Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis
Identifieur interne : 000541 ( Ncbi/Checkpoint ); précédent : 000540; suivant : 000542Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis
Auteurs : David R. Boulware ; David B. Meya ; Conrad Muzoora ; Melissa A. Rolfes ; Katherine Huppler Hullsiek ; Abdu Musubire ; Kabanda Taseera ; Henry W. Nabeta ; Charlotte Schutz ; Darlisha A. Williams ; Radha Rajasingham ; Joshua Rhein ; Friedrich Thienemann ; Melanie W. Lo ; Kirsten Nielsen ; Tracy L. Bergemann ; Andrew Kambugu ; Yukari C. Manabe ; Edward N. Janoff ; Paul R. Bohjanen ; Graeme MeintjesSource :
- The New England journal of medicine [ 0028-4793 ] ; 2014.
Abstract
Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome–related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.
We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.
The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P = 0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P = 0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P = 0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P = 0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.
Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT
Url:
DOI: 10.1056/NEJMoa1312884
PubMed: 24963568
PubMed Central: 4127879
Affiliations:
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PMC:4127879Le document en format XML
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<author><name sortKey="Boulware, David R" sort="Boulware, David R" uniqKey="Boulware D" first="David R." last="Boulware">David R. Boulware</name>
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<author><name sortKey="Meya, David B" sort="Meya, David B" uniqKey="Meya D" first="David B." last="Meya">David B. Meya</name>
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<author><name sortKey="Muzoora, Conrad" sort="Muzoora, Conrad" uniqKey="Muzoora C" first="Conrad" last="Muzoora">Conrad Muzoora</name>
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<author><name sortKey="Rolfes, Melissa A" sort="Rolfes, Melissa A" uniqKey="Rolfes M" first="Melissa A." last="Rolfes">Melissa A. Rolfes</name>
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<author><name sortKey="Huppler Hullsiek, Katherine" sort="Huppler Hullsiek, Katherine" uniqKey="Huppler Hullsiek K" first="Katherine" last="Huppler Hullsiek">Katherine Huppler Hullsiek</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis</title>
<author><name sortKey="Boulware, David R" sort="Boulware, David R" uniqKey="Boulware D" first="David R." last="Boulware">David R. Boulware</name>
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<author><name sortKey="Meya, David B" sort="Meya, David B" uniqKey="Meya D" first="David B." last="Meya">David B. Meya</name>
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<author><name sortKey="Muzoora, Conrad" sort="Muzoora, Conrad" uniqKey="Muzoora C" first="Conrad" last="Muzoora">Conrad Muzoora</name>
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<author><name sortKey="Rolfes, Melissa A" sort="Rolfes, Melissa A" uniqKey="Rolfes M" first="Melissa A." last="Rolfes">Melissa A. Rolfes</name>
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<author><name sortKey="Huppler Hullsiek, Katherine" sort="Huppler Hullsiek, Katherine" uniqKey="Huppler Hullsiek K" first="Katherine" last="Huppler Hullsiek">Katherine Huppler Hullsiek</name>
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<author><name sortKey="Musubire, Abdu" sort="Musubire, Abdu" uniqKey="Musubire A" first="Abdu" last="Musubire">Abdu Musubire</name>
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<author><name sortKey="Taseera, Kabanda" sort="Taseera, Kabanda" uniqKey="Taseera K" first="Kabanda" last="Taseera">Kabanda Taseera</name>
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<author><name sortKey="Nabeta, Henry W" sort="Nabeta, Henry W" uniqKey="Nabeta H" first="Henry W." last="Nabeta">Henry W. Nabeta</name>
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<author><name sortKey="Schutz, Charlotte" sort="Schutz, Charlotte" uniqKey="Schutz C" first="Charlotte" last="Schutz">Charlotte Schutz</name>
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<author><name sortKey="Williams, Darlisha A" sort="Williams, Darlisha A" uniqKey="Williams D" first="Darlisha A." last="Williams">Darlisha A. Williams</name>
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<author><name sortKey="Rajasingham, Radha" sort="Rajasingham, Radha" uniqKey="Rajasingham R" first="Radha" last="Rajasingham">Radha Rajasingham</name>
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<author><name sortKey="Rhein, Joshua" sort="Rhein, Joshua" uniqKey="Rhein J" first="Joshua" last="Rhein">Joshua Rhein</name>
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<author><name sortKey="Lo, Melanie W" sort="Lo, Melanie W" uniqKey="Lo M" first="Melanie W." last="Lo">Melanie W. Lo</name>
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<author><name sortKey="Bergemann, Tracy L" sort="Bergemann, Tracy L" uniqKey="Bergemann T" first="Tracy L." last="Bergemann">Tracy L. Bergemann</name>
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<author><name sortKey="Kambugu, Andrew" sort="Kambugu, Andrew" uniqKey="Kambugu A" first="Andrew" last="Kambugu">Andrew Kambugu</name>
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<author><name sortKey="Manabe, Yukari C" sort="Manabe, Yukari C" uniqKey="Manabe Y" first="Yukari C." last="Manabe">Yukari C. Manabe</name>
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<author><name sortKey="Janoff, Edward N" sort="Janoff, Edward N" uniqKey="Janoff E" first="Edward N." last="Janoff">Edward N. Janoff</name>
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<author><name sortKey="Bohjanen, Paul R" sort="Bohjanen, Paul R" uniqKey="Bohjanen P" first="Paul R." last="Bohjanen">Paul R. Bohjanen</name>
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<author><name sortKey="Meintjes, Graeme" sort="Meintjes, Graeme" uniqKey="Meintjes G" first="Graeme" last="Meintjes">Graeme Meintjes</name>
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<series><title level="j">The New England journal of medicine</title>
<idno type="ISSN">0028-4793</idno>
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<imprint><date when="2014">2014</date>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title>
<p id="P1">Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome–related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P = 0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P = 0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P = 0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P = 0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link>
number, NCT01075152.)</p>
</sec>
</div>
</front>
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<affiliations><list></list>
<tree><noCountry><name sortKey="Bergemann, Tracy L" sort="Bergemann, Tracy L" uniqKey="Bergemann T" first="Tracy L." last="Bergemann">Tracy L. Bergemann</name>
<name sortKey="Bohjanen, Paul R" sort="Bohjanen, Paul R" uniqKey="Bohjanen P" first="Paul R." last="Bohjanen">Paul R. Bohjanen</name>
<name sortKey="Boulware, David R" sort="Boulware, David R" uniqKey="Boulware D" first="David R." last="Boulware">David R. Boulware</name>
<name sortKey="Huppler Hullsiek, Katherine" sort="Huppler Hullsiek, Katherine" uniqKey="Huppler Hullsiek K" first="Katherine" last="Huppler Hullsiek">Katherine Huppler Hullsiek</name>
<name sortKey="Janoff, Edward N" sort="Janoff, Edward N" uniqKey="Janoff E" first="Edward N." last="Janoff">Edward N. Janoff</name>
<name sortKey="Kambugu, Andrew" sort="Kambugu, Andrew" uniqKey="Kambugu A" first="Andrew" last="Kambugu">Andrew Kambugu</name>
<name sortKey="Lo, Melanie W" sort="Lo, Melanie W" uniqKey="Lo M" first="Melanie W." last="Lo">Melanie W. Lo</name>
<name sortKey="Manabe, Yukari C" sort="Manabe, Yukari C" uniqKey="Manabe Y" first="Yukari C." last="Manabe">Yukari C. Manabe</name>
<name sortKey="Meintjes, Graeme" sort="Meintjes, Graeme" uniqKey="Meintjes G" first="Graeme" last="Meintjes">Graeme Meintjes</name>
<name sortKey="Meya, David B" sort="Meya, David B" uniqKey="Meya D" first="David B." last="Meya">David B. Meya</name>
<name sortKey="Musubire, Abdu" sort="Musubire, Abdu" uniqKey="Musubire A" first="Abdu" last="Musubire">Abdu Musubire</name>
<name sortKey="Muzoora, Conrad" sort="Muzoora, Conrad" uniqKey="Muzoora C" first="Conrad" last="Muzoora">Conrad Muzoora</name>
<name sortKey="Nabeta, Henry W" sort="Nabeta, Henry W" uniqKey="Nabeta H" first="Henry W." last="Nabeta">Henry W. Nabeta</name>
<name sortKey="Nielsen, Kirsten" sort="Nielsen, Kirsten" uniqKey="Nielsen K" first="Kirsten" last="Nielsen">Kirsten Nielsen</name>
<name sortKey="Rajasingham, Radha" sort="Rajasingham, Radha" uniqKey="Rajasingham R" first="Radha" last="Rajasingham">Radha Rajasingham</name>
<name sortKey="Rhein, Joshua" sort="Rhein, Joshua" uniqKey="Rhein J" first="Joshua" last="Rhein">Joshua Rhein</name>
<name sortKey="Rolfes, Melissa A" sort="Rolfes, Melissa A" uniqKey="Rolfes M" first="Melissa A." last="Rolfes">Melissa A. Rolfes</name>
<name sortKey="Schutz, Charlotte" sort="Schutz, Charlotte" uniqKey="Schutz C" first="Charlotte" last="Schutz">Charlotte Schutz</name>
<name sortKey="Taseera, Kabanda" sort="Taseera, Kabanda" uniqKey="Taseera K" first="Kabanda" last="Taseera">Kabanda Taseera</name>
<name sortKey="Thienemann, Friedrich" sort="Thienemann, Friedrich" uniqKey="Thienemann F" first="Friedrich" last="Thienemann">Friedrich Thienemann</name>
<name sortKey="Williams, Darlisha A" sort="Williams, Darlisha A" uniqKey="Williams D" first="Darlisha A." last="Williams">Darlisha A. Williams</name>
</noCountry>
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