A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy Johannesburg, South Africa 2016 / Introduction: Neonatal infections contribute to 25% of all neonatal deaths, which account for approximately 44% of all under-5 childhood deaths globally. Pathogens responsible for sepsis in neonates and young infants can be acquired vertically prior to or during labour, or from the environment (community or hospital). This project evaluated the burden and aetiology of sepsis in neonates and young infants (≤90 days), and explored this association to in-utero exposure to human immunodeficiency virus. The study also included a specific focus on the epidemiology of invasive Group B Streptococcal disease in young infants. Additionally, we assessed the efficacy of intrapartum chlorhexidine vaginal washes for: (i) preventing early-onset neonatal sepsis; and (ii) vertical transmission of potentially pathogenic bacteria to the newborns. Furthermore, we evaluated risk factors for poor outcomes due to neonatal sepsis. Materials and methods: (i) A bacterial surveillance system was established at Chris Hani Baragwanath Academic Hospital (CHBAH) from 2004-2008 to identify young infants with bacterial sepsis hospitalised in the neonatal and paediatric wards. Medical and microbiological records were utilised to obtain clinical and laboratory data. Maternal HIV results were obtained from antenatal testing records or admission records. (ii) A blinded, randomised, placebo-controlled trial of 0.5% chlorhexidine maternal vaginal intrapartum wipes and newborn skin wipes was conducted at CHBAH between 2004 and 2007. Consented, eligible participants were randomised during labour to receive either chlorhexidine vaginal wipes or water external genitalia wipes. Newborns received either chlorhexidine full-body wipes (intervention arm) or foot wipes (control arm). Maternal and infant participants were followed up for admissions during the first month after delivery/ birth. A subset of 5144 maternal participants had an intrapartum lower vaginal swab collected, and skin swabs were collected from their newborns to assess colonisation with potentially pathogenic bacteria (Group B streptococcus, Escherichia coli and Klebsiella pneumoniae). Results: Group B streptococcus (GBS) was the most commonly isolated bacterial pathogen, causing 35.2% of culture-confirmed sepsis in infants ≤90 days, 41.6% of early-onset disease (EOD, 0-6 days), 40.5% of late-onset neonatal disease (LOD, 7-27 days) and 18.7% of young-infant community-acquired disease (YI-CAD, 28-90 days). Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) contribute 16.2%, 12.2% and 3.4% to sepsis in young infants. Overall, incidence (per 1000 live births) of invasive GBS disease was 2.72 (95% confidence interval [95% CI]: 2.46 to 3.01), including an incidence of 1.50 and 1.22, respectively, in infants 0-6 days and 7-90 days of age. HIV-exposed infants were at greater risk of EOD (Relative risk [RR]: 1.69; 95% CI: 1.28-2.24) and LOD (RR= 3.18; 95% CI: 2.34-4.36) than HIV-unexposed infants. GBS serotypes Ia and III caused 84.0% of invasive GBS disease in young infants. Intrapartum chlorhexidine interventional wipes was not efficacious in prevention of any of: (i) vertical transmission of pathogenic bacteria (54% vs. 55%; efficacy -0.05, 95% CI: -9.5 to 7.9) to the newborns; (ii) sepsis in first 3 days of life (3% vs. 4%; p=0.65,); (iii) sepsis in the later neonatal period (both <1%; p=0.4444); or (iv) maternal puerperal sepsis(both <1%; p=0.56). Conclusion: GBS, S. aureus, E. coli and K. pneumoniae are the most commonly isolated bacterial pathogens in neonates and infants ≤90 days old. HIV-exposed infants are at greater risk of GBS sepsis. Intrapartum chlorhexidine intervention was not efficacious in reducing vertical transmission of pathogenic bacteria, neonatal or maternal sepsis. Alternative interventions to prevent sepsis in young infants, including maternal immunisation, need to be investigated in setting such as ours where there is a high prevalence of maternal HIV infection. / MT2017

一個大型的多中心臨床試驗 (HPTN052) 於2011年發表研究結論，假如治療中的愛滋病患者能保持病毒載量低水平，他們傳播愛滋病予性伴侶的機會是十分輕微的。這些結論促使利用病毒載量數據去形容愛滋病流行概况及評估高效抗逆轉錄病毒療法 (HAART) 干預策略對流行概况的影響。本研究旨在應用社區病毒載量去模擬香港愛滋病流行概况。 / 本研究收集了香港兩間主要愛滋病專科裡愛滋病患者縱向臨床數據，這些匿名的數據根據美國疾病預防控制中心所提議的人群病毒載量框架整合成流行病數據。其中社區、護理群及監測群病毒載量的計算是為了描述愛滋病流行概況，而新創的全社區病毒載量是用於估計社區裡確診與尚未確診的愛滋病感染者的集體病毒載量。香港未來愛滋病流行概況則利用決定性倉室模型模擬。異性模型透過性別分成兩個 (男女) 有聯繫的小模型，同性模型則用系統進化分析的近鄰結合法去劃分成16個獨立的小模型。除了基於現有情況模擬概況，治療、測試和混合干預策略以及外來感染的影響也被模擬。 / 從4362個病患中，一共收集了76,350CD4、64,412病毒載量和1042基因序列的回顧數據 (1985-2012)。當中有83%病患是男性、72%是中國人、89%是透過性接觸感染、74%曾經接受治療。能達到低病毒載量的病患百分比由1997年11%升至2012年76%，與HAART的推行情況方向一致。全社區病毒載量所顯示的上升趨勢於異性群和同性群中較其他病毒載量指標早五年出現。於2010-2020，異性群的愛滋病流行概況將維持不變，而同性群的流行概況將穩步上升但不是指數上升。干預策略中，以混合干預加上高治療保留率的策略對同性和異性群最有效，但增加重點測試對異性群比較可行，因為它舒緩了診斷延誤。另外，外來感染會影響干預策略的成效。 / 假如沒有包含病毒載量因素、外來感染和劃分模型，推測結果會高估流行概況，而治療覆蓋率的影響也不能被反映。基於人群病毒載量的重要性，定期收集所有專科的病毒載量數據並加以整合應該成為監測的一部份。這對於有廣泛治療覆蓋率的香港去研究流行概況是十分重要。 / Introduction: In 2011, a large multicentre trial (HPTN052) concluded that HIV+ persons on treatment with suppressed viral load (SVL) have minimal risk of virus transmission to their seronegative partners through sexual intercourse. These results provided evidence for the epidemiological use of viral load data to describe the HIV epidemics and assess impacts of treatment interventions. This study aims at modelling the HIV epidemic in Hong Kong by incorporating population-level viral load measures. / Methods: Longitudinal clinical data of patients attending two major HIV specialist services in Hong Kong were collected. The anonymized data were combined, adjusted and incorporated in an epidemiologic dataset in accordance with the CDC framework of viral load measures at population level. Specifically, community, in-care and monitored viral load were calculated to describe the HIV epidemic. Full community viral load, a new measure, was developed to infer the viral load burden of both diagnosed and undiagnosed individuals in the community. The HIV epidemic was then projected in a deterministic compartmental model. Gender was used to divide heterosexual model into two interrelated sub-models, while phylogenetic analysis (neighbour-joining tree) was applied to divide men-who-have-sex-with-men (MSM) model into 16 independent sub-models. Intervention scenarios of treatment coverage, testing coverage and retention expansion, and influence of non-local infection were projected and compared by modelling. / Results: A total of 76,350 CD4 and 64,412 viral load measurements of 4362 patients, and 1042 sequences were collected retrospectively (1985-2012). Among the patients included, 89% had acquired infection through sexual intercourse, and 74% had been started on highly active antiretroviral therapy (HAART). From viral load perspective, the proportion of patients in care with SVL (≤500copies/mL) increased sharply from 11% in 1997 to 76% in 2012, coinciding with the implementation of HAART. The growth curve of full community viral load was 5 years ahead of other viral load measures of heterosexuals and MSM. In 2010-2020, the HIV epidemic in heterosexuals would neither grow nor die down while the epidemic in MSM would continue to grow steadily but not exponentially. Among scenarios examined, test-and-treat intervention with high retention rate would be the most effective strategy for controlling the MSM and heterosexual epidemic. However, increasing the HIV testing rate for high risk people would be more feasible and impactful for the heterosexual, as a result of the early detection of HIV which would otherwise become late diagnoses. Non-local infection would affect the impact of interventions on epidemic control. / Conclusion: Without the inclusion of viral load measures, non-local infection and model delineation by subpopulations, epidemiologic projection results could be overestimated. Also, the impacts of treatment coverage on epidemic cannot be reflected if viral load measure is not included for describing epidemic growth. Acknowledging the importance of viral load measure, regular collection and aggregation of viral load measurements from all HIV clinics is recommended to form part of the HIV surveillance system. Such provision is important for studying HIV epidemiology descriptively and analytically in Hong Kong where coverage of HIV care is relatively extensive. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wong, Ngai Sze. / Thesis (Ph.D.) Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 204-219). / Abstracts also in Chinese.

South Africa has had one of the fastest growing HIV epidemics in the world and almost 30% of women attending public antenatal clinics (ANC) are currently infected with the virus. But as the epidemic is starting to level off and antiretroviral therapy (ART) is becoming increasingly available, few methods exist to determine the impact of ART or other interventions on the epidemic in South Africa. This thesis explores the epidemiology and dynamics of HIV infection and investigates the potential impact of ART. Methods Total and age-specific prevalence data are analysed in time and space and are used to investigate patterns of infection in men and women, urban and rural, and low and high risk populations. Dynamical models are developed to estimate incidence from age-specific prevalence and trends over time and are compared to laboratory-based estimates of recent HIV sero-conversion. Incidence is estimated in different populations in South Africa. A dynamical model is developed to estimate the impact of ART on the future course of the HIV epidemic. Results HIV prevalence varies geographically and by age, sex and race. The average female-tomale HIV prevalence ratio is 1.7 and prevalence peaks at an older age among men than women. The age at which prevalence peaks among women has increased from 23.0 to 26.5 years between 1995 and 2002. Four patterns of infection are identified: among pregnant women attending ANCs, among men and women in the general population, and among migrant workers. HIV incidence among ANC attendees peaked in the mid to late 1990s (at 6.6% per year nationally) with variation between provinces. Current estimates of HIV prevalence and incidence among the general population in South Africa (aged 15-49 year) are 18.8% and 2.4% per year, respectively. Age-specific incidence estimates from dynamical models and laboratory methods are in good agreement provided the window period for the laboratory method is increased. Over the next ten years the provision of ART could avert 1 to 1.5 million deaths depending on whether it is provided when the CD4 cell count falls to 200 or 350 cells/ul. By 2015 about 1.1 million people will be receiving ART but this will have little impact on the incidence of HIV and scaling up of prevention efforts remains urgent. Conclusions The thesis explores some of the determinants and patterns of HIV prevalence and incidence in South Africa in order to find better ways to manage the epidemic of HIV, monitor changes and evaluate progress in control efforts. In order to fight the epidemic we need to mobilize the best possible science in support of those people and communities affected by the epidemic. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2007.

Background: HIV transmission is greatly reduced when antiretroviral treatment (ART) suppresses an infected person’s HIV viral load. It is unclear, however, whether the contextual risk of incident HIV is optimally reduced by widespread individual-level suppression of HIV viral load alone or in combination with other HIV prevention services. HIV service coverage and community norms can influence risk in small area geographies; and contextual factors, like gender inequality and stigma, may foster environments conducive to HIV transmission. Yet, the relationship between places with high HIV levels and the clustering of area risk factors is unknown. The goal of this dissertation is to learn if and how a geographically focused combination implementation strategy could reduce population-level HIV risk. Analyses explored whether small area risk profiles explain area differences in HIV. The guiding hypothesis is that in high HIV prevalence settings, low HIV service uptake in a geographically defined area increases the prevalence of high HIV viremia, leading to greater HIV transmission and incident HIV. Methods: A systematic review was conducted to examine the association between population-level measures of HIV viral load and incident HIV infection in generalized and concentrated epidemics. Publications were English, peer-reviewed articles published from January 1, 1995 through February 15, 2019 that explicitly defined HIV viral load and assessed outcomes of HIV recency, incidence, seroconversion, or new diagnosis. Studies sampled general or key populations through population-based surveillance registries, household-based enumeration, cluster sampling, or respondent driven sampling. Descriptive statistics summarized review findings. The Swaziland HIV Incidence Measurement Survey (SHIMS) data were used for the remaining analyses. Using a two-stage cluster-based design, a nationally representative, household-based sample of adults, ages 18-49 years was enrolled from December 2010 to June 2011 in Eswatini. Consenting adults completed an interview and received home-based rapid HIV testing and counseling. All seropositive samples were tested for HIV viral load using the COBAS AmpliPrep/Taqman HIV-1 Test, v 2.0. Adults testing HIV-seronegative were enrolled in a prospective cohort for the direct observation of HIV seroconversion, completing an interview and home-based rapid HIV testing six months later. Multi-level latent class modeling was performed to identify statistically significant combinations of HIV risk factors and to classify the combinations into small area risk profiles. In the cross-sectional sample, linear regression with robust standard errors assessed the correlation between area profiles and places with high levels of uncontrolled HIV infection, or HIV core areas, measured by the area prevalence of detectable virus (≥20 copies/milliliter) among HIV-positive adults and among all adults, regardless of HIV status. In the prospective cohort, generalized linear regression of longitudinal data assessed the association between area profiles and places prone to new HIV infections (i.e., HIV susceptible areas), measured by area-level HIV seroconversions. Results: The systematic review found an evidence base primarily of lower quality studies and inconsistent HIV viral exposure measurement. Overall findings supported a relationship between increasing levels of suppressed HIV in HIV-infected populations and fewer new infections over time. Better quality studies consistently showed higher population viremia (i.e. HIV viral quantity among all persons, regardless of HIV status) associated with HIV incidence in high prevalence populations; population viral load (i.e., HIV viral quantity among only HIV-positive persons) did not show an association with incident HIV in high prevalence, general populations and was inconsistent in key populations. To determine whether area risk profiles can pinpoint HIV core areas, latent class modeling was used to categorize 18,172 adults into one of six HIV risk types. The risk typology, classified through unique combinations of HIV service uptake and sexual risk behaviors, conveyed an adult’s propensity for HIV transmission and/or acquisition risk. The model next identified the area-level composite prevalences of HIV risk types; estimated the three most frequent, unique composite combinations; and categorized them into area risk profiles characterizing HIV risk: low-moderate acquisition risk, moderate acquisition/transmission risk, and high acquisition/transmission risk. The high acquisition/transmission areas comprised the largest proportions of highest risk transmission and acquisition types. The prevalence of detectable viremia progressively increased from low-moderate acquisition, moderate acquisition/transmission, and high acquisition/transmission profiles [17.7%, 25.4%, and 35.1%, respectively]. When compared with low-moderate acquisition areas, the prevalence of detectable viremia was 7.4% [p<.001] higher in moderate acquisition/transmission areas and 17.1% [p<.001] higher in high acquisition/transmission areas. The prevalence of detectable viral load significantly decreased from low-moderate acquisition to moderate acquisition/transmission areas [76.6% versus 68.7%, p<.001], and was significantly higher in high acquisition/transmission areas by 7.3% [p<.001], when compared with low-moderate acquisition areas. To determine whether area risk profiles can predict HIV susceptible areas, a total of 18,172 adults were surveyed of which 4396 [24%] had detectable viremia. 11,880 [96%; n=12,357] HIV-seronegative adults enrolled in the prospective cohort and 11,155 [94%] of them completed an endline visit. Four area profiles were identified, defined by unique patterns in prevalence of HIV viremia and of sexual risk behaviors. The proportion of HIV susceptible areas progressively increased from Profiles A, B, C, and D [14.3%, 21.8%, 24.6%, and 30.8%, respectively]. HIV susceptible areas were more than twice as likely to occur in Profile D than Profile A environments [RR 2.13, 95% confidence interval (CI) (1.13, 4.00); p=0.02]. Profile D areas had prevalences of unknown partner HIV status and detectable viremia at 28% and 24%, respectively. In contrast, Profile A areas had prevalences of only 8% with unknown HIV status and 31% with detectable viremia. Conclusion: This dissertation shows that geographic risk profiles can explain differences in population-level HIV outcomes. Risk factors spatially cluster in predictable, meaningful combinations that can inform an area typology of HIV risk. The co-location of adults predisposed to greater HIV risk may heighten levels of uncontrolled HIV infection, thereby creating potential area sources of ongoing transmission; however, the concurrent levels of other risk factors may have more influence in reducing population-level incidence than previously considered. A composite indicator of contextual HIV risk may reveal places core to HIV transmission and susceptible to HIV acquisition. Such area profiles may help identify the combination of locally specific risk factors that readily promulgate HIV and better inform the design of place-based HIV intervention packages to enhance current strategies towards global HIV control.

Thesis (MSc)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: At the end of 2002, human immunodeficiency virus (HIV) had infected 42 million people worldwide. The morbidity and mortality rate, as well as the epidemic proportions of the disease have led to concentrated scientific efforts to reveal the disease's pathogenesis and develop effective preventative and treatment measures. Advances have been made to inhibit viral replication by suppressing the virus' ability to replicate by developing antiretroviral treatments, although development of a save and effective vaccine is the only way to stem the pandemic. Advances in vaccine design, animal models and clinical research have led to the creation of promising candidate vaccines to counter this rampage, but most of these vaccines entering phase I-III clinical trials are based mainly only subtype B genomes. HIV-1 subtype C is the most commonly transmitted subtype worldwide, and is the predominant subtype in India, China, East and Southern Africa. A subtype C vaccine is critical for the developing nations such as South Africa, where antiretroviral therapies are largely unaffordable. The envelope gene (env) is an attractive target as immunogen to be included in a HIV vaccine. The envelope protein (Env) elicits neutralising antibodies and cytotoxic T-Iymphocyte (CTl) responses. This protein will therefore be useful in creating a humoral and cellular immune response in the host. A shortage in characterised subtype C env gene sequences from South Africa was recognised, and this study focussed on the characterisation of generated sequences, as well as the expression of selected env genes. These immunogens were created for possible use in a prime-boost vaccine modality. The env genes from recent circulating strains in South Africa were amplified by polymerase chain reaction (PCR). The genes were then cloned for sequencing and expression purposes. Phylogenetic relationships were determined by comparing the sequences to reference subtype strains and subtype C strains. Expression of the genes was assessed by Western Blot in 293 cells with HIV- 1 positive patient sera. Sequence analysis showed a more conserved third variable (V3) loop in South African subtype C sequences, with a more variable region downstream from the loop. The crown sequence (GPGQ) and positions of uncharged or negatively charged residues in the V3 loop indicated a non-syncytium-inducing (NSI) phenotype for the isolates. Phylogenetic analysis showed the sequences to all belong to the C subtype, and further that the sequences were not recombinant, which was confirmed by recombination analysis. The intersample diversity observed for strains from South Africa was significantly higher than distances observed to the subtype C consensus sequence. The South African sequences were distributed across several subclusters in a subtype C phylogenetic tree, highlighting the concept that these infections represent a more longstanding epidemic with multiple introductions from different geographic areas. Western Blot with HIV-1 positive patient sera showed the expression of uncleaved gp160 Env proteins, which were Rev dependent. This study has generated much needed subtype C South African env gene sequences that can be used as basis for modification for use as immunogens in a South African vaccine. / AFRIKAANSE OPSOMMING: Teen die einde van 2002 was 42 miljoen mense wêreldwyd geïnfekteer met die menslike immuniteitsgebrekvirus (MIV). Die dode- en sterfte syfers, asook die skaal van die epidemie, het gelei tot 'n wetenskaplike poging om die siekte se patogenese te openbaar en om effektiewe voorkomende en terapeutiese middels te ontwikkel. Vordering is reeds gemaak om die virus se replikasie te hinder deur die ontwerp van antivirale middels, alhoewel die ontwikkeling van 'n doeltreffende en veilige entstof die enigste manier is om die pandemie te stuit. As gevolg van die vordering in entstof ontwerp, diere modelle en kliniese navorsing is belowende kandidaat entstowwe wat die infeksie kan teenwerk ontwikkel, maar die meeste van hierdie enstowwe wat vir fase I-III kliniese proewe gebruik word is gebaseer op subtipe B genome. MIV-subtipe C is wêreldwide die algemeenste subtipe wat oorgedra word en is die oorheersende subtipe in lande soos Indië, China, oostelike en suidelike Afrika. 'n Subtipe C entstof word dringend benodig in ontwikkelende lande soos Suid-Afrika waar antivirale middels onbekostigbaar is. Die membraangeen is 'n aanloklike teiken om as immunogeen in 'n MIV entstof te dien. Die membraanproteïen lok neutraliserende teenliggame en sitotoksiese T-limfosiet reaksies uit. Die proteïen sal dus 'n humorale en sellulêre immuunrespons in die gasheer ontlok. 'n Tekort aan gekarakteriseerde subtipe C membraangeen volgordes van Suid-Afrika is opgemerk, en dus fokus hierdie studie op die karakterisering van gegenereerde volgordes, asook die uitdrukking van geselekteerde membraangene. Die immunogene is geskep om moontlik gebruik te word in 'n stimuleer-versterkingsenstof toedieningstrategie. Die membraangene van onlangs sirkulerende virusstamme in Suid-Afrika was geamplifiseer deur polimerase kettingreaksie (PKR). Die gene is daarna gekloneer vir beide volgordebepalings en uitdrukkingdoeleindes. Filogenetiese verhoudings is uitgewerk deur die volgordes met verwysingsstamme en subtipe C stamme te vergelyk. Uitdrukking van die gene is waargeneem in 293 selle deur die Westerse kladtegniek te gebruik met MIV-1 positiewe pasiëntsera as teenliggaam. Volgorde-analise het aangetoon dat die derde varieerbare (V3) lus meer gekonserveer is, en dat die gedeelte wat op die lus volg meer varieerbaar is. Die kroonvolgorde (GPGQ) asook posisies van ongelaaide of negatief gelaaide aminosure in die V3 lus het aangedui dat die isolate 'n nie-syncytia induserende fenotipe het. Filogenetiese analise het aangedui dat al die volgordes subtipe C is en dat die volgordes nie rekombinant is nie. Dit is ook deur rekombinasie analise bewys. Die inter-monster diversiteit van die Suid-Afrikaanse volgordes was hoër as die waargenome afstand vanaf die subtipe C konsensus volgorde. Die Suid-Afrikaanse volgordes is versprei oor verskeie subgroepe in 'n subtipe C boom, wat die konsep dat hierdie infeksies 'n meer gevestigde epidemie voorstel waar veelvuldige infeksies met verskillende geografiese oorspronge plaasgevind het beklemtoon. Die Westerse klad het ongeprosesseerde gp160 membraanproteïne aangetoon wat Rev afhanklik was. Hierdie studie het hoogs benodigde subtipe C Suid-Afrikaanse volgordes van membraangene geproduseer. Die volgordes kan as basis dien om die gene te modifiseer sodat dit gebruik kan word as immunogene in 'n entstof vir Suid-Afrika.

Research report submitted in partial fulfilment for MSc (Med) in Epidemiology and Biostatistics in the School of Public Health, 2013 / Concurrent sexual partnerships are a sexual network pattern that speeds the spread of HIV/AIDS and Sexual Transmitted Infections(1). Multiple and concurrent Sexual Partnerships (MCP) are part of behavioural drivers and are playing main role in the increase of HIV incidence(2). The main aim of the study is to identify the possible socio-demographic and behavioural factors that are associated with concurrent sexual partnership in 4 communities of South Africa(SA), so as to inform HIV prevention programmes in designing targeted interventions for addressing this problem in specific communities. The ultimate goal is to reduce the incidence of new HIV infections

The prevalence and the incidence are two primary epidemiological parameters in infectious disease modelling. The incidence is also closely related to the force of infection or the hazard of infection in survival analysis terms. The two measures carry the same information about a disease because they measure the rate at which new infections occur. The disease prevalence gives the proportion of infected individuals in the population at a given time, while the incidence is the rate of new infections. The thesis discusses methods for estimating HIV prevalence, incidence rates and the force of infection, against age and time, using cross-sectional seroprevalence data for pregnant women attending antenatal clinics. The data was collected on women aged 12 to 47 in rural KwaZulu-Natal for each of the years 2001 to 2006. The generalized linear model for binomial response is used extensively. First the logistic regression model is used to estimate annual HIV prevalence by age. It was found that the estimated prevalence for each year increases with age, to peaks of between 36% and 57% in the mid to late twenties, before declining steadily toward the forties. Fitted prevalence for 2001 is lower than for the other years across all ages. Several models for estimating the force of infection are discussed and applied. The fitted force of infection rises with age to a peak of 0.074 at age 15, and then decreases toward higher ages. The force of infection measures the potential risk of infection per individual per unit time. A proportional hazards model of the age to infection is applied to the data, and shows that additional variables such as partner’s age and the number of previous pregnancies do have a significant effect on the infection hazard. Studies for estimating incidence from multiple prevalence surveys are reviewed. The relative inclusion rate (RIR), accounting for the fact that the probability of inclusion in a prevalence sample depends on the individual’s HIV status, and its role in incidence estimation is discussed as a possible future approach of extending the current work. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.

Thesis (MScMedSc (Pathology. Medical Virology))--University of Stellenbosch, 2005. / There are currently an estimated 5.3 million people infected with human immunodeficiency virus / acquired immunodeficiency syndrome (HIV/AIDS) in South Africa. HIV-1 group M Subtype C is currently responsible for the majority of HIV infections in sub-Saharan Africa (56% worldwide). The Khayelitsha informal settlement, located 30 km outside Cape Town, has one of the highest HIV prevalence rates in the Western Cape. The objective of this study was to investigate the molecular epidemiology of HIV-1 in Khayelitsha using serotyping and genotyping techniques. Patient samples were received from the Matthew Goniwe general health clinic located at site C in Khayelitsha. Serotyping was performed through a competitive enzymelinked immunosorbent assay (cPEIA). RNA was isolated from patient plasma and a two step RT-PCR amplification of the gag p24, env gp41 IDR, env gp120 V3 and pol genome regions performed. Sequences obtained were used for detailed sequence and phylogenetic analysis. Neighbour-joining and maximum likelihood phylogenetic trees were drawn to assess the relationship between the Khayelitsha sequences obtained and a set of reference sequences obtained from the Los Alamos National Library (LANL) HIV database (http://www.hiv.lanl.gov/). Through serotyping and genotyping the majority of HIV strains were characterised as HIV-1 group M subtype C. One sample (1154) was characterised as a possible C / D recombinant strain. In 9 other samples HIV-1 recombination cannot be excluded, as only one of the gene regions investigated could be amplified and characterised in these samples. The gag p24 genome region was found to be more conserved than the env gp41 IDR, with the env gp41 IDR more conserved than the env gp120 V3. The variability of the env gp120 V3 region indicates that patients might be dually infected with variant HIV-1 subtype C strains or quasispecies. Conserved regions identified in the Khayelitsha sequences can induce CD4+ T-cell responses and are important antibody recognition target sites. These conserved regions can play a key role in the development of an effective HIV-1 immunogen reactive against all HIV-1 subtypes. The majority of subtype C viruses were predicted to use CCR5 as their major chemokine co-receptor. The pol sequences analysed indicate that mutations associated with minor resistance to Protease Inhibitors (PIs) might be present in the Khayelitsha community. The identification of resistant mutations is vital for people receiving antiretroviral treatment (ART). It can influence the success of their treatment and delay the onset of AIDS. Serotyping is a quick characterisation method, but not always accurate. With genotyping detailed molecular analysis can be performed. However, with genotyping the success of amplification often depends on viral load. In Southern Africa a subtype C candidate vaccine appears to be the best option for future vaccine considerations. The sporadic detection of non-subtype C and recombinant subtype C viruses remains a concern and will thus have to be closely monitored. Phylogenetic analysis can help to classify and monitor the spread and evolution of these viruses.

A infecção pelo vírus da imunodeficiência humana na Amazônia tem-se mostrado como um dos mais recentes desafios para o enfrentamento da epidemia de HIV/aids no Brasil. Estudos epidemiológicos baseados em dados de incidência mostram tendência de crescimento da epidemia na região Norte do país. O Serviço de Assistência Especializada de Santarém é referência em assistência às pessoas com HIV/aids de 25 municípios das mesorregiões do baixo Amazonas e sudoeste do Pará. Os objetivos do presente trabalho consistem em descrever as características sociodemográficas, clínicas e laboratoriais de pessoas vivendo com HIV à admissão nesse serviço de referência, comparando-as entre os períodos: 1999 a 2002(P1), 2003 a 2006(P2) e 2007 a 2010(P3) e analisar as tendências de incidência de aids em Santarém entre 1999 e 2010. As informações referentes às variáveis de interesse foram obtidas em revisão de prontuários. Foram calculados os coeficientes de incidência padronizados a partir dos casos notificados de aids em Santarém, obtidos em bases de dados nacionais e locais. A análise de tendência de incidência foi realizada por modelos de regressão polinomial. A maioria dos 527 sujeitos (62,4%) foi admitida em P3, com 24,1% e 13,5% em P2 e P1, respectivamente. Observou-se aumento significativo da participação de indivíduos não procedentes de Santarém em P3 em comparação a P1. Verificou-se diferença significativa entre os sexos com relação ao motivo de realização da testagem pelo fato do conhecimento da soropositividade do parceiro ter motivado a testagem entre as mulheres em P1 e P2. Enquanto a presença de sinais e sintomas sugestivos de HIV/aids motivou o teste em homens durante todo o período avaliado. Houve redução significativa das medianas de linfócitos T CD4+ à admissão em P3, em relação a P1 e P2. Foram notificados 336 casos novos de aids em Santarém no período de 1999 a 2010. Foi encontrada tendência significativa de crescimento da epidemia em Santarém em ambos os sexos, e nas categorias de exposição ao HIV heterossexual e homo/bissexual no sexo masculino. O crescimento da demanda assistencial no serviço de Santarém, com incremento do número de pacientes procedentes de municípios menores e, admitidos em estadios tardios da infecção, associada à tendência de crescimento de incidência de aids em Santarém no período estudado, sugerem que as intervenções programáticas implementadas na região podem ter contribuído para o reconhecimento de maior número de casos de aids, porém ainda não possibilitaram o diagnóstico mais precoce. Acredita-se que estratégias de vigilância epidemiológica de segunda geração poderiam subsidiar de modo mais eficiente as intervenções programáticas voltadas ao controle da epidemia em uma região caracterizada por apresentar fatores individuais, sociais e programáticos que conferem vulnerabilidade acrescida à infecção pelo HIV. / Infection with human immunodeficiency virus within the Amazon region has been shown as one of the latest challenges confronting the HIV/AIDS epidemic in Brazil. Epidemiological studies based on incidence data show an increasing trend in AIDS incidence in the Brazilian North region. The specialized HIV/AIDS outpatient clinic of Santarém is the reference healthcare setting that provides care for people living with HIV/AIDS (PLHA) from 25 municipalities of the Lower Amazon and southwestern Pará regions. The aims of this study are to describe socio-demographic, clinical and laboratory features of PLHA at time of admission to this reference clinic, comparing them among the following periods: 1999 to 2002 (P1), 2003 and 2006 (P2) and 2007 and 2010 (P3), and to analyze AIDS incidence trends in Santarém between 1999 and 2010. Information about variables of interest was obtained by review of medical records. Standardized AIDS incidence rates were calculated, based on cases reported in Santarém, using data obtained from national and local databases. Incidence trend analysis was performed by polynomial regression. Out of 527 records, 62.4% of patients were admitted to the clinic in P3, 24.1% and 13.5% in P2 and P1, respectively. A significant increase was seen in the participation of individuals from cities other than Santarém in P3, as compared to P1. There was a significant gender difference in the reason to be tested for HIV, as women were more likely to have been tested due to a seropositive partner in P1 and P2, whereas existing signs and symptoms of HIV/AIDS predominated among men as the reason for testing throughout the study period. A significant reduction in median CD4+ cell counts at admission was noticed comparing P3 to P1 and P2. 336 AIDS cases were reported in Santarém from 1999 to 2010. An increasing AIDS incidence trend was found for both genders, and for both heterosexual and homo/bisexual among males. The increasing local demand for HIV/AIDS care, with larger numbers of cases coming from smaller cities and admitted in later stages of HIV infection, taken together with the increasing AIDS incidence trend in Santarém during the study period suggest that even though programmatic interventions may have succeeded in identifying more AIDS cases, they were not able to lead to an earlier diagnosis. We believe that the implementation of second generation surveillance strategies in this region could guide programmatic interventions for the control of the epidemic more efficiently, in a context characterized by individual, social and programmatic factors related to a high vulnerability to HIV infection.

Com a finalidade de estudar a soroprevalência do Vírus da Imunodeficiência Humana, HIV, e infecções com transmissão relacionadas, entrevistamos e colhemos sangue de 197 usuários de drogas injetáveis, UDIs, amostrados através da metodologia de \"bola de neve\" (snow-balling), da cidade de Santos, São Paulo, Brasil. Nesta cidade a estimativa de UDIs, 10.000 indivíduos, compreende cerca de 2% de sua população. Soroprevalências de HIV, hepatites B e C, sífilis e HTLV (1 ou 2) foram obtidas e comparadas com 197 doadores de sangue pareados por idade e sexo. As soroprevalências encontradas foram de 62% para HIV, 75% para HCV, 75% para HBV, 34% para sífilis, e 25% para o HTLV (1 e 2) entre os UDIs, comparado com 0%; 2%; 23%; 12% e 1% entre os doadores do banco de sangue, respectivamente. Os fatores de risco para transmissões parenterais nesta comunidade de UDIs são mais importantes que para transmissão sexual, embora a última deva ser considerada quando se planejar estratégias de controle. Além disso, estimamos a Razão de Reprodutibilidade Basal, R0, para o HIV entre os UDIs. Usando um modelo clássico para infecções transmitidas por vetores de Macdonald adaptado para \"agulhas\", o valor de R0 foi estimado em 28 e 98, considerando uma distribuição dos inóculos infectantes como homogênea ou heterogênea respectivamente . Esta estimativa foi baseada somente em parâmetros de transmissão parenteral nesta comunidade de UDIs. Usando este modelo a estimativa da soroprevalência do HIV no equilíbrio (0,67) é bem próxima à soroprevalência observada (0,62). / In order to study the seroprevalence of HIV and infections with related transmission patterns, as hepatitis B and C, syphilis and HTLV (1 and 2), we interviewed and bled 197 IDUs, sampled by snow-balling and compared with 197 blood donors matched for age and sex, both groups from the city of Santos, Sao Paulo, Brazil. Seroprevalences found were 62% for HIV, 75% for HCV, 75% for HBV, 34% for syphilis and 25% for HTLV (1 or 2) among IDUs, which compare with 0.0%, 2%, 23%, 12%, and 1% for blood donors, respectively. The risk for parenterally transmitted infections in this IDUs community is higher than that for sexually transmitted one. We also estimated the Basic Reproduction Ratio, R0, for HIV among IDUs. Using a model adapted from the classical Macdonald\'s model for vector-born infection, the R0 resulted in 28 and 98, assuming an homogeneous or heterogeneous distribution of infective inoculae, respectively. This estimation was based only on parenteral transmission. Using this model the expected equilibrium for HIV seroprevalence (0.67) is close to the observed seroprevalence (0.62)