Post exposure prophylaxis regimens in Europe should exclude AZT, according to a pan-European group of researchers who have been studying drug resistance in newly infected patients throughout the continent since 1996. They argue that reduced susceptibility to AZT is so widespread in newly infected patients it may reduce the ability of any triple combination that includes AZT to a prevent new infection.
Their findings, presented on Tuesday at the Ninth European AIDS Conference in Warsaw, are based on analysis of data from 2208 seroconverters in 19 European countries, and analysis of drug susceptibility in 195 isolates with identifiable drug resistance mutations.
10.5% had evidence of resistance to at least one drug, 2% were resistant to drugs in at least two classes, 8% to at least one NRTI, 3% to at least one NNRTI and 2% to at least one protease inhibitor.
56% of patients with drug resistant virus had reduced susceptibility to AZT, compared whilst only 16% had reduced susceptibility to 3TC. AZT and 3TC are commonly paired in recommended post-exposure prophylaxis regimens, often with nelfinavir. Susceptibility to this protease inhibitor was more commonly reduced when compared with other protease inhibitors.
In contrast, susceptibility to lopinavir was reduced in only four patients, and no patients were fully resistant to either lopinavir or to amprenavir. One third had reduced susceptibility to the NNRTIs nevirapine and efavirenz.
However, these findings may not tell the whole story about possible reduced susceptibility to drugs in PEP regimens, according to some observers. For example, the finding that reduced susceptibility to 3TC is uncommon may reflect the relative difficulty of transmitting the less fit 3TC-resistant virus through sexual intercourse. No one is certain how easily 3TC-resistant virus might be transmitted through the parenteral route, such as needlestick injuries.
Also, the findings give a pan-European picture of drug resistance. Local conditions may vary, and the CATCH researchers recommended that where genotyping information is not available (for example where the index case is unidentified), a decision on the PEP regimen should take into account not only local patterns of transmitted drug resistance, but also the frequency of high level resistance to drugs currently recommended in local PEP regimens.
Some clinicians at the meeting were uneasy about excluding AZT from PEP regimens. "It's the only drug proven to work in a clinical trial," said one Italian researcher during the question and answer session following the presentation. "The mechanism of protection is not fully understood and we do not know if other drugs are equally effective."
Whilst this is true up to a point, studies of post-partum prophylaxis in infants suggest that nevirapine or 3TC are also effective in preventing HIV infection, and a study in ten macaques showed that monkeys given tenofovir up to one day after exposure did not become infected, In contrast, ten macaques not treated with tenofovir all became infected after HIV exposure.
Further information on this website
Post-exposure prophylaxis - overview
Prevention technologies - review of post-exposure prophylaxis use and research
Nevirapine for PEP: should use be restricted due to liver toxicity risk? - news story, August 26 2003
Wensing A et al. Drug susceptibility patterns in 195 European patients de novo infected with drug-resistant virus: implications for post-exposure prophylaxis. Ninth European AIDS Conference, Warsaw, abstract LBF6/1, 2003.