Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial
Abstract Objectives To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults. Methods In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting co...
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| Veröffentlicht in: | Journal of antimicrobial chemotherapy 2019-02, Vol.74 (2), p.480-488 |
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| creator | Tan, Darrell H S Raboud, Janet M Szadkowski, Leah Grinsztejn, Beatriz Madruga, José Valdez Figueroa, Maria Ines Cahn, Pedro Barton, Simon E Clarke, Amanda Fox, Julie Zubyk, Wendy Walmsley, Sharon L |
| description | Abstract
Objectives
To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.
Methods
In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.
Results
We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P |
| doi_str_mv | 10.1093/jac/dky433 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6337901</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/jac/dky433</oup_id><sourcerecordid>2127197408</sourcerecordid><originalsourceid>FETCH-LOGICAL-c408t-3392a78c84577103c43742fa824f241afb246506fb99bc10006aa9c08fdf4ad63</originalsourceid><addsrcrecordid>eNp9kU9LJDEQxYO46Oh68QNILoIIrZVOutPtQZDxLwh72fUaatKJZswkY7p7wP30GxkVveypqlI_Xr3wCNlncMKg5adz1Kfd86vgfINMmKihKKFlm2QCHKpCiopvk52-nwNAXdXNFtnmwGXNoJmQ-ZW1Rg80WrpCj9ppH1cu0Rjo9FJQHccw0M5o74KhLtA8JoOD6ejt3cMZxZAfB5MCDi4G9DRh6OLC_c2AjpmN3ud2SA79T_LDou_N3nvdJX-ur35Pb4v7Xzd304v7QgtohoLztkTZ6EZUUjLgWnApSotNKWwpGNpZKeoKajtr25lmb59CbDU0trMCu5rvkvO17nKcLUynTbaBXi2TW2B6VRGd-r4J7kk9xpWqOZctsCxw9C6Q4sto-kEtXK-N9xhMHHtVslKyVma3GT1eozrFvk_Gfp5hoN7CUTkctQ4nwwdfjX2iH2lk4HANxHH5P6F_GkqZRQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2127197408</pqid></control><display><type>article</type><title>Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Tan, Darrell H S ; Raboud, Janet M ; Szadkowski, Leah ; Grinsztejn, Beatriz ; Madruga, José Valdez ; Figueroa, Maria Ines ; Cahn, Pedro ; Barton, Simon E ; Clarke, Amanda ; Fox, Julie ; Zubyk, Wendy ; Walmsley, Sharon L</creator><creatorcontrib>Tan, Darrell H S ; Raboud, Janet M ; Szadkowski, Leah ; Grinsztejn, Beatriz ; Madruga, José Valdez ; Figueroa, Maria Ines ; Cahn, Pedro ; Barton, Simon E ; Clarke, Amanda ; Fox, Julie ; Zubyk, Wendy ; Walmsley, Sharon L ; VALIDATE Study Group ; the VALIDATE Study Group</creatorcontrib><description>Abstract
Objectives
To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.
Methods
In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.
Results
We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events.
Conclusions
Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dky433</identifier><identifier>PMID: 30376108</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adult ; Anti-HIV Agents - administration & dosage ; Argentina ; Brazil ; Canada ; CD4 Lymphocyte Count ; Disease Progression ; Female ; HIV Infections - immunology ; HIV Infections - virology ; HIV Seropositivity ; Humans ; Internationality ; Male ; Middle Aged ; Original Research ; Treatment Outcome ; United Kingdom ; Valacyclovir - administration & dosage ; Viral Load - drug effects</subject><ispartof>Journal of antimicrobial chemotherapy, 2019-02, Vol.74 (2), p.480-488</ispartof><rights>The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-3392a78c84577103c43742fa824f241afb246506fb99bc10006aa9c08fdf4ad63</citedby><cites>FETCH-LOGICAL-c408t-3392a78c84577103c43742fa824f241afb246506fb99bc10006aa9c08fdf4ad63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30376108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tan, Darrell H S</creatorcontrib><creatorcontrib>Raboud, Janet M</creatorcontrib><creatorcontrib>Szadkowski, Leah</creatorcontrib><creatorcontrib>Grinsztejn, Beatriz</creatorcontrib><creatorcontrib>Madruga, José Valdez</creatorcontrib><creatorcontrib>Figueroa, Maria Ines</creatorcontrib><creatorcontrib>Cahn, Pedro</creatorcontrib><creatorcontrib>Barton, Simon E</creatorcontrib><creatorcontrib>Clarke, Amanda</creatorcontrib><creatorcontrib>Fox, Julie</creatorcontrib><creatorcontrib>Zubyk, Wendy</creatorcontrib><creatorcontrib>Walmsley, Sharon L</creatorcontrib><creatorcontrib>VALIDATE Study Group</creatorcontrib><creatorcontrib>the VALIDATE Study Group</creatorcontrib><title>Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>Abstract
Objectives
To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.
Methods
In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.
Results
We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events.
Conclusions
Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.</description><subject>Adult</subject><subject>Anti-HIV Agents - administration & dosage</subject><subject>Argentina</subject><subject>Brazil</subject><subject>Canada</subject><subject>CD4 Lymphocyte Count</subject><subject>Disease Progression</subject><subject>Female</subject><subject>HIV Infections - immunology</subject><subject>HIV Infections - virology</subject><subject>HIV Seropositivity</subject><subject>Humans</subject><subject>Internationality</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Original Research</subject><subject>Treatment Outcome</subject><subject>United Kingdom</subject><subject>Valacyclovir - administration & dosage</subject><subject>Viral Load - drug effects</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kU9LJDEQxYO46Oh68QNILoIIrZVOutPtQZDxLwh72fUaatKJZswkY7p7wP30GxkVveypqlI_Xr3wCNlncMKg5adz1Kfd86vgfINMmKihKKFlm2QCHKpCiopvk52-nwNAXdXNFtnmwGXNoJmQ-ZW1Rg80WrpCj9ppH1cu0Rjo9FJQHccw0M5o74KhLtA8JoOD6ejt3cMZxZAfB5MCDi4G9DRh6OLC_c2AjpmN3ud2SA79T_LDou_N3nvdJX-ur35Pb4v7Xzd304v7QgtohoLztkTZ6EZUUjLgWnApSotNKWwpGNpZKeoKajtr25lmb59CbDU0trMCu5rvkvO17nKcLUynTbaBXi2TW2B6VRGd-r4J7kk9xpWqOZctsCxw9C6Q4sto-kEtXK-N9xhMHHtVslKyVma3GT1eozrFvk_Gfp5hoN7CUTkctQ4nwwdfjX2iH2lk4HANxHH5P6F_GkqZRQ</recordid><startdate>20190201</startdate><enddate>20190201</enddate><creator>Tan, Darrell H S</creator><creator>Raboud, Janet M</creator><creator>Szadkowski, Leah</creator><creator>Grinsztejn, Beatriz</creator><creator>Madruga, José Valdez</creator><creator>Figueroa, Maria Ines</creator><creator>Cahn, Pedro</creator><creator>Barton, Simon E</creator><creator>Clarke, Amanda</creator><creator>Fox, Julie</creator><creator>Zubyk, Wendy</creator><creator>Walmsley, Sharon L</creator><general>Oxford University Press</general><scope>TOX</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190201</creationdate><title>Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial</title><author>Tan, Darrell H S ; Raboud, Janet M ; Szadkowski, Leah ; Grinsztejn, Beatriz ; Madruga, José Valdez ; Figueroa, Maria Ines ; Cahn, Pedro ; Barton, Simon E ; Clarke, Amanda ; Fox, Julie ; Zubyk, Wendy ; Walmsley, Sharon L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-3392a78c84577103c43742fa824f241afb246506fb99bc10006aa9c08fdf4ad63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Anti-HIV Agents - administration & dosage</topic><topic>Argentina</topic><topic>Brazil</topic><topic>Canada</topic><topic>CD4 Lymphocyte Count</topic><topic>Disease Progression</topic><topic>Female</topic><topic>HIV Infections - immunology</topic><topic>HIV Infections - virology</topic><topic>HIV Seropositivity</topic><topic>Humans</topic><topic>Internationality</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Original Research</topic><topic>Treatment Outcome</topic><topic>United Kingdom</topic><topic>Valacyclovir - administration & dosage</topic><topic>Viral Load - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tan, Darrell H S</creatorcontrib><creatorcontrib>Raboud, Janet M</creatorcontrib><creatorcontrib>Szadkowski, Leah</creatorcontrib><creatorcontrib>Grinsztejn, Beatriz</creatorcontrib><creatorcontrib>Madruga, José Valdez</creatorcontrib><creatorcontrib>Figueroa, Maria Ines</creatorcontrib><creatorcontrib>Cahn, Pedro</creatorcontrib><creatorcontrib>Barton, Simon E</creatorcontrib><creatorcontrib>Clarke, Amanda</creatorcontrib><creatorcontrib>Fox, Julie</creatorcontrib><creatorcontrib>Zubyk, Wendy</creatorcontrib><creatorcontrib>Walmsley, Sharon L</creatorcontrib><creatorcontrib>VALIDATE Study Group</creatorcontrib><creatorcontrib>the VALIDATE Study Group</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of antimicrobial chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tan, Darrell H S</au><au>Raboud, Janet M</au><au>Szadkowski, Leah</au><au>Grinsztejn, Beatriz</au><au>Madruga, José Valdez</au><au>Figueroa, Maria Ines</au><au>Cahn, Pedro</au><au>Barton, Simon E</au><au>Clarke, Amanda</au><au>Fox, Julie</au><au>Zubyk, Wendy</au><au>Walmsley, Sharon L</au><aucorp>VALIDATE Study Group</aucorp><aucorp>the VALIDATE Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2019-02-01</date><risdate>2019</risdate><volume>74</volume><issue>2</issue><spage>480</spage><epage>488</epage><pages>480-488</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><abstract>Abstract
Objectives
To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.
Methods
In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.
Results
We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events.
Conclusions
Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>30376108</pmid><doi>10.1093/jac/dky433</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Adult Anti-HIV Agents - administration & dosage Argentina Brazil Canada CD4 Lymphocyte Count Disease Progression Female HIV Infections - immunology HIV Infections - virology HIV Seropositivity Humans Internationality Male Middle Aged Original Research Treatment Outcome United Kingdom Valacyclovir - administration & dosage Viral Load - drug effects |
| title | Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial |
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