Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina
Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and...
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Veröffentlicht in: | The Lancet (British edition) 1997-09, Vol.350 (9082), p.922-927 |
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creator | Mostad, Sara B Overbaugh, Julie DeVange, Dana M Welch, Mary J Chohan, Bhavna Mandaliya, Kishorchandra Nyange, Patrick Martin, Harold L Ndinya-Achola, Jeckoniah Bwayo, Job J Kreiss, Joan K |
description | Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells.
Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of
gag DNA sequences.
HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p=0·00001 and p=0·003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2·9, 95% Cl 1·5–5·7), and with use of low-dose and high-dose oral contraceptive pills (3·8, 1·4–9·9 and 12·3, 1·5–101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12·9, 8·0, and 4·9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3·1, 1·1–9·8) and vaginal candidiasis (2·6, 1·2–5·4) were also correlated with significant increases in HIV-1 DNA detection, but
Chlamydia trachomatis and
Trichomonas vaginalis were not.
Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions. |
doi_str_mv | 10.1016/S0140-6736(97)04240-2 |
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Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of
gag DNA sequences.
HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p=0·00001 and p=0·003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2·9, 95% Cl 1·5–5·7), and with use of low-dose and high-dose oral contraceptive pills (3·8, 1·4–9·9 and 12·3, 1·5–101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12·9, 8·0, and 4·9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3·1, 1·1–9·8) and vaginal candidiasis (2·6, 1·2–5·4) were also correlated with significant increases in HIV-1 DNA detection, but
Chlamydia trachomatis and
Trichomonas vaginalis were not.
Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(97)04240-2</identifier><identifier>PMID: 9314871</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>London: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; AIDS/HIV ; Biological and medical sciences ; Birth control ; Cervix Uteri - drug effects ; Cervix Uteri - virology ; Contraceptives, Oral, Hormonal - pharmacology ; Cross-Sectional Studies ; Deoxyribonucleic acid ; Disease transmission ; DNA ; DNA, Viral - isolation & purification ; Female ; Health risk assessment ; HIV ; HIV Infections - transmission ; HIV Seropositivity ; HIV-1 - immunology ; HIV-1 - isolation & purification ; Hormones ; Human immunodeficiency virus ; Humans ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunopathology ; Infectious Disease Transmission, Vertical ; Kenya ; Lymphocytes ; Medical research ; Medical sciences ; Middle Aged ; Polymerase Chain Reaction ; Population ; Public health ; Risk Factors ; Sexually transmitted diseases ; Sexually Transmitted Diseases, Bacterial - diagnosis ; STD ; Vagina - drug effects ; Vagina - virology ; Vitamin A ; Vitamin A Deficiency - virology</subject><ispartof>The Lancet (British edition), 1997-09, Vol.350 (9082), p.922-927</ispartof><rights>1997 Elsevier Ltd</rights><rights>1997 INIST-CNRS</rights><rights>Copyright Lancet Ltd. Sep 27, 1997</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-a0a93e0a5b25330aeac9f283691395bb3574f460aaa836be991efbc136d6728d3</citedby><cites>FETCH-LOGICAL-c441t-a0a93e0a5b25330aeac9f283691395bb3574f460aaa836be991efbc136d6728d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0140673697042402$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2818872$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9314871$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mostad, Sara B</creatorcontrib><creatorcontrib>Overbaugh, Julie</creatorcontrib><creatorcontrib>DeVange, Dana M</creatorcontrib><creatorcontrib>Welch, Mary J</creatorcontrib><creatorcontrib>Chohan, Bhavna</creatorcontrib><creatorcontrib>Mandaliya, Kishorchandra</creatorcontrib><creatorcontrib>Nyange, Patrick</creatorcontrib><creatorcontrib>Martin, Harold L</creatorcontrib><creatorcontrib>Ndinya-Achola, Jeckoniah</creatorcontrib><creatorcontrib>Bwayo, Job J</creatorcontrib><creatorcontrib>Kreiss, Joan K</creatorcontrib><title>Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells.
Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of
gag DNA sequences.
HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p=0·00001 and p=0·003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2·9, 95% Cl 1·5–5·7), and with use of low-dose and high-dose oral contraceptive pills (3·8, 1·4–9·9 and 12·3, 1·5–101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12·9, 8·0, and 4·9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3·1, 1·1–9·8) and vaginal candidiasis (2·6, 1·2–5·4) were also correlated with significant increases in HIV-1 DNA detection, but
Chlamydia trachomatis and
Trichomonas vaginalis were not.
Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.</description><subject>Adolescent</subject><subject>Adult</subject><subject>AIDS/HIV</subject><subject>Biological and medical sciences</subject><subject>Birth control</subject><subject>Cervix Uteri - drug effects</subject><subject>Cervix Uteri - virology</subject><subject>Contraceptives, Oral, Hormonal - pharmacology</subject><subject>Cross-Sectional Studies</subject><subject>Deoxyribonucleic acid</subject><subject>Disease transmission</subject><subject>DNA</subject><subject>DNA, Viral - isolation & purification</subject><subject>Female</subject><subject>Health risk assessment</subject><subject>HIV</subject><subject>HIV Infections - transmission</subject><subject>HIV Seropositivity</subject><subject>HIV-1 - immunology</subject><subject>HIV-1 - isolation & purification</subject><subject>Hormones</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immunodeficiencies</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Infectious Disease Transmission, Vertical</subject><subject>Kenya</subject><subject>Lymphocytes</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Polymerase Chain Reaction</subject><subject>Population</subject><subject>Public health</subject><subject>Risk Factors</subject><subject>Sexually transmitted diseases</subject><subject>Sexually Transmitted Diseases, Bacterial - diagnosis</subject><subject>STD</subject><subject>Vagina - drug effects</subject><subject>Vagina - virology</subject><subject>Vitamin A</subject><subject>Vitamin A Deficiency - virology</subject><issn>0140-6736</issn><issn>1474-547X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkU-LFDEQxYMo67j6ERaCiChsa9Lp7nROsizqLCx48A_eQnVS2c06ncwmPYN794Obnhnm4MVTqNSvHlXvEXLG2TvOePf-K-MNqzopujdKvmVNXar6EVnwRjZV28ifj8niiDwlz3K-Y4w1HWtPyIkSvOklX5A_y5jGGGBFTQxTAoPrycdwTrd-gtEHekEtOm88BvNwTiFYGqdbTDT5_Is6MFNMmbqYaL5Fa324odHR5dWPilMfHJoJLTW4WhUoxZGW2VKmrf-909rCjQ_wnDxxsMr44vCeku-fPn67XFbXXz5fXV5cV6Zp-FQBAyWQQTvUrRAMEIxydS86xYVqh0G0snHlQAAonwMqxdENhovOdrLurTglr_e66xTvN5gnPfo8LwcB4yZrWWzpuagL-PIf8C5uUnEpa64UY6JXrEDtHjIp5pzQ6XXyI6QHzZmeI9K7iPTsv1ZS7yLSs_jZQXwzjGiPU4dMSv_VoQ_ZwMolCMbnI1b3vO_lLPNhj2FxbOsx6bxLCa1PxXZto__PIn8BONGtMA</recordid><startdate>19970927</startdate><enddate>19970927</enddate><creator>Mostad, Sara B</creator><creator>Overbaugh, Julie</creator><creator>DeVange, Dana M</creator><creator>Welch, Mary J</creator><creator>Chohan, Bhavna</creator><creator>Mandaliya, Kishorchandra</creator><creator>Nyange, Patrick</creator><creator>Martin, Harold L</creator><creator>Ndinya-Achola, Jeckoniah</creator><creator>Bwayo, Job J</creator><creator>Kreiss, Joan K</creator><general>Elsevier Ltd</general><general>Lancet</general><general>Elsevier Limited</general><scope>IQODW</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>0TT</scope><scope>0TZ</scope><scope>0U~</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88C</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AN0</scope><scope>ASE</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FPQ</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K6X</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>KB~</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope></search><sort><creationdate>19970927</creationdate><title>Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina</title><author>Mostad, Sara B ; Overbaugh, Julie ; DeVange, Dana M ; Welch, Mary J ; Chohan, Bhavna ; Mandaliya, Kishorchandra ; Nyange, Patrick ; Martin, Harold L ; Ndinya-Achola, Jeckoniah ; Bwayo, Job J ; Kreiss, Joan K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-a0a93e0a5b25330aeac9f283691395bb3574f460aaa836be991efbc136d6728d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>AIDS/HIV</topic><topic>Biological and medical sciences</topic><topic>Birth control</topic><topic>Cervix Uteri - drug effects</topic><topic>Cervix Uteri - virology</topic><topic>Contraceptives, Oral, Hormonal - pharmacology</topic><topic>Cross-Sectional Studies</topic><topic>Deoxyribonucleic acid</topic><topic>Disease transmission</topic><topic>DNA</topic><topic>DNA, Viral - isolation & purification</topic><topic>Female</topic><topic>Health risk assessment</topic><topic>HIV</topic><topic>HIV Infections - transmission</topic><topic>HIV Seropositivity</topic><topic>HIV-1 - immunology</topic><topic>HIV-1 - isolation & purification</topic><topic>Hormones</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Immunodeficiencies</topic><topic>Immunodeficiencies. Immunoglobulinopathies</topic><topic>Immunopathology</topic><topic>Infectious Disease Transmission, Vertical</topic><topic>Kenya</topic><topic>Lymphocytes</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Polymerase Chain Reaction</topic><topic>Population</topic><topic>Public health</topic><topic>Risk Factors</topic><topic>Sexually transmitted diseases</topic><topic>Sexually Transmitted Diseases, Bacterial - diagnosis</topic><topic>STD</topic><topic>Vagina - drug effects</topic><topic>Vagina - virology</topic><topic>Vitamin A</topic><topic>Vitamin A Deficiency - virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mostad, Sara B</creatorcontrib><creatorcontrib>Overbaugh, Julie</creatorcontrib><creatorcontrib>DeVange, Dana M</creatorcontrib><creatorcontrib>Welch, Mary J</creatorcontrib><creatorcontrib>Chohan, Bhavna</creatorcontrib><creatorcontrib>Mandaliya, 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mostad, Sara B</au><au>Overbaugh, Julie</au><au>DeVange, Dana M</au><au>Welch, Mary J</au><au>Chohan, Bhavna</au><au>Mandaliya, Kishorchandra</au><au>Nyange, Patrick</au><au>Martin, Harold L</au><au>Ndinya-Achola, Jeckoniah</au><au>Bwayo, Job J</au><au>Kreiss, Joan K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>1997-09-27</date><risdate>1997</risdate><volume>350</volume><issue>9082</issue><spage>922</spage><epage>927</epage><pages>922-927</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells.
Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of
gag DNA sequences.
HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p=0·00001 and p=0·003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2·9, 95% Cl 1·5–5·7), and with use of low-dose and high-dose oral contraceptive pills (3·8, 1·4–9·9 and 12·3, 1·5–101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12·9, 8·0, and 4·9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3·1, 1·1–9·8) and vaginal candidiasis (2·6, 1·2–5·4) were also correlated with significant increases in HIV-1 DNA detection, but
Chlamydia trachomatis and
Trichomonas vaginalis were not.
Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.</abstract><cop>London</cop><pub>Elsevier Ltd</pub><pmid>9314871</pmid><doi>10.1016/S0140-6736(97)04240-2</doi><tpages>6</tpages></addata></record> |
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ispartof | The Lancet (British edition), 1997-09, Vol.350 (9082), p.922-927 |
issn | 0140-6736 1474-547X |
language | eng |
recordid | cdi_proquest_miscellaneous_79318132 |
source | MEDLINE; Business Source Complete (EBSCO); ScienceDirect Freedom Collection (Elsevier) |
subjects | Adolescent Adult AIDS/HIV Biological and medical sciences Birth control Cervix Uteri - drug effects Cervix Uteri - virology Contraceptives, Oral, Hormonal - pharmacology Cross-Sectional Studies Deoxyribonucleic acid Disease transmission DNA DNA, Viral - isolation & purification Female Health risk assessment HIV HIV Infections - transmission HIV Seropositivity HIV-1 - immunology HIV-1 - isolation & purification Hormones Human immunodeficiency virus Humans Immunodeficiencies Immunodeficiencies. Immunoglobulinopathies Immunopathology Infectious Disease Transmission, Vertical Kenya Lymphocytes Medical research Medical sciences Middle Aged Polymerase Chain Reaction Population Public health Risk Factors Sexually transmitted diseases Sexually Transmitted Diseases, Bacterial - diagnosis STD Vagina - drug effects Vagina - virology Vitamin A Vitamin A Deficiency - virology |
title | Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T17%3A04%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hormonal%20contraception,%20vitamin%20A%20deficiency,%20and%20other%20risk%20factors%20for%20shedding%20of%20HIV-1%20infected%20cells%20from%20the%20cervix%20and%20vagina&rft.jtitle=The%20Lancet%20(British%20edition)&rft.au=Mostad,%20Sara%20B&rft.date=1997-09-27&rft.volume=350&rft.issue=9082&rft.spage=922&rft.epage=927&rft.pages=922-927&rft.issn=0140-6736&rft.eissn=1474-547X&rft.coden=LANCAO&rft_id=info:doi/10.1016/S0140-6736(97)04240-2&rft_dat=%3Cproquest_cross%3E19228832%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=199003890&rft_id=info:pmid/9314871&rft_els_id=S0140673697042402&rfr_iscdi=true |