Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa
Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensu...
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| Veröffentlicht in: | Infection, genetics and evolution genetics and evolution, 2007-09, Vol.7 (5), p.562-569 |
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| creator | Holmgren, Gabrielle Hamrin, Johan Svärd, Jenny Mårtensson, Andreas Gil, José Pedro Björkman, Anders |
| description | Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites.
We have studied if mutations in the
pfcrt and
pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy.
Samples for molecular analysis were derived from three clinical trials on children |
| doi_str_mv | 10.1016/j.meegid.2007.03.005 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_570390</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S156713480700041X</els_id><sourcerecordid>19615043</sourcerecordid><originalsourceid>FETCH-LOGICAL-c429t-f3840f25baff4875dda78fb7fee4a26a3200b16c4f00e5a7f01d18b1b4851ca23</originalsourceid><addsrcrecordid>eNqFkU-P1SAUxRujccbRb2AMK3etlwKlb2MymYx_kklcqGtC4aI8S-lAq5mVX12erRo3uuLm8jvnwj1V9ZRCQ4F2L45NQPzkbdMCyAZYAyDuVedUdLKWrZD395oy3p9Vj3I-AlAJbf-wOqOSd5Jxfl59f48jmsXHiURHZhdsoiSsiz61MtFuwUR0iNbr29VPSEKc4vIZk57viJ7sX3fzuBZJWjD47Cc_ERPD4KefXuSXqLSvdV7IpUve6MfVA6fHjE_286L6-Or6w9Wb-ubd67dXlze14e1hqR3rObhWDNo53kthrZa9G6RD5LrtNCtLGGhnuANAoaUDamk_0IH3ghrdsouq3nzzN5zXQc3JB53uVNRe7a0vpUIlJLADFP75xs8p3q6YF1X-ZHAc9YRxzarrW8EYsP-C9NBRAfwE8g00Keac0P1-AwV1SlQd1ZaoOiWqgKmSaJE92_3XIaD9I9ojLMDLDcCyvq8ek8rG42TQ-lSSVTb6f0_4AV1at1Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19615043</pqid></control><display><type>article</type><title>Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Holmgren, Gabrielle ; Hamrin, Johan ; Svärd, Jenny ; Mårtensson, Andreas ; Gil, José Pedro ; Björkman, Anders</creator><creatorcontrib>Holmgren, Gabrielle ; Hamrin, Johan ; Svärd, Jenny ; Mårtensson, Andreas ; Gil, José Pedro ; Björkman, Anders</creatorcontrib><description>Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites.
We have studied if mutations in the
pfcrt and
pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy.
Samples for molecular analysis were derived from three clinical trials on children <5 years old with uncomplicated
Plasmodium falciparum malaria; one AQ monotherapy study conducted in Kenya 2003 and two AQ plus ART combination therapy studies conducted in Zanzibar 2002–2003 and 2005, respectively.
The PCR-adjusted treatment failure rates in the three studies were 19%, 8% and 9%, respectively. After monotherapy there was a significant selection of
pfcrt 76T in re-infections (OR not calculable;
p
=
0.048) and of
pfmdr1 86Y in recrudescent infections (OR 8.0;
p
=
0.048). No such selection was found after combination therapy. A selection of
pfmdr1 1246Y and the
pfmdr1 haplotype (a.a 86, 184, 1246) YYY was found in recrudescent infections both after monotherapy (OR 7.6;
p
=
0.009 and OR 3.1;
p
=
0.029) and combination therapy in 2005 (OR 3.6;
p
=
0.017 and OR 5.4;
p
<
0.001).
Hence,
pfmdr1 1246Y with synergistic or compensatory addition of
pfmdr1 86Y and 184Y appears to be involved in AQ/DEAQ resistance and treatment failure. Our results suggest that ART may protect against a selection of these SNPs initially, but maybe not after continuous drug pressure in a population. However, treatment failure rate and spread of
pfmdr1 SNPs may remain at a low level because of the suggested opposite selection by ART and the pharmacodynamic advantages with ACT.</description><identifier>ISSN: 1567-1348</identifier><identifier>EISSN: 1567-7257</identifier><identifier>DOI: 10.1016/j.meegid.2007.03.005</identifier><identifier>PMID: 17467344</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>ACT ; Amodiaquine ; Amodiaquine - administration & dosage ; Amodiaquine - pharmacology ; Amodiaquine - therapeutic use ; Animals ; Artemisinins - administration & dosage ; Artemisinins - pharmacology ; Artemisinins - therapeutic use ; Child, Preschool ; Clinical Trials as Topic ; Desethylamodiaquine ; Humans ; Kenya ; Malaria ; Membrane Transport Proteins - genetics ; Multidrug Resistance-Associated Proteins - genetics ; Odds Ratio ; pfcrt ; pfmdr1 ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - genetics ; Protozoan Proteins - genetics ; Resistance ; Selection, Genetic ; Tanzania ; Zanzibar</subject><ispartof>Infection, genetics and evolution, 2007-09, Vol.7 (5), p.562-569</ispartof><rights>2007 Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-f3840f25baff4875dda78fb7fee4a26a3200b16c4f00e5a7f01d18b1b4851ca23</citedby><cites>FETCH-LOGICAL-c429t-f3840f25baff4875dda78fb7fee4a26a3200b16c4f00e5a7f01d18b1b4851ca23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S156713480700041X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17467344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:116078691$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Holmgren, Gabrielle</creatorcontrib><creatorcontrib>Hamrin, Johan</creatorcontrib><creatorcontrib>Svärd, Jenny</creatorcontrib><creatorcontrib>Mårtensson, Andreas</creatorcontrib><creatorcontrib>Gil, José Pedro</creatorcontrib><creatorcontrib>Björkman, Anders</creatorcontrib><title>Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa</title><title>Infection, genetics and evolution</title><addtitle>Infect Genet Evol</addtitle><description>Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites.
We have studied if mutations in the
pfcrt and
pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy.
Samples for molecular analysis were derived from three clinical trials on children <5 years old with uncomplicated
Plasmodium falciparum malaria; one AQ monotherapy study conducted in Kenya 2003 and two AQ plus ART combination therapy studies conducted in Zanzibar 2002–2003 and 2005, respectively.
The PCR-adjusted treatment failure rates in the three studies were 19%, 8% and 9%, respectively. After monotherapy there was a significant selection of
pfcrt 76T in re-infections (OR not calculable;
p
=
0.048) and of
pfmdr1 86Y in recrudescent infections (OR 8.0;
p
=
0.048). No such selection was found after combination therapy. A selection of
pfmdr1 1246Y and the
pfmdr1 haplotype (a.a 86, 184, 1246) YYY was found in recrudescent infections both after monotherapy (OR 7.6;
p
=
0.009 and OR 3.1;
p
=
0.029) and combination therapy in 2005 (OR 3.6;
p
=
0.017 and OR 5.4;
p
<
0.001).
Hence,
pfmdr1 1246Y with synergistic or compensatory addition of
pfmdr1 86Y and 184Y appears to be involved in AQ/DEAQ resistance and treatment failure. Our results suggest that ART may protect against a selection of these SNPs initially, but maybe not after continuous drug pressure in a population. However, treatment failure rate and spread of
pfmdr1 SNPs may remain at a low level because of the suggested opposite selection by ART and the pharmacodynamic advantages with ACT.</description><subject>ACT</subject><subject>Amodiaquine</subject><subject>Amodiaquine - administration & dosage</subject><subject>Amodiaquine - pharmacology</subject><subject>Amodiaquine - therapeutic use</subject><subject>Animals</subject><subject>Artemisinins - administration & dosage</subject><subject>Artemisinins - pharmacology</subject><subject>Artemisinins - therapeutic use</subject><subject>Child, Preschool</subject><subject>Clinical Trials as Topic</subject><subject>Desethylamodiaquine</subject><subject>Humans</subject><subject>Kenya</subject><subject>Malaria</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Multidrug Resistance-Associated Proteins - genetics</subject><subject>Odds Ratio</subject><subject>pfcrt</subject><subject>pfmdr1</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - genetics</subject><subject>Protozoan Proteins - genetics</subject><subject>Resistance</subject><subject>Selection, Genetic</subject><subject>Tanzania</subject><subject>Zanzibar</subject><issn>1567-1348</issn><issn>1567-7257</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU-P1SAUxRujccbRb2AMK3etlwKlb2MymYx_kklcqGtC4aI8S-lAq5mVX12erRo3uuLm8jvnwj1V9ZRCQ4F2L45NQPzkbdMCyAZYAyDuVedUdLKWrZD395oy3p9Vj3I-AlAJbf-wOqOSd5Jxfl59f48jmsXHiURHZhdsoiSsiz61MtFuwUR0iNbr29VPSEKc4vIZk57viJ7sX3fzuBZJWjD47Cc_ERPD4KefXuSXqLSvdV7IpUve6MfVA6fHjE_286L6-Or6w9Wb-ubd67dXlze14e1hqR3rObhWDNo53kthrZa9G6RD5LrtNCtLGGhnuANAoaUDamk_0IH3ghrdsouq3nzzN5zXQc3JB53uVNRe7a0vpUIlJLADFP75xs8p3q6YF1X-ZHAc9YRxzarrW8EYsP-C9NBRAfwE8g00Keac0P1-AwV1SlQd1ZaoOiWqgKmSaJE92_3XIaD9I9ojLMDLDcCyvq8ek8rG42TQ-lSSVTb6f0_4AV1at1Q</recordid><startdate>20070901</startdate><enddate>20070901</enddate><creator>Holmgren, Gabrielle</creator><creator>Hamrin, Johan</creator><creator>Svärd, Jenny</creator><creator>Mårtensson, Andreas</creator><creator>Gil, José Pedro</creator><creator>Björkman, Anders</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20070901</creationdate><title>Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa</title><author>Holmgren, Gabrielle ; Hamrin, Johan ; Svärd, Jenny ; Mårtensson, Andreas ; Gil, José Pedro ; Björkman, Anders</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-f3840f25baff4875dda78fb7fee4a26a3200b16c4f00e5a7f01d18b1b4851ca23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>ACT</topic><topic>Amodiaquine</topic><topic>Amodiaquine - administration & dosage</topic><topic>Amodiaquine - pharmacology</topic><topic>Amodiaquine - therapeutic use</topic><topic>Animals</topic><topic>Artemisinins - administration & dosage</topic><topic>Artemisinins - pharmacology</topic><topic>Artemisinins - therapeutic use</topic><topic>Child, Preschool</topic><topic>Clinical Trials as Topic</topic><topic>Desethylamodiaquine</topic><topic>Humans</topic><topic>Kenya</topic><topic>Malaria</topic><topic>Membrane Transport Proteins - genetics</topic><topic>Multidrug Resistance-Associated Proteins - genetics</topic><topic>Odds Ratio</topic><topic>pfcrt</topic><topic>pfmdr1</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Plasmodium falciparum - genetics</topic><topic>Protozoan Proteins - genetics</topic><topic>Resistance</topic><topic>Selection, Genetic</topic><topic>Tanzania</topic><topic>Zanzibar</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Holmgren, Gabrielle</creatorcontrib><creatorcontrib>Hamrin, Johan</creatorcontrib><creatorcontrib>Svärd, Jenny</creatorcontrib><creatorcontrib>Mårtensson, Andreas</creatorcontrib><creatorcontrib>Gil, José Pedro</creatorcontrib><creatorcontrib>Björkman, Anders</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Infection, genetics and evolution</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Holmgren, Gabrielle</au><au>Hamrin, Johan</au><au>Svärd, Jenny</au><au>Mårtensson, Andreas</au><au>Gil, José Pedro</au><au>Björkman, Anders</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa</atitle><jtitle>Infection, genetics and evolution</jtitle><addtitle>Infect Genet Evol</addtitle><date>2007-09-01</date><risdate>2007</risdate><volume>7</volume><issue>5</issue><spage>562</spage><epage>569</epage><pages>562-569</pages><issn>1567-1348</issn><eissn>1567-7257</eissn><abstract>Despite the pharmacodynamic advantages with artemisinin-based combination therapy (ACT) and some potentially opposite molecular mechanisms of tolerance to amodiaquine (AQ)/desethylamodiaquine (DEAQ) and artesunate (ART), there is a risk for rapid decay in efficacy if the two drugs are unable to ensure mutual prevention against a selection and spread of drug-resistant parasites.
We have studied if mutations in the
pfcrt and
pfmdr1 genes selected in recurrent infections after AQ monotherapy are also selected after AQ plus ART combination therapy.
Samples for molecular analysis were derived from three clinical trials on children <5 years old with uncomplicated
Plasmodium falciparum malaria; one AQ monotherapy study conducted in Kenya 2003 and two AQ plus ART combination therapy studies conducted in Zanzibar 2002–2003 and 2005, respectively.
The PCR-adjusted treatment failure rates in the three studies were 19%, 8% and 9%, respectively. After monotherapy there was a significant selection of
pfcrt 76T in re-infections (OR not calculable;
p
=
0.048) and of
pfmdr1 86Y in recrudescent infections (OR 8.0;
p
=
0.048). No such selection was found after combination therapy. A selection of
pfmdr1 1246Y and the
pfmdr1 haplotype (a.a 86, 184, 1246) YYY was found in recrudescent infections both after monotherapy (OR 7.6;
p
=
0.009 and OR 3.1;
p
=
0.029) and combination therapy in 2005 (OR 3.6;
p
=
0.017 and OR 5.4;
p
<
0.001).
Hence,
pfmdr1 1246Y with synergistic or compensatory addition of
pfmdr1 86Y and 184Y appears to be involved in AQ/DEAQ resistance and treatment failure. Our results suggest that ART may protect against a selection of these SNPs initially, but maybe not after continuous drug pressure in a population. However, treatment failure rate and spread of
pfmdr1 SNPs may remain at a low level because of the suggested opposite selection by ART and the pharmacodynamic advantages with ACT.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>17467344</pmid><doi>10.1016/j.meegid.2007.03.005</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1567-1348 |
| ispartof | Infection, genetics and evolution, 2007-09, Vol.7 (5), p.562-569 |
| issn | 1567-1348 1567-7257 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_570390 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | ACT Amodiaquine Amodiaquine - administration & dosage Amodiaquine - pharmacology Amodiaquine - therapeutic use Animals Artemisinins - administration & dosage Artemisinins - pharmacology Artemisinins - therapeutic use Child, Preschool Clinical Trials as Topic Desethylamodiaquine Humans Kenya Malaria Membrane Transport Proteins - genetics Multidrug Resistance-Associated Proteins - genetics Odds Ratio pfcrt pfmdr1 Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Protozoan Proteins - genetics Resistance Selection, Genetic Tanzania Zanzibar |
| title | Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa |
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