Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

Abstract

Summary Background People with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting. Methods We analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking. Findings We included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1.82, 95% CI 1.49–2.21; p<0.0001), subtype C infection (1.75, 1.06–2.88; p=0·028), and boosted protease inhibitor-based regimens (1.55, 1.45–2.11; p=0.004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1.92, 95% CI 1.30–2.83; p=0.002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B. Interpretation Our findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries.

Wide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency

“…PIs may target subtype C protease less efficiently and patients infected with subtype C viruses have poorer treatment outcomes on PI-based therapy1617. Inclusion of co-evolved Gag affected LPV susceptibility of subtype C molecular clones18 and susceptibility of resistant protease from paediatric patients failing PI-therapy in in vitro phenotypic assays13.…”

No Evidence That HIV-1 Subtype C Infection Compromises the Efficacy of Tenofovir-Containing Regimens: Cohort Study in the United Kingdom

“…In an analysis limited to white patients, the Swiss HIV Cohort Study found superior virological outcomes in subjects infected with a non-B subtype, but only 18% of patients were receiving a tenofovir-containing regimen, and only 13% of the non-B infections were subtype C [22]. A recent article from Sweden reported an increased rate of virological failure in patients with subtype C infection but did not report the NRTIs that were prescribed (their primary interest was the interaction between subtype and NNRTI-based vs PI-based regimens) [9]. A similar finding was reported in a nested case-cohort study of AIDS Clinical Trials Group A5175, which randomly allocated patients to receive one of 3 first-line regimens [10].…”

“…Data on the relationship between viral subtype and response to antiretroviral therapy are surprisingly limited, although 2 recent studies reported a higher rate of virological failure associated with subtype C infection [9, 10]. Here, we present data from a large cohort study conducted in the United Kingdom, which has a universal public healthcare system and a highly diverse HIV epidemic with a wide representation of viral subtypes [11].…”

HIV-1 Subtype C, Tenofovir, and the Relationship With Treatment Failure and Drug Resistance

“…Subtype C viruses may only require a single point mutation at position 65 to select for K65R. Several clinical studies have suggested that this mechanism may contribute to higher treatment failure rates and higher rates of the emergence of the K65R mutations observed in HIV subtype C–infected, compared with subtype B–infected, individuals treated with TDF-containing regimens [5–9], although others could not confirm different response rates between subtype B and C [10–12]. …”

“…Why is it that some previous studies demonstrated increased failure and resistance rates in subtype C– as compared to subtype B–infected patients treated with TDF [5–9]? The major factor explaining these discrepancies most likely is confounding by adherence or continuous access to treatment, which was more difficult to adjust for in other studies that were performed across various countries and healthcare systems.…”