Paediatrics and Child Health

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Assessing reported adherence to antiretroviral therapy using the method of verbal recall in children from Kwa-Zulu Natal, South Africa.
(2017) Ebrahim, Hassina.; Bobat, Raziya Ahmed.
Sub-Saharan Africa has the highest number of children living with HIV. HIV is one of the major causes of under-five mortality in Africa. Antiretroviral therapy in the paediatric population has improved mortality, led to a better quality of life, as well as overall health and well-being of children. Adherence is a critical factor in determining treatment outcomes and success. Non-adherence to therapy increases risk of treatment failure, delays immunological recovery and increases opportunistic infections. In the paediatric population, there is a paucity of studies assessing adherence rates, particularly in resource limited settings. Adherence behaviour is found to be more complex in children. A number of factors affect adherence in children. These include socio-economic factors, medication factors as well as healthcare provider dynamics. The purpose of this secondary analysis of a prospective study was to describe adherence in a cohort of children attending a regional hospital in Kwa-Zulu Natal, South Africa, from September 2006 until October 2009. This study also examined factors associated with adherence such as age of the child, gender, as well as the role of the primary caregiver. Since there is no “gold standard” for assessing adherence to antiretroviral therapy, this area of research needs to be explored further. Secondly, assessing factors associated with adherence will assist in looking at ways to improve treatment outcome. In the main study, prospective patients who were treatment naïve and met criteria to commence antiretroviral therapy were identified in outpatients and clinics. Baseline and follow-up questionnaires were used to capture information including adherence details over the preceding week as well as since the last visit to hospital. Adherence was assessed using the method of verbal recall. Missed doses and the reasons for these were recorded and analysed. Additional factors possibly associated with adherence were also recorded and analysed further. This study reported an overall adherence rate of 94 per cent, similar to rates reported in other studies. Adherence rates over the past week as well as since the patient’s last visit were similar. There was a substantial degree of agreement between verbal recall for the preceding week as well as since the last visit (kappa statistic 0.64, p < 0.005). It was found that children older than five years were more likely to be adherent than those under five years (OR 0.871, 95 % CI 0.22-3.376) and males were twice as likely to adhere as females (OR=2.05, 95% CI 0.49 -8.59). The impact of this study is that it will provide information on adherence in children in Kwa-Zulu Natal, South Africa. This could encourage other such studies to be undertaken to improve adherence rates and hence treatment success. By examining factors associated with adherence as well as identifying possible barriers, we may improve treatment success in children. Adherence to antiretroviral therapy is important, especially in the paediatric population as it is shown to increase survival, improve immunity, as well as help prevent the development of opportunistic infections. Sub-optimal adherence is associated with treatment failure and drug resistance. The use of verbal recall as a measure of adherence is useful in a resource limited setting.
Human immunodeficiency virus-1 infection and the acquired immunodeficiency syndrome in African children : natural history from birth to early childhood.
(1999) Bobat, Raziya Ahmed.; Coovadia, Hoosen Mahomed.
Background: in 1987, the first child with HIV-1 infection was identified in the paediatric wards at King Edward VIII Hospital in Durban. This made paediatricians aware that the epidemic had spread to the children of KwaZulu/Natal. Although information on transmission and natural history was becoming available from developed countries, little was known about the disease in developing countries. It was important to determine transmission rates and disease patterns in the local population, in order to appropriately counsel women, and for management of infected infants. In addition, with resources for laboratory diagnoses being limited in developing countries, much emphasis had to be placed on clinical findings for identification of infected children. In 1989, a retrospective analysis was made of the HIV-infected children seen over a 2-year period, between 1987 and 1989. Nine such children were identified and their clinical and biochemical features were described. It was concluded that HIV infected children presented with an identifiable pattern of signs, fairly similar to that described for children in industrialised countries. With these findings, a prospective study was undertaken, to determine the vertical transmission rate, the factors affecting this rate, and natural history of vertically transmitted I-IIV-1 infection. ix KwaZulu/Natal, being at the epicentre of the epidemic in South Africa, was a natural site for the study. Patients and Methods: a trained research worker was placed in the antenatal clinic at King Edward VIII Hospital for the specific purpose of educating, counselling, and testing of all women attending the clinic. Women attending the clinic for the first time in the index pregnancy were offered HIV testing if informed consent was obtained. Blood for HIV serology was drawn at the same time as sampling for the obligatory syphilis serology. The acceptance rate for sampling was > 95%. The majority of the women attending the clinic were black, and first attendance was generally late, into the third trimester. The same research worker was responsible for post-test counselling which was offered to all the women, not only those who tested positive. This research worker was also responsible for obtaining maternal consent for entering the newborn infant into the study. All newborn infants were seen within 48 hours of birth. At this time they were examined, growth parameters were recorded, and initial blood samples taken. These infants were then followed-up at 1 month, 2 months, 3 months, then at 3-month intervals up to 18 months, then at 6-month intervals. At each visit, a thorough clinical examination was performed, growth measurements taken, and development assessed. Record was made of any interim illness and visits to health centres, and of hospital admissions. Method of feeding was note& and details on immunisation obtained from the child's immunisation card. The children received all the x routine childhood immunisations according to the national regimen, based on WHO recommendations. Mothers were asked to bring the child to the follow up clinic for any problem, so that episodes of illness would not be missed. The women were reimbursed for transport costs to encourage follow up visits. Calculation of transmission rate and classification of infection status were made according to the recommendations of the Ghent workshop. Children were regarded as infected if they were antibody positive at 18 months or had an HIV related death. They were classified as uninfectd if the antibody test was negative at 9 months of age. Those infants who were lost to follow up before the age of nine months whilst still antibody positive and those whose cause of death could not be determined, were classified as indeterminate. The diagnosis of AIDS was based on the WHO criteria. Blood samples were taken at birth, at age one and three months, then at three month intervals to 18 months; thereafter at six month intervals. Sera were tested for HIV1 antibodies by a commercial enzyme-linked immunosorbent assay,ELISA. Samples that tested positive were confirmed by two tests, a Roche Elisa and by an immunoflourescent assay (IFA). A sample was regarded as being positive if both the second ELISA as well as the IFA or the Western Blot tested positive. xi Results: between October 1990 and March 1993, 234 infants and their 229 mothers were entered into the study. Those who did not attend a single follow up after birth were excluded from the study. The final cohort comprised 181 infants, of whom 48 were classified as infected ( including 17 deaths); 93 not infected, and 40 as indeterminate ( including 8 deaths). Maternal Data: about 60% of the mothers were under 30 years of age and were multiparous; 18% tested positive for syphilis serology; 22.9% were anaemic during pregnancy, and 37% were delivered by caesarean section. Most women lived in urban areas, and 16% chose to bottle-feed exclusively. Vertical Transmission Rate and Factors affecting this Rate: the median vertical transmission rate was 34%, (95% confidence intervals, CI 26%-42%). This figure is similar to that found in most parts of Africa, but much higher than those for Europe and USA. The maternal factors found to be associated with an increased risk of transmission were vaginal deliveries and a low haemoglobin level during pregnancy. Breastfeeding, Transmission, and Outcome: breastfeeding was found to have an increased risk of transmission, by 15 % (CI 1.8-31.8). On assessing growth and morbidity, it was noted that breastfed infants were not protected against such common childhood infections as pneumonia and diarrhoea, and that failure to thrive occurred with equal frequency in both those breastfed as well as those receiving artificial feeds. Newborn Data: when comparing newborn data between those infants who were subsequently found to be infected with those who were uninfected, it was found that there were no major differences between these groups with regard to growth parameters and neonatal complications. However, those infants with rapidly progressive disease (those who died within 24 months), were noted to have lower mean birth weights and lengths, a higher frequency of low birth weights, and tended to have more neonatal problems. Clinical Manifestations: the first differences between the infected and the uninfected infants generally manifested from about 3 months of age. HIV infected children were identifiable by higher frequencies of thrush, lymphadenopathy, skin rash, and hepatosplenomegaly in the early stages, and later on with a higher tendency to neurological and developmental abnormalities, as well as of diarrhoea. Pneumonia was found with equal frequencies in both the infected and uninfected children. The HIV infected child could be distinguished fairly early in life by the combination of the manifestations described above. Progression to AIDS: AIDS was diagnosed in 44% of all the infected children during the study period. Ninety five percent of these children were identified by 12 months of life, showing a rapid progression of the disease Longitudinal Growth: when longitudinal growth parameters were analysed in this cohort, it was found that HIV infected children were stunted from as early as 3 months of age, and remained below the international standards into early childhood. Infected children were also found to be malnourished (i.e. weight for age below international means), from an early age, and this persisted throughout early childhood. Of note, the uninfected childrens' weights, although comparable to international means initially, dropped after the first year of life. However, both groups did not have significant wasting, when compared to international means. Mortality: there were 25 known deaths during the study period. Of these, 17 were classified as HIV-related, and 8 as indeterminate. The mean age at death was 10.1 months, with 83% of all the HIV-related deaths occurring within the first year of life. The commonest diagnoses at the ti me of death were diarrhoea, pneumonia, and failure to thrive; also, thrush was common, as were neurological abnormalities.
The interaction between human leucocyte antigen-G and natural killer cells at the placental interface in HIV-1 infected pregnant women and the significance, if any, to in utero transmission.
(2007) Moodley, Shamala.; Carpenter, S.; Bobat, Raziya Ahmed.
This study was undertaken to investigate the relationship between Natural Killer cells and HLA-G at the placental barrier in HIV-I infected pregnant women and to establish the significance, if any, to in utero infection. Fifty-five HIV -I infected pregnant women were recruited into the study after consent was obtained. Blood samples were collected from both mothers and babies for viral loads and CD4+ cell counts. Placental samples were obtained from pregnancies at delivery and examined by immunoperoxidase immunohistochemistry methods using monoclonal antibodies to p24 antigens and Natural Killer (CD56+) cells. HLA-G expression was quantified using real-time polymerase chain reaction. Analysis of viral loads and CD4+ cell counts were undertaken in categories. No significant association was observed between the viral load of mothers and their CD4+ cell counts. Eighteen percent of the women in this study population had 5 log viral loads with a transmission rate of 0.27(95% Cl, 0.15 - O. 39). Maternal viraemia was significantly associated with transmission of infection to babies (p = 0.047). The odds ratio indicated that for every 1 log increase in maternal viral load the babies were 3.1 times more likely to acquire the infection (Exp (B) = 3.137 (95%CI, 1.015-9.696). Furthermore, the study found that a higher number of female babies were infected than males. Although not statistically significant the odds ratio indicated that female babies were 3.1 times more likely to become infected than males (Exp (B) = 3.110 (95%CI, 0.819-11.808). We report here the results of immunohistochemistry for p24 antigens and NK (CD56+) cells and compare them to the immunological responses of both mothers and babies at birth. HIV-1 antigens were detected in 94.5% of all placentas by immunohistochemistry. Infiltration of CD56+ was found in 98% of placental tissue. The analysis revealed that the presence of p24 antigens in placental tissue was not influenced by maternal viral load or CD4+ cell counts. Lower median NK cell values were observed in placentas of mothers with infected babies as compared with the uninfected cluster. Although not statistically significant, the risk of vertical transmission was increased 3.4 times more in placentas which had lower NK cell values. According to the odds ratio, babies CD4+ counts were affected by every 1 log increase in mother's viral load. Overall, maternal viral load emerged as a strong predictor for risk of infection from infected mothers to their infants. Our analysis indicated that female babies were 3.7 times more likely to acquire the infection than males. Using data obtained from real-time PCR we investigated the relationship between maternal viral load and the quantity of HLA-G expression (p = 0.045; 95%CI 1.029- 11.499). Logistic regression models revealed that mother's viral load was the strongest risk factor for vertical transmission. No statistically significant correlation was noted with HLA-G and viral transmission. However, the odds ratio indicated that the risk of infection increased by 1.3 with every 1 fold increase in HLA-G expression. An analysis of mother-to-child transmission rates by gender revealed that the odds ratio for transmission was 3.4 times more in female babies than in males. We then investigated the relationship between maternal viraemia and HLA-G expression. A positive correlation between maternal viral load and placental HLA-G was observed (p = 0.038). When gender susceptibility to HLA-G expression was explored a statistically significant association was observed in placental tissue of mothers with infected and uninfected male babies and HLA-G expression (p = 0.013). To conclude, the analysis found that HLA-G was up regulated 3.95 times more in placental tissue of mothers with infected babies than in mothers with uninfected babies.
Severe acute malnutrition and antiretroviral treatment in children with HIV.
(2016) Archary, Moherndran.; Bobat, Raziya Ahmed.
Background: Childhood malnutrition remains a common problem in many parts of the world and is a contributing factor in 45% of the 5.9 million annual deaths in children under 5 years. HIV-infected children have a disproportionately higher prevalence of malnutrition and higher mortality associated with malnutrition as compared to non-infected children. Physiological changes associated with malnutrition and re-nutrition complicate antiretroviral treatment in these children. This thesis explores aspects related to antiretroviral treatment (ART) in severely malnourished HIV-infected children, including the timing of ART initiation, pharmacokinetics of antiretroviral drugs, co-infections with bacterial and mycobacterial infections and the effect of microbial translocation on immune restoration. Methods: Eight-two patients were enrolled in this randomized controlled trial, where HIV-infected children admitted with severe acute malnutrition (SAM) were initiated on ART either early (within 14 days of admission) or delayed (after 14 days with evidence of nutritional recovery). Clinical and laboratory parameters were collected during the admission and patients were followed up at 4, 8, 12, 24 and 48 weeks post admission. A pharmacokinetic evaluation of lopinavir (LPV) was conducted on Day1 and 14 of ART initiation. Samples for evaluation of microbial translocation and immune restoration were collected in 32 study patients and 75 additional patients in 3 control groups. Results/Discussion: There were no significant differences in immunologic, virologic or anthropometric responses at 48 weeks between the early and delayed arms. However, significantly improved rates in the changes in viral load, WAZ (weight-for-age Z score) and HAZ (height-for-age Z score) favoured the delayed arm. Pharmacokinetic (pk) evaluation of the LPV, displayed significant pk variability, reduced bioavailability and consequently greater apparent clearance (CL/F) estimates in comparison to other pk studies of LPV in non-malnourished children. Fat-free Mass (FFM) was shown to affect LPV variability; however delay in ART initiation and “super-boosted” LPV/rtv did not affect LPV variability. Bacterial pathogens were identified in 51% of patients. Of the hospital acquired infections (HAI), 41% were extended spectrum beta-lactamase (ESBL)-producing gram-negative infections. Tuberculosis (TB) co-infection was common (25.6%), with bacteriological confirmation in 38% of treated cases. Malnutrition was associated with increased microbial translocation, immune activation and immune exhaustion, with a negative impact on immune recovery in HIV-infected children on ART. Conclusions: Delaying ART initiation to at least 14 days after starting nutritional support is associated with improved rates of clinical (changes in WAZ and HAZ) and virologic outcomes. However this delay did not improve LPV exposures and dose adjustment of LPV during nutritional recovery needs to be further evaluated. These results can be used to inform changes in clinical practice and national and international guidelines for the management of severely malnourished HIV-infected children.

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