The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study
Identifieur interne : 000663 ( Pmc/Corpus ); précédent : 000662; suivant : 000664The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study
Auteurs : Katie Wakeham ; Richard Harding ; Jonathan Levin ; Rosalind Parkes-Ratanshi ; Anatoli Kamali ; David G. LallooSource :
- BMC Palliative Care [ 1472-684X ] ; 2017.
Abstract
Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda.
HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures.
During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more.
Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes.
CRYPTOPRO [ISRCTN
The online version of this article (doi:10.1186/s12904-017-0215-y) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12904-017-0215-y
PubMed: 28705181
PubMed Central: 5508714
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PMC:5508714Le document en format XML
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Lalloo</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9764</institution-id><institution-id institution-id-type="GRID">grid.48004.38</institution-id><institution></institution><institution>Liverpool School of Tropical Medicine,</institution></institution-wrap>Liverpool, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28705181</idno><idno type="pmc">5508714</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508714</idno><idno type="RBID">PMC:5508714</idno><idno type="doi">10.1186/s12904-017-0215-y</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000663</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000663</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study</title><author><name sortKey="Wakeham, Katie" sort="Wakeham, Katie" uniqKey="Wakeham K" first="Katie" last="Wakeham">Katie Wakeham</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 6116</institution-id><institution-id institution-id-type="GRID">grid.415861.f</institution-id><institution></institution><institution>MRC/UVRI Uganda Research Unit on AIDS,</institution></institution-wrap>Entebbe, Uganda</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9764</institution-id><institution-id institution-id-type="GRID">grid.48004.38</institution-id><institution></institution><institution>Liverpool School of Tropical Medicine,</institution></institution-wrap>Liverpool, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.410725.5</institution-id><institution>Sussex Cancer Centre,</institution><institution>Brighton and Sussex University Hospital,</institution></institution-wrap>Eastern Road, Brighton, BN2 5DA UK</nlm:aff></affiliation></author><author><name sortKey="Harding, Richard" sort="Harding, Richard" uniqKey="Harding R" first="Richard" last="Harding">Richard Harding</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2322 6764</institution-id><institution-id institution-id-type="GRID">grid.13097.3c</institution-id><institution>Department of Palliative Care, Policy & Rehabilitation,</institution><institution>King’s College London, Cicely Saunders Institute,</institution></institution-wrap>London, UK</nlm:aff></affiliation></author><author><name sortKey="Levin, Jonathan" sort="Levin, Jonathan" uniqKey="Levin J" first="Jonathan" last="Levin">Jonathan Levin</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 6116</institution-id><institution-id institution-id-type="GRID">grid.415861.f</institution-id><institution></institution><institution>MRC/UVRI Uganda Research Unit on AIDS,</institution></institution-wrap>Entebbe, Uganda</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 1135</institution-id><institution-id institution-id-type="GRID">grid.11951.3d</institution-id><institution>School of Public Health, Faculty of Health Sciences,</institution><institution>University of Witwatersrand,</institution></institution-wrap>Johannesburg, South Africa</nlm:aff></affiliation></author><author><name sortKey="Parkes Ratanshi, Rosalind" sort="Parkes Ratanshi, Rosalind" uniqKey="Parkes Ratanshi R" first="Rosalind" last="Parkes-Ratanshi">Rosalind Parkes-Ratanshi</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 6116</institution-id><institution-id institution-id-type="GRID">grid.415861.f</institution-id><institution></institution><institution>MRC/UVRI Uganda Research Unit on AIDS,</institution></institution-wrap>Entebbe, Uganda</nlm:aff></affiliation></author><author><name sortKey="Kamali, Anatoli" sort="Kamali, Anatoli" uniqKey="Kamali A" first="Anatoli" last="Kamali">Anatoli Kamali</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 6116</institution-id><institution-id institution-id-type="GRID">grid.415861.f</institution-id><institution></institution><institution>MRC/UVRI Uganda Research Unit on AIDS,</institution></institution-wrap>Entebbe, Uganda</nlm:aff></affiliation></author><author><name sortKey="Lalloo, David G" sort="Lalloo, David G" uniqKey="Lalloo D" first="David G" last="Lalloo">David G. Lalloo</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9764</institution-id><institution-id institution-id-type="GRID">grid.48004.38</institution-id><institution></institution><institution>Liverpool School of Tropical Medicine,</institution></institution-wrap>Liverpool, UK</nlm:aff></affiliation></author></analytic><series><title level="j">BMC Palliative Care</title><idno type="eISSN">1472-684X</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda.</p></sec><sec><title>Methods</title><p id="Par2">HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures.</p></sec><sec><title>Results</title><p id="Par3">During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more.</p></sec><sec><title>Conclusion</title><p id="Par4">Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes.</p></sec><sec><title>Trial registration</title><p id="Par5">CRYPTOPRO [ISRCTN <ext-link ext-link-type="uri" xlink:href="https://www.isrctn.com/ISRCTN76481529?q=76481529&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search">76481529</ext-link>], November 2004.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12904-017-0215-y) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Selwyn, Pa" uniqKey="Selwyn P">PA Selwyn</name></author><author><name sortKey="Rivard, M" uniqKey="Rivard M">M Rivard</name></author><author><name sortKey="Kappell, D" uniqKey="Kappell D">D Kappell</name></author><author><name sortKey="Goeren, B" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Palliat Care</journal-id><journal-id journal-id-type="iso-abbrev">BMC Palliat Care</journal-id><journal-title-group><journal-title>BMC Palliative Care</journal-title></journal-title-group><issn pub-type="epub">1472-684X</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28705181</article-id><article-id pub-id-type="pmc">5508714</article-id><article-id pub-id-type="publisher-id">215</article-id><article-id pub-id-type="doi">10.1186/s12904-017-0215-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Wakeham</surname><given-names>Katie</given-names></name><address><email>katiewakeham@nhs.net</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Harding</surname><given-names>Richard</given-names></name><address><email>Richardharding@kcl.ac.uk</email></address><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Levin</surname><given-names>Jonathan</given-names></name><address><email>Jonathan.Levin@mrcuganda.org</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Parkes-Ratanshi</surname><given-names>Rosalind</given-names></name><address><email>rp549@medschl.cam.ac.uk</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kamali</surname><given-names>Anatoli</given-names></name><address><email>Anatoli.Kamali@mrcuganda.org</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lalloo</surname><given-names>David G</given-names></name><address><email>David.Lalloo@lstmed.ac.uk</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1790 6116</institution-id><institution-id institution-id-type="GRID">grid.415861.f</institution-id><institution></institution><institution>MRC/UVRI Uganda Research Unit on AIDS,</institution></institution-wrap>Entebbe, Uganda</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9764</institution-id><institution-id institution-id-type="GRID">grid.48004.38</institution-id><institution></institution><institution>Liverpool School of Tropical Medicine,</institution></institution-wrap>Liverpool, UK</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.410725.5</institution-id><institution>Sussex Cancer Centre,</institution><institution>Brighton and Sussex University Hospital,</institution></institution-wrap>Eastern Road, Brighton, BN2 5DA UK</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2322 6764</institution-id><institution-id institution-id-type="GRID">grid.13097.3c</institution-id><institution>Department of Palliative Care, Policy & Rehabilitation,</institution><institution>King’s College London, Cicely Saunders Institute,</institution></institution-wrap>London, UK</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 1135</institution-id><institution-id institution-id-type="GRID">grid.11951.3d</institution-id><institution>School of Public Health, Faculty of Health Sciences,</institution><institution>University of Witwatersrand,</institution></institution-wrap>Johannesburg, South Africa</aff></contrib-group><pub-date pub-type="epub"><day>13</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2018</year></pub-date><volume>17</volume><elocation-id>8</elocation-id><history><date date-type="received"><day>28</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>23</day><month>6</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s). 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda.</p></sec><sec><title>Methods</title><p id="Par2">HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures.</p></sec><sec><title>Results</title><p id="Par3">During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more.</p></sec><sec><title>Conclusion</title><p id="Par4">Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes.</p></sec><sec><title>Trial registration</title><p id="Par5">CRYPTOPRO [ISRCTN <ext-link ext-link-type="uri" xlink:href="https://www.isrctn.com/ISRCTN76481529?q=76481529&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search">76481529</ext-link>], November 2004.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12904-017-0215-y) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Symptom burden</kwd><kwd>Symptom control</kwd><kwd>Palliative care</kwd><kwd>HIV</kwd><kwd>Africa</kwd><kwd>ART</kwd><kwd>Pain</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000265</institution-id><institution>Medical Research Council</institution></institution-wrap></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2018</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p id="Par12">An estimated 36.7 million individuals in Sub-Saharan Africa are infected with HIV [<xref ref-type="bibr" rid="CR1">1</xref>]. The rapid roll-out of anti-retroviral therapy (ART) has led to a treatment coverage of approximately 50% [<xref ref-type="bibr" rid="CR1">1</xref>]. ART suppresses viral replication, restores immune function and has led to significant reductions in morbidity and improved survival. Where treatment is available, HIV infection is transitioning into a chronic disease. A high prevalence of troublesome symptoms is reported at all stages of HIV infection and persists during treatment [<xref ref-type="bibr" rid="CR2">2</xref>–<xref ref-type="bibr" rid="CR5">5</xref>]; if identified, these symptoms can be successfully controlled [<xref ref-type="bibr" rid="CR6">6</xref>]. Growing evidence suggests that unpleasant symptoms are associated with poor treatment adherence [<xref ref-type="bibr" rid="CR7">7</xref>], unprotected sexual intercourse [<xref ref-type="bibr" rid="CR8">8</xref>], HIV viral load rebound [<xref ref-type="bibr" rid="CR9">9</xref>], and reduced quality of life [<xref ref-type="bibr" rid="CR10">10</xref>] potentially influencing HIV transmission [<xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR11">11</xref>]. Furthermore, HIV positive people receiving ART report a higher prevalence of mental health illness [<xref ref-type="bibr" rid="CR5">5</xref>] and perceived stigma than the general population [<xref ref-type="bibr" rid="CR12">12</xref>]. Therefore, managing physical and psychological symptoms through palliation becomes a major challenge in HIV care.</p><p id="Par13">We have previously published evidence of a high prevalence and burden of physical and psychological symptoms among individuals in Uganda who were eligible to begin receiving ART but had not yet started ART [<xref ref-type="bibr" rid="CR4">4</xref>]. Studies that have investigated longitudinal changes in global quality of life of people taking ART in sub-Saharan Africa suggest improvements in some measured outcomes [<xref ref-type="bibr" rid="CR13">13</xref>–<xref ref-type="bibr" rid="CR15">15</xref>]. Individuals with HIV may have multiple physical and psychological symptoms and a detailed assessment and management of illness burden is a vital part of quality of life assessment. However, to date there has been a paucity of longitudinal reports describing detailed clinical symptomatology as an outcome for HIV-infected individuals in sub-Saharan Africa accessing treatment. This study aimed to measure longitudinal symptom burden from before commencing ART and during the first year of treatment in a population of adults with a CD4 count <200 cells /uL in Uganda.</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Setting</title><p id="Par14">The Symptom Burden Longitudinal Cohort Study was conducted in a rural district in South Western Uganda. It was conducted within a double-blind randomised placebo controlled trial which determined that primary prophylaxis with fluconazole reduced morbidity and mortality from invasive cryptococcal disease in HIV infected Ugandan adults [<xref ref-type="bibr" rid="CR16">16</xref>]. ART-naive adults were referred to the CRYPTOPRO study clinic following voluntary testing and counselling at one of the five local HIV care and treatment organisations.</p></sec><sec id="Sec4"><title>Study population</title><p id="Par15">In line with the selection criteria of the main study, study subjects comprised consenting ART-naive adults, with laboratory confirmation of HIV, CD4 count <200 cells/uL, and a negative cryptococcal antigen test. Exclusion criteria included pregnancy and liver function tests greater than three times the upper limit of normal [<xref ref-type="bibr" rid="CR16">16</xref>]. Participants received either 200 mg of fluconazole or an identical placebo (Cipla, India) three times per week from the baseline enrolment visit until the end of the trial (minimum 12 weeks) or until their CD4 count reached 200 cells/μl.</p></sec><sec id="Sec5"><title>Antiretroviral therapy</title><p id="Par16">Local ART providers managed initiating ART independently of the CRYPTOPRO trial team and chose the drug combination and monitored antiretroviral regimens (two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor). Patients were offered routine co-trimoxazole prophylaxis (960 mg three times a week) according to standard Ugandan guidelines.</p></sec><sec id="Sec6"><title>Symptom burden procedure and tools</title><p id="Par17">All ART-naïve participants enrolling in CRYPTOPRO on one randomly chosen day per week between 2007 and 2008 were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) [<xref ref-type="bibr" rid="CR17">17</xref>] with a trained counsellor. The MSAS-SF was translated into local languages, back-translated, and administered to clients in the language of their choice (available as Additional file <xref rid="MOESM1" ref-type="media">1</xref>) . The MSAS-SF was then repeated at either one or two follow-up visits after commencing ART over a one-year period. MSAS-SF is a patient-rated symptom measurement tool, which records the seven-day period prevalence and associated burden of 28 physical and four psychological symptoms. For each symptom the respondent indicated whether or not they have experienced it in the previous 7 days. For those symptoms experienced, each is then scored according to perceived burden. A burden score is allocated to each prevalent physical symptom depending on the level of discomfort reported (not at all = 0.8, a little = 1.6, somewhat = 2.4, quite a bit = 3.2, very much = 4). Similarly, a score is allocated to each prevalent psychological symptom depending on the frequency (rarely = 1, occasionally = 2, frequently = 3, almost constantly = 4). For any symptom (either physical or psychological) that is not experienced, a burden score of zero is allocated. Each MSAS-SF subscale is then calculated from the mean burden score for a pre-defined subset of the items. The Global Distress Index (GDI) is based on 10 parameters; six physical symptoms (pain, lack of energy, lack of appetite, dry mouth, drowsiness and constipation) and four psychological factors (feeling sad, worried, irritated and nervous). The Physical Symptom Distress Score (PHYS) is based on 12 physical symptoms (pain, lack of energy, lack of appetite, feeling drowsy, constipation, dry mouth, nausea, vomiting, change in taste, weight loss, feeling bloated and dizziness). The Psychological Symptom Distress Score (PSYCH) is based on burden of six psychological symptoms (feeling sad, worried, nervous, difficulty sleeping, feeling irritable and difficulty concentrating). Significant symptom distress is suggested by a MSAS-SF subscales scores greater than one. A pilot study of MSAS-SF in Uganda (personal communication, Dr. K. Frame) identified a further nine prevalent physical symptoms (hunger, difficulty moving, difficulty walking, muscle aches, poor vision, poor hearing, sore lumps on private parts, discharge from private parts and bad smell/body odour,) and these were added to our questionnaire, as described previously [<xref ref-type="bibr" rid="CR4">4</xref>].</p></sec><sec id="Sec7"><title>Statistical analysis</title><p id="Par18">Data from hand-annotated symptom burden questionnaire were entered into a database created in MS-ACCESS and patient data was extracted from the main CRYPTOPRO study database. The prevalence of each symptom was tabulated to allow comparison between the pre- and post-ART visits. Individual physical symptom burden reported as “quite a bit” or “very much” was regarded as experiencing “high distress”. Similarly, individuals who reported a psychological symptom causing distress “frequently” or “constantly” were regarded as experiencing “high frequency” distress. The three subscale symptom distress indices (GDI, PHYS and PSYCH) were calculated from the mean burden scores. Changes in subscale symptom distress indices with time on ART was assessed by fitting Linear Mixed Models (LMMs) for repeated measurements [<xref ref-type="bibr" rid="CR18">18</xref>, <xref ref-type="bibr" rid="CR19">19</xref>] to investigate whether, and if so, how, the total symptom score, the global distress index, the physical symptom score and the psychological symptom score changed with time on ART. Scores recorded before initiation of ART were assumed to be at time zero, for other observations time was number of days on ART. Regression analyses carried out on the scales at baseline suggested the use of a square root transformation of the outcome in order to satisfy the assumption of homogeneity of variance. Thus the square-root of each scale was used as the outcome variable, which also ensured that predicted values from the model would always be positive after back-transformation to the original scale. In addition, the models investigated whether there was evidence of non-linearity of the effect of time on ART; the models were fitted using Maximum Likelihood Estimation (MLE) rather than the more conventional Residual Maximum Likelihood Estimation (REML) in order to assess extra fixed effect terms in the model. A quadratic term in days post-ART was added if it significantly increased the model deviance (minus twice the log-likelihood) at the 5% level; the square root of days since ART was used instead of a quadratic model if it resulted in a lower residual deviance than the quadratic model. The number of days post-ART was scaled by dividing by 100 to give greater numerical stability.</p><p id="Par19">Further linear mixed models were fitted to investigate whether the total number of symptoms and the symptom scores were associated with either the ART regimen or the CRYPTOPRO treatment arm (fluconazole vs. placebo), adjusting for CD4 cell count and length of time on ART.</p><p id="Par20">All analyses were carried out using Stata release 11.2 (College Station, TX).</p></sec><sec id="Sec8"><title>Ethics</title><p id="Par21">This study received ethical approval from the Uganda Virus Research Institute and Uganda National Council for Science and Technology.</p></sec></sec><sec id="Sec9"><title>Results</title><sec id="Sec10"><title>Study participant characteristics</title><p id="Par22">From the cohort the MSAS-SF was completed by 97 participants at study baseline before and after initiating ART (Table <xref rid="Tab1" ref-type="table">1</xref>). The median length of time on ART was 300 days (IQR 140–377). Individuals completed two or three data points after initiating ART.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Study participants characteristics (<italic>n</italic> = 97)</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Factor</th><th></th><th><italic>n</italic> (%)</th></tr></thead><tbody><tr><td rowspan="2">Sex</td><td>Male</td><td>30 (31%)</td></tr><tr><td>Female</td><td>67 (69%)</td></tr><tr><td>Age</td><td>Mean (s.d.)</td><td>36 (8)</td></tr><tr><td rowspan="4">WHO HIV stage</td><td>1</td><td>3 (3%)</td></tr><tr><td>2</td><td>34 (35%)</td></tr><tr><td>3</td><td>54 (56%)</td></tr><tr><td>4</td><td>6 (6%)</td></tr><tr><td rowspan="4">CD4 cells (cells/ul)</td><td><50</td><td>22 (23%)</td></tr><tr><td>50–99</td><td>19 (19%)</td></tr><tr><td>100–149</td><td>24 (25%)</td></tr><tr><td>150–199</td><td>32 (33%)</td></tr><tr><td rowspan="3">Main study treatment arm</td><td>Median (IQR)</td><td>120 (58–163)</td></tr><tr><td>Fluconazole</td><td>47 (48%)</td></tr><tr><td>Placebo</td><td>50 (52%)</td></tr><tr><td rowspan="3">Anti-retroviral treatment backbone (missing = 2)</td><td>AZT/3TC</td><td>77 (81%)</td></tr><tr><td>D4T/3TC</td><td>16 (17%)</td></tr><tr><td>Truvada</td><td>2 (2%)</td></tr><tr><td rowspan="2">Non-nucleoside reverse-transcriptase inhibitors (missing = 1)</td><td>Nevirapine</td><td>70 (73%)</td></tr><tr><td>Efavirenz</td><td>26 (27%)</td></tr><tr><td rowspan="2">Died during study</td><td>No</td><td>88 (91%)</td></tr><tr><td>Yes</td><td>9 (9%)</td></tr></tbody></table><table-wrap-foot><p><italic>AZT</italic> zidovudine; <italic>3TC</italic> lamivudine; d4T Stavudine; Truvada emtricitabine and tenofovir disoproxil fumarate</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec11"><title>Seven-day period prevalence of symptoms and symptom distress indices</title><p id="Par23">The prevalence of pain, weight loss, lack of appetite, feeling sad, difficulty sleeping and walking, problems urinating, irritability, feeling nervous and mouth sores reduced in frequency during the early phases of taking ART (Table <xref rid="Tab2" ref-type="table">2</xref>). In cases where individuals had more than one follow-up visit while on ART, the symptom burden at the longest time on ART has been used. The remaining 31 symptoms remained at a similar burden with 16 persistent symptoms having a frequency of over 25%. While the prevalence of pain reduced from 79 to 60% on commencing ART, the burden remains high and of those with pain, 25% reported high distress associated with this symptom. Of concern is that half or more study participants remained with symptoms of itching (%), skin changes (%) and numbness (%) after starting ART. A high prevalence of distress at follow-up was reported for sexual activity (36%), hunger (34%), changes to skin (27%), pain (25%), numbness and tingling (22%), feeling sad (21%) and worry (21%) (Table <xref rid="Tab2" ref-type="table">2</xref>). New symptoms after initiating ART were particularly prevalent for hunger (26%), problems with sexual activity (25%) and cough (20%) (Table <xref rid="Tab2" ref-type="table">2</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Frequency of symptoms in past week prior to starting ART and frequency, distress and prevalence of new symptoms after starting ART for 97 study participants</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Symptom</th><th>Burden of symptoms prior to starting ART [n (%)]</th><th>Burden of symptoms after starting ART [n (%)]</th><th>Prevalence of high distress in participants with symptom after starting ART [n [%)]</th></tr></thead><tbody><tr><td>Pain</td><td>77 (79%)</td><td>58 (60%)</td><td>34 (25%)</td></tr><tr><td>Itching</td><td>69 (69%)</td><td>55 (57%)</td><td>30(31%)</td></tr><tr><td>Changes in skin</td><td>49 (51%)</td><td>51 (53%)</td><td>26 (27%)</td></tr><tr><td>Numbness/tingling in the hands/feet</td><td>52 (54%)</td><td>50 (52%)</td><td>21 (22%)</td></tr><tr><td>Hunger</td><td>47 (43%)</td><td>47 (43%)</td><td>33 (34%)</td></tr><tr><td>Cough</td><td>44 (45%)</td><td>45 (46%)</td><td>14(14%)</td></tr><tr><td>Worrying</td><td>58 (60%)</td><td>44 (45%)</td><td>20(21%)</td></tr><tr><td>Lack of energy</td><td>51 (52%)</td><td>42 (43%)</td><td>17(18%)</td></tr><tr><td>Problems with sexual interest/activity</td><td>37 (33%)</td><td>41 (42%)</td><td>35 (36%)</td></tr><tr><td>Feeling drowsy/tired</td><td>53 (55%)</td><td>40 (41%)</td><td>11 (11%)</td></tr><tr><td>Weight loss</td><td>65 (67%)</td><td>30 (31%)</td><td>11 (11%)</td></tr><tr><td>Lack of appetite</td><td>45 (46%)</td><td>27 (23%)</td><td>16(16%)</td></tr><tr><td>Sores or lumps on private parts</td><td>22 (29%)</td><td>27 (23%)</td><td>11 (11%)</td></tr><tr><td>Dizziness</td><td>38 (39%)</td><td>26(27%)</td><td>12(12%)</td></tr><tr><td>Changes in the way food tastes</td><td>30 (31%)</td><td>24 (25%)</td><td>9 (9%)</td></tr><tr><td>Feeling sad</td><td>50 (52%)</td><td>24 (25%)</td><td>20(21%)</td></tr><tr><td>Difficulty sleeping</td><td>34 (35%)</td><td>22 (23%)</td><td>12(12%)</td></tr><tr><td>Dry mouth</td><td>32 (33%)</td><td>20 (21%)</td><td>5 (5%)</td></tr><tr><td>Nausea</td><td>20 (21%)</td><td>20 (21%)</td><td>8 (8%)</td></tr><tr><td>Difficulty walking</td><td>35 (36%)</td><td>19 (20%)</td><td>7(7%)</td></tr><tr><td>I do not like myself</td><td>28 (29%)</td><td>18 (19%)</td><td>13(13%)</td></tr><tr><td>Muscle aches</td><td>27 (28%)</td><td>18 (19%)</td><td>9 (9%)</td></tr><tr><td>Difficulty seeing well - poor vision</td><td>18 (19%)</td><td>17 (18%)</td><td>6 (6%)</td></tr><tr><td>Constipation</td><td>16 (16%)</td><td>15 (15%)</td><td>7(7%)</td></tr><tr><td>Problems urinating</td><td>18 (19%)</td><td>14 (14%)</td><td>5 (5%)</td></tr><tr><td>Sweats</td><td>29 (30%)</td><td>14 (14%)</td><td>4 (4%)</td></tr><tr><td>Diarrhea</td><td>16 (16%)</td><td>13 (13%)</td><td>7(7%)</td></tr><tr><td>Feeling bloated</td><td>17 (18%)</td><td>13 (13%)</td><td>4 (4%)</td></tr><tr><td>Difficulty swallowing</td><td>I5 (16%)</td><td>12 (12%)</td><td>11 (11%)</td></tr><tr><td>Feeling irritable</td><td>26 (27%)</td><td>11(11%)</td><td>2 (2%)</td></tr><tr><td>Difficulty concentrating</td><td>7 (7%)</td><td>10 (10%)</td><td>3 (3%)</td></tr><tr><td>Difficulty moving</td><td>14 (14%)</td><td>10 (10%)</td><td>2 (2%)</td></tr><tr><td>Shortness of breath</td><td>16 (17%)</td><td>10 (10%)</td><td>4 (4%)</td></tr><tr><td>Bad smell/odour from body</td><td>8(8%)</td><td>8(8%)</td><td>2 (2%)</td></tr><tr><td>Feeling nervous</td><td>27 (28%)</td><td>8(8%)</td><td>4 (4%)</td></tr><tr><td>Difficulty hearing well - poor hearing</td><td>6 (6%)</td><td>7(7%)</td><td>2 (2%)</td></tr><tr><td>Hair loss</td><td>11 (11%)</td><td>7(7%)</td><td>3 (3%)</td></tr><tr><td>Swelling of arms or legs</td><td>9 (9%)</td><td>7(7%)</td><td>3 (3%)</td></tr><tr><td>Discharge from private parts</td><td>15 (16%)</td><td>6(6%)</td><td>4 (4%)</td></tr><tr><td>Vomiting</td><td>8 (8%)</td><td>5(5%)</td><td>1 (1%)</td></tr><tr><td>Mouth sores</td><td>19 (20%)</td><td>3(3%)</td><td>3 (3%)</td></tr></tbody></table></table-wrap></p><p id="Par24">The proportions of participants experiencing numbness or tingling after starting ART were similar for those on an AZT based regimen (51%) and those on a d4T-based regimen (56%). The prevalence of symptoms that could potentially be altered by the trial drug fluconazole, namely pain, weight loss, lack of appetite, sore or discharging private parts, difficult swallowing and mouth sores did not differ between those on the active drug and the placebo in this study.</p></sec><sec id="Sec12"><title>Changes in subscale symptom distress indices with time on ART</title><p id="Par25">The mean total number of symptoms decreased after commencing ART from 12.8 (11.7–13.9) to 7.8 (6.8–8.9) (p = <0.0001) (Table <xref rid="Tab3" ref-type="table">3</xref>). The summary scores for GDI, PHYS and PSYCH all approximately halved after starting ART (Table <xref rid="Tab3" ref-type="table">3</xref>). The change in the total number of symptoms and the three indices with time on ART were investigated through fitting LMMs for repeated measures; the number of symptoms and each index was subject to a square-root transformation to meet the assumption of homogeneity of variance (Table <xref rid="Tab4" ref-type="table">4</xref>, Fig. <xref rid="Fig1" ref-type="fig">1</xref>).<table-wrap id="Tab3"><label>Table 3</label><caption><p>Mean number of symptoms and mean symptom distress indices by visit</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th colspan="2">All Participants (<italic>n</italic> = 97)</th></tr></thead><tbody><tr><td>Index</td><td>Before starting ART, mean value [95% Cl)</td><td>After starting ART, mean value [95% Cl)</td></tr><tr><td>Total number of symptoms</td><td>12.8 (11.7–13.9)</td><td>7.8 (6.8–8.9)</td></tr><tr><td>Global Distress Index</td><td>1.29 (1.1–1.4)</td><td>0.7 (0.6–0.8)</td></tr><tr><td>Physical Symptom Distress</td><td>1.0 (0.9–1.1)</td><td>0.5 (0.4–0.6)</td></tr><tr><td>Psychological Symptom Distress</td><td>1.0 (0.8–1.2)</td><td>0.5 (0.4–0.6)</td></tr></tbody></table></table-wrap><table-wrap id="Tab4"><label>Table 4</label><caption><p>Results for total number of symptoms and symptom distress indices when fitting linear mixed models to transformed sclaes</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Parameter</th><th>Square root of total Number of Symptoms</th><th>Square root of Global Distress Score</th><th>Square root of Physical Symptom Distress Score</th><th>Square root of Psychological Symptom Distress Score</th></tr></thead><tbody><tr><td>Constant</td><td>3.5 (3.4; 3.7)</td><td>1.1 (1.0; 1.1)</td><td>1 (0.9; 1.0)</td><td>0.8 (0.7; 0.9)</td></tr><tr><td>Days/100</td><td>−0.9 (−1.3; −0.6)</td><td>–</td><td>−0.4 (−0.5; −0.3)</td><td>–</td></tr><tr><td>(Days/100)<sup>2</sup></td><td>0.2 (0.04; 0.3)</td><td>–</td><td>0.1 (0.02; 0.1)</td><td>–</td></tr><tr><td>√(Days/100)</td><td>–</td><td>−0.3 (−0.4; −0.2)</td><td>–</td><td>−0.3 (−0.4; −0.2)</td></tr><tr><td>σ<sub>u</sub> (Between subjects)</td><td>0.5 (0.4: 0.7)</td><td>0.1 (0.06; 0.3)</td><td>0.1 (0.1; 0.2)</td><td>0.2 (0.2; 0.4)</td></tr><tr><td>σ<sub>e</sub>(Within subjects)</td><td>0.7 (0.6; 0.8)</td><td>0.4 (0.3; 0.4)</td><td>0.3 (0.3; 0.4)</td><td>0.5 (0.4; 0.5)</td></tr></tbody></table><table-wrap-foot><p>Note that each cell contains the parameter estimate together with 95% confidence limits where appropriate (i.e. if the given <italic>parameter is</italic> included in the model)</p></table-wrap-foot></table-wrap><fig id="Fig1"><label>Fig. 1</label><caption><p>Observed values and fitted curves using a linear mixed model with study participants regarded as having random effects for total number of symptoms (panel <bold>a</bold>), Global Distress Index (panel <bold>b</bold>), Physical Symptom Distress Score (panel <bold>c</bold>) and Psychological Symptom Distress Score (panel <bold>d</bold>)</p></caption><graphic xlink:href="12904_2017_215_Fig1_HTML" id="MO1"></graphic></fig></p><p id="Par26">The model for square-root of the number of symptoms included terms in days post ART and days-squared, leading to the fitted equation for the predicted number of symptoms as follows: SYMPTOMfit = (0.164*(days/100)<sup>2</sup>–0.942*days/100 + 3.51)<sup>2</sup>.</p><p id="Par27">The model for the square root of the Global Distress Index included a term for the square-root of the number of days post ART, leading to the following equation to predict the GDI as follows: GDIfit = (1.07–0.316 * √(days/100))<sup>2</sup>.</p><p id="Par28">The model for the square root of the Physical Symptom Score included terms for day and day-squared, leading to the following equation: PHYSfit = (0.077*(days/100)<sup>2</sup>–0.402*days/100 + .951)<sup>2</sup>.</p><p id="Par29">The model for the square root of the Psychological Symptom Score included a term for the square-root of the number of days post ART, leading to the following equation to predict the score as follows: PSYCHfit = (0.820–0.268 * √(days/100))<sup>2</sup>.</p><p id="Par30">The fitted curve shows that the expected total number of symptoms declines from an initial value of 12.3 at day 0 down to 0.43 at 300 days. The decline is initially fairly rapid and then slows down (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). The graph also shows the great variation between subjects; initially some individuals experience more than 25 symptoms, however after about 100 days no one has more than 20 symptoms and after about 200 days, no one has more than 10 symptoms.</p><p id="Par31">The graph of observed and predicted GDI against days on ART shows that the expected GDI drops from an initial value of 1.15 to 0.27 by day 300 (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). The initial drop in total number of symptoms is relatively quick and it then levels off. The graph of physical symptom scores against days on ART shows that the expected physical symptom score drops from an initial value of 0.90 to 0.19 by day 300. There is however a great deal of variability in this score and some participants still have scores close to 1 towards day 300. As the number of days on ART increases, the psychological symptom expected score drops from an initial value of 0.67 to 0.13 by day 300.</p><p id="Par32">There was no association found between total number of symptoms or the symptom distress indices and ART regimen, CRYPTOPRO treatment arm (fluconazole vs. placebo) or CD4 cell count.</p></sec></sec><sec id="Sec13"><title>Discussion</title><p id="Par33">This longitudinal study of symptom burden during the first year of ART treatment shows that while ART reduces symptom profile in HIV infected individuals, certain symptoms retain a high burden. Of particular concern is the high burden and high distress associated with the top 10 most prevalent symptoms despite commencing ART caused by pain (60%), itch (57%), skin changes (53%), numbness and tingling in hand and feet (52%) and hunger (48%), cough (46%), worry (45%), lack of energy (43%), problems sexual activity (42%) and fatigue (41%).</p><p id="Par34">In accordance with other studies we found that the greatest improvement in patient self-reported outcomes were in the initial months of ART with more modest reductions after longer periods of therapy [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR14">14</xref>]. The MSAS-SF allows collection of extensive information on common physical and psychological symptoms, giving it the advantage of being a clinically useful tool. Symptom burden and quality of life instruments that group markers of wellbeing together enables the comparison of study participants with other populations with chronic illness and further, allows quantification of the outcomes of interventions [<xref ref-type="bibr" rid="CR10">10</xref>]. While quality of life scores are an important outcome, global indices do not allow understanding of changes among individual symptoms. Distressing symptoms may be masked by improvements in global parameters.</p><p id="Par35">There are notable improvements in the overall burden of the majority of both prevalent physical and psychological symptoms, but persistent or residual burden remains in some areas. About 60% of the participants continued to report pain, with one in five people with this symptom continuing to experience high distress. The causes of pain in the setting of HIV illness are multifactorial and it is particularly concerning in a setting with a lack of symptom control management and access to opioid analgesics. Numbness/tingling are reported in about half of study participants before and after commencing ART. Neuropathy is a common complication of HIV and is associated with advanced immunosuppression and low CD4 cell counts [<xref ref-type="bibr" rid="CR20">20</xref>] and has been used as a predictor of death in resource limited settings [<xref ref-type="bibr" rid="CR21">21</xref>]. In this study about 20% of patients developed a new symptom of peripheral neuropathy on commencing ART, but this was not related to the use of stavudine, a drug associated with neuropathy [<xref ref-type="bibr" rid="CR22">22</xref>]. It is feasible that symptoms of pain and neuropathy could be managed effectively and at low cost with analgesics. It is of great concern that there is so little infrastructure available to address the profound symptom burden need [<xref ref-type="bibr" rid="CR23">23</xref>].</p><p id="Par36">Hunger does not decrease with commencing ART. In our study population, barriers to eating such as lack of appetite, nausea, a dry mouth and mouth sores all declined with ART and self-reported weight loss was reduced. However, hunger remained common and reported by about one-half of our participants throughout our study duration. A recent study conducted in Tanzania, Uganda and Zambia identified ART related hunger or not having enough food as a significant contributor to poor ART adherence [<xref ref-type="bibr" rid="CR24">24</xref>]. ART driving increased appetite has been reported and food insecurity in poor populations cannot be overlooked. The integration of food assistance into HIV care programmes improves drug adherence [<xref ref-type="bibr" rid="CR25">25</xref>].</p><p id="Par37">ART was associated with clinically meaningful improvement in psychological symptom burden and feelings of being sad, irritable, and nervous and agreement with the statement “I do not like myself”. However, the psychological burden of worry remained in about a half of adults questioned and was a new symptom in about a third of patients commencing ART. The reasons behind these reports of psychological symptom burden were outside the scope of this study but one could postulate that, as the HIV infection moves from an acute to a chronic illness, a patient’s attitude changes as they realize that they are no longer at risk of an imminent death. Concerns about the future and pressures to adhere to ART, however, may explain the stubborn persistence of worry. A recent study of HIV infected individuals’ views on HIV treatment reported many negative psychosocial effects of ART, including a perceived trade-off between longevity and quality of life with issues surrounding career, finances, relationships with health care workers, housing security, sexual health and stigma [<xref ref-type="bibr" rid="CR26">26</xref>].</p><p id="Par38">The number of symptoms and symptom distress indices reduced to around half of their original score during the duration of this study. Improvements in quality of life subscales, but persistence of a relatively high frequency of specific symptoms after commencing ART is reported in other studies in sub-Saharan Africa [<xref ref-type="bibr" rid="CR13">13</xref>–<xref ref-type="bibr" rid="CR15">15</xref>]. Pitt and colleagues reported that despite a statistically significant improvement in health quality overall, the physical health score declined for nearly one quarter of the subjects and the mental health score declined for over one third [<xref ref-type="bibr" rid="CR13">13</xref>]. In another study, the health related quality of life score for the study population after 12 months of ART had significantly improved, but nearly one-third of patients still experienced some or severe pain after 12 months of ART [<xref ref-type="bibr" rid="CR15">15</xref>]. In a study of the impact of the first 6 months of ART on economic activity in South Africa [<xref ref-type="bibr" rid="CR27">27</xref>] ART was associated with less functional impairment, fewer symptoms and better work performance. But over one-third continued to have functional impairment and the frequency of absenteeism, prevalence of body pain or headaches, fatigue, feeling unwell and depression all remained high. The reasons behind the lack of further improvement with ART are unclear but warrant further investigation; it may represent residual HIV symptoms, treatment related toxicity or complex psychosocial stresses. Data on long-term ART with immunological recovery from Western cohorts suggests a changing profile but persistent burden of symptoms [<xref ref-type="bibr" rid="CR28">28</xref>–<xref ref-type="bibr" rid="CR30">30</xref>]. The implication of this is that ART alone is not sufficient to reverse HIV-associated symptom burden and that clinical support to address physical and psychological needs will be required during the entire disease course.</p><p id="Par39">This study highlights the significant impact that ART can have on improving symptom outcomes during the first year of initiation, but the enduring physical and psychological burden that remains is sobering. Recognition of a residual, often high, burden of symptoms is of key importance for clinicians and policy makers. While relief from pain and suffering is a basic human right [<xref ref-type="bibr" rid="CR31">31</xref>] and requires no further justification, there are other reasons to pay attention to and monitor symptoms. Symptoms may well have a negative impact on ART adherence and risky behavior and hence HIV transmission. A study reported psychological symptom burden was significantly and independently associated with having unprotected sexual intercourse, and poor ART drug adherence [<xref ref-type="bibr" rid="CR11">11</xref>]. Furthermore, physical symptoms including nausea and pain are known to be barriers to ART adherence [<xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR32">32</xref>–<xref ref-type="bibr" rid="CR34">34</xref>].</p><p id="Par40">We believe that this study could have underrepresented the burden of symptoms in the population. Recruitment through a clinical trial with a defined inclusion and exclusion criteria means that participants may have differed in some ways from other HIV-infected Ugandans. The study participants were well enough to travel to a health clinic to be interviewed, and fulfilled strict trial criteria for enrolment. Further, our participants had access to trained medical staff, free diagnostics and treatment throughout the duration of the study and standard protocols existed for investigation and treatment of common HIV related conditions. More women were recruited than men, but the higher female to male ratio is consistent with the gender ratio starting HIV treatment in Uganda [<xref ref-type="bibr" rid="CR35">35</xref>]. Although this was a trial population, the immune status of the study population was broadly representative of individuals at initial presentation for ART in sub-Saharan African countries at the current time [<xref ref-type="bibr" rid="CR36">36</xref>]. We employed a counselor to assist in completing the questionnaire, although the counselors were trained this may have potentially introduced bias.</p></sec><sec id="Sec14"><title>Conclusions</title><p id="Par41">While reductions in symptom burden indices following commencement of ART are encouraging, a high residual frequency of symptoms remains. Commencing ART heralds the mark of personal acceptance of HIV status. ART potentially allows individuals to return to work and normality, and contribute to society. However, the transition from a fatal illness to a chronic disease is placed at risk if symptoms are perceived to out-weigh benefits. On-going symptoms may erode previous improvements in behavior that reduce HIV transmission if symptom burden leads to poor ART adherence and attrition from HIV care [<xref ref-type="bibr" rid="CR37">37</xref>]. It is essential that symptom control measures are applied through the disease and treatment trajectory and is valued for its practical and humanitarian gains.</p></sec></body><back><app-group><app id="App1"><sec id="Sec15"><title>Additional file</title><p id="Par49"><media position="anchor" xlink:href="12904_2017_215_MOESM1_ESM.doc" id="MOESM1"><label>Additional file 1:</label><caption><p>MSAS-SF questionnaire in English and Luganda available in the Additional file section. (DOC 85 kb)</p></caption></media></p></sec></app></app-group><glossary><title>Abbreviations</title><def-list><def-item><term>ART</term><def><p id="Par6">Anti-retroviral therapy</p></def></def-item><def-item><term>GDI</term><def><p id="Par7">Global distress index</p></def></def-item><def-item><term>HIV</term><def><p id="Par8">Human immunodeficiency virus</p></def></def-item><def-item><term>MSAS-SF</term><def><p id="Par9">Memorial Symptom Assessment Scale-Short Form</p></def></def-item><def-item><term>PHYS</term><def><p id="Par10">Physical Symptom Distress Score</p></def></def-item><def-item><term>PSYCH</term><def><p id="Par11">Psychological Symptom Distress Score</p></def></def-item></def-list></glossary><fn-group><fn><p><bold>Electronic supplementary material</bold></p><p>The online version of this article (doi:10.1186/s12904-017-0215-y) contains supplementary material, which is available to authorized users.</p></fn></fn-group><ack><title>Acknowledgements</title><p>We would like to thank the trial participants, staff of The AIDS Support Organisation (TASO) Masaka, Kitovu Mobile AIDS Organisation, Uganda Cares Masaka and Ministry of Health teams. We also thank Dr. Karen Frame of Hospice Africa Uganda for providing us with the prevalent physical symptoms identified in her study. We thank Mr. John Kissa for assistance with data entry and cleaning and Mrs. Doreen Bamukama for participant enrolment.</p><sec id="FPar1"><title>Funding</title><p id="Par42">This research was supported by the Medical Research Council, UK. The funding source had no involvement in the design, data collection, analysis, writing or decision to submit for publication.</p></sec><sec id="FPar2"><title>Availability of data and materials</title><p id="Par43">The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. A link to access the MSAS-SF is as follows: <ext-link ext-link-type="uri" xlink:href="http://www.npcrc.org/files/news/memorial_symptom_assessment_scale_short.pdf">http://www.npcrc.org/files/news/memorial_symptom_assessment_scale_short.pdf</ext-link>.</p><p id="Par44">The adapted verison of the MSAS-SF used in this study is also available.</p></sec></ack><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>KW, RH, AK, DGL study design, KW, JL, RPR, JK acquisition of data, JL, KW analysis, KW, RH, JL interpretation of data, KW, RH, JL, RPR, JK, AK, DGL drafting and finalising manuscript, KW, RH, JL, RPR, JK, AK, DGL approved final version.</p></notes><notes notes-type="COI-statement"><sec id="FPar3"><title>Ethics approval and consent to participate</title><p id="Par45">This study received ethical approval from the Uganda Virus Research Institute and Uganda National Council for Science and Technology. Written informed consent was obtained from all particpants.</p></sec><sec id="FPar4"><title>Consent for publication</title><p id="Par46">Not applicable.</p></sec><sec id="FPar5"><title>Competing interests</title><p id="Par47">The authors declare that they have no competing interest.</p></sec><sec id="FPar6"><title>Publisher’s Note</title><p id="Par48">Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></sec></notes><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><mixed-citation publication-type="other">Global AIDS Update 2016. [<ext-link ext-link-type="uri" xlink:href="http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf">http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf</ext-link>]. 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