Should We Be Testing for Baseline Integrase Resistance in Patients Newly Diagnosed With Human Immunodeficiency Virus?

Abstract

Background: Current guidelines recommend genotype resistance testing at diagnosis to guide initial selection of antiretroviral therapy (ART). Many standard resistance genotypes exclude testing for resistance to integrase inhibitors ("IR testing"), although this class of drugs is a component of most recommended first-line regimens.

Methods: We compared the 96-week clinical outcomes and cost-effectiveness of 2 strategies: no IR testing vs IR testing performed at human immunodeficiency virus (HIV) diagnosis. The base case prevalence of transmitted integrase strand transfer inhibitor (INSTI)-resistant (INSTI-R) virus is estimated at 0.1%. With no IR testing, all patients start dolutegravir (DTG)-based ART after genotype; 12-week suppression rates are 90% (INSTI-susceptible [INSTI-S] virus) and 35% (INSTI-R virus). Those not suppressed at 12 weeks undergo IR testing; if diagnosed with INSTI-R virus, they change to ritonavir-boosted darunavir (DRV/r)-based ART. With IR testing, all patients are diagnosed with INSTI-S/INSTI-R virus prior to ART initiation and start DTG- or DRV/r-based regimens, respectively. Costs include IR tests (175 US dollars [USD]) and ART (41100-44900 USD/year). We examined the impact of key parameters in sensitivity analyses.

Results: IR testing resulted in worse clinical outcomes compared to no IR testing and increased costs by 200 USD/person/year. Prevalence of transmitted INSTI-R virus did not affect the favored strategy. No IR testing remained clinically preferred unless DTG suppression of INSTI-R virus was <20% or 96-week DRV/r suppression was >92%. If quality of life was worse with DRV/r- than DTG-based ART, no IR testing was clinically preferred over an even broader range of parameters.

Conclusions: In patients with newly diagnosed HIV, IR testing is projected to result in worse outcomes and is not cost-effective. Pretreatment assessment for INSTI resistance should not be recommended in treatment guidelines.

Keywords: ART-naive; HIV; cost-effectiveness analysis; integrase resistance.

Figure 1.

Decision tree to evaluate the clinical benefits and cost-effectiveness of integrase strand transfer inhibitor (INSTI) resistance testing (IR testing) at time of human immunodeficiency virus diagnosis. Simulated patients start at the square decision node (far left) where they receive either the standard genotype and no IR testing (top, green circle), or standard genotype and IR testing (bottom, red circle). In the no IR testing strategy, it is not known if patients have INSTI-resistant (INSTI-R) or INSTI-susceptible (INSTI-S) virus (gray box); all patients start dolutegravir (DTG)–based antiretroviral therapy (ART) and are assessed for virologic failure at 12 weeks. Those patients who are failing at 12 weeks then undergo repeat standard genotype and first-time IR testing (red circle). In the IR testing strategy, patients undergo both standard genotype and IR testing prior to ART initiation. If IR testing demonstrates INSTI-S virus, patients start DTG-based ART. If INSTI-R virus is diagnosed, patients start ritonavir-boosted darunavir (DRV/r)–based ART. Patients are assessed for suppression at 12 weeks if on DTG-based ART or at 16 weeks if on DRV/r-based ART; those not suppressed are tested with a repeat standard genotype and a repeat IR test. All patients receive a total of 96 weeks of ART and are followed to the end of the 96-week period (represented by triangles).

Figure 2.

Multivariate sensitivity analysis of the clinical impact (quality-adjusted life-years [QALYs]) of integrase strand transfer inhibitor (INSTI) resistance testing (IR testing) compared to no IR testing while varying the probability of dolutegravir (DTG) suppression of INSTI-resistant (INSTI-R) virus (vertical axis) and ritonavir-boosted darunavir (DRV/r) suppression (horizontal axis). Prevalence of transmitted INSTI-R virus is 0.1% in the base case (A). IR testing is clinically preferred (red and orange) when DTG suppression of INSTI-R virus is low (bottom) and suppression with DRV/r is high (right); no IR testing is clinically preferred (dark green and light green) when DTG suppression of INSTI-R virus is high (top) and virologic suppression with DRV/r is low (left). A–C, Quality of life (QoL) on DRV/r-based antiretroviral therapy (ART) is equivalent to DTG-based ART. D, QoL on DRV/r-based ART is reduced to 99% of that on DTG-based ART. Beginning at an INSTI-R prevalence of 4%, the no IR testing strategy showed a gain of ≥10^–3 QALYs compared to the testing strategy (light green) (B); at an INSTI-R prevalence of 28%, the IR testing strategy resulted in a gain of ≥10^–3 QALYs (orange) (C).