Toxicity rates on d4T
Dr Moses Kamya highlighted surprising results from Uganda, where researchers at Mulago and Mbarara hospitals calculated the differences in treatment failure rates between patients who started treatment with d4T/3TC/nevirapine (usually a generic fixed dose triple combination tablet) and AZT/3TC/efavirenz (in the form of branded products in separate tablets).
The analysis included 776 patients (526 adults and 250 children).
Overall, 75% of patients who started treatment had viral load below 400 copies/ml after one year – the remainder were either dead, lost to follow-up, had switched treatment due to side-effects or had changed to a second-line regimen due to virological or clinical failure of treatment.
Patients receiving the d4T-based combination were 2.59 times more likely to experience treatment failure when compared with the efavirenz-treated group, although the confidence intervals of this estimate were wide (1.20-5.59).
“Why did the d4T regimen perform less well?” asked Dr Kamya. “We really don’t know. We suspect it is tolerability but we did not document that enough.”
But he also speculated that the results might reflect a greater potency of efavirenz, although the results of the 2NN study showed no difference between a nevirapine and an efavirenz-based regimen in rates of virologic suppression.
There were also suggestions that the generic products might not be as effective as the branded products, although no evidence was supplied to support this view.
Replacing d4T: what can you afford?
The limitations of d4T-based treatment have already led some countries in Africa to dispense with it.
Alwyin Mwinga of Zambia told the conference that her country had already replaced d4T-based treatment with a first-line regimen of tenofovir, 3TC and efavirenz, using Aspen’s South African-manufactured version of Atripla, a fixed dose tablet containing all three drugs in one tablet.
Zambia has 100,000 patients already on treatment through 293 sites, with less than 300 patients currently requiring second-line treatment.
Although tenofovir-based treatment will prove more expensive than a d4T-based regimen, a lower frequency of adverse events can be expected, together with less potential for cross-resistance in second-line treatment.
However for most countries second-line treatment is a hypothetical exercise at present, due not to cost but to the very low rates of patients experiencing virologic failure of first-line treatment. The more pressing concern is the poor tolerability of d4T-based treatment.
In Namibia d4T-based treatment has also been phased out, in favour of an AZT-based regimen.
“Namibia cannot afford tenofovir,” said Dr Ndapewa Hamunime of the Namibian Ministry of Health, explaining why her country had chosen AZT as the basis for future treatment. Henceforth patients will start treatment with AZT/3TC/nevirapine. Tenofovir is being reserved as first-line therapy for HIV-infected patients with active hepatitis B.
Meanwhile thousands continuing to do well on d4T will be switched over to AZT after two years; those with lipoatrophy, peripheral neuropathy or liver enzymes elevated more than three times above the upper limit of normal are being switched immediately.
“No patient is to be switched from d4T without good reason,” said Dr Hamunime, reminding the conference audience that for a treatment programme like Namibia, even stepping up to AZT-based therapy imposes a significant additional burden. Namibia has 2.5 million people, an estimated HIV prevalence of 19%, 80,000 needing treatment and 35,000 already on treatment. AZT-based treatment costs an additional $48 a year per person.
Tenofovir in first-line treatment
Tenofovir is currently unaffordable for most countries, but that is set to change, according to Anil Soni of the Clinton HIV/AIDS Initiative, which has been working with generic manufacturers to bring down tenofovir costs in the past year. He said that four manufacturers will have submitted dossiers for WHO prequalification of generic versions of Atripla (tenofovir, 3TC and efavirenz) by the end of the year, and eight manufcaturers will have submitted generic tenofovir tablets by the end of the year.As more products become available the prices will be driven down, although tenofovir and efavirenz-based combinations will always remain more expensive because they contain a larger volume of chemicals and the raw materials required for their manufacture are more expensive than d4T and nevirapine.
But tenofovir also poses a practical difficulty for treatment programmes in Africa: safety monitoring. A rare side-effect of the drug is kidney toxicity, most likely to occur in people with pre-existing kidney problems or taking other drugs that are also toxic to the kidneys.
Zambia will carry out creatinine monitoring to detect impaired kidney function, but said Professor Charles Gilks of the World Health Organization, “the problem with putting a barrier of creatinine [monitoring] in front-line therapy is that it may exclude all those without access to creatinine or urea testing. CD4 counts are more widely available than reliable and reproducible chemistry in Africa.”
The balancing act between first-line and second-line therapy
Prof. Gilks summed up the dilemmas facing national treatment programmes as they strive to balance the cost of first-line therapy and the efficacy of second-line therapy.“There is going to be a major trade-off between what programmes put into first-line therapy and second-line. We think first-line is our best shot for obtaining durable viral suppression.”
In other words, the first-line regimen should be as tolerable and potent as possible - even if it proves more expensive. But, the more that countries spend on first-line treatment, the less will be available to spend on second-line treatment.
“Between 500,000 and 800,000 people could need second-line treatment by 2010,” Prof. Gilks warned.
Conversely, using a cheaper first-line regimen which has a high failure rate and leaves patients with a high level of cross-resistance to nucleoside analogues may make second-line treatment more difficult.
“[We recognise that] current second-line regimen recommendations are not very practical and there is a lot of pressure on WHO to be clearer about the NRTI backbone and the preferred protease inhibitor, partly in order to consolidate the market and drive down prices further,” said Prof. Gilks.
He highlighted data from WHO showing the current utilisation pattern of second-line regimens in resource-limited settings (three-quarters of the 40,000 second-line patients are currently in Brazil).
Twenty-four per cent are taking AZT/ddI and lopinavir/ritonavir, 19% are taking ddI/3TC and lopinavir/ritonavir (despite no evidence that this is an effective second-line regimen, since first-line failures are highly likely to have resistance to 3TC already), and 6% are taking saquinavir plus lopinavir/ritonavir.
“It is very easy to construct a second-line regimen when someone has been on tenofovir, using AZT,” said Dr Moses Kamya. “Perhaps the use of cheaper AZT second-line squares out [the higher cost of tenofovir] first-line.”
However Anil Soni of the Clinton HIV/AIDs Initiative highlighted the biggest potential variable in the cost of second-line therapy: the willingness or otherwise of countries to consider atazanavir/ritonavir as the recommended second-line protease inhibitor.
“Lopinavir/ritonavir will never be as cheap as atazanavir/ritonavir – that will determine the cost of second-line therapy and few countries are considering that choice at the moment.”
WHO is due to publish new, more definitive guidelines for second-line treatment soon, making clearer which ritonavir-boosted protease inhibitor is preferred, said Prof. Gilks.
The other variable affecting the long-term cost of second-line treatment will be the cost and availability of new drug classes in developing countries. Integrase inhibitors - which according to Anil Soni could be quite cheap to make – and chemokine antagonists may be available by the end of this year in the United States and Europe, but their accessibility in the nations most severely affected by HIV is still in doubt.
“I think we have to lobby very hard both the manufacturers and the implementers to start looking at these drugs in resource-limited settings,” said Prof. Gilks. “They present a potentially exciting option where we could use two drug classes in first-line and two completely different classes in second-line.”