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. 2016 Apr;3(4):e166-74.
doi: 10.1016/S2352-3018(16)00023-0. Epub 2016 Mar 14.

Virological Failure in Patients With HIV-1 Subtype C Receiving Antiretroviral Therapy: An Analysis of a Prospective National Cohort in Sweden

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Free PMC article

Virological Failure in Patients With HIV-1 Subtype C Receiving Antiretroviral Therapy: An Analysis of a Prospective National Cohort in Sweden

Amanda Häggblom et al. Lancet HIV. .
Free PMC article

Abstract

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.

Funding: Karolinska Institutet Research Foundation, Swedish Research Council, Stockholm County Council, Swedish Physicians against AIDS, US National Institutes of Health, University of Missouri.

Conflict of interest statement

Declaration of interests

We declare no competing interests.

Figures

Figure 1
Figure 1. Country of infection of patients with HIV-1C (A) and phylogenetic origin of the virus (B, C)
Phylogenetically 74% of the patients were infected with HIV-1C strains representative of east Africa. No intra-HIV-1C differences in primary or secondary viralogical failure were observed (C).
Figure 2
Figure 2. Analysis of time-to-secondary virological failure
NNRTI=non-nucleoside reverse transcriptase inhibitor. PI/r=ritonavir-boosted protease inhibitor.
Figure 3
Figure 3. Logistic regression model of odds of having missed one dose in the past 7 days
NNRTI=non-nucleoside reverse transcriptase inhibitor. PI/r=ritonavir-boosted protease inhibitor.
Figure 4
Figure 4. Molecular model of HIV-1C protease dimer
The backbone of protease is shown in secondary structure representation: α-helices as helical ribbon, β strands as flat arrows, and unordered structure as thin tubes (A). The two dimers are coloured magenta and green. The Cα atoms of the residues that are not conserved between HIV-1B and HIV-1C proteases are shown as solid balls. Superposition in HIV-1B and HIV-1C is shown for lopinavir (B) and darunavir (C). The protease inhibitors are rendered in balls-and-stick (cyan carbons in HIV-1B, and orange carbons in HIV-1C) in two proteases. The other atoms are coloured by atom type (red for oxygen, blue for nitrogen, and yellow for sulphur). The ribbon diagram shows the backbone of HIV-1C proteases. The difference in conformation of different moieties for the drugs in the two proteases is circled by dotted lines.

Comment in

  • Lancet HIV. 2016 Apr;3(4):e149-51

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