Effect of HIV drug resistance followed by therapeutic switch on the clinical course of HIV-infection

Amanda Häggblom 1,2, Michele Santacatterina4, 2, Ujjwal Neogi1. Anders Sönnerborg1,3, Equal contribution
1Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden, 2Department of Infectious Diseases, County Council of Gävleborg, Gävle, Sweden, 3 Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, 4Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Background
Antiretroviral therapy (ART) has improved survival among adherent patients with viral and immunological response to treatment. However, developments of antiretroviral drug resistance mutations (DRMs) still occur. The long-term effect of DRM followed by therapeutic switch on disease progression among HIV-infected patients has never been assessed in Sweden. Thus, we analyzed the effect of DRM followed by therapeutic switch on time to second line ART failure and CD4-t cell progression and time to AIDS and Death.

Methods
We used data from the Swedish HIV cohort collected between 1999-2014. Therapeutic switch was as any change from the first line to the second line treatment. Treatment lines were defined as 2 nucleoside reverse transcriptase inhibitors (NRTI) and a protease inhibitor (PI) or 2 NRTI together with a non-nucleoside reverse transcriptase inhibitor (NNRTI). Therapeutic switch was categorized into: (1) switch with no virologic failure and no DRM; (2) switch with virologic failure and no DRM; (3) switch with virologic failure and minor DRM and (4) switch with virologic failure and major DRM.
Primary outcome were time to virologic failure of second line ART. Virologic failure was defined as 1 VL>=200 copies/mL after at least 9 months. Secondary outcome was the CD4-t cell count progression on second line ART. Time to virologic failure of second line ART was modeled using a pooled logistic regression model. The mean CD4-t cell progression was modeled using a mixed effect model, including a random effect for each patient. Patients were weighted using the inverse of the probability of switching to second line ART and censoring. Differences in time to AIDS and death (5th, 25th, 50th, 75th, and 95th percentiles) were estimated using Laplace regression.

Results
1043 patients (7409 clinical visits) starting second line ART with were included. Patients with switch without failure 600(58%), Switch with virologic failure only 211 (20%), Switch with a failure and minor DRM 147 (14%), Switch with failure and major DRM 85 (8%).
There is a significant difference in time to treatment failure between the patient category Switch and failure with a major DRM and Switch without a failure and no DRM (table 1). Among death and AIDS cases within 12/18 months of second line ART, those with major DRM have a shorter time to die or get AIDS (table2). There was no significant difference in long-term CD4-t cell count progression (table1). In a sensitivity analysis we found that patients with a CD4-t-cell count <150 and a major DRM had slower CD4-t-cell count progression within the first 24 month of second line ART (not shown).

Conclusions
Patients switching with DRM are more likely to have second line virologic failure and to die and get AIDS within the first 12-18 month of second line ART. This is probably explained by a slower CD4-t-cell count progression among patients with a low CD4-t-cell count and a major DRM within the same period of time.