Drop d4T from first-line therapy, WHO advises low-income countries – if you can afford to

Keith Alcorn
Published: 08 August 2006

Pricing may hinder action on WHO guidelines

According to the latest edition of Médecins sans Frontières` Untangling the web of price reductions, a report which monitors the prices of antiretroviral drugs for resource-limited settings, the cheapest alternative to a d4T-based combination is currently AZT/3TC/nevirapine, manufactured by Hetero of India, at $263 a year.

In comparison the most expensive d4T/3TC/nevirapine fixed dose product is currently manufactured by Ranbaxy, priced at $153 a year.

Tenofovir and abacavir continue to be more expensive as individual products than most fixed dose triple combinations, due in part to more complex manufacturing processes but also because the low volume of orders until now has prevented price reductions through economies of scale.

The guidelines recommend that for second-line treatment, heat-stable lopinavir/ritonavir (Kaletra) is the most advantageous product currently available for use in hot climates. It should be combined with didanosine (ddI) and another nucleoside not used in first-line treatment, such as tenofovir or abacavir. Nelfinavir is an alternative protease inhibitor that does not need cold storage, but is less potent than a ritonavir-boosted protease inhibitor.

Fixed dose combinations containing d4T should be phased out in favour of less toxic drugs in resource-limited settings, the World Health Organization said this week in new guidelines for adult antiretroviral treatment in resource-limited settings, now available on the WHO website.

Fixed dose combinations containing d4T, 3TC and nevirapine were considered to be the cornerstone of treatment scale-up in developing countries because of their convenience and cheapness when guidelines for resource-limited settings were first published in December 2003.

Since then it has become clear that d4T-based treatment is associated with a much higher rate of drug substitution due to toxicity, chiefly due to peripheral neuropathy and lactic acidosis. The drug also causes fat loss, and research groups in South Africa, India and Rwanda have all reported that growing numbers of patients are suffering from stigmatising fat loss (lipoatrophy).

The new guidelines, due to be formally unveiled at the World AIDS Conference next week in Toronto, recommend that first line treatment should be composed of two nucleoside reverse transcriptase inhibitors (NRTis) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a triple NRTI regimen.

The NRTI `backbone` should be composed of either 3TC (lamivudine) or emtricitabine (FTC) plus either AZT (zidovudine) or abacavir or tenofovir. This recommendation brings the WHO guidelines into line with treatment guidelines in the United States and the United Kingdom, where d4T-based therapy has been discouraged due to toxicity for several years.

However, WHO admits that its recommendations may be difficult for some countries to follow.

“Because of the current wide availability of FDCs and considerably lower prices, d4T-containing regimens may still remain the most accessible option for people in urgent need of treatment in the short to medium term. At the same time, WHO notes that it is important to begin planning to move away from d4T-containing regimens to as to avoid or minimise the predictable toxicities associated with this drug.”

In the case of lactic acidosis, the guidelines recommend dropping d4T and stopping treatment for at least four weeks and until symptoms resolve, then resuming treatment with tenofovir or abacavir in place of d4T. In the case of lipoatrophy caused by d4T, a switch to tenofovir or abacavir is also recommended.

The guidelines warn that the incidence of the key side-effect associated with abacavir, a life-threatening hypersensitivity syndrome, has not been established in resource-limited settings, and there is some evidence that it may vary between ethnic groups.

Although there were concerns that widespread use of nevirapine in resource-limited settings might lead to unacceptable levels of toxicity, the drug has not proved to be as problematic as d4T. However the new guidelines do discuss in detail the use of nevirapine-based antiretroviral therapy in pregnant women with CD4 counts above 250 cells/mm3 where there may be an increased risk of hepatotoxicity.

CD4 counting

The guidelines also urge national programmes to invest in CD4 cell counting in order to improve the identification of patients in need of treatment.

Current practice in many countries, such as Malawi, is to use WHO clinical staging to identify people eligible for treatment. Anyone with stage 4 (severe) symptomatic HIV disease should be treated immediately, and anyone with WHO stage 3 disease (advanced, including tuberculosis and oral candidiasis) should receive treatment if they have a CD4 cell count below 350 cells/mm3.

However the guidelines point out that “pulmonary tuberculosis or severe bacterial infections can occur at any CD4 count level and it is reasonable to monitor patients with CD4 cell counts above 350 cells/mm3.”

CD4 counts are also useful in identifying patients with milder symptoms, such as herpes zoster, who may be at risk of rapid disease progression if they have a CD4 cell count below 200.

However, reliable and affordable point of care CD4 testing technologies are still some way off.

The guidelines note that using total lymphocyte counts, an easier and cheaper marker, to monitor when to start treatment has not proved to be a useful tool for monitoring when to start treatment in asymptomatic patients or the response to treatment, and that it should gradually be eliminated from adult ARV guidelines.

The full guidelines document may be downloaded from the WHO website at http://www.who.int/hiv/pub/guidelines/adult/en/index.html