotho. Inpatient care and essential drug costs were higher for people on d4T than for those on tenofovir. The tenofovir-containing regimen generated higher life years saved and quality-adjusted life years than d4T-based treatment.
Dr Goemaere and Vuyiseka Dubula both argued that cost concerns were not a good enough motivation for the study to go forward, as both MSF and TAC have a history of successfully advocating for a decrease in the cost of ARVs. For Prof. Venter, this study is critical to establish how d4T could be used more safely assuming that widespread use will continue in many African countries.
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