Resistance to Integrase Inhibitors Increasing

Drug resistance to antiretroviral therapy is a persistent and, in my opinion, pernicious challenge to successful HIV treatment. The US Department of Health and Human Services HIV guidelines (as of July 16, 2016) recommends sensitivity testing to determine initial regimen selection.¹

The availability of integrase strand transfer inhibitors (INSTI) provides an additional means of suppressing HIV in both treatment-experienced and naive patients. But integrase inhibitors aren’t reserved as last-resort drugs of for patients exhibiting extensive resistance. In fact, 5 of 6 recommended regimens for naïve patients inexperienced to treatment include an INSTI. The first 2 FDA-approved INSTIs, raltegravir and elvitegravir, show cross-resistance. The third-class member, dolutegravir, doesn’t have cross-resistance issues with the other 2 members of the INSTI class.

Previous testing has been limited to testing for reverse transcriptase and protease gene mutations. The newest guideline update encourages including INSTI genotypic resistance testing. Providers should complete INSTI genotypic resistance testing if a patient experiences virologic failure on an INSTI-based regimen. The guideline reserves phenotypic resistance testing for persons with known or suspected complex drug-resistance mutation patterns.

A recently published meta-analysis compares relative resistance development of integrase strand transfer inhibitors.²

The authors searched the Web of Science, MEDLINE, EMBASE, and Cochrane databases for relevant randomized controlled trials, case-control studies, cohort studies, and case reports published from January 2007 to March 2015.

Ten different INSTI resistance mutations have emerged affecting raltegravir and elvitegravir more than dolutegravir. Medications resistance is most common for raltegravir and least common for dolutegravir. This pattern reflects the length of time the medications have been available (since 2007, 2012, and 2013) and the cross-resistance between raltegravir and elvitegravir.

Only 0.1% of strains were resistant to dolutegravir at the time of the included studies, but resistant strains are increasing in prevalence. Five studies have documented strains resistant to all 3 members of the INSTI class. Long-acting cabotegravir, yet to be FDA approved, is structurally similar to dolutegravir and may have cross-resistance.³ Providers should no longer assume a patient’s HIV is susceptible to INSTIs (even dolutegravir).

Integrase strand transfer inhibitor resistance is developing progressively and affects raltegravir (the first to market) the most and dolutegravir (the most recent entry) the least. Resistance rates are low at present, but the increasing rate of resistance development requires comprehensive genotypic resistance testing of patients prior to initiating a regimen with these medications.

References

• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services website. aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
• You J, et al. Therapy-emergent drug resistance to integrase strand transfer inhibitors in HIV-1 patients: a subgroup meta-analysis of clinical trials. PLoS One. 2016;11(8): e0160087.
• Cabotegravir. AIDSinfo Drug Database. aidsinfo.nih.gov/drugs/513/cabotegravir/0/professional.