The objectives of the study were (1) to quantify adherence rate among the study participants in the ART unit and (2) to identify factors that contribute to non-adherence. This cross sectional study was carried out at Nekemete referral clinic. Data was collected using a self-developed structured questionnaire where a total of 338 participants grouped into adherent and non-adherent based on a score derived from an adherence assessment were interviewed. Data was analysed using the Statistical Package for Social Sciences (SPSS) version 17.0. By using multivariate analysis of variables identified as correlates of adherence, non-adherence was common among those; with age between 18-30 yrs, with no education, who were not married, who had no pipe water supply, those with no electricity in the house, who perceived had no access to assistance from providers, who perceived the health care providers (HCPs) did not keep information confidentially, who had a language barrier with providers, and who were treated with a psychiatric illness. The study concludes that adherence is multi-factorial and varies significantly by individual and care setting. Psychosocial factors were found to impact adherence and should be analysed in more detail by further studies. Three psychosocial factors were independently associated with poor adherence: the study found that patients perceiving poor access; those perceiving problems in information confidentiality (and possibly experiencing stigmatisation); and having psychiatric morbidity (and possibly with less social support) are more likely to be non-adherent. Furthermore, individuals without electricity and those without piped water supply, implying low income, are at risk for non-adherence / Health Studies / M.A. (Public Health)

The earlier optimism generated by the efficacy of antiretroviral drugs in human immuno-deficiency virus (HIV) patients has been dissipated in the face of the enormous chal-lenge of maintaining a nearly perfect adherence indefinitely. This study set to determine the influence of HIV adherence self-efficacy and beliefs about medicines on antiretrovi-ral therapy adherence, with the aim of developing a framework for enhancing antiretrovi-ral therapy (ART) adherence through focused intervention on modifiable factors from study variables that are strongly associated with ART adherence. A descriptive correlational design was used to assess the predictive relationships of HIV adherence Self-Efficacy, Beliefs about Medicines and ART adherence among 232 HIV-infected patients in a large public health facility in Pretoria. Participants' medication be-liefs were assessed using the Beliefs about Medicines Questionnaire, HIV adherence self-efficacy was assessed with HIV adherence self-efficacy scale (HIV-ASES) and ART adherence was assessed using the AIDS Clinical Trial Group questionnaire. Pearson correlation analysis was used to assess bivariate associations among the variables, and multiple regression analysis was used to examine the relationships among the inde-pendent variables and ART adherence. Mean adherence for the 232 participants was 95% (SD=13.2). Correlation analysis re-vealed positive bivariate associations between perceived general harm and overuse of medications, and ART adherence (p<0.05); between specific necessity and concerns about ARVs, and perceived general harm and overuse of medications (p<0.05); be-tween HIV adherence self efficacy and ART non-adherence (p<0.05). Multiple regres-sion analysis showed significance for perceived general harm and overuse of medica-tions on ART adherence (F(1;231)=11,583;p<0,001) with perceived general harmful ef-fects and overuse of medications explaining 4.8% of the variance. There was signifi-cance for HIV adherence self-efficacy on ART non-adherence (F(1;41)=4.440; p<0.041), with HIV-ASES explaining 9,8% of the variance. Based on the results, a framework for enhancing ART adherence was developed. Activities in the framework consist of baseline screening for adherence facilitators and barriers using the beliefs about medicine questionnaire and HIV ASES, this is followed by focused interventions on identified barriers of ART adherence / Health Studies / D.Litt. et Phil. (Health Studies)

The purpose of this study was to evaluate the antiretroviral therapy program in primary health care settings in Lesotho. Mixed methods research using a convergent parallel mixed methods design was used to collect both quantitative and qualitative data which were analysed during the same phase of the research process. Two groups of participants participated in the study, the registered nurse group was composed of registered nurses/midwives/nurse clinicians involved in ART service provision and the second group was composed of adults aged 18 years and older who were HIV/AIDS positive. Quantitative data had a compliance rate of 92% and it were analysed using SPSS (23). Qualitative data were analysed using constant comparison analysis and seven themes, fourteen categories and twenty two sub-categories emerged from the data analysis. Findings of the study revealed that the majority of PHC facilities were staffed by registered nurse midwives and nurse clinicians who were qualified, confident, knowledgeable and competent in the execution of duties. Generally there were a large number of patients that sought ART services which were offered on a weekly basis although there was variation in the actual number of days the services were provided. The time patients spent seeking ART services varied across the facilities and ARVs and other drugs were usually available. Challenges in the delivery of ART services included unsatisfactory staffing resulting in the provision of inadequate services and work overload, lack of knowledge of some patients, use of incentives by some partners and too many partners being involved in ART, inadequate documentary evidence and stigma pertaining to the HIV status of individuals. Furthermore, ARVs were reported to make patients feel hungry hence resulting in lack of satisfaction in ART services, ART services were inadequate due to dysfunctional equipment and some patients had been lost due to inability to screen for cancer and there was incomplete monitoring and evaluation of the ART program. However, participants in this study generally showed their acknowledgement of the ART services as they generally improved their health status despite the many challenges that were being faced. / Health Studies / D.Litt.et Phil. (Health Studies)

The objectives of the study were (1) to quantify adherence rate among the study participants in the ART unit and (2) to identify factors that contribute to non-adherence. This cross sectional study was carried out at Nekemete referral clinic. Data was collected using a self-developed structured questionnaire where a total of 338 participants grouped into adherent and non-adherent based on a score derived from an adherence assessment were interviewed. Data was analysed using the Statistical Package for Social Sciences (SPSS) version 17.0. By using multivariate analysis of variables identified as correlates of adherence, non-adherence was common among those; with age between 18-30 yrs, with no education, who were not married, who had no pipe water supply, those with no electricity in the house, who perceived had no access to assistance from providers, who perceived the health care providers (HCPs) did not keep information confidentially, who had a language barrier with providers, and who were treated with a psychiatric illness. The study concludes that adherence is multi-factorial and varies significantly by individual and care setting. Psychosocial factors were found to impact adherence and should be analysed in more detail by further studies. Three psychosocial factors were independently associated with poor adherence: the study found that patients perceiving poor access; those perceiving problems in information confidentiality (and possibly experiencing stigmatisation); and having psychiatric morbidity (and possibly with less social support) are more likely to be non-adherent. Furthermore, individuals without electricity and those without piped water supply, implying low income, are at risk for non-adherence / Health Studies / M.A. (Public Health)

The earlier optimism generated by the efficacy of antiretroviral drugs in human immuno-deficiency virus (HIV) patients has been dissipated in the face of the enormous chal-lenge of maintaining a nearly perfect adherence indefinitely. This study set to determine the influence of HIV adherence self-efficacy and beliefs about medicines on antiretrovi-ral therapy adherence, with the aim of developing a framework for enhancing antiretrovi-ral therapy (ART) adherence through focused intervention on modifiable factors from study variables that are strongly associated with ART adherence. A descriptive correlational design was used to assess the predictive relationships of HIV adherence Self-Efficacy, Beliefs about Medicines and ART adherence among 232 HIV-infected patients in a large public health facility in Pretoria. Participants' medication be-liefs were assessed using the Beliefs about Medicines Questionnaire, HIV adherence self-efficacy was assessed with HIV adherence self-efficacy scale (HIV-ASES) and ART adherence was assessed using the AIDS Clinical Trial Group questionnaire. Pearson correlation analysis was used to assess bivariate associations among the variables, and multiple regression analysis was used to examine the relationships among the inde-pendent variables and ART adherence. Mean adherence for the 232 participants was 95% (SD=13.2). Correlation analysis re-vealed positive bivariate associations between perceived general harm and overuse of medications, and ART adherence (p<0.05); between specific necessity and concerns about ARVs, and perceived general harm and overuse of medications (p<0.05); be-tween HIV adherence self efficacy and ART non-adherence (p<0.05). Multiple regres-sion analysis showed significance for perceived general harm and overuse of medica-tions on ART adherence (F(1;231)=11,583;p<0,001) with perceived general harmful ef-fects and overuse of medications explaining 4.8% of the variance. There was signifi-cance for HIV adherence self-efficacy on ART non-adherence (F(1;41)=4.440; p<0.041), with HIV-ASES explaining 9,8% of the variance. Based on the results, a framework for enhancing ART adherence was developed. Activities in the framework consist of baseline screening for adherence facilitators and barriers using the beliefs about medicine questionnaire and HIV ASES, this is followed by focused interventions on identified barriers of ART adherence / Health Studies / D.Litt. et Phil. (Health Studies)

AIM: This study aimed to explore the factors influencing antiretroviral therapy patients` data quality at Princess Marina Hospital Pharmacy in Botswana. METHODS: A phenomenological approach was adopted in this study. Specifically, Interpretative Phenomenological Analysis qualitative design was used to explore the factors influencing antiretroviral therapy patients` data quality at Princess Marina Hospital Pharmacy in Botswana. Data were collected using a semi-structured interview format on 18 conveniently selected pharmacy staff. Data were analysed using Smith’s (2005) Interpretative Phenomenological Analysis framework. RESULT: Five thematic categories emerged from data analysis: data capturing: an extra task, knowledge and experience of IPMS, training and education, mentoring and supervision, and data quality: impact on patients’ care. The findings of this study have implications for practice, training and research. CONCLUSION: Pharmacy staff had limited knowledge of IPMS and its utilisation in data capturing. Such limitations have implications in the context of the quality of data captured / Health Studies / M.A. (Health Studies)

Purpose of the study - Identify predictors of mortality and develop a related care plan for patients who are on antiretroviral therapy (ART) in Gondar, Ethiopia. Design - A quantitative, retrospective cohort study was conducted analysing medical records of HIV patients who presented to Gondar University Hospital (GUH), Gondar, and started ART between 1 January 2007 and 30 June 2010. Results - In defining the predictors of mortality, the findings in bivariate analysis revealed: female sex, CD4 cell count ≤ 50/μl, CD4 cell count 51-199/μl, a haemoglobin concentration ≤8g/dl, a history of oral candidiasis, tuberculosis and Cryptococcus meningitis were all statistically significant. A female sex, CD4 cell count ≤ 50/μl and CD4 cell count 51-199/μl maintain their significance level in the multivariate analysis. Conclusions - The study therefore recommends that clinicians and case managers be vigilant of these predictors of mortality while managing HIV patients who are on ART / Health Studies / M.A. (Public Health)

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Introduction: Since the South African public sector antiretroviral roll-out programme started in 2004, the success of antiretroviral combination therapy (cART) has been experienced in terms of survival, prevention of mother-to-child transmission (PMTCT) and quality of life. However, as the programme matures, viral resistance to the constituent drugs will increase. Monitoring antiretroviral drug resistance (ARVDR) should therefore be a priority in the public health approach to HIV treatment. Methods: A cross-sectional investigation of genotypic antiretroviral drug resistance in: a) HIV-infected mothers who were exposed to a PMTCT regimen of short course azidothymidine (AZT) with single dose nevirapine (NVP) during labour. b) HIV-infected adults and children who were cART-naïve (transmitted or initial resistance). c) HIV-infected adults and children who were failing cART (drug-induced or acquired resistance). In case of adults, this includes patients on a first-line, non-nucleoside reverse transcriptase (NNRTI)-based regimen, or on a second-line, protease inhibitor (PI)-based regimen, and in case of children, this includes patients on a first-line PI-based regimen. Results: In mothers who received a PMTCT-regimen that combined AZT and NVP the prevalence of NNRTI resistance mutations was 17.1% (95% CI: 8.7-25.6%). The prevalence of transmitted ARVDR in adults was low, as was initial ARVDR in young children (mostly PMTCT-exposed), except for NNRTI resistance in children who had received NVP as part of PMTCT. Drug-induced resistance was found in adults failing first-line NNRTI-based cART, with 83% having resistance to ≥1 drug. In contrast, adult patients failing second-line PI-based cART had a low prevalence of PI resistance; the predominant reason for failure was poor drug exposure, as detected by measuring lopinavir concentrations in blood plasma and hair samples. In contrast, PI resistance in children was not rare, largely due to historic exposure to un-boosted PIs. This resulted in extensive resistance to PIs and reverse transcriptase inhibitors (RTI) in some children. Conclusions: A combined regimen of short course AZT with intrapartum NVP for PMTCT may, in addition to reducing the risk of neonatal infection, also reduce the risk of NVP resistance in the mothers compared to a regimen of NVP only. In South Africa, the prevalence of transmitted ARVDR remains low relative to industrialised countries, probably as comparatively little time has elapsed since the scale-up of cART. Adults failing first-line cART are likely to respond to second-line cART, without failure due to resistance. However some children with PI and RTI resistance cannot be adequately treated with drugs currently available through the roll-out programme. This emphasizes the urgent need for a rational and science-based approach to managing cART-experienced children, including access to additional drugs to form a third-line paediatric cART regimen. / AFRIKAANSE OPSOMMING: Inleiding: Sedert die begin van die Suid Afrikaanse publieke sektor antiretrovirale uitrol program in 2004 is die sukses van antiretrovirale kombinasie-behandeling (k-ARB) ervaar in terme van oorlewing, voorkoming van moeder na kind oordrag (VMKO) en lewenskwaliteit. Nietemin, sal weerstandigheid teen die middels wat in die antiretrovirale program gebruik word toeneem soos wat die program gevestig raak. Die monitoring van antiretrovirale middel-weerstandigheid is derhalwe ‘n prioriteit in gemeenskap-gesondheid benadering tot MIV behandeling. Metodes: ‘n Deursnit ondersoek van genotipiese antiretrovirale middel-weerstandigheid in: a) MIV-geïnfekteerde moeders wat blootgestel is aan VMKO regimen bestaande uit ‘n kort kursus AZT met ‘n enkeldosis nevirapien (NVP) tydens kraam. b) MIV-geïnfekteerde volwassenes en kinders wat komibinasieterapie-naïef (oorgedraagde of inisiële weerstandigheid) is. c) MIV-geïnfekteerde volwassenes en kinders wat k-ARB faal (middel-geïnduseerde weerstandigheid). In geval van volwassenes, sluit dit pasiënte op ‘n eerste-linie, non-nucleosied tru-transkriptase inhibitor (NNRTI)-regimen, en tweede-linie protease inhibitor (PI)-gebaseerde regimen, en in geval van kinders, sluit dit pasiënte in op ‘n eerste-linie PI-gebaseerde regimen. Resultate: In moeders wat ‘n gekombineerde AZT en NVP VMKO-regimen ontvang het, was die voorkoms van NNRTI weerstandigheid 17.1% (95%-vertrouensinterval: 8.7-25.6%). Die voorkoms van oorgedraagde ARVMW in MIV-geïnfekteerde volwassenes en kinders wat kombinasieterapie-naïef is, was laag, so ook ARVMW in jong kinders (meestal VMKO-blootgestel), behalwe vir non-nukleosied tru-transkriptase inhibitor (NNRT) weerstandigheid in kinders wat NVP ontvang het deur VMKO. Middel-geïnduseerde weerstandigheid was gevind in volwassenes wat die eerste-linie NNRTI-gebaseerde k-ARB gefaal het, met 83% wat weerstandigheid teen ≥1 middel het. Volwassenes wat ‘n tweede-linie protease inhibitor (PI) –gebaseerde k-ARB gefaal het , het ‘n lae voorkoms van PI weerstandigheid, met die oorwegenede oorsaak, swak middel-bloostelling, soos bepaal deur van lopinavir-konsentrasies in bloed plasma en hare. In teenstelling hiermee was PI weerstandigheid nie skaars in kinders nie, hoofsaaklik weens historiese blootstelling an ongeskraagde PI-behandeling. Dit het tot uitgebreide weerstandigheid tot PIs en tru-transkritptase inhibitors (RTI) in sommige kinders gelei. Gevolgtrekkings: ‘n Gekombineerde regimen van ‘n kort kursus AZT met NVP tydens kraam vir VKMO, mag bykomend tot die vermindering die risiko van pasgebore infeksie, ook die kans vir weerstandigheid teen NVP in die moeders verlaag in vergelyking met ‘n regimen van NVP-alleen. Die voorkoms van oorgedraagde ARVMW is tans laag in vergelyking met geïndustrialiseerde lande, waarskynlik aangesien daar nog betreklik min tyd verloop het sedert k-ART wyd beskikbaar gemaak is. Volwassenes wat eerstelyn kombinasie terapie faal sal waarskynlik goed reageer op tweede-linie terapie, sonder terapie faling weens middelweerstandigheid. Daarenteen kan sommige kinders met protease inhibitor en tru-transkriptase weerstandigheid nie voldoende behandel word met die huidig-beskikbare middels in die uitrol program nie. Dit beklemtoon die dringende noodsaaklikheid van ‘n rasionele en wetenskaplike benadering tot k-ART in kinders, met ‘n lang terapie geskiedenis, wat toegang tot bykomende medikasie behels om `n derde-linie regimen saam te stel.

Uganda has registered more than a million deaths since the HIV virus was first offi¬cially reported in the country over 3 decades ago. The governments in partnership with different groups have implemented different programmes to address the epidemic. The support from different donors and reduction in prices of treatment resulted in the focus on antiretroviral therapy access to those affected. Presently only a quarter of the approximately 1 million infected by HIV in Uganda are undergoing antiretroviral therapy. The number of patients pause a challenge in monitoring of therapy given the overall resource needs for health care in the country. Furthermore the numbers on antiretroviral therapy are set to increase in addition to the stringent requirements in tracking and monitoring of each individual patient during therapy. This research aimed at developing a framework for adopting knowledge engineering in information systems for monitoring HIV/AIDS patients. An open source approach was adopted due to the resource constrained context of the study to ensure a cost effec¬tive and sustainable solution. The research was motivated by the inconclusive literature on open source dimensional models for data warehouses and data mining for monitor¬ing antiretroviral therapy. The first phase of the research involved a situational analysis of HIV in health care and different health care information systems in the country. An analysis of the strengths, weaknesses and opportunities of the health care system to adopt knowledge bases was done. It proposed a dimensional model for implementing a data warehouse focused on monitoring HIV patients. The second phase involved the development of a knowledge base inform of an open source data warehouse, its simulation and testing. The study involved interdisciplinary collaboration between different stakeholders in the research domain and adopted a participatory action research methodology. This involved identification of the most appropriate technologies to foster this collabora¬tion. Analysis was done of how stakeholders can take ownership of basic HIV health information system architecture as their expertise grow in managing the systems and make changes to reflect even better results out of system functionality. Data mining simulations was done on the data warehouse out of which two machine learning algorithms (regression and classification) were developed and tested using data from the data warehouse. The algorithms were used to predict patient viral load from CD4 count test figures and to classify cases of treatment failure with 83% accu¬racy. The research additionally presents an open source dimensional model for moni¬toring antiretroviral therapy and the status of information systems in health care. An architecture showing the integration of different knowledge engineering components in the study including the data warehouse, the data mining platform and user interac-tion is presented.

<p>UVOD: Neurokognitivni poremećaj udružen sa HIVinfekcijom (HIV associated neurocognitive disorder- HAND) javlja se u oko polovine pacijenata sa HIV-om. HAND obuhvata spektar neurolo&scaron;kih poremećaja koji variraju od asimptomatskog neurokognitivnog poremećaja(ANI), preko blagog kognitivnog o&scaron;tećenja, koje se naziva blagi kognitivni poremećaj (MND) do demencije udružene sa HIV-om (HAD). U evaluaciji i dijagnostici ovog poremećaja koriste se razne laboratorijske, kliničke i metode imidžinga, među kojima magnetno-rezonantni imidžing (MRI) zauzima posebno mesto u pogledu dijagnostike strukturnih poremećaja. Međutim, za dijagnostiku suptilnih supcelularnih neurobiohemijskih poremećaja neophodno je kori&scaron;ćenje magnetno-rezonantne spektroskopije (MRS). Klasično shvatanje promena u neurobiohemijskom profilu kod pacijenata sa HIV infekcijom uključuje: sniženje NAA (neuronskog markera) kao odraz neurodegeneracije, povi&scaron;enje Cho (markera razgradnje membrana) kao odraz inflamacije/ apoptoze, povi&scaron;enje mI (markera proliferacije mikroglije) kao odraz inflamacije i povi&scaron;enje Glx+Gln (markera glutaminergične ravnoteže) kao odraz ekscitotoksičnosti. Do sada u literaturi nije opisano kori&scaron;ćenje multivokselske MRS mozga na HIV+ pacijentima. CILJEVI: Ciljevi studije su bili: utvrditi da li postoje promene u odnosima koncentracija metabolita u mozgu dobijenih metodom multivokselske MRS u neurolo&scaron;ki asimptomatskih HIV+ pacijenata u poređenju sa zdravim kontrolnim ispitanicima,zatim da li postoje razlike između pacijenata na kombinovanoj antiretroviralnoj terapiji (cART) i pacijenata bez cART; utvrditi da li postoji i kakva je povezanost odnosa metabolita dobijenih MRS sa imunolo&scaron;kim parametrima HIV+ pacijenata i nivoom nadir CD4+ T-limfocita; i konačno, utvrditi da li postoji i kakva je povezanost dobijenih odnosa metabolita sa parametrima penetracije antiretroviralne terapije u centralni nervni sistem. ISPITANICI I METODE: U studiju je uključeno ukupno 114 ispitanika (32 HIV+ pacijenta na cART, prosečne starosti 41.97 godina (25-61); 28 HIV+ pacijenata bez cART, prosečne starosti 35.21 godina (24-52); 50 kontrolnih, zdravih subjekata prosečne starosti 36.56.godina (19-53)). Svi ispitanici su potpisali informisani pristanak za uče&scaron;će u studiji. Ispitivanje je odobreno od strane Etičke komisije Instituta za onkologiju Vojvodine, kao i Etičke komisije Medicinskog fakulteta Univerziteta u Novom Sadu. Kriterijum za uključenje pacijenata u studiju je bio prisustvo HIV infekcije. Kriterijumi za isključivanje pacijenata iz studije su bili: prisustvo aktivne oportunističke infekcije, prisustvo aktivnog neurolo&scaron;kog oboljenja, podatak o aktivnoj zloupotrebi narkotika, koinfekcija virusom hepatitisa B i C, prisustvo lezija bele ili sive mase i kontraindikacije za snimanje na aparatu za magnetnu rezonancu. 4 ispitanika su isključena iz ispitivanja. Svim ispitanicima urađeni su skrining neurokognitivni testovi, kao i rutinska laboratorijska ispitivanja (broj CD4+, CD3+ i CD8+ limfocita). Nakon toga, svim ispitanicima urađen je konvencionalni MRI praćen multivokselskom MRS supratentorijalne suprakalozalne bele mase. Ispitivano je ukupno 12 voksela (6 u sivoj i 6 u beloj masi), odnosno preko 7900 spektara. Određeni su pikovi karakterističnih metabolita. Na metodi dugog eha analizirana su tri glavna pika: NAA na 2.0ppm, Cho na 3.2ppm i tCr na 3.ppm, izražena preko odnosa koncentracija NAA/Cr i Cho/Cr. Na metodi kratkog eha analizirani su signali NAA, Cho, Cr te mI na 3.5ppm i Glx+Gln na 2.2-2.4ppm. Ovi signali su izraženi kroz odnose koncentracija NAA/Cr, Cho/Cr, mI/Cr i (Glx+Gln)/Cr. Za statističku obradu podataka kori&scaron;ćen je IBM SPSS ver. 21.0. Deskriptivna statistika je uključila određivanje srednje vrednosti, minimuma, maksimuma i standardne devijacije. Razlike između posmatranih grupa ispitanika za sve kontinuirane varijable ispitivane su jednofaktorskom analizom varijanse (ANOVA) sa naknadnim (post-hoc) testovima za koje je kori&scaron;ćena metoda po Tukey-ju. Rezultati su prikazani u vidu srednjih vrednosti, standardne devijacije, najvi&scaron;e i najniže izmerene vrednosti (maksimum i minimum), i za svaki ispitivani parametar pridružena je vrednost F i p. Veza između kontinuiranih varijabli je ispitivana pomoću koeficijenta Pirsonove linearne korelacije, uz prethodnu proveru zadovoljavanja uslova o homogenosti varijansi, normalnosti raspodele i linearnosti. Vrednosti p&lt;0.05 su uzimane kao statistički značajne. REZULTATI: Pokazano je da su HIV+ pacijenti na cART značajno stariji od druge dve grupe ispitanika. Nije pokazana značajna razlika u stepenu obrazovanja među grupama. Pokazano je da godine života statistički značajno utiču samo na koncentracije NAA/Cr, dok na odnose drugih metabolita ne utiču značajno. Utvrđeno je statistički značajno sniženje (p&lt;0.05) koncentracija NAA/Cr dobijenih metodom dugog eha između tri grupe ispitanika na svim posmatranim vokselima. Naknadnim analizama utvrđena je statistički značajna razlika na 10/12 voksela između HIV+ pacijenata sa cART i zdravih, kao i između HIV+ pacijenata bez terapije i zdravih, dok su se koncentracije NAA/Cr značajno razlikovale između HIV+ pacijenata sa i bez cART samo na jednom vokselu (duboka frontalna bela masa levo). Utvrđena je statistički značajna razlika u smislu sniženja Cho/Cr odnosa dobijenih metodom dugog eha u 5/12 voksela, sa pojedinačnim vokselima koji su prikazivali razlike između grupa. Na metodi kratkog eha utvrđeno je značajno sniženje odnosa koncentracija NAA/Cr kod HIV+ pacijenata samo na tri voksela, pri čemu nisu prikazane značajne razlike između dve grupe pacijenata sa HIV infekcijom (sa i bez cART). Rezultati odnosa koncentracija Cho/Cr između tri gurpe pacijenata dobijeni metodom kratkog eha slični su rezultatima dobijenim na metodi dugog eha (statistički značajna razlika dobijena je na 5/12 voksela). &Scaron;to se tiče odnosa koncentracija mI/Cr, uočeno je značajno povi&scaron;enje ovog odnosa kod HIV+ pacijenata u odnosu na zdrave na 6/12 voksela. Prikazano je statistički značajno povi&scaron;enje ovog markera kod pacijenata bez cART u odnosu na pacijente sa cART samo u regiji levog dorzalnog anteriornog cinguluma. Statistički značajno povi&scaron;enje (Glx+Gln)/Cr odnosa je prikazano u regiji zadnjeg cinguluma desno kod pacijenata na terapiji u odnosu na pacijente bez terapije, dok na drugim vokselima nije prikazana značajna razlika. Vokseli 4, 7 i 10 su dali najvi&scaron;e informacija(supkortikalna bela masa frontalno levo, dorzalni prednji cingulum levo te parijetalni supkorteks leve cerebralne hemisfere), sa prikazanim značajnim razlikama u bar 4 odnosa metabolita. Prikazana je značajna pozitivna korelacija nadir CD4 + broja limfocita sa koncentracijama NAA/Cr, a negativna sa odnosima Cho/Cr i mI/Cr, &scaron;to čini nadir CD4+ najboljim serolo&scaron;kim prediktorom neurodegenerativnog o&scaron;tećenja. Pokazana je pozitivna korelacija indeksa penetracije lekova u monocite (ME) sa odnosima NAA/Cr i negativna korelacija indeksa penetracije lekova u centralni nervni sistem (CPE) sa Cho/Cr i mI/Cr. Do&scaron;li smo do zakljulka da je ME indeks bolji marker neurodegenerativnog odgovora a CPE indeks bolji u monitoringu kontrole inflamacije. ZAKLJUČAK: Smatra se da HIV virus uzrokuje prerano starenje mozga&scaron;to je prvenstveno posledica direktnog o&scaron;tećenja nervnih ćelija samim virusom (preko viralnih proteina, indukovanih citokina i hemokina). Pokazali smo da su neuronski gubitak i neurodegeneracija proces koji zahvata celokupan volumen mozga, dok su procesi inflamacije i proliferacije mikroglije svedeni na tačno određene regione, pretežno sive mase. Visoka senzitivnost multivokselske 1H-MRS sa kori&scaron;ćenjem senzitivnih povr&scaron;inskih kalemova omogućava mapiranje metabolita sa prostornom rezolucijom. MRS može dati ključni uvid u promene koncentracija metabolita mozga tokom razvoja infekcije od akutne i primarne do hronične. Vrlo brzo nakon serokonverzije, dolazi do detektabilnih promena u metabolitima mozga u smislu neuronskog o&scaron;tećenja i inflamacije. U na&scaron;em istraživanju su po prvi put analizirani rezultati protonske multivokselske MRS bele i sive mase velikog mozga u suprakalozalnom regionu. Utvrđeno je da postoje difuzne, ali ipak visoko regionalno-zavisne promene u odnosima neurometabolita kod pacijenata koji dobijaju antiretroviralnu terapiju i kod pacijenata koji je ne dobijaju, u poređenju sa zdravim kontrolnim ispitanicima (odgovarajućim po polu i starosti). Dodatne studije sa posmatranjem apsolutnih koncentracija neurometabolita, kao i longitudinalne studije u koje su uključeni HIV+ pacijenti u različitim fazama bolesti, su neophodne za dalje i bolje razumevanje neuropatogeneze HAND-a. MRS se pokazala uspe&scaron;nom u detekciji efikasnosti određenih terapijskih opcija. Dva postojeća indeksa za procenu efikasnosti antiretroviralne terapije (CPE, ME) odvojeno pogađaju dva puta neuropatogeneze kognitivnog poremećaja, sa različitim uspehom u sveobuhvatnoj proceni efekta i efikasnosti terapije. U budućnosti je potrebna njihova pojedinačna modulacija ili kreiranje jedinstvenog indeksa, koji bi obuhvatio i efikasnost prolaza leka kroz hematoencefalnu barijeru i dejstvo na latentni rezervoar HIV-a u ćelijama monocitno-makrofagne loze.</p> / <p>INTRODUCTION: HIV associated neurocognitive disorder- HAND appears in about half of the HIV+ patients. HAND represents a spectrum of neurological disorders varying from asymptomatic neurocognitive impairment (ANI), over mild neurocognitive disorder (MND) to HIV associated dementia (HAD). For evaluation and diagnostics of this disorder, many laboratory, clinical and imaging methods are used, first of all magnetic resonance imaging (MRI). Nevertheless, for detecting subtle subcellullar neurobiochemical disorders, the use of magnetic resonance spectroscopy (MRS) is necessary. Classical pattern of neurobiochemical changes in HIV infection consist of: decrease in NAA (neuronal marker) depicting neurodegeneration, increase in Cho (metabolism on membrane marker) depicting inflammation/ apoptosis, increase in mI (marker of microglial proliferation) depicting inflammation and increase in Glx+Gln (glutaminergic balance marker) depicting the effect of excytotoxicity. To the best of our knowledge, this is the first study using multivoxel MRS of the brain in HIV+ patients. AIMS: The aims of this study were: to show whether there are differences in metabolites&#39; ratios on multivoxel MRS in neurologically asymptomatic HIV+ patients compared to control subjects; whether there are differences in metabolites&#39; ratios between patients on combined antiretroviral therapy (cART) and therapy-naive ones; whether there are correlations between matebolites&#39; ratios and immunological parameters in HIV+ patients as well as with nadir CD4+ count; whether there are correlations between metabolites&#39; ratios with parameters of drugs&#39; penetration in central nervous system (CNS). SUBJECTS AND METHODS: Overall of 114 subjects were enrolled in the study (32 HIV+ paients on cART, average age 41.97 years (25-61); 28 HIV+ patients off cART, average age 35.21 years (24-52); 50 control subjects, average age 36.56 years (19-53)). All the subjects signed the informed consent. The study was ethically approved by Ethical committee of Vojvodina Oncology Institute and Ethical committee of Faculty of Medicine, University of Novi Sad. Inclusion criteria for HIV+ subjects were: the presence of HIV infection. Exclusion criteria included: active opportunistic infection, active neurological illness, usage of drugs of abuse, hepatitis B or C coinfection, presence of both white or grey matter lesions, and contraindications that apply for magnetic resonance (MR) examination. 4 subjects were excluded from the study due to the presence of white matter lesions (3 HIV+ and one control subject). Each patient performed International HIV Dementia Scale (IHDS), a screening test for evaluation of global cognitive status in HIV-infected patients. Baseline study laboratory variables were assessed (CD4+ T-lymphocyte count and plasma HIV RNA, nadir CD4+ counts and CD4+ T-cell counts at the moment of MR scan. Conventional MRI scan was followed by multivoxel MRS with both long and short echo. We analyzed 12 voxels (6 in grey and 6 in white matter) with overall of over 7900 spectra. Finally, we analyzed following dominant signals: on the long echo tCr (creatine plus phosphocreatine) at 3.0 ppm, NAA (N-acetyl-aspartate) at 2.0 ppm and Cho (choline containing compounds) at 3.2ppm (ratios of NAA/Cr and Cho/Cr were assessed); on the short echo tCr, NAA, Cho, (Glx+Gln) at 2.2-2.4ppm and mI (myoinositol) at 3.5ppm (ratios of NAA/Cr, Cho/Cr, (Glx+Gln)/Cr and mI/Cr were assessed. All statistical calculations were performed using IBM SPSS software (version 21.0, Chicago, IL, USA). Descriptive statistics included determination of mean values, minimum, maximum and standard deviation. Among-group differences (HIV infected subjects versus healthy controls) in acquired metabolite ratios were evaluated using ANOVA with post hoc Tukey test to determine the differences between separate groups. Due to a known impact of age and education on the NAA concentrations, differences in NAA/Cr ratios among groups were tested using ANCOVA, with age as a covariate variable. Testing relationships between continuous variables was performed using Pearson linear correlation. Statistical significance was set at value p&lt;0.05. RESULTS: We showed that HIV+ patients on therapy were significantly older than the other two groups of patients. There was no significant difference in the level of education. We confirmed that the age significantly affects the level of NAA/Cr only.There was significant decrease (p&lt;0.05) in NAA/Cr level on long echo MRS among three groups on all the observed voxels. Post hoc analysis showed that there was significant difference in 10/12 voxels between HIV+ patients on cART and healthy controls and between HIV+ patients off cART and controls, while NAA/Cr differed significantly between HIV+ patients on and off cART in only one voxel (deep frontal white matter on the left). There was decrease in Cho/Cr levels on long echo MRS in 5/12 voxels among three groups. On short echo MRS, we showed decrease in NAA/Cr level in 3/12 voxels, while there were no differences between two groups of HIV+ patients. Results of short echo MRS in the means of Cho/Cr resembled long echo MRS. There was significant increase in mI/Cr level in HIV+ patients in 6/12 voxels compared to healthy controls, while there was difference in only one voxel between HIV+ patients on and off therapy (dorsal part of anterior cingulate on the left). Significant increase in (Glx+Gln)/Cr level was present between HIV+ patients on and off therapy in the region of right posterior cingulate. Voxels 4, 7 and 10 were the most informative ones (subcortical frontal white matter on the left, dorsal part of left anterior cingulate and right posterior cingulate), showing significant differences in 4 metabolites&#39; ratios. We showed positive correlation between nadir CD4+ count and NAA/Cr and negative correlation between nadir CD4+ count and Cho/Cr, and nadir CD4+ count and mI/Cr, which made nadir CD4+ count the best serological predictor of neurodegeneration. Positive correlation was showed between monocyte efficacy (ME) index and NAA/Cr, while negative correlation was present between CNS penetration efficacy (CPE), Cho/Cr and mI/Cr. We concluded that ME better depicted neurodegenerative process while CPE was better in monitoring of inflammation. CONCLUSIONS: HIV causes premature ageing of the brain, in the means of cognition, attention, working memory and executive function. These effects are due to direct affection of neurons by virus per se (viral proteins, induced cytokines and chemokynes). We showed tha neuronal loss and neurodegeneration affect the whole volume of the brain while inflammation and glial proliferation affect restricted areas predominantly in grey matter. High sensitivity of multivoxel MRS with use of sensitive surface coils enables metabolite mapping with high spatial resolution. MRS can give essential data on metabolites&#39; changes during the evolution of the infection from acute, over primary to chronic. Early after seroconversion, metabolites&#39; changes can be detected (neuronal dysfunction and inflammation).To the best of our knowledge, this is the first study using multivoxel MRS of the brain in HIV infection in human population, analyzing data from supracallosal grey and white matter. We showed the presence of diffuse but regionally highly specific changes in metabolites&#39; ratios in patients on cART and off cART, compared to age and gender matched healthy controls. Additional studies with absolute concentrations of metabolites, as well as longitudinal studies with HIV+ patients in different stages of the disease, are necessary for better understanding of neuropathogenesis of HAND. We showed that MRS can be useful tool in evaluation of therapy regimens efficacy. Two available indices for evaluation of cART efficacy target two separate pathways of cognitive disorder pathogenesis, with different reliability in evaluation of effect and efficacy of applied therapy. In the future, their modulation or creation of new index is needed, in order to include drug delivery through the blood-brain barrier as well as the effect on latent reservoir of HIV in monocyte/macrophage cells.</p>