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Browsing by Author "Rabie, Helena"

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Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir
(2020-05) Rabie, Helena; Tikiso, Tjokosela; Lee, Janice
ABSTRACT In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopi-navir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interac-tions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing 15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of anti-tuberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treat-ment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with ﬁrst-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identiﬁed: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treat-ment with rifampin and LPV/r-4:4 but remained within the median adult recom-mended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure signiﬁcantly decreased dur-ing concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identiﬁer NCT02348177.)
And therapeutic outcomes lopinavir-ritonavir and a rifampicin containing anti-tuberculosis pharmacokinetics in children with tuberculosis/hiv co-infection treated with regimen
(Stellenbosch : Stellenbosch University, 2019-10-15) Rabie, Helena; Cotton, Mark F.; Schaaf, Hendrik Simon; Gie, Robert Peter; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Background Despite the scale-up of the prevention of mother to child transmission of HIV, an estimated 240,000 children were infected in 2013. Currently, The Joint United Nations Programme on HIV and AIDS (UNAIDS) estimates that 110,000 to 260,000 children less than 14 years of age are newly infected annually. Tuberculosis remains an important cause of morbidity and mortality in HIV co-infected children. The overlapping epidemiology of tuberculosis and HIV in sub-Saharan Africa is well known. Despite reductions in incident tuberculosis cases brought about by both the general roll out of antiretroviral therapy (ART) and the improvement of personal health of HIVpositive children, HIV-positive children remain at high risk for tuberculosis. Currently the World Health Organization (WHO) recommends rifampicin containing fixed-dose combinations for treatment of tuberculosis. Rifampicin induces its own metabolism and concentrations are affected by SLCO1B1CT (rs4149032) polymorphism. Rifampicin is well known to cause significant drug-drug interactions through activation of the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This activation causes significant drug interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors. In addition, SLCO1B1 521 TC (rs4149056) and CYP3A5 polymorphisms may affect lopinavir exposures through altering uptake and metabolism. Abacavir, together with the protease inhibitor lopinavir co-formulated with the pharmacokinetic enhancing protease inhibitor, ritonavir, is a preferred first-line medication for young children with HIV. Rifampicin causes up to 90% reduction in lopinavir exposure, but there are no data on its effect on abacavir in children. Understanding these interactions is essential to ensure effective co-treatment that will suppress HIV replication during co-treatment. For co-formulated lopinavir with ritonavir in a 4:1 ratio, achieving a morning trough concentration (Ctrough) of ≥1mg/L is associated with acceptable viral load outcomes. Doubling the dose of co-formulated lopinavir-ritonavir-4:1 does not consistently achieve this target in children, but limited data suggested that adding ritonavir to achieve a 1:1 ratio of lopinavir-ritonavir (LPV/RTV-1:1) is successful. Furthermore, modelling data suggested that an 8-hourly adjusted dose may achieve this lopinavir trough concentration target, but there was no pharmacokinetic data to this effect. We undertook studies to evaluate two strategies to adjust medication in co-treated children and performed pharmacokinetic evaluation and safety evaluations during these studies and assessed virological outcomes in the larger study. We also studied the pharmacokinetic profile of abacavir during rifampicin containing first-line tuberculosis therapy. Methods To study the lopinavir morning Ctrough and the abacavir area under the curve from 0- 12 hours (AUC0-12) during LPV/RTV-1:1 we prospectively enrolled HIV-positive children with tuberculosis requiring co-treatment with rifampicin and oral solution lopinavir-ritonavir-4:1. Children weighing 3 kg to 15 kg and a post-conception age more than 42 weeks were included into a prospective, multicentre, open-label, nonrandomized study. Children received lopinavir-ritonavir-4:1 with additional ritonavir to achieve a 1:1 ratio. Weight-banded doses of anti-tuberculosis and antiretroviral medications were used. Three intensive pharmacokinetic evaluations were done: the first in the intensive phase of tuberculosis treatment, the second in the last month of tuberculosis treatment and the third evaluation two weeks after completing tuberculosis treatment. We compared a model-based morning Ctrough of lopinavir at the second assessment and the third assessment and tested for non-inferiority, using a non-inferiority margin of 10%. We also assessed model-based abacavir AUC0-12 during LPV/RTV-1:1 superboosting and thereafter. Safety, tolerability and virological outcomes were assessed through special investigations, including hepatic enzymes, electrocardiogram, viral load tests and resistant tests as well as questionnaires. In the second study, children were switched from standard of care (super-boosted lopinavir-ritonavir 1:1) to receive 2 weeks of adjusted dose 3 times daily lopinavirritonavir 4:1. After 2 weeks an intensive pharmacokinetic evaluation was performed and the patient switched back to standard of care ART. We determined the number of children with a morning Ctrough of lopinavir ≥1mg/L. Safety was assessed by measuring hepatic enzymes. Results For the first strategy (LPV/RTV-1:1) 96 children with a median age of 18.2 months enrolled into a non-inferiority study of super-boosting lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Of these 96 children, 80 (83%) completed all three pharmacokinetic evaluations. The model-based lopinavir morning Ctrough on super-boosted lopinavir ritonavir 4:1 with additional ritonavir to achieve a 1:1 ratio whilst receiving rifampicinbased tuberculosis treatment was non-inferior to the model-based morning Ctrough in children on lopinavir-ritonavir-4:1 after the end of tuberculosis therapy and superboosting. The model-predicted percentage of morning Ctrough less than 1.0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% confidence interval [CI] 0·6–19·8), versus 7·6% (95% CI 0·4–16·2) during super-boosting and tuberculosis treatment. At the non-inferiority margin of 10%, this difference of –1·1% (95% CI –6·9 to 3·2) met the criterion for non-inferiority. This strategy was safe and the viral load outcomes were acceptable: children who failed to suppress HIV did not develop resistance. Caretakers reported poor palatability and tolerability of both lopinavirritonavir-4:1 oral solution and ritonavir oral solution. For the second strategy (8-hourly adjusted dosing) 11 children were enrolled into the study assessing adjusted-dose 8-hourly lopinavir-ritonavir 4:1. Children were divided into two weight bands: 5 (45%) were 10–13.9 kg and received 20–24 mg/kg/dose, and 6 (55%) children weighed 6–9.9 kg and received 20–23 mg/kg/dose of lopinavir. Seven children (63.6%) met the suggested morning Ctrough target. Children with a lopinavir mg/kg dose below the median of 21.5mg/kg/dose were more likely to have a morning Ctrough below 1 mg/L (p=0.02). There was a strong correlation between lopinavir and ritonavir concentrations. To model the AUC0-12 of abacavir we included 85 children at PK1, 74 at children at PK2 and 72 children at PK3 on abacavir and in whom pharmacokinetic information was available. Children were participating in the non-inferiority study of super-boosted lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Abacavir pharmacokinetics was described by a two-compartment model with first-order elimination and transit compartment absorption. Clearance was predicted to reach half its mature value at around 2 months after birth and to be fully mature by approximately 2 years of age. During coadministration of rifampicin and super-boosting with ritonavir, a 36% decrease in bioavailability (and AUC0-12) was found. Conclusions Super-boosting lopinavir-ritonavir-4:1 with ritonavir to a 1:1 ratio during rifampicin containing tuberculosis treatment is non-inferior to lopinavir-ritonavir-4:1 without rifampicin. It is also safe and effective but it is poorly tolerated and has poor palatability. Adjusted 8-hourly dosing requires further study. During super-boosting of lopinavir-ritonavir while on rifampicin containing tuberculosis treatment, there is a drug interaction causing a 36% reduction in abacavir AUC0-12
Bronchoscopy in children with COVID‐19 : a case series
(John Wiley & Sons, 2020) Goussard, Pierre; Van Wyk, Lizelle; Burke, Jonathan; Malherbe, Annemie; Retief, Francois; Andronikou, Savvas; Mfingwana, Lunga; Ruttens, Dries; Van der Zalm, Marieke; Dramowski, Angela; Da Costa, Aishah; Rabie, Helena
Introduction: The coronavirus disease‐2019 (COVID‐19) era is a challenging time for respiratory teams to protect their patients and staff. COVID‐19 is predominantly transmitted by respiratory droplets; in the clinical setting, aerosol generating procedures pose the greatest risk for COVID‐19 transmission. Bronchoscopy is associated with increased risk of patient‐to‐health care worker transmission, owing to aerosolized viral particles which may be inhaled and also result in environmental contamination of surfaces. Methods: We describe our experience with the use of modified full‐face snorkeling masks for pediatric bronchoscopy procedures in four COVID‐19 infected children when filtering facepieces/respirators were in limited supply. Results: Bronchoscopy was urgently required in four children, and could not be delayed until COVID‐19 test results were available. During the pandemic peak, when respirators were in short supply, modified full‐face snorkel masks (SEAC Libera, SEAC, Italy) were worn by the bronchoscopy team. Each mask was fitted with an O‐ring, adapter, and heat and moisture exchanger filter. To date, there have been no COVID‐19 infections among the bronchoscopy team staff, whereas the overall Hospital staff COVID‐19 prevalence rate has exceeded 13.5% (667/4949). Conclusion: Emergency bronchoscopy procedures on COVID‐19 infected patients or patients with unknown infection status can be safely performed using modified full‐ face snorkel masks.
Clinical experience with severe acute respiratory syndrome Coronavirus 2-related illness in children : hospital experience in Cape Town, South Africa
(Oxford University Press, 2020-11-10) van der Zalm, Marieke M.; Lishman, Juanita; Verhagen, Lilly M.; Redfern, Andrew; Smit, Liezl; Barday, Mikhail; Ruttens, Dries; da Costa, A’ishah; van Jaarsveld, Sandra; Itana, Justina; Schrueder, Neshaad; Van Schalkwyk, Marije; Parker, Noor; Appel, Ilse; Fourie, Barend; Claassen, Mathilda; Workman, Jessica J.; Goussard, Pierre; Van Zyl, Gert; Rabie, Helena
Background: Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. Methods: We collected clinical data of children aged <13 years with laboratory-confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town, between 17 April and 24 July 2020. Results: One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0-106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8-43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5-120.5 months]; P < .01.). Thirty-three of 159 (20.8%) children had preexisting medical conditions. Fifty-one of 62 (82.3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21 of 51 (41.2%) children, and in 11 of 16 (68.8%) children <3 months of age. Respiratory support was required in 25 of 51 (49.0%) children; 13 of these (52.0%) were <3 months of age. One child was HIV infected and 11 of 51 (21.2%) were HIV exposed but uninfected, and 7 of 51 (13.7%) children had a recent or new diagnosis of tuberculosis. Conclusions: Children <1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support. Access to oxygen may be limited in some low- and middle-income countries, which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis, and SARS-CoV-2 should be explored.
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.
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
High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy : a cross-sectional study
(BioMed Central, 2012-11) Innes, Steve; Cotton, Mark F.; Haubrich, Richard; Conradie, Maria M.; Van Niekerk, Margaret; Edson, Clair; Rabie, Helena; Jain, Sonia; Sun, Xiaoying; Zollner, Ekkehard W.; Hough, Stephen; Browne, Sara H.
Background: Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. Methods: In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. Results: Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). Conclusions: The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resourcelimited settings where specialized skills and equipment are not available.
HIV testing and antiretroviral therapy initiation at birth : views from a primary care setting in Khayelitsha
(AOSIS Publishing, 2015-04-28) Nelson, Aurelie; Maritz, Jean; Giddy, Janet; Frigati, Lisa; Rabie, Helena; Van Cutsem, Gilles; Mutseyekwa, Tabitha; Jange, Nomfusi; Bernheimer, Jonathan; Cotton, Mark F.; Cox, Vivian
No abstract available.
Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome : a case report
(BioMed Central, 2020-06-05) Glanzmann, Brigitte; Möller, Marlo; Schoeman, Mardelle; Urban, Michael; Van Helden, Paul D.; Frigati, Lisa; Grewal, Ravnit; Pieters, Hermanus; Loos, Ben; Hoal, Eileen G.; Glashoff, Richard H.; Cornelissen, Helena; Rabie, Helena; Esser, Monika M.; Kinnear, Craig J.
Background: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. Case presentation: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. Conclusion: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.
It is time to consider third-line options in antiretroviral-experienced paediatric patients?
(BioMed Central, 2011-11) Van Zyl, Gert U.; Rabie, Helena; Nuttall, James J.; Cotton, Mark F.
Abstract Background The historic use of full-dose ritonavir as part of an unboosted protease inhibitor (PI)-based antiretroviral therapy regimen in some South African children contributes to the frequent accumulation of major PI resistance mutations. Methods In order to describe the prevalence of major PI resistance in children failing antiretroviral therapy and to investigate the clinical, immunological and virological outcomes in children with PI resistance, we conducted a cross-sectional study, with a nested case series, following up those children with major PI resistance. The setting was public health sector antiretroviral clinics in the Western Cape province of South Africa, and the subjects were children failing antiretroviral therapy. The following outcome measures were investigated: CD4 count, viral load and resistance mutations. Results Fourteen (17%) of 82 patients, referred from tertiary hospitals, had major PI resistance. All these patients were exposed to regimens that included ritonavir as a single PI. Immune reconstitution and clinical benefit were achieved when using a lopinavir/ritonavir-based treatment regimen in these children with prior PI resistance. At first HIV-1 viral load follow up after initial resistance testing (n = 11), only one patient had a viral load of less than 400 copies/ml; at a subsequent follow up (n = 9), the viral loads of five patients were less than 400 copies/ml. Patients retained on LPV/r had lower viral loads than those switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, two of three patients with follow-up resistance tests accumulated additional PI resistance. Conclusions In children with pre-existing PI resistance, although initially effective, the long-term durability of a lopinavir/ritonavir-based treatment regimen can be compromised by the accumulation of resistance mutations. Furthermore, a second-line NNRTI regimen is often not durable in these patients. As genotypic resistance testing and third-line treatment regimens are costly and limited in availability, we propose eligibility criteria to identify patients with high risk for resistance and guidance on drug selection for children who would benefit from third-line therapy.
Lamivudine monotherapy as a holding regimen for HIV-positive children
(Public Library of Science, 2018-10-11) Patten, Gabriela; Bernheime, Jonathan; Fairlie, Lee; Rabie, Helena; Sawry, Shobna; Technau, Karl; Eley, Brian; Davies, Mary-Ann
Background: In resource-limited settings holding regimens, such as lamivudine monotherapy (LM), are used to manage HIV-positive children failing combination antiretroviral therapy (cART) to mitigate the risk of drug resistance developing, whilst adherence barriers are addressed or when access to second- or third-line regimens is restricted. We aimed to investigate characteristics of children placed on LM and their outcomes. Methods: We describe the characteristics of children (age <16 years at cART start) from 5 IeDEA-SA cohorts with a record of LM during their treatment history. Among those on LM for >90 days we describe their immunologic outcomes on LM and their immunologic and virologic outcomes after resuming cART. Findings: We included 228 children in our study. At LM start their median age was 12.0 years (IQR 7.3–14.6), duration on cART was 3.6 years (IQR 2.0–5.9) and median CD4 count was 605.5 cells/μL (IQR 427–901). Whilst 110 (48%) had no prior protease inhibitor (PI)-exposure, of the 69 with recorded PI-exposure, 9 (13%) patients had documented resistance to all PIs. After 6 months on LM, 70% (94/135) experienced a drop in CD4, with a predicted average CD4 decline of 46.5 cells/μL (95% CI 37.7–55.4). Whilst on LM, 46% experienced a drop in CD4 to <500 cells/μL, 18 (8%) experienced WHO stage 3 or 4 events, and 3 children died. On resumption of cART the average gain in CD4 was 15.65 cells/uL per month and 66.6% (95% CI 59.3–73.7) achieved viral suppression (viral load <1000) at 6 months after resuming cART. Interpretation: Most patients experienced immune decline on LM. Its use should be avoided in those with low CD4 counts, but restricted use may be necessary when treatment options are limited. Managing children with virologic failure will continue to be challenging until more treatment options and better adherence strategies are available.
The last and first frontier : emerging challenges for HIV treatment and prevention in the first week of life with emphasis on premature and low birth weight infants
(International AIDS Society, 2015-12-02) Cotton, Mark F.; Holgate, Sandi; Nelson, Aurelie; Rabie, Helena; Wedderburn, Catherine; Mirochnick, Mark
Abstract Introduction: There is new emphasis on identifying and treating HIV in the first days of life and also an appreciation that low birth weight (LBW) and preterm delivery (PTD) frequently accompany HIV-related pregnancy. Even in the absence of HIV, PTD and LBW contribute substantially to neonatal and infant mortality. HIV-exposed and -infected infants with these characteristics have received little attention thus far. As HIV programs expand to meet the 90-90-90 target for ending the HIV pandemic, attention should focus on newborn infants, including those delivered preterm or of LBW. Discussion: In high prevalence settings, infant diagnosis of HIV is usually undertaken after the neonatal period. However, as in utero infection may be diagnosed at birth, earlier initiation of therapy may limit viral replication and prevent early damage. Globally, there is growing awareness that preterm and LBW infants constitute a substantial proportion of births each year. Preterm infants are at high risk for vertical transmission. Feeding difficulties, apnoea of prematurity and vulnerability to sepsis occur commonly. Feeding intolerance, a frequent occurrence, may compromise oral administration of medications. Although there is growing experience with post-exposure prophylaxis for HIV-exposed term newborn infants, there is less experience with preterm and LBW infants. For treatment, there are even fewer options for preterm infants. Only zidovudine has adequate dosing recommendations for treating term and preterm infants and has an intravenous formulation, essential if feeding intolerance occurs. Nevirapine dosing for prevention, but not treatment, is well established for both term and preterm infants. HIV diagnosis at birth is likely to be extremely stressful for new parents, more so if caring for preterm or LBW infants. Programs need to adapt to support the medical and emotional needs of young infants and their parents, where interventions may be lifesaving. Conclusions: New focus is required for the newborn baby, including those born preterm, with LBW or small for gestational age to consolidate gains already made in early diagnosis and treatment of young children.
Monitoring the South African National Antiretroviral Treatment Programme, 2003-2007 : the IeDEA Southern Africa collaboration
(Health and Medical Publishing Group (HMPG), 2009-09) Cornell, Morne; Technau, Karl; Fairall, Lara; Wood, Robin; Moultrie, Harry; Van Cutsem, Gilles; Giddy, Janet; Mohapi, Lerato; Eley, Brian; MacPhail, Patrick; Prozesky, Hans; Rabie, Helena; Davies, Mary-Ann; Maxwell, Nicola; Boulle, Andrew
Objectives. To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. Design and setting. Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. Subjects. Adults and children (<16 years old) who initiated ART with ≥3 antiretroviral drugs before 2008. Results. Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17 835 patients per site. Among 45 383 adults and 6 198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/μl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/μl, p<0.001) and for those in stage IV (39-89 cells/μl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001). Conclusions. IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.
Nevirapine plasma concentrations in premature infants exposed to single-dose nevirapine for prevention of mother-to-child transmission of HIV-1
(Health and Medical Publishing Group (HMPG), 2011-09) Mugabo, Pierre; Els, Ilse; Smith, Johan; Rabie, Helena; Smith, Peter; Mirochnick, Mark; Steyn, Wilhelm; Hall, David R.; Madsen, Richard; Cotton, Mark F.
Background. No pharmacokinetic data exist for premature infants receiving single-dose nevirapine (sd NVP) for prevention of mother-to-child transmission (MTCT) of HIV. Aim. To describe NVP decay pharmacokinetics in two groups of premature infants - those whose mothers either received or did not receive NVP during labour. Methods. Infants less than 37 weeks' gestation were prospectively enrolled. Mothers received sd NVP during labour if time allowed. Infants received sd NVP and zidovudine. Blood was collected on specified days after birth and NVP concentrations were determined by liquid chromatography-mass spectrometry. Results. Data were obtained from 81 infants, 58 born to mothers who received sd NVP during labour (group I) and 23 to mothers who did not receive NVP (group II). Of the infants 29.6% were small for gestational age (SGA). Median (range) maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the plasma concentration-time curve (AUC) and halflife (T) were 1 438 (350-3 832) ng/ml, 25h50 (9h40-83h45), 174 134 (22 308-546 408) ng×h/ml and 59.0 (15.4-532.6) hours for group I and 1 535 (635-4 218) ng/ml, 17h35 (7h40-29h), 168 576 (20 268-476 712) ng×h/ml and 69.0 (22.12-172.3) hours for group II. For group II, the median (range) volume of distribution (Vd) and body clearance (Cl) were 1 702.6 (623.7-6 189.8) ml and 34.9 (6.2-163.8) ml/h. The AUC was higher (p=0.006) and Cl lower (p<0.0001) in SGA infants. Plasma concentrations exceeding 100 ng/ml were achieved over 8 days in 78% infants in group I and 70.0% in group II. The MTCT rate was 4.8%. Conclusion. Women in preterm labour often deliver with little advance warning. Our study suggests that NVP dosing of preterm infants as soon as possible after birth without maternal intrapartum dosing may be as effective as combined maternal and infant dosing.
Outcomes of the South African national antiretroviral treatment programme for children : the IeDEA southern Africa collaboration
(Health and Medical Publishing Group (HMPG), 2009-10) Davies, Mary-Ann; Keiser, Olivia; Technau, Karl; Eley, Brian; Rabie, Helena; Van Cutsem, Gilles; Giddy, Janet; Wood, Robin; Boulle, Andrew; Egger, Matthias; Moultrie, Harry
Objectives. To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. Design and setting. Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and. KwaZulu-Natal provinces. Subjects. ART-naïve children (?16 years) who commenced treatment with ≥3 antiretroviral drugs before March 2008. Outcome measures. Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. Results. The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being <18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (<400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1-82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. Conclusions. Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.
A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries
(PLoS, 2019-07-01) Cotton, Mark F.; Rabie, Helena; Nemes, Elisa; Mujuru, Hilda; Bobat, Raziya; Njau, Boniface; Violari, Avy; Mave, Vidya; Mitchell, Charles; Oleske, James; Zimmer, Bonnie; Varghese, George; Pahwa, Savita
Background: The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. Methods and findings: We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). Conclusions: IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.
Reviewing co-trimoxazole for HIV-exposed, uninfected infants
(Elsevier, 2019) Rabie, Helena; Slogrove, Amy; Bwakura-Dangarembizi, Mutsa
No abstract available.
Single dose abacavir pharmacokinetics and safety in neonates exposed to human immunodeficiency virus (HIV)
(Oxford University Press, 2021-06) Bekker, Adrie; Decloedt, Eric H.; Slade, Gretchen; Cotton, Mark F.; Rabie, Helena; Cressey, Tim R.
Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.
Trends in paediatric bloodstream infections at a South African referral hospital
(BioMed Central, 2015-04) Dramowski, Angela; Cotton, Mark F.; Rabie, Helena; Whitelaw, Andrew
Background: The epidemiology of paediatric bloodstream infection (BSI) in Sub-Saharan Africa is poorly documented with limited data on hospital-acquired sepsis, impact of HIV infection, BSI trends and antimicrobial resistance. Methods: We retrospectively reviewed paediatric BSI (0–14 years) at Tygerberg Children’s Hospital between 1 January 2008 and 31 December 2013 (excluding neonatal wards). Laboratory and hospital data were used to determine BSI rates, blood culture contamination, pathogen profile, patient demographics, antimicrobial resistance and factors associated with mortality. Fluconazole resistant Candida species, methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Acinetobacter baumannii and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were classified as antimicrobial resistant pathogens. Results: Of 17001 blood cultures over 6 years, 935 cultures isolated 979 pathogens (5.5% yield; 95% CI 5.3-5.7%). Contamination rates were high (6.6%, 95% CI 6.4-6.8%), increasing over time (p = 0.003). Discrete BSI episodes were identified (n = 864) with median patient age of 7.5 months, male predominance (57%) and 13% HIV prevalence. BSI rates declined significantly over time (4.6–3.1, overall rate 3.5 per 1000 patient days; 95% CI 3.3–3.7; Chi square for trend p = 0.02). Gram negative pathogens predominated (60% vs 33% Gram positives and 7% fungal); Klebsiella pneumoniae (154; 17%), Staphylococcus aureus (131; 14%) and Escherichia coli (97; 11%) were most prevalent. Crude BSI mortality was 20% (176/864); HIV infection, fungal, Gram negative and hospital-acquired sepsis were significantly associated with mortality on multivariate analysis. Hospital-acquired BSI was common (404/864; 47%). Overall antimicrobial resistance rates were high (70% in hospital vs 25% in community-acquired infections; p < 0.0001); hospital-acquired infection, infancy, HIV-infection and Gram negative sepsis were associated with resistance. S. pneumoniae BSI declined significantly over time (58/465 [12.5%] to 33/399 [8.3%]; p =0.04). Conclusion: Although BSI rates declined over time, children with BSI had high mortality and pathogens exhibited substantial antimicrobial resistance in both community and hospital-acquired infections. Blood culture sampling technique and local options for empiric antimicrobial therapy require re-evaluation.
Tuberculosis : opportunities and challenges for the 90-90-90 targets in HIV-infected children
(International AIDS Society, 2015-12-02) Rabie, Helena; Frigati, Lisa; Hesseling, Anneke C.; Garcia-Prats, Anthony J.
Introduction: In 2014 the Joint United Nations Programme on HIV/AIDS defined the ambitious 90 90 90 targets for 2020, in which 90% of people living with HIV must be diagnosed, 90% of those diagnosed should be on sustained therapy and 90% of those on therapy should have an undetectable viral load. Children are considered to be a key focus population for these targets. This review will highlight key components of the epidemiology, prevention and treatment of tuberculosis (TB) in HIV-infected children in the era of increasing access to antiretroviral therapy (ART) and their relation to the 90 90 90 targets. Discussion: The majority of HIV-infected children live in countries with a high burden of TB. In settings with a high burden of both diseases such as in sub-Saharan Africa, up to 57% of children diagnosed with and treated for TB are HIV-infected. TB results in substantial morbidity and mortality in HIV-infected children, so preventing TB and optimizing its treatment in HIV-infected children will be important to ensuring good long-term outcomes. Prevention of TB can be achieved by increasing access to ART to both children and adults, and appropriate provision of isoniazid preventative therapy. Co-treatment of HIV and TB is complicated by drug-drug interactions particularly due to the use of rifampicin; these may compromise virologic outcomes if appropriate corrective actions are not taken. There remain substantial operational challenges, and improved integration of paediatric TB and HIV services, including with antenatal and routine under-five care, is an important priority. Conclusions: TB may be an important barrier to achievement of the 90 90 90 targets, but specific attention to TB care in HIV-infected children may provide important opportunities to enhance the care of both TB and HIV in children.

Browsing by Author "Rabie, Helena"

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