Do Resistance Consequences of Initial Treatment Regimens Favor Boosted PI-containing Regimens over NNRTI-containing Regimens?

By Ronald Baker, PhD

There is now a wide variety of treatment options for use in initial combination HAART as well as in the sequencing of HAART among HIV patients. Although differing in their criteria, both the European and US treatment guidelines provide numerous options for initiation of HAART. Both sets of recommendations emphasize that the choice of regimen should be based on a number of different factors. Further, these guidelines emphasize the importance of the preservation of future treatment options through the strategic choice and sequencing of drugs.

Drug resistance can lead to a significant reduction in the effectiveness of a HAART regimen. Cross- resistance may also restrict the effectiveness of unused agents. This can result in the rapid elimination of treatment options for HAART if close monitoring and selection of the initial HAART regimen are not implemented.

In a study published in the current issue (March 21, 2006) of the Journal of Acquired Immune Deficiency Syndromes (JAIDS), John Bartlett, MD, and colleagues seek to identify the optimal first-line HAART regimens based on their rate of virologic success and the preservation of future therapy options in treatment-naïve individuals. This work by Dr. Bartlett et al represents a systematic overview of the available trials of combination antiretroviral therapy and drug resistance results. It is hoped that the study results will assist front-line physicians in recommending to their patients the most strategic decisions about first-line therapy and minimize the consequences of drug resistance after virologic failure on initial antiretroviral combination therapy.

The study authors searched a variety of sources for published studies of treatment-naïve patients that included rates of virologic response and genotypes from patients who experienced virologic failure. They utilized the genotypic resistance guidelines from the International AIDS Society-USA to calculate regimen resistance cost (RCreg) and the number of active drug (AD) scores for each regimen and to rank the regimens.

Results

176 citations of studies on combination ART were located in a search of the literature.

Studies fulfilling inclusion/exclusion criteria of 3-drug combination ART with data on virologic failure were abstracted.

Comparisons showed higher virologic success (VS) rates for non nucleoside reverse transcriptase inhibitor (NNRTI) regimens and boosted protease inhibitor (boosted PI) regimens.

Boosted PI failures had the lowest RCreg and the highest AD scores.

NNRTI failures had higher RCreg and the highest AD scores.

Based on these findings, the authors conclude, “NNRTI and boosted PI regimens provide the highest rates of virologic success in treatment-naive HIV-infected persons. Treatment option scores were higher in subjects who failed boosted PI- containing regimens versus NNRTI-containing regimens, however.”

Discussion

The authors state that the criteria used for the choice of the optimal initial regimen for HIV patients should be based on “therapeutic efficacy, minimal drug-related toxicities, and potential future drug options (FDOs).”

The results of this study suggest there are overlapping virologic success rates of NNRTI-containing regimens and boosted PI-containing regimens. “However,” note the authors, “the resistance consequences of initial treatment regimens favored boosted PI-containing regimens over NNRTI-containing regimens.”

The association of boosted PI-containing regimens with reduced resistance has been noted in other, smaller studies. This systematic overview has expanded these observations to larger numbers of subjects “and to boosted regimens containing lopinavir (LPV) [Kaletra], amprenavir [Agenerase], or fosamprenavir [Lexiva],” according to Dr. Bartlett and colleagues.

“In summary,” write the authors, “this systematic overview has extended the results of individual clinical trials that identified the potent activity of NNRTI-containing regimens and boosted PI-containing combinations as well as the delayed appearance of resistance mutations in subjects receiving boosted PI-containing ART. Clinicians should seriously consider this factor in combination with regimen efficacy and toxicity when choosing an initial regimen.”

“Important new results are likely to be generated from ongoing clinical trials directly comparing NNRTI-containing regimens with boosted PI-containing regimens such as Adult Clinical Trials Group (ACTG) 5142.”

03/17/06

Reference
J A Bartlett and others. Minimizing Resistance Consequences After Virologic Failure on Initial Combination Therapy: A Systematic Overview. Journal of Acquired Immune Deficiency Syndromes 41(3): 323-331. March 21, 2006.