P5. Factors influencing the efficacy of rilpivirine on HIV-1 subtype C in low- and middle-income countries

Ujjwal Neogi1, Amanda Häggblom1, Kamalendra Singh2, Leonard C. Rogers2, Wondwossen Amogne3, Eugen Schülter4, Maurizio Zazzi5, Eddy Arnold6, Stefan G. Sarafianos2, Anders S önnerborg1

Affiliates: Karolinska Institute1, University of Missouri2, Addis Ababa University3, University of Cologne4, University of Siena5, Rutgers University6.

The use of the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) in low- and middle-income countries (LMICs) is under debate. The main objective of this study was therefore to provide further clinical insights and biochemical evidence on the usefulness of RPV in LMICs.

RPV-resistance was assessed in 5340 therapy-naïve individuals and in 13,750 patients from Europe or HIV-1 subtype C (HIV-1C) dominated India and Ethiopia, who had failed first generation NNRTI-based therapies. Also, therapy response was assessed in 117 patients who underwent RPV-based therapy. RPV-inhibition and binding affinity assays were performed using patient derived HIV-1C RTs.

Primary RPV-resistance was rare (Fig 1A), but the proportion of patients with >100,000 HIV-1 RNA copies/ml pre-antiretroviral therapy was high in patients from LMICs (Fig 1B), which limits the usefulness of RPV as a first-line drug in LMICs. In patients failing first line NNRTI treatments, cross-resistance patterns suggested that 73% of the patients could benefit from switching to RPV-based therapy. In vitro inhibition assays showed ~2-fold higher RPV IC50 values in HIV-1C RT than HIV-1B (Fig 1C). Pre-steady state determination of RPV-binding affinities revealed a 3.2-fold lower binding to HIV-1C than HIV-1B RT. Structural analysis indicated that naturally occurring polymorphisms close to the NNRTI-binding pocket may reduce RPV-binding, leading to a lower susceptibility of HIV-1C to RPV (Fig 1D).

Our clinical and biochemical findings indicate that the usefulness of RPV has limitations in HIV-1C dominated epidemics in LMICs, but the drug could still be of benefit in patients failing first line therapy, if genotypic resistance testing is performed.

Figure 1. A. Primary resistance to RPV using Stanford HIVDB ver 7.0.1. B. Subtype tailored viral load (log10 copies/mL) at initiation of antiretroviral therapy (ART). The indicated percentages correspond to the proportion of treatment naïve patients with a HIV-1 RNA load of >100.000 copies/mL at initiation of ART. C. Inhibition of reverse transcriptase activity by patients RTs. D. The superposition of crystal structure of HIV-1B (cyan) and modeled structures of HIV-1C RT bound to RPV (pink). Residues E138 and K101 (known positions for RPV resistance) are also shown in this figure. The salt-bridge between E138 and K101 has been shown important for RPV efficacy. YMDD (red broken arrow) represents conserved 183-YMDD-186 residues of the active site of HIV-1 RT.

14_Ujjwal Neogi