Special Report on Drug Resistance

New studies highlight HIV-resistance trends

NNRTIs show upward trend

Two separate studies have found that some types of HIV drug resistance have declined or leveled off at the same time others have increased.

One of the studies showed a resistance trend among HIV samples of declining or flat levels of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), while showing increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), says Lee Bacheler, PhD, vice president of clinical virology for VircoLab Inc. of Durham, NC.1

The study was presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Oct. 30 to Nov. 2, 2004, in Washington, DC.

"What we wanted to do was look and see whether there were trends in resistance over time among the kinds of samples submitted for resistance testing," she says.

"We thought we’d look at VircoLab’s large database for resistance testing and a selected subset of the database representing those samples submitted for routine clinical care," Bachelor notes.

When the samples with resistance to one or more drugs were analyzed, investigators saw that over a six-month period the resistance to nucleosides was declining, as was the resistance to PIs, she adds.

"However, the resistance to non-nukes was increasing," Bachelor says. "That’s not inconsistent with changing patterns of drug utilization over that period of time, where there’s been more use of NNRTIs and slightly less use of PIs."

Another study presented at ICAAC analyzed HIV infection among 317 people across the United States who presented for their initial antiretroviral treatment.2

"We wanted to try to determine whether virus from any of these patients has genotypic evidence of drug resistance-associated mutations or phenotypic resistance to antiretroviral drugs, so that we could better understand who was at increased risk of infection with drug-resistant strains of HIV," says Lisa Ross, a researcher with GlaxoSmithKline in Research Triangle Park, NC.

"As HIV treatment strategies evolve and drug prescribing patterns change, so the patterns of transmitted drug-resistance mutations could be changing within the U.S.," she notes.

Investigators found 23% of the subjects had reduced susceptibility to one or more antiviral drugs, and 14% of the samples had drug resistance-associated mutations, Ross says.

The prevalence of reduced drug susceptibility varied by drug class, with reduced susceptibility to NNRTIs being more common at 18%, while resistance to nucleosides was less than 1% and resistance to protease inhibitors was 6%, she adds.

"We may be seeing a shift in the prevalence of transmitted resistance among the drug classes, and I think transmitted resistance to NRTIs seems to be about the same or declining compared to what people have seen previously," Ross says. "For PIs, the level of transmitted resistance is remaining stable or maybe increasing a little."

When investigators further divided the NNRTIs by drugs, they found that most of the drug resistance (16%) was to delavirdine (Rescriptor), she explains.

"We wanted to know why delavirdine resistance was so high, and what we found was that the delavirdine resistance when seen was a low-level resistance," Ross says. "It confers reduced susceptibility on phenologic support."

Also, there wasn’t a significant cross-resistance across the NNRTI class, she adds.

"The most widely prescribed NNRTI in the U.S. is efavirenz, and there didn’t appear to be significant cross-resistance with these mutations to efavirenz, only delavirdine," Ross points out.

"Cross-resistance to the entire class of three prescribed NNRTIs was 6%, including nevirapine, and that is probably the most clinically relevant finding rather than the overall NNRTI cross resistance since it includes low level delavirdine resistance," she adds.

VircoLab’s resistance analysis also looked at the extent of resistance and found that for some protease inhibitors, there was a trend between 1998 and 2003 toward the most resistant viruses becoming even more resistant, Bacheler notes.

"So for example, if one looked at resistance to lopinavir/Ritonavir [Kaletra], [when it was] a relatively new PI, about 10% of the samples had more than fortyfold resistance, which is what Abbott suggests is the clinical cutoff, above which the patient won’t derive much benefit from the drug," she continues.

"In 2004, more than 35% were more than fortyfold resistant," Bacheler says. "This is not an epidemiological survey — we’re just looking at what people sent us, so we make no claims about this representing everything that’s out there."

VircoLab has seen a similar increase for resistance to amprenavir (Agenerase), with the most resistant viruses becoming even more resistant over a six-year period, she says.

The analysis is not able to address questions about the patients’ length of time on various drugs and treatment history, Bacheler notes.

Investigators hypothesize that physicians are using resistance testing more frequently and more often now than they were in the late 1990’s, she says.

"Then, also I think the patterns of resistance are changing over time as the epidemic evolves," Bacheler adds.

"There are some positive patterns in terms of reduction in prevalence to nucleosides and some not so positive patterns in terms of the most PI resistant viruses are getting even more resistant, even while the whole class of how many PI-resistant viruses submitted are shrinking," she explains.

References

1. Rinehart AR, Lecocoq P, McKenna P, et al. Predicted phenotypic resistance in routine clinical samples: 1998-2003. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; November 2004. Poster H-174.

2. Ross L, Lim ML, Liao Q, et al. Prevalence of antiretroviral drug resistance and resistance mutations in antiretroviral therapy (ART)-naïve HIV-infected individuals from 40 U.S. cities during 2003. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; November 2004. Poster H-173.