Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort

István Bartha, Matthias Assel, Peter M A Sloot, Maurizio Zazzi, Carlo Torti, Eugen Schülter, Andrea D. Luca, Anders Sönnerborg, Ana B. Abecasis, Kristel Van Laethem, Andrea Rosi, Jenny Svärd, Roger Paredes, David A M C van de Vijver, Anne Mieke Vandamme, V. Müller

Research output: Contribution to journalArticle

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Abstract

Background: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients. Methods: We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples. Results: 4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient. Conclusions: Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

Original languageEnglish
Article number537
JournalBMC Infectious Diseases
Volume13
Issue number1
DOIs
Publication statusPublished - Nov 12 2013

Fingerprint

Superinfection
HIV
Pharmaceutical Preparations
Drug Resistance
Therapeutics
Databases
RNA-Directed DNA Polymerase
Phylogeny
Computational Biology
Base Pairing
Cluster Analysis
Peptide Hydrolases

Keywords

  • HIV
  • Sequence analysis
  • Superinfection
  • Transmitted drug resistance

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort. / Bartha, István; Assel, Matthias; Sloot, Peter M A; Zazzi, Maurizio; Torti, Carlo; Schülter, Eugen; Luca, Andrea D.; Sönnerborg, Anders; Abecasis, Ana B.; Van Laethem, Kristel; Rosi, Andrea; Svärd, Jenny; Paredes, Roger; van de Vijver, David A M C; Vandamme, Anne Mieke; Müller, V.

In: BMC Infectious Diseases, Vol. 13, No. 1, 537, 12.11.2013.

Research output: Contribution to journalArticle

Bartha, I, Assel, M, Sloot, PMA, Zazzi, M, Torti, C, Schülter, E, Luca, AD, Sönnerborg, A, Abecasis, AB, Van Laethem, K, Rosi, A, Svärd, J, Paredes, R, van de Vijver, DAMC, Vandamme, AM & Müller, V 2013, 'Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort', BMC Infectious Diseases, vol. 13, no. 1, 537. https://doi.org/10.1186/1471-2334-13-537
Bartha, István ; Assel, Matthias ; Sloot, Peter M A ; Zazzi, Maurizio ; Torti, Carlo ; Schülter, Eugen ; Luca, Andrea D. ; Sönnerborg, Anders ; Abecasis, Ana B. ; Van Laethem, Kristel ; Rosi, Andrea ; Svärd, Jenny ; Paredes, Roger ; van de Vijver, David A M C ; Vandamme, Anne Mieke ; Müller, V. / Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort. In: BMC Infectious Diseases. 2013 ; Vol. 13, No. 1.
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AU - Bartha, István

AU - Assel, Matthias

AU - Sloot, Peter M A

AU - Zazzi, Maurizio

AU - Torti, Carlo

AU - Schülter, Eugen

AU - Luca, Andrea D.

AU - Sönnerborg, Anders

AU - Abecasis, Ana B.

AU - Van Laethem, Kristel

AU - Rosi, Andrea

AU - Svärd, Jenny

AU - Paredes, Roger

AU - van de Vijver, David A M C

AU - Vandamme, Anne Mieke

AU - Müller, V.

PY - 2013/11/12

Y1 - 2013/11/12

N2 - Background: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients. Methods: We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples. Results: 4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient. Conclusions: Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

AB - Background: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients. Methods: We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples. Results: 4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient. Conclusions: Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

KW - HIV

KW - Sequence analysis

KW - Superinfection

KW - Transmitted drug resistance

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