SUNScholar - Browsing by Author "Cotton, Mark F."

Browsing by Author "Cotton, Mark F."

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Accelerating clinical evaluation of repurposed combination therapies for COVID-19
(American Society of Tropical Medicine and Hygiene, 2020-08-21) Rayner, Craig R.; Dron, Louis; Park, Jay J. H.; Decloedt, Eric H.; Cotton, Mark F.; Niranjan, Vis; Smith, Patrick F.; Dodds, Michael G.; Brown, Fran; Reis, Gilmar; Wesche, David; Mills, Edward J.
As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.
Acceptability and feasibility of mHealth and community-based directly observed antiretroviral therapy to prevent mother-to-child HIV transmission in South African pregnant women under Option B+ : an exploratory study
(Dove Medical Press, 2016) Nachega, Jean B.; Skinner, Donald; Jennings, Larissa; Magidson, Jessica F.; Altice, Frederick L.; Burke, Jessica G.; Lester, Richard T.; Uthman, Olalekan A.; Knowlton, Amy R.; Cotton, Mark F.; Anderson, Jean R.; Theron, Gerhard B.
ENGLISH SUMMARY : Objective: To examine the acceptability and feasibility of mobile health (mHealth)/short message service (SMS) and community-based directly observed antiretroviral therapy (cDOT) as interventions to improve antiretroviral therapy (ART) adherence for preventing mother-to-child human immunodeficiency virus (HIV) transmission (PMTCT). Design and methods: A mixed-method approach was used. Two qualitative focus group discussions with HIV-infected pregnant women (n=20) examined the acceptability and feasibility of two ART adherence interventions for PMTCT: 1) SMS text messaging and 2) patient-nominated cDOT supporters. Additionally, 109 HIV-infected, pregnant South African women (18–30 years old) receiving PMTCT services under single-tablet antiretroviral therapy regimen during pregnancy and breastfeeding and continuing for life (“Option B+”) were interviewed about mobile phone access, SMS use, and potential treatment supporters. Setting: A community primary care clinic in Cape Town, South Africa. Participants: HIV-infected pregnant women. Main outcomes: Acceptability and feasibility of mHealth and cDOT interventions. Results: Among the 109 women interviewed, individual mobile phone access and SMS use were high (>90%), and 88.1% of women were interested in receiving SMS ART adherence support messages such as reminders, motivation, and medication updates. Nearly all women (95%) identified at least one person close to them to whom they had disclosed their HIV status and would nominate as a cDOT supporter. Focus group discussions revealed that cDOT supporters and adherence text messages were valued, but some concerns regarding supporter time availability and risk of unintended HIV status disclosure were expressed. Conclusion: mHealth and/or cDOT supporter as interventions to improve ART adherence are feasible in this setting. However, safe HIV status disclosure to treatment supporters and confidentiality of text messaging content about HIV and ART were deemed crucial.
African multi-site 2-year neuropsychological study of school-age children perinatally infected, exposed, and unexposed to human immunodeficiency virus
(Oxford University Press, 2020-10) Boivin, Michael J.; Chernoff, Miriam; Fairlie, Lee; Laughton, Barbara; Zimmer, Bonnie; Joyce, Celeste; Barlow-Mosha, Linda; Bwakura-Dangarembizi, Mutsawashe; Vhembo, Tichaona; Ratswana, Mmule; Kamthunzi, Portia; McCarthy, Katie; Familiar-Lopez, Itziar; Jean-Philippe, Patrick; Coetzee, Joan; Abrahams, Nasreen; Gous, Hermien; Violari, Avy; Cotton, Mark F.; Palumbo, Paul E.
Background Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). Methods We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child’s age and sex, and selected personal/family control variables. Results The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. Conclusions Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.
Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life
(American Society for Microbiology, 2013-01) Reikie, Brian A.; Naidoo, Shalena; Ruck, Candice E.; Slogrove, Amy L.; De Beer, Corena; La Grange, Heleen; Adams, Rozanne C. M.; Ho, Kevin; Smolen, Kinga; Speert, David P.; Cotton, Mark F.; Preiser, Wolfgang; Esser, Monika; Kollmann, Tobias R.
HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following theWHOextended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.
Antiretroviral therapy for the management of HIV in children
(Health & Medical Publishing Group, 2014-12) Frigati, L.; Cotton, Mark F.; Rabie, H.
Since 2004, when antiretroviral therapy (ART) was first available to children through the National Department of Health, there has been significant progress in preventing and treating paediatric HIV. Large cohort studies and prospective trials confirmed that young children require early diagnosis with rapid access to ART regardless of CD4+ lymphocyte count. Studies also confirmed the importance of ritonavir-boosted protease inhibitors during therapy, regardless of prior nevirapine exposure. As prevention strengthens and the paediatric population ages, the goal posts are shifting towards even earlier diagnosis, targeting newborn infants on the first day of life and also the perinatally infected adolescent. There is an increasing focus on the long-term health, social, developmental and scholastic outcomes of HIV-infected children. Clinicians require new skills to assist children with transition into adulthood. In this article we focus on the care of infants and children.
Antiretroviral therapy in children - increased benefit from increased complexity
(Health & Medical Publishing Group, 2000-10) Cotton, Mark F.
Antiretroviral therapy (ART) started as monotherapy with significant short-term gains. With the advent of newer drugs management has become more complex, but with significant gains in quality and quantity of life. The evolution of ART in children lags behind that of adults for many reasons. These include an unwillingness to use new medications in children before efficacy has been established and also difficulty in developing suitable formulations for children. ART has progressed from monotherapy to dual, triple and even quadruple therapy, stimulated by insights into the rapidity of viral replication, development of resistance, and availability of new agents. The most pressing concern with ART is its lack of accessibility to the majority of patients that need it. Other important issues are how and when to use it in ways that promote durability of response but avoid unnecessary use. Most information is derived from studies with relatively short periods of follow-up. The long-term durability of therapy is not known, but with development of new agents should be sustained.
The association between the ratio of monocytes : lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life
(BioMed Central, 2014-07-17) Naranbhai, Vivek; Kim, Soyeon; Fletcher, Helen; Cotton, Mark F.; Violari, Avy; Mitchell, Charles; Nachman, Sharon; McSherry, George; McShane, Helen; Hill, Adrian V. S.; Madhi, Shabir A.
Background: Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV. Methods: We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious. Results: Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%). Conclusion: Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.
Bacterial disease and antimicrobial susceptibility patterns in HIV-Infected, hospitalized children: A retrospective cohort study
(PLOS, 2008-09-24) Jaspan, Heather B.; Huang, Lyen C.; Cotton, Mark F.; Whitelaw, Andrew; Myer, Landon
Background: Serious bacterial infections are a major source of morbidity and mortality in HIV-infected children. The spectrum of disease is wide, and responsible organisms vary according to setting. The use of antibiotic prophylaxis and the emergence of multi-drug resistant bacteria necessitate examination of responsible organisms and their antibiotic susceptibility. Methodology/Principal Findings: A retrospective cohort study of all HIV-positive pediatric admissions at an urban public sector hospital in Cape Town between January 2002 and June 2006 was conducted. Children between the ages of one month and nine years with laboratory confirmed HIV status, serious bacterial infection, and a hospital length of stay of 5 days or more, were eligible for inclusion. Organisms isolated from blood, urine, and cerebral spinal fluid cultures and their antimicrobial susceptibility were examined, and compared according to timing of isolation to distinguish nosocomial versus community-acquired. One hundred and forty-one children were identified (median age 1.2 years), 39% of whom were on antiretrovirals started before or during this hospitalization. Bacterial infections involved all organ systems, however pneumonia was most common (67%). S. pneumoniae and S. aureus were the most common gram positive and K. pneumoniae was the most common gram negative organism. K pneumoniae isolates were resistant to many first and second line antibiotics, and were all considered nosocomial. All S. aureus isolates were methicillin resistant, some of which were community-acquired. Conclusions/Significance: Bacterial infections are an important source of co-morbidity in HIV-infected children in resourcelimited settings. Clinicians should have a low threshold to initiate antibiotics in children requiring hospitalization. Broadspectrum antibiotics should be used judiciously. Clinicians caring for HIV-infected children should be cognizant of the most common organisms affecting such children, and of their local antimicrobial susceptibilities, when treating empirically for serious bacterial infections.
The challenge of chronic lung disease in HIV-infected children and adolescents
(BioMed Central, 2013) Weber, Heinrich C.; Gie, Robert P.; Cotton, Mark F.
Until recently, little attention has been given to chronic lung disease (CLD) in HIV-infected children. As the HIV epidemic matures in sub-Saharan Africa, adolescents who acquired HIV by vertical transmission are presenting to health services with chronic diseases. The most common is CLD, which is often debilitating. This review summarizes the limited data available on the epidemiology, pathophysiology, clinical picture, special investigations and management of CLD in HIV-infected adolescents. A number of associated conditions: lymphocytic interstitial pneumonitis, tuberculosis and bronchiectasis are well described. Other pathologies such as HIV-associated bronchiolitis obliterans resulting in non-reversible airway obstruction, has only recently been described. In this field, there are many areas of uncertainty needing urgent research. These areas include the definition of CLD, pathophysiological mechanisms and common pathologies responsible. Very limited data are available to formulate an effective plan of investigation and management.
The challenges of success : adolescents with perinatal HIV infection
(Wiley, 2013) Mofenson, Lynne M.; Cotton, Mark F.
The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults.
A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation
(Nature Research (part of Springer Nature), 2019) Violari, Avy; Cotton, Mark F.; Kuhn, Louise; Schramm, Diana B.; Paximadis, Maria; Loubser, Shayne; Shalekoff, Sharon; Da Costa Dias, Bianca; Otwombe, Kennedy; Liberty, Afaaf; McIntyre, James; Babiker, Abdel; Gibb, Diana; Tiemessen, Caroline T.
ENGLISH ABSTRACT: Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.
Clinical features and lung function in HIV-infected children with chronic lung disease
(Health and Medical Publishing Group, 2015) Weber, Heinrich Christoph; Gie, Robert P.; Wills, Karen; Cotton, Mark F.
Background. Although chronic lung disease (CLD) is commonly seen in children with advanced HIV disease, it is poorly studied. Objectives. To report on the clinical manifestations and lung function tests in children with advanced HIV disease at a tertiary care centre, and determine clinical predictors of poor lung function. Methods. We undertook a cross-sectional study of children with advanced HIV disease in whom CLD was suspected. We undertook clinical evaluation and lung function tests, accompanied by a retrospective chart review. Results. In 56 children identified, the median age was 5 (interquartile range (IQR) 2 - 8) years with equal gender ratio. The majority (93%) had been previously treated for tuberculosis and/or pneumonia (71%). The most common CLD identified was lymphocytic interstitial pneumonitis (54%). The median nadir CD4 percentage was 13% (IQR 8.5 - 16%) and the median highest reported viral load was log5.8 (IQR log5.0 - log6.5). The median duration of antiretroviral therapy was 9.8 (IQR 1.1 - 19.5) months. Lung function tests were performed in 27 (48%) children. The median forced expiratory volume in 1 second (FEV1) was 60% (IQR 45.3 - 86.3%) predicted. Previous hospitalisation, respiratory rate, digital clubbing, chest hyperinflation and hyperpigmented skin lesions were associated with a decreased FEV1 in a univariate relationship. In a multiple linear regression analysis, hyperinflation, increased respiratory rate and hyperpigmented skin lesions were associated with poor lung function (percentage FEV1). Conclusion. We identified useful clinical signs predictive of poor lung function in HIV-infected children with CLD, especially in resource-limited settings.
Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy
(BioMed Central, 2008-01) Walters, Elisabetta; Cotton, Mark F.; Rabie, Helena; Schaaf, H. Simon; Walters, Lourens O.; Marais, Ben J.
Background: The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART. Methods: We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005. Results: Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%). Conclusion: We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.
Comparative study of different brands of stavudine capsules for the off-label 'opened capsule' dosing method recommended for HIV-infected infants and children in resource-limited settings
(Health and Medical Publishing Group, 2009) Innes, Steve; Smuts, Marlize; Cotton, Mark F.; Seifart, Heiner; Rosenkranz, Bernd
Introduction. If a caregiver does not have access to a refrigerator, the South African National Department of Health advises that stavudine adult capsule formulations be employed using the off-label 'opened capsule' dosing method. The accuracy of this dosing method has not previously been validated. Aim. To assess the accuracy of the off-label opened capsule method for stavudine dosing in infants and children. In addition, we assessed the relative ease of dispersion of generic and original capsule preparations in water to determine which preparations, if any, are suitable for the off-label opened capsule dosing method. Method. We evaluated 10 Zerit (Bristol-Myers Squibb), 5 Stavudine (Aspen), and 5 Stavir (Cipla) capsules. Each capsule was dispersed in 30 ml water, creating 20 separate solutions. Timed dispersion of each generic was compared with that of the original (Zerit). Each solution was then centrifuged to remove sediment, and the concentration of active drug (mg/ml) was analysed by high-performance liquid chromatography. Results. The ease of dispersion of the contents of Aspen Stavudine capsules was equivalent to that of Zerit, and resulted in a mean recovery of active drug from solution of over 97%, confirming the accuracy of this dosing method. The contents of Stavir capsules, however, were extremely difficult to disperse in water despite prolonged agitation; consequently, the recovery of active drug from the solution was reduced. Conclusion. The accuracy of the off-label opened capsule dosing method for stavudine is acceptable. There is no need to instruct caregivers to include sediment in the aliquot given to the infant. However, studies that confirm adequate bioavailability and efficacy are needed. In addition, it is important to avoid supplying generic capsules the contents of which do not disperse easily in water, as this may lead to a significant reduction in the amount of active drug that a child receives.
Cross‐cultural assessment of HIV‐associated cognitive impairment using the Kaufman assessment battery for children : a systematic review
(Wiley Open Access, 2017) Van Wyhe, Kaylee S.; Van de Water, Tanya; Boivin, Michael J.; Cotton, Mark F.; Thomas, Kevin G. F.
Introduction: Despite improved efficacy of, and access to, combination antiretroviral therapy (cART), HIV‐associated cognitive impairments remain prevalent in both children and adults. Neuropsychological tests that detect such impairment can help clinicians formulate effective treatment plans. The Kaufman Assessment Battery for Children (KABC), although developed and standardized in the United States, is used frequently in many different countries and cultural contexts to assess paediatric performance across various cognitive domains. This systematic review investigated the cross‐cultural utility of the original KABC, and its 2nd edition (KABC‐II), in detecting HIV‐associated cognitive impairment in children and adolescents. Methods: We entered relevant keywords and MeSH terms into the PubMed, PsycInfo, EBSCOHost, ProQuest, and Scopus databases, with search limits set from 1983–2017. Two independent reviewers evaluated the retrieved abstracts and manuscripts. Studies eligible for inclusion in the review were those that (a) used the KABC/KABC‐II to assess cognitive function in children/adolescents aged 2–18 years, (b) featured a definition of cognitive impairment (e.g. >2 SD below the mean) or compared the performance of HIV‐infected and uninfected control groups, and (c) used a sample excluded from population on which the instruments were normed. Results and discussion: We identified nine studies (eight conducted in African countries, and one in the United Kingdom) to comprise the review's sample. All studies detected cognitive impairment in HIV‐infected children, including those who were cART‐naïve or who were cART treated and clinically stable. KABC/KABC‐II subtests assessing simultaneous processing appeared most sensitive. Evaluation of the methodological quality of the selected studies by two independent reviews suggested that shortcomings included reporting and selection biases. Conclusions: This systematic review provides evidence for the cross‐cultural utility of the KABC/KABC‐II, particularly the simultaneous processing subtests, in detecting cognitive impairment in HIV‐infected children (including those who are clinically stable). Although the current results suggest there is justification for using the KABC/KABC‐II primarily in East Africa, further investigation is required to explore the instrument's utility in other HIV‐prevalent regions of the globe.
Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments
(BMC (part of Springer Nature), 2020-05-19) Ackermann, Christelle; Andronikou, Savvas; Saleh, Muhammad G.; Kidd, Martin; Cotton, Mark F.; Meintjes, Ernesta M.; Laughton, Barbara
Background: Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods: DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results: 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion: Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.
Disclosure of human immunodeficiency virus status to children in South Africa : a comprehensive analysis
(AOSIS Publishing, 2019) Van Elsland, Sabine L.; Peters, Remco P. H.; Grobbelaar, Cornelis; Ketelo, Patiswa; Kok, Maarten O.; Cotton, Mark F.; Van Furth, A. Marceline
Background: The extent of disclosure of HIV status to children and adolescents and the context facilitating their disclosure process have received little attention. Objectives: To assess disclosure and provide a comprehensive analysis of characteristics associated with disclosure to children (3–14 years) receiving antiretroviral treatment in a South African semi-urban clinic. Methods: This cross-sectional study used structured interview administered questionnaires which were supplemented with medical record data. Predictors included child, caregiver, clinical and socio-economic characteristics, viral suppression, immune response, adherence, health-related quality of life and family functioning. Results: We included 190 children of whom 45 (23.7%) received disclosure about their HIV status, of whom 28 (14.7%) were partially disclosed and 17 (8.9%) were fully disclosed. Older age of the child and higher education of the caregiver were strongly associated with disclosure. Female caregivers, detectable viral load, syrup formulation, protease inhibitor (PI) regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure. Conclusion: When children do well on treatment, caregivers feel less stringent need to disclose. Well-functioning families, higher educated caregivers and better socio-economic status enabled and promoted disclosure. Non-disclosure can indicate a sub-optimal social structure which could negatively affect adherence and viral suppression. There is an urgent need to address disclosure thoughtfully and proactively in the long-term disease management. For the disclosure process to be beneficial, an enabling supportive context is important, which will provide a great opportunity for future interventions.
Early antiretroviral therapy reduces the incidence of otorrhea in a randomized study of early and deferred antiretroviral therapy : evidence from the Children with HIV Early antiretroviral therapy (CHER) Study.
(2011-10) Hainline, Clotilde; Taliep, Reghana; Sorour, Gill; Nachman, Sharon; Rabie, Helena; Dobbels, Els; Janse van Rensburg, Anita; Cornell, Morna; Violari, Avy; Madhi, Shabir A.; Cotton, Mark F.
Abstract Background Although otorrhea occurs commonly in HIV-infected infants, there are few data. We compared the incidence of otorrhea in infants receiving early vs deferred ART in the Children with HIV Early Antiretroviral (CHER) trial. Infants aged 6 to 12 weeks of age with confirmed HIV infection and a CD4 percentage greater than or equal to 25% were randomized to early or deferred ART at two sites in South Africa. Medical records from one study site were reviewed for otorrhea. Findings Data were reviewed from the start of the trial in July 2005 until 20 June 2007, when the Data Safety Monitoring Board recommended that randomization to the deferred arm should stop and that all infants in this arm be reviewed for commencing antiretroviral therapy. Infants entered the study at a median of 7.4 weeks of age. Eleven of 38 (29%) on deferred therapy and 7 of 75 (9%) in the early-therapy group developed otorrhea (risk ratio 3.1, 95% confidence interval (CI) 1.31-7.36; p = 0.01). Conclusions Early initiation of antiretroviral therapy is associated with significantly less otorrhea than when a deferred strategy is followed. Trial registration NCT00102960. ClinicalTrials.Gov
Early ART results in greater immune reconstitution benefits in HIV-infected infants : working with data missingness in a longitudinal dataset
(Public Library of Science, 2015) Azzoni, Livio; Barbour, Russell; Papasavvas, Emmanouil; Glencross, Deborah K.; Stevens, Wendy S.; Cotton, Mark F.; Violari, Avy; Montaner, Luis J.
Background: Early initiation of anti-retroviral treatment (ART) decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis. Methods: We characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0–1 year of age) enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42) or upon disease progression (n = 24). A convenience cohort of 23 uninfected infants aged 0–6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK) cells, plasmacytoid dendritic cells (pDC), and CD4+ or CD8+ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI) or Bayesian modeling and multivariate analysis was conducted on the imputed datasets. Results: HIV-1-infected infants had greater frequency of CD4+ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. Both methods indicate that early ART initiation results in higher CD4+ T cell frequency, lower expression of CD95 in CD8+ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors appeared to be similar independently of the timing of ART initiation. Conclusions: Early ART initiation in infants with perinatal HIV infection reduces immune activation and preserves an early expansion of naïve T-cells with undiminished innate cell numbers, giving greater immune reconstitution than achieved with deferred ART. Both statistical approaches concurred in this finding.
Early severe HIV disease precedes early antiretroviral therapy in infants : are we too late?
(International AIDS Society, 2014-06) Innes, Steve; Lazarus, Erica; Otwombe, Kennedy; Afaaf Liberty, Afaaf; Germanus, Ramona; Janse van Rensburg, Anita; Grobbelaar, Nelis; Hurter, Theunis; Eley, Brian; Violari, Avy; Cotton, Mark F.
Objective: To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa. Design: This was a programmatic cohort study. Methods: Electronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t-test and Kaplan Meier methods. Results: A total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2 9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% B25% or absolute CD4B1500 cells/mm3 or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2 11.9) weeks in Cape Town and 8.6 (IQR: 7.7 10.0) weeks in Soweto infants (pB0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (pB0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36 0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05 2.71). Conclusions: ART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality.

Browsing by Author "Cotton, Mark F."

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