Browsing by Author "Otwombe, Kennedy"

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    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.
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    Comparing rates of mycobacterial clearance in sputum smear-negative and smear-positive adults living with HIV
    (BMC (part of Springer Nature), 2021-05-22) Machowski, Edith E.; Letutu, Matebogo; Lebina, Limakatso; Waja, Ziyaad; Msandiwa, Reginah; Milovanovic, Minja; Gordhan, Bhavna G.; Otwombe, Kennedy; Friedrich, Sven O.; Chaisson, Richard; Diacon, Andreas H.; Kana, Bavesh; Martinson, Neil
    Background: Pulmonary tuberculosis (TB) in people living with HIV (PLH) frequently presents as sputum smearnegative. However, clinical trials of TB in adults often use smear-positive individuals to ensure measurable bacterial responses following initiation of treatment, thereby excluding HIV-infected patients from trials. Methods: In this prospective case cohort study, 118 HIV-seropositive TB patients were assessed prior to initiation of standard four-drug TB therapy and at several time points through 35 days. Sputum bacillary load, as a marker of treatment response, was determined serially by: smear microscopy, Xpert MTB/RIF, liquid culture, and colony counts on agar medium. Results: By all four measures, patients who were baseline smear-positive had higher bacterial loads than those presenting as smear-negative, until day 35. However, most smear-negative PLH had significant bacillary load at enrolment and their mycobacteria were cleared more rapidly than smear-positive patients. Smear-negative patients’ decline in bacillary load, determined by colony counts, was linear to day 7 suggesting measurable bactericidal activity. Moreover, the decrease in bacterial counts was comparable to smear-positive individuals. Increasing cycle threshold values (Ct) on the Xpert assay in smear-positive patients to day 14 implied decreasing bacterial load. Conclusion: Our data suggest that smear-negative PLH can be included in clinical trials of novel treatment regimens as they contain sufficient viable bacteria, but allowances for late exclusions would have to be made in sample size estimations. We also show that increases in Ct in smear-positive patients to day 14 reflect treatment responses and the Xpert MTB/RIF assay could be used as biomarker for early treatment response.
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    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.
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    Five year neurodevelopment outcomes of perinatally HIV-infected children on early limited or deferred continuous antiretroviral therapy
    (Wiley Open Access, 2018) Laughton, Barbara; Cornell, Morna; Kidd, Martin; Springer, Priscilla Estelle; Dobbels, Els; Van Rensburg, Anita Janse; Otwombe, Kennedy; Babiker, Abdel; Gibb, Diana M.; Violari, Avy; Kruger, Mariana; Cotton, Mark F.
    Introduction: Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV-infected (HIV-positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long-term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIVinfected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART-Def); immediate time-limited ART for 40 weeks (ART-40W) or 96 weeks (ART-96W). ART was restarted in the time-limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants. Methods: A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests for visual motor integration at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms. Results: In this study, 28 ART-Def, 35 ART-40W, 33 ART-96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART-Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV-infected children (mean standard scores: 75.8 ART-Def, 79.8 ART-40W, 75.9 ART-96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)). Conclusions: Early locomotor delay in the ART-Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV-infected children on early time-limited ART were similar to uninfected controls, apart from visual perception where HIVinfected children scored lower. Poorer visual perception performance warrants further investigation.
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    Thymic output and CD4 T-cell reconstitution in HIV-infected children on early and interrupted antiretroviral treatment : evidence from the children with HIV early antiretroviral therapy trial
    (Frontiers, 2017-09) Lewis, Joanna; Payne, Helen; Walker, A. Sarah; Otwombe, Kennedy; Gibb, Diana M.; Babiker, Abdel G.; Panchia, Ravindre; Cotton, Mark F.; Violari, Avy; Klein, Nigel; Callard, Robin E.
    Objectives: Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants’ immune systems are more plastic and dynamic than older children’s or adults’, and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart. Methods: Data from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children’s CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART. Results: Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption. Conclusion: Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children’s CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children’s CD4 levels.