Reports from the

5th Resistance Workshop on HIV Drug Resistance & Treatment Strategies

June 4-8, 2001 Scottsdale, Arizona

Report 5

Treatment Interruption Leading to 3TC Resistance
     Reported By Jules Levin

There were two small studies presented at the Resistance Workshop showing 3TC resistance emerging following treatment interruptions. These studies raise concerns about resistance developing during interruptions of therapy. Previously, it was recognized that if a person were taking efavirenz or nevirapine and the person stopped therapy there is a risk of resistance because these two NNRTIs have a long halflife (ie, they remain in the blood at decreasing amounts at suboptimal levels for several days after stopping a regimen and after other drugs in the regimen are eliminated). However, the risk of 3TC resistance has not received much attention before these studies at the Workshop. Are there other potential causes of resistance resulting from a treatment interuption that we have not recognized yet?? For example, can drug levels & pharmacokinetics play a role in the development of drug resistance following treatment interruptions??

The first study (abstract 19) was reported by Cecile Tremblay from Massachusetts General and reported on treatment interruptions taken by the group of patients receiving HAART in acute infection under the supervision of the Bruce Walker group. She found the 3TC 184 mutation was seen after the first and second STI and suggested that the reason may be because intracellular 3TC levels may persist longer than other drugs, as EFV & NVP blood levels persist longer.

You can more detail about this study and comments and insights on this study by Joep Lange, MD, University of Amsterdam, at: Safety of STIs: 3TC resistance and HIV reservoirs.

In a second study reported at the Workshop (abstract 19), K Morales-Lopetegi, a Spanish research group, and Chris Petrpoulos at Virologic reported that consecutive treatment interruptions may promote the emergence of resistant virus that was present prior to the STI. 12 HIV chronically infected patients with viral load <50 copies/ml for more than 2 years interrupted HAART 3 consecutive times. In 2 of the patients, the 3TC 184 mutation was detected by genotypic analysis and these 2 patients had previously received a 3TC containing regimen. The study reported finding a stepwise/incremental increase in the 184 mutation over the 3 STIs. 3TC susceptibility decreased as the 184 mutation became more dominant. Although the 184 mutation was not detected in PBMC proviral DNA, 3TC sensitive viruses lacking the 184 had 90% reduced replicative capacity than the wild-type virus used for comparison. The authors concluded that expansion of the resistnt virus population takes placeduring the treatment phase, with increases in resistant viruses occurring during the relatively shorttime periods without treatment (during interruptions).