Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model
Identifieur interne : 001491 ( Istex/Corpus ); précédent : 001490; suivant : 001492Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model
Auteurs : Daniel Westreich ; Joseph Eron ; Frieda Behets ; Charles Van Der Horst ; Annelies Van RieSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2007-03-15.
Abstract
Background. Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. Methods. We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. Results. Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy. Conclusions. Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy
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DOI: 10.1086/511276
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Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Van Der Horst, Charles" sort="Van Der Horst, Charles" uniqKey="Van Der Horst C" first="Charles" last="Van Der Horst">Charles Van Der Horst</name><affiliation><mods:affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Van Rie, Annelies" sort="Van Rie, Annelies" uniqKey="Van Rie A" first="Annelies" last="Van Rie">Annelies Van Rie</name><affiliation><mods:affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: vanrie@email.unc.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Annelies Van Rie, University of North Carolina at Chapel Hill, Dept. of Epidemiology, 2104 McGavran Greenberg Hall, Chapel Hill, NC 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Westreich</name><affiliation><mods:affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Eron, Joseph" sort="Eron, Joseph" uniqKey="Eron J" first="Joseph" last="Eron">Joseph Eron</name><affiliation><mods:affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Behets, Frieda" sort="Behets, Frieda" uniqKey="Behets F" first="Frieda" last="Behets">Frieda Behets</name><affiliation><mods:affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Van Der Horst, Charles" sort="Van Der Horst, Charles" uniqKey="Van Der Horst C" first="Charles" last="Van Der Horst">Charles Van Der Horst</name><affiliation><mods:affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</mods:affiliation></affiliation></author><author><name sortKey="Van Rie, Annelies" sort="Van Rie, Annelies" uniqKey="Van Rie A" first="Annelies" last="Van Rie">Annelies Van Rie</name><affiliation><mods:affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: vanrie@email.unc.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Annelies Van Rie, University of North Carolina at Chapel Hill, Dept. of Epidemiology, 2104 McGavran Greenberg Hall, Chapel Hill, NC 27599-7435</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: vanrie@email.unc.edu</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2007-03-15">2007-03-15</date><biblScope unit="volume">195</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="837">837</biblScope><biblScope unit="page" to="846">846</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. Methods. We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. Results. Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy. Conclusions. Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Daniel Westreich</name><affiliations><json:string>Department of Epidemiology University of North Carolina at Chapel Hill</json:string></affiliations></json:item><json:item><name>Joseph Eron</name><affiliations><json:string>Department of School of Medicine, University of North Carolina at Chapel Hill</json:string></affiliations></json:item><json:item><name>Frieda Behets</name><affiliations><json:string>Department of Epidemiology University of North Carolina at Chapel Hill</json:string></affiliations></json:item><json:item><name>Charles van der Horst</name><affiliations><json:string>Department of School of Medicine, University of North Carolina at Chapel Hill</json:string></affiliations></json:item><json:item><name>Annelies Van Rie</name><affiliations><json:string>Department of Epidemiology University of North Carolina at Chapel Hill</json:string><json:string>E-mail: vanrie@email.unc.edu</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. Methods. We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. Results. Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy. Conclusions. Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy</abstract><qualityIndicators><score>9.496</score><pdfWordCount>5693</pdfWordCount><pdfCharCount>36742</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>208</abstractWordCount><abstractCharCount>1454</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model</title><genre><json:string>research-article</json:string></genre><host><title>The Journal of Infectious 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Epidemiology University of North Carolina at Chapel Hill</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Joseph</forename><surname>Eron</surname></persName><affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Frieda</forename><surname>Behets</surname></persName><affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Charles</forename><surname>van der Horst</surname></persName><affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</affiliation></author><author xml:id="author-0004" corresp="yes"><persName><forename type="first">Annelies</forename><surname>Van Rie</surname></persName><email>vanrie@email.unc.edu</email><email>vanrie@email.unc.edu</email><affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</affiliation><affiliation>Reprints or correspondence: Dr. Annelies Van Rie, University of North Carolina at Chapel Hill, Dept. of Epidemiology, 2104 McGavran Greenberg Hall, Chapel Hill, NC 27599-7435</affiliation></author><idno type="istex">403CFAF596B8EEEEB66F3B1FEFF130BE1D759369</idno><idno type="ark">ark:/67375/HXZ-M25GDJ4D-V</idno><idno type="DOI">10.1086/511276</idno></analytic><monogr><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="publisher-id">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2007-03-15"></date><biblScope unit="volume">195</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="837">837</biblScope><biblScope unit="page" to="846">846</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007</date></creation><abstract><p>Background. Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. Methods. We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. Results. Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy. Conclusions. Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy</p></abstract><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>HIV/AIDS</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Major Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-03-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
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<article-meta>
<article-id pub-id-type="doi">10.1086/511276</article-id>
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<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group>
<subject>HIV/AIDS</subject>
<subj-group>
<subject>Major Article</subject>
</subj-group>
</subj-group>
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<title-group>
<article-title>Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Westreich</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Eron</surname>
<given-names>Joseph</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Behets</surname>
<given-names>Frieda</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>van der Horst</surname>
<given-names>Charles</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Van Rie</surname>
<given-names>Annelies</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="cor1" ref-type="corresp"></xref>
</contrib>
<aff id="A1">
<label>1</label>
<institution>Department of Epidemiology University of North Carolina at Chapel Hill</institution>
</aff>
<aff id="A2">
<label>2</label>
<institution>Department of School of Medicine, University of North Carolina at Chapel Hill</institution>
</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Annelies Van Rie, University of North Carolina at Chapel Hill, Dept. of Epidemiology, 2104 McGavran Greenberg Hall, Chapel Hill, NC 27599-7435 (<email>vanrie@email.unc.edu</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>15</day>
<month>3</month>
<year>2007</year>
</pub-date>
<volume>195</volume>
<issue>6</issue>
<fpage>837</fpage>
<lpage>846</lpage>
<history>
<date date-type="received">
<day>22</day>
<month>6</month>
<year>2006</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>10</month>
<year>2006</year>
</date>
</history>
<copyright-statement>© 2007 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2007</copyright-year>
<abstract>
<p><bold><italic>Background.</italic></bold> Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown.</p>
<p><bold><italic>Methods.</italic></bold> We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens.</p>
<p><bold><italic>Results.</italic></bold> Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy.</p>
<p><bold><italic>Conclusions.</italic></bold> Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy</p>
</abstract>
</article-meta>
</front>
<body>
<p>Mother-to-child transmission (MTCT) of HIV is the leading cause of HIV infection in children [<xref ref-type="bibr" rid="R1">1</xref>]. Although the combination of highly active antiretroviral therapy (HAART), elective cesarean section, and postpartum formula feeding has virtually eliminated MTCT of HIV in the developed world [<xref ref-type="bibr" rid="R1">1</xref>], these interventions are not always feasible in resource-poor settings; thus, the vast majority of new infections in children occur in sub-Saharan Africa [<xref ref-type="bibr" rid="R1">1</xref>, <xref ref-type="bibr" rid="R2">2</xref>]. The effectiveness of several simple, low-cost regimens for prevention of MTCT (PMTCT) in resource-poor settings has been demonstrated [<xref ref-type="bibr" rid="R1">1</xref>, <xref ref-type="bibr" rid="R4">4</xref>]. The most widely adopted of these regimens is single-dose nevirapine (sdNVP), which comprises 1 dose given to the mother at onset of labor and 1 dose given to the infant ≤72 h postpartum [<xref ref-type="bibr" rid="R3">3</xref>]. sdNVP has been shown to reduce MTCT by ∼50% in a breast-feeding population at 4 months of age, compared with the reduction that results from a short course of zidovudine monotherapy [<xref ref-type="bibr" rid="R3">3</xref>], and has been recommended by the World Health Organization (WHO) as an interim PMTCT therapy while more effective and comprehensive interventions are being implemented [<xref ref-type="bibr" rid="R1">1</xref>].</p>
<p>NVP-resistant HIV develops among a proportion of women after exposure to sdNVP for PMTCT [<xref ref-type="bibr" rid="R5">5</xref>–<xref ref-type="bibr" rid="R9">9</xref>]. One early study [<xref ref-type="bibr" rid="R6">6</xref>] reported that NVP resistance-associated mutations were found in a minority (19%) of women and that mutations “faded” and were no longer detectable 12–24 months postpartum. However, more-recent studies have indicated that rates may be much higher, depending on HIV subtype [<xref ref-type="bibr" rid="R5">5</xref>] and the sensitivity of the assay used [<xref ref-type="bibr" rid="R7">7</xref>, <xref ref-type="bibr" rid="R9">9</xref>]; these studies have estimated that the prevalence of mutations among women infected with subtype C may be as high as 65%–70% [<xref ref-type="bibr" rid="R5">5</xref>, <xref ref-type="bibr" rid="R9">9</xref>] and have suggested that resistance mutations may not fade completely [<xref ref-type="bibr" rid="R7">7</xref>]. These findings are of special concern because the first-line HAART regimens most commonly used in resource-poor settings contain either NVP or efavirenz [<xref ref-type="bibr" rid="R10">10</xref>]. Like NVP, efavirenz is a nonnucleoside reverse-transcriptase inhibitor (NNRTI) and is affected by most common resistance mutations emerging from exposure to sdNVP [<xref ref-type="bibr" rid="R6">6</xref>, <xref ref-type="bibr" rid="R11">11</xref>].</p>
<p>Results of the PHPT-2 study of PMTCT therapy in Thailand, which randomized women and infants to receipt of either sdNVP or placebo against a background of universal zidovudine monotherapy, suggest that exposure to sdNVP can impede NVP-based HAART's ability to suppress HIV 6 months after therapy initiation, if HAART is initiated at a median 6 months after PMTCT therapy [<xref ref-type="bibr" rid="R12">12</xref>]. New data from Botswana likewise suggest that initiation of NVP-based HAART soon after sdNVP can have a serious effect on the ability to suppress virus [<xref ref-type="bibr" rid="R13">13</xref>]. However, there are no data on the impact that resistance to NVP has on the long-term mortality of women who begin HAART after participation in a program of PMTCT therapy.</p>
<p>Despite WHO's endorsement, the issue of resistance to NVP continues to raise ethical and scientific concerns [<xref ref-type="bibr" rid="R14">14</xref>, <xref ref-type="bibr" rid="R15">15</xref>] and demands serious reflection on the impact that sdNVP-based PMTCT therapy has on future treatment options for women. We developed a stochastic computer-simulation model to explore the long-term impact that resistance to NVP has on the survival of sub-Saharan African women who participate in programs of PMTCT therapy.</p>
<sec sec-type="methods">
<title>Methods</title>
<p><bold><italic>Model outcome and scenarios.</italic></bold> The main outcome of interest was the 5-and 10-year population-level mortality attributable to exposure to sdNVP for PMTCT. The main outcome was assessed by comparison of mortality in 2 counterfactual PMTCT-therapy scenarios: sdNVP [<xref ref-type="bibr" rid="R3">3</xref>] and “Full-TOPS.” The “Full-TOPS” regimen is a theoretical counterfactual for the sdNVP regimen, similar to the combination of sdNVP and a 4–7-day course of Combivir (zidovudine + lamivudine) administered to the mother, as used in the Treatment Options Preservation Study (TOPS) protocol [<xref ref-type="bibr" rid="R16">16</xref>]. However, in our model this theoretical Full-TOPS regimen removes 100% of NVP resistance attributable to sdNVP—in contrast to the 80% reduction in NVP resistance 6 weeks postpartum, as observed in the TOPS study [<xref ref-type="bibr" rid="R16">16</xref>]. In both the sdNVP and the Full-TOPS scenarios, NVP-based HAART (hereafter denoted simply as “HAART”) was available, at no cost, to 100% of eligible women—that is, to women with a CD4 cell count of <200 cells/mm<sup>3</sup>. The main outcome was calculated by comparing the predicted deaths per 100 women receiving standard sdNVP versus the predicted deaths per 100 women receiving the counterfactual Full-TOPS regimen (with deaths per 100 women expressed as a percentage). To contextualize our model's predictions, we simulated 3 additional scenarios: (1) HAART-based PMTCT therapy, with HAART beginning in the second trimester of pregnancy and continuing 6 months postpartum for all women, regardless of CD4 cell count [<xref ref-type="bibr" rid="R17">17</xref>]; (2) sdNVP only, with HAART subsequently available to 50% of eligible women; and (3) sdNVP only, with HAART subsequently available to 10% of eligible women.</p>
<p><bold><italic>Model structure.</italic></bold> We created a stochastic agent-based state-transition computer model to simulate the long-term survival of 10,000 pregnant sub-Saharan African women participating in programs of PMTCT therapy. We chose an agent-based simulation because we were modeling not transmission events but, instead, only individual life experiences. Thus, each woman was considered from her first antenatal visit until either 10 years later or death and experienced a series of events including entry to antenatal care, PMTCT therapy, gradually declining CD4 cell count, and initiation of HAART if she was eligible to receive it; the states and transitions represented in our model are shown in <xref ref-type="fig" rid="F1">figure 1</xref>. Key events in our model were determined stochastically, on the basis of a time-varying CD4 cell count, because parameters such as risk of death by CD4 cell count or rate of change in CD4 cell count were highly complex and included substantial uncertainty, due to varying availability and quality of the data sources. The predictions of our model were limited to a 10-year time horizon because the data describing experiences with HAART are limited to this time period.</p>
<p><bold><italic>Model assumptions.</italic></bold> As is required in any modeling study, simplifying assumptions about parameters, model structure, and model scenarios were made. We assumed that the quality of programs of PMTCT therapy, adherence to HAART, and adverse-event rates were equal in all scenarios and were similar to those in the source data used. We assumed that a CD4-based model could adequately predict mortality when stratifying by HAART status (before HAART, during HAART, and continuation of HAART after virologic failure). The only HAART regimen available in this simulation was the WHO-recommended and most commonly used first-line NNRTI-based triple-drug combination therapy [<xref ref-type="bibr" rid="R10">10</xref>]. We assumed that no second-line or “rescue therapy” was available, that first-line HAART was available for free, and that every 3 months women were evaluated for HAART eligibility.</p>
<p>The baseline parameters assumed that, as had been observed in the Thai PHPT-2 study [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R18">18</xref>], women exposed to sdNVP were twice as likely as NVP-naive women to fail to suppress HIV to <400 viral copies/mL of peripheral blood at 6 months after HAART initiation. In the baseline scenario, we made the conservative assumption that the presence of resistance mutations after exposure to sdNVP would not fade over time—and, therefore, that, once exposed to sdNVP, a woman would always be at higher risk for virologic failure. For simplicity, we assumed that women in our model would not experience a second pregnancy during follow-up, because there are no data available to model a second exposure to sdNVP and such an exposure's impact on the effectiveness of subsequent HAART.</p>
<p><bold><italic>>Model data.</italic></bold> Model parameters, including characteristics of each woman and the timing of events, were generated probabilistically from distributions derived from an extensive review of published and unpublished data. We performed a variety of key-word searches relevant to each parameter in the PubMed database; searched for scientific and policy documents in online sources including the Web sites of the World Health Organization, the Centers for Disease Control and Prevention, and UNAIDS; and examined proceedings and abstracts from major recent conferences, including the XV and XVI International AIDS Conferences (Thailand and Canada, respectively), the 12th and 13th Conferences on Retroviruses and Opportunistic Infections (United States), and the 3rd IAS Conference on HIV Pathogenesis and Treatment (Brazil). Data from studies in sub-Saharan Africa were included preferentially, but we were obliged to use developed-world data when reliable data from sub-Saharan Africa were not available.</p>
<p>Model parameters are summarized in <xref ref-type="fig" rid="T1">Table 1</xref>. Key parameters include the probability of viral suppression (defined as HIV of <400 viral copies/mL of peripheral blood) at 6 months after initiation of HAART (80% when there is no exposure to NVP and 60% when there is exposure to NVP) [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R18">18</xref>–<xref ref-type="bibr" rid="R25">25</xref>]; the risk of death after virologic failure (∼10%/year, approximately twice what is seen in developed-world cohorts, including PLATO)[<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R27">27</xref>]; and initial CD4 cell count at first antenatal visit (median, 400/mm<sup>3</sup> [interquartile range {IQR}, 260–560/mm<sup>3</sup>]) [<xref ref-type="bibr" rid="R28">28</xref>; and L. A. Guay, personal communication].</p>
<p><bold><italic>Analysis.</italic></bold> The primary outcome of interest was the population-level mortality, 5 and 10 years after PMTCT therapy, attributable to exposure to sdNVP. We estimated this parameter as the difference between the percentage of women surviving in the sdNVP scenario and the percentage surviving in the (counterfactual) Full-TOPS scenario, described above. We report the median and IQR of this difference, from 1000 independent simulations. We also calculated estimates and IQRs of this outcome by CD4-count stratum. Finally, we produced projected survival curves for all modeled PMTCT-therapy scenarios; survival curves were also generated as the median of 1000 model iterations.</p>
<p><bold><italic>Sensitivity analysis.</italic></bold> In sensitivity analysis, we report estimates of the primary outcome under different parameter assumptions. We performed univariate sensitivity analysis on key parameters in all PMTCT-therapy scenarios and report medians and IQRs based on 1000 independent simulations. Rates of CD4 decline in the absence of HAART were varied from 0.75 to 1.5 times as fast as baseline values. Mortality risks before initiation of HAART and before virologic failure were 0.5–1.5 times baseline values. Among women in both the sdNVP and Full-TOPS scenario, overall rates of virologic failure were varied from 0.5 to 2.0 times the baseline values. Also in the sensitivity analysis, we allowed the presence of resistance to NVP after exposure to sdNVP to fade over time. This was modeled as abrupt fading of NVP resistance 18 months after exposure to sdNVP, consistent with a preliminary report on the subject [<xref ref-type="bibr" rid="R29">29</xref>]. Mortality after virologic failure with continuing HAART was varied from a worst case of no benefit of HAART after virologic failure (i.e., mortality reverts to pre-HAART levels) to a best case of the relatively low mortality seen in the developed world after virologic failure [<xref ref-type="bibr" rid="R26">26</xref>]. Last, the HAART-eligibility cutoff was varied from the baseline 200 cells/mm<sup>3</sup> to 275 and 350 cells/mm<sup>3</sup>.</p>
<p>Multivariate sensitivity analyses were performed by grouping factors from univariate sensitivity analysis into “clinical best” and “clinical worst” groups (all those factors that increased or decreased overall survival) and “impact best” and “impact worst” groups (all those factors that increased or decreased the impact that sdNVP had on survival).</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p>Computer simulations predict that exposure to sdNVP will have a relatively modest impact on the subsequent 10-year survival of HIV-infected women in sub-Saharan Africa. Under baseline assumptions and with 100% HAART access for eligible immunosuppressed women, the predicted excess mortality (expressed as a proportion of that in the baseline cohort) in women exposed to the sdNVP regimen is 1.1% (IQR, 0.6%–1.5%) at 5 years and 3.5% (IQR, 3.1%–3.9%) at 10 years after PMTCT therapy (<xref ref-type="fig" rid="T2">Table 2</xref>). Stochastic variation around these point estimates is shown in <xref ref-type="fig" rid="F2">figure 2</xref> (“Baseline”). Predicted excess mortality 10 years after sdNVP for PMTCT is highest, 6.9% (IQR, 6.4%–7.3%), among women with CD4 cell counts in the range of 201–350 cells/mm<sup>3</sup>. The impact of sdNVP decreases as CD4 cell counts at first antenatal-care visit increase (<xref ref-type="fig" rid="T2">Table 2</xref>).</p>
<p>Our model predicts a survival benefit when women receive HAART for PMTCT. The absolute survival benefit of HAART for PMTCT, compared with that of sdNVP for PMTCT, is 8.2% at 2.5 years after PMTCT therapy and wanes gradually thereafter (<xref ref-type="fig" rid="F3">figure 3</xref>).</p>
<p>Reduced HAART access for eligible immunosuppressed women dramatically decreases survival at all time points. When only 10% of eligible women have access to HAART, a level that still exceeds current levels of HAART access in many sub-Saharan African countries, excess mortality at 10 years is ∼19% (or 19 deaths/100 women, at baseline), compared with that in a comparable scenario with 100% HAART access (<xref ref-type="fig" rid="F3">figure 3</xref>).</p>
<p><bold><italic>Sensitivity analysis.</italic></bold> The predictions of our model were robust to univariate changes in key parameters, at both 5 and 10 years after PMTCT therapy. The 5-year excess mortality was 0.2%–3.2% and the 10-year excess mortality was 0.6%–5.8%, compared with baseline values of 1.1% and 3.5% (<xref ref-type="fig" rid="T2">Table 2</xref>). In addition, the estimate of 10-year mortality for HAART for PMTCT is 71% (<xref ref-type="fig" rid="F3">figure 3</xref>) and decreases to 66% when the CD4cell-count eligibility criterion is changed to 350 cells/mm<sup>3</sup> (data not shown). The estimates of mortality attributable to exposure to sdNVP do not change substantially when the CD4-cell-count eligibility cutoffs are varied (<xref ref-type="fig" rid="T2">Table 2</xref>).</p>
<p>We performed “best/worst clinical case” and “best-/worst impact case” multivariate sensitivity analyses (<xref ref-type="fig" rid="T2">Table 2</xref>). In the worst clinical case, with all parameters reflecting a pessimistic clinical outcome, our model predicts that the absolute excess mortality due to exposure to sdNVP will be 5.3% (IQR, 4.9%–5.8%) and 5.1% (IQR, 4.9%–5.4%), respectively, at 5 and 10 years after PMTCT therapy; in the worst-impact case, with all parameters conspiring to produce the largest impact that exposure to sdNVP has on mortality, our model predicts an absolute excess mortality of 4.7% (IQR, 4.2%–5.1%) and 10.4% (IQR, 10.0%–10.9%), respectively, at 5 and 10 years after PMTCT therapy. In contrast, our model predicts a 10-year excess mortality of only 0.3% (IQR, −0.1% to 0.8%) and 0.0% (IQR, −0.4% to 0.4%), respectively, in the best clinical and best-impact cases. Stochastic variation produced by 1000 individual model iterations for the baseline scenario and all multivariate sensitivity analyses are shown in <xref ref-type="fig" rid="F2">figure 2</xref>.</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>The use of sdNVP for PMTCT can lead to drug resistance in both the mother and the child [<xref ref-type="bibr" rid="R3">3</xref>, <xref ref-type="bibr" rid="R5">5</xref>, <xref ref-type="bibr" rid="R6">6</xref>, <xref ref-type="bibr" rid="R30">30</xref>]. Recent reports have demonstrated that NVP resistance developed during PMTCT therapy has a deleterious effect on the short-term virologic efficacy of subsequent NVP-based HAART [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R18">18</xref>]. The present report's computer-simulation study suggests that, when HAART is available to 100% of eligible women, the effects that NVP resistance has on survival after PMTCT therapy will be relatively small, with an excess mortality of ∼1.1% and ∼3.5% at 5 and 10 years, respectively, after PMTCT therapy. These estimates are robust to significant univariate changes in key parameters. The worst impact predicted by a pessimistic combination of parameters was a 10.4% excess mortality 10 years after PMTCT therapy. The largest impact that exposure to sdNVP had on subsequent mortality was among women who entered antenatal care with CD4 cell counts of 200–350 cells/mm<sup>3</sup>—that is, those women who become eligible for HAART soonest after other PMTCT therapy. Our baseline results are consistent with the observation of no significant increase in 1year risk of death in a large Zambian cohort of women followed after receiving sdNVP for PMTCT [<xref ref-type="bibr" rid="R31">31</xref>].</p>
<p>Our model projects a short-term survival benefit of HAART therapy for PMTCT. Although our modeling study assumed that second-line HAART regimens would not be available, a recent modeling study by Holmes et al. [<xref ref-type="bibr" rid="R32">32</xref>] examined optimal sequencing of HAART regimens after exposure to sdNVP in South Africa, where both NNRTI-based HAART and second-line protease inhibitor (PI)-based HAART are available. These investigators concluded that a PI-based regimen followed by an NNRTI-based regimen resulted in the longest life expectancy; however, their model did not directly estimate the mortality impact that sdNVP therapy had at the population level, nor are the results directly applicable to many parts of sub-Saharan Africa, where access is limited to first-line HAART and where PI-based therapy is not yet available. The sensitivity analysis of our model does indicate that mortality attributable to exposure to sdNVP decreases as mortality after virologic failure decreases. It can therefore be predicted that widespread access to second-line HAART in sub-Saharan Africa would further decrease the excess mortality due to sdNVP. This prediction is complicated, however, by the possibility that resistance mutations against first-line drugs other than NVP could develop, which, in turn, could reduce the effectiveness of second-line HAART.</p>
<p>Our model predicts that, compared with what is observed for the sdNVP regimen, a small but distinct survival benefit (an increase of ∼2 months in median survival time) is associated with the Full-TOPS scenario. Similarly, Holmes et al. predict a 3.7-month life-expectancy difference between women receiving only sdNVP and women receiving sdNVP combined with a TOPS-like regimen (a treatment that eliminates ∼80% of detectable NVP resistance), when both treatments are followed by NVP-based HAART.</p>
<p>Furthermore, our model predicts that mortality attributable to an overall lack of HAART access will far outweigh that attributable to NVP resistance following sdNVP for PMTCT. When only 50% of eligible women have access to HAART, the 10-year mortality increases by 10 deaths per 100 women at baseline. Similarly, when only 10% of women have HAART access, the 10-year mortality increases by 19 deaths per 100 women at baseline (<xref ref-type="fig" rid="F3">figure 3</xref>).</p>
<p>The present study has significant limitations. First, because of the limited available data on long-term outcomes of HAART in sub-Saharan Africa, we were sometimes forced to use or adapt data from the developed world. Preliminary data from sub-Saharan Africa indicates that, in contrast to the published data from Thailand [<xref ref-type="bibr" rid="R12">12</xref>], the impact of exposure to sdNVP may fade with time [<xref ref-type="bibr" rid="R13">13</xref>, <xref ref-type="bibr" rid="R29">29</xref>]. To obtain conservative estimates of the effect of sdNVP, our model deliberately assumed that the effect of sdNVP does not fade over time. However, if these preliminary results from South Africa and Botswana are confirmed, the clinical impact of sdNVP may be more like what is estimated in our model's best-case scenarios. Published data also suggest that the development of NVP resistance after sdNVP therapy depends on HIV clade [<xref ref-type="bibr" rid="R5">5</xref>], thereby limiting the generalizability of results obtained from a single region of the world. Nevertheless, sensitivity analyses show that, despite uncertainties introduced by using data from multiple settings, our results are largely robust.</p>
<p>A second limitation is that we chose to model disease progression and risk of death by use of CD4 cell counts rather than viral load, a decision that may be important in light of recent reports suggesting a disconnect between immune reconstitution and virologic suppression [<xref ref-type="bibr" rid="R33">33</xref>]. However, because of the expense of viral-load monitoring, there are few reliable viral-load data on HIV-positive individuals living in sub-Saharan Africa; therefore, using viral load to track disease progression would have created more uncertainty than it would have eliminated. The key role played by CD4 cell counts may have contributed to the overall high 10-year mortality projected by our model (<xref ref-type="fig" rid="F3">figure 3</xref>), even when HAART was universally available for eligible women (i.e., those with CD4 cell counts of 200 cells/mm<sup>3</sup>). In the HAART era, this mortality rate is substantially higher than those in cohort studies in developed-world settings [<xref ref-type="bibr" rid="R25">25</xref>–<xref ref-type="bibr" rid="R27">27</xref>, <xref ref-type="bibr" rid="R34">34</xref>]. One explanation is the relatively low CD4 cell counts of women at the first antenatal visit; 75% had a CD4 cell count of <560/mm<sup>3</sup> (<xref ref-type="fig" rid="T1">Table 1</xref>). Furthermore, some mortality parameters were derived from populations without access to HAART and may tend to overestimate mortality when HAART is available, especially when CD4 cell counts are near the eligibility cutoff. Both univariate and multivariate sensitivity analyses demonstrate that the results of our model remain valid even if the baseline parameters overestimate overall mortality rates, suggesting that the impact of exposure to sdNVP will remain relatively small even if the mortality of the entire cohort improves.</p>
<p>Perhaps most important, our modeling study examined mortality, which is only a single, although key, issue in the sdNVP debate. Other important concerns include the (1) effectiveness of the various PMTCT regimens; (2) differences, in stigma, cost, and logistics, related to the implementation of those PMTCT regimens; (3) potential increases in morbidity and reductions in quality of life, because of reduced effectiveness of HAART administered after sdNVP; (4) transmission of NVP-resistant virus to infants and partners; and (5) potential decreased efficacy of sdNVP for PMTCT in future pregnancies. Any discussion of sdNVP must give full consideration to all of these factors.</p>
<p>The results of our model predict 3.5% excess mortality 10 years after administration of sdNVP for PMTCT, a prediction that is optimistic in comparison with the initial forecasts based on short-term virologic outcome in women who initiated HAART soon after PMTCT therapy. Predicting population-level outcomes on the basis of this select group of women and using virologic failure as a proxy for immunologic endpoints may therefore overestimate the impact that exposure to sdNVP has on mortality. Indeed, observations from the developed world suggest that virologic failure is not a good predictor of mortality if the patient continues to receive HAART [<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R35">35</xref>], and preliminary data from a large cohort in Zambia are consistent with our more optimistic predictions [<xref ref-type="bibr" rid="R31">31</xref>].</p>
<p>Although our model predicts that sdNVP therapy will have a modest impact on mortality, it is axiomatic that, whenever possible, NVP resistance should be avoided, via the use of a short course of either Combivir for the mother (TOPS protocol) or alternative PMTCT regimens [<xref ref-type="bibr" rid="R1">1</xref>]. On the other hand, the growing pediatric HIV epidemic in resource-poor countries demands rapid and universal access to PMTCT therapy. In light of the proven effectiveness of the “simple” sdNVP-based PMTCT regimen, our results imply that, in resource-poor settings, its rollout should not be delayed because of fear of compromising women's response to HAART.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank Prof. Alun Lloyd (Department of Mathematics, North Carolina State University) for helpful conversations in the development of our model. We also thank two anonymous reviewers for very helpful comments.</p>
</ack>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="F1" position="float">
<label>Figure 1.</label>
<caption><p>State-transition diagram for the model. Women enter the model during pregnancy and are monitored through the states presented in the diagram, until either death or the end of a 10-year follow-up.</p></caption>
<graphic mimetype="image" xlink:href="195-6-837-fig001.tif"></graphic>
</fig>
<fig id="F2" position="float">
<label>Figure 2.</label>
<caption><p>Results of 1000 runs of the model. The outcome is the excess mortality (measured as a percentage of that in the baseline population) attributable to exposure to single-dose nevirapine (sdNVP) for the prevention of mother-to-child transmission of HIV, 5 years (<italic>black dots</italic>) and 10 years (<italic>white dots</italic>) after initiation of antenatal care. The worst-impact case combines all univariate factors that create a higher overall impact of exposure to sdNVP; the worst clinical case combines all factors leading to worse clinical outcomes in women in the model; the best-impact and best clinical cases are defined analogously.</p></caption>
<graphic mimetype="image" xlink:href="195-6-837-fig002.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Figure 3.</label>
<caption><p>Predicted 10-year survival curves for 5 regimens for prevention of mother-to-child transmission (PMTCT) of HIV, when baseline parameters are used.</p></caption>
<graphic mimetype="image" xlink:href="195-6-837-fig003.tif"></graphic>
</fig>
<fig id="T1" position="float">
<label>Table 1.</label>
<caption><p>Baseline values of parameters in model.</p></caption>
<graphic mimetype="image" xlink:href="195-6-837-tbl001.tif"></graphic>
</fig>
<fig id="T2" position="float">
<label>Table 2.</label>
<caption><p>Median and intraquartile range (IQR) of excess mortality attributable to exposure to single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT) of HIV, at baseline and in sensitivity analyses.</p></caption>
<graphic mimetype="image" xlink:href="195-6-837-tbl002.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="conflict">
<p>Potential conflicts of interest: J.E. receives funding as an ad hoc consultant to Boehringer Ingelheim, the manufacturer of nevirapine, and is also a consultant to LabCorp.</p>
</fn>
<fn fn-type="presented-at">
<p>Presented in part: 12th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 22–25 February 2005 (oral abstract 73LB); 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil, 24–27 July 2005 (session MoFo0102); XVI International AIDS Conference, Toronto, Canada, 13–18 August 2006 (abstract MOPE0321).</p>
</fn>
<fn fn-type="financial-disclosure">
<p>Financial support: University of North Carolina (UNC) Graduate School Merit Assistantship (to D.W.); UNC-Global AIDS Program (Centers for Disease Control and Prevention [CDC] grant U62 CCU422 to D.W., F.B., and A.V.R.); UNC-Center for AIDS Research (grant P30-AI50410 to J.E. and C. v.d.H.); CDC Breastfeeding, Antiretroviral, and Nutrition (BAN) in HIV (CDC Special Interest Project 26-04, U48/DP000059-01 to C.v.d.H.).</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Survival in Women Exposed to Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV: A Stochastic Model</title></titleInfo><name type="personal"><namePart type="given">Daniel</namePart><namePart type="family">Westreich</namePart><affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joseph</namePart><namePart type="family">Eron</namePart><affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frieda</namePart><namePart type="family">Behets</namePart><affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Charles</namePart><namePart type="family">van der Horst</namePart><affiliation>Department of School of Medicine, University of North Carolina at Chapel Hill</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Annelies</namePart><namePart type="family">Van Rie</namePart><affiliation>Department of Epidemiology University of North Carolina at Chapel Hill</affiliation><affiliation>E-mail: vanrie@email.unc.edu</affiliation><affiliation>Reprints or correspondence: Dr. Annelies Van Rie, University of North Carolina at Chapel Hill, Dept. of Epidemiology, 2104 McGavran Greenberg Hall, Chapel Hill, NC 27599-7435</affiliation><affiliation>E-mail: vanrie@email.unc.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2007-03-15</dateIssued><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><abstract>Background. Single-dose nevirapine (sdNVP)-based regimens reduce mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) but result in resistance to NVP and may reduce the ability of highly active antiretroviral therapy (HAART) used for prevention of MTCT (PMTCT). The impact that sdNVP has on survival in the era of increasing access to HAART is unknown. Methods. We developed a stochastic simulation model to predict survival and sdNVP-attributable mortality in sub-Saharan African women exposed to different PMTCT regimens. Results. Our model predicts that mortality attributable to exposure to sdNVP is low—1.1% (interquartile range [IQR], 0.6%–1.5%) and 3.5% (IQR, 3.1%–3.9%) at 5 and 10 years after PMTCT therapy—when all eligible women receive HAART after PMTCT therapy. Predictions were robust to univariate sensitivity analysis. In the worst-case multivariate sensitivity analysis, the increased mortality attributable to sdNVP was 10.4% (IQR, 10.0%–10.8%) at 10 years after PMTCT therapy. Conclusions. Concern has been expressed that widespread use of sdNVP for PMTCT in resource-poor settings will compromise the effectiveness of HAART in HIV-infected women. Although our model does not address other important outcomes of PMTCT regimens, such as transmission of resistant virus, it provides strong arguments that sdNVP for PMTCT should not be delayed because of fear of compromising the survival of women after PMTCT therapy</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><subject><topic>HIV/AIDS</topic></subject><subject><topic>Major Article</topic></subject><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2007</date><detail type="volume"><caption>vol.</caption><number>195</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>837</start><end>846</end></extent></part></relatedItem><identifier type="istex">403CFAF596B8EEEEB66F3B1FEFF130BE1D759369</identifier><identifier type="DOI">10.1086/511276</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2007 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© 2007 by the Infectious Diseases Society of America</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/metadata/json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/403CFAF596B8EEEEB66F3B1FEFF130BE1D759369/annexes/gif</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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