Diana Gibb - Academia.edu (original) (raw)

Papers by Diana Gibb

Trials, Jan 19, 2018

Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB a... more Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recrui...

Sexually Transmitted Infections, 2003

Clinical pharmacology and therapeutics, 2007

The recommended dose of lamivudine in children is higher when compared with adults: 4 mg/kg vs ap... more The recommended dose of lamivudine in children is higher when compared with adults: 4 mg/kg vs approximately 2 mg/kg (150 mg) and administered twice a day. Limited data are available to demonstrate that this increased dose results in adequate exposure to lamivudine in children with human immunodeficiency virus (HIV) infection. Data were selected from children who were using lamivudine for at least 2 weeks before a full pharmacokinetic (PK) study was conducted. Lamivudine PK parameters were significantly related to age. The age of 6 years appeared to be a cutoff for a change in PK parameters of lamivudine, with children <6 years of age (n=17) having a median area under the curve 43% lower and a median peak plasma concentration 47% lower (both P<0.001) than older children (n=34). In conclusion, further investigation of the relationship between decreased lamivudine exposure and treatment outcome and long-term resistance development in younger children with HIV infection is warran...

Antiviral therapy, 2007

To investigate nevirapine concentrations in African HIV-infected children receiving divided Triom... more To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine). Cross-sectional study. Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination (P<0.1). Of the 71 Malawian and 56 Zambian children (median age 8.4 vs 8.5 years, height-for-age -3.15 vs -1.84, respectively), only 1 (3%) of those prescribed > or =300 mg/m2/day nevirapine had subtherapeutic concentrations (<3 mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrations were independently as...

The Lancet Infectious Diseases, 2015

Co-trimoxazole is an inexpensive, broad-spectrum antimicrobial drug that is widely used in develo... more Co-trimoxazole is an inexpensive, broad-spectrum antimicrobial drug that is widely used in developing countries. Before antiretroviral therapy (ART) scale-up, co-trimoxazole prophylaxis reduced morbidity and mortality in adults and children with HIV by preventing bacterial infections, diarrhoea, malaria, and Pneumocystis jirovecii pneumonia, despite high levels of microbial resistance. Co-trimoxazole prophylaxis reduces early mortality by 58% (95% CI 39-71) in adults starting ART. Co-trimoxazole provides ongoing protection against malaria and non-malaria infections after immune reconstitution in ART-treated individuals in sub-Saharan Africa, leading to a change in WHO guidelines, which now recommend long-term co-trimoxazole prophylaxis for adults and children in settings with a high prevalence of malaria or severe bacterial infections. Co-trimoxazole prophylaxis is recommended for HIV-exposed infants from age 4-6 weeks; however, the risks and benefits of co-trimoxazole during infancy are unclear. Co-trimoxazole prophylaxis reduces anaemia and improves growth in children with HIV, possibly by reducing inflammation, either through direct immunomodulatory activity or through effects on the intestinal microbiota leading to reduced microbial translocation. Ongoing trials are now assessing the ability of adjunctive co-trimoxazole to reduce mortality in children after severe anaemia or severe acute malnutrition. In this Review, we discuss the mechanisms of action, benefits and risks, and clinical trials of co-trimoxazole in developing countries.

The Pediatric Infectious Disease Journal, 2003

In children younger than 2 years of age vertically infected with HIV-1, the recommended pediatric... more In children younger than 2 years of age vertically infected with HIV-1, the recommended pediatric dosing regimen for nelfinavir (20 to 30 mg/kg three times a day) provides insufficient drug exposure. This study was conducted to determine the steady state pharmacokinetics of nelfinavir and its active metabolite, M8, in this population. Fourteen infants (2.3 to 8.5 months) underwent 18 intensive pharmacokinetic studies of nelfinavir and M8 at steady state. Nelfinavir and M8 concentrations were measured by high performance liquid chromatography coupled with mass spectrometry, and individual pharmacokinetic values were determined. A mean nelfinavir daily dose of 135.7 +/- 18.8 mg/kg (twice or three times a day) resulted in median C(min), C(max), area under the plasma concentration-time curve (AUC(0-24 h)) and CL/ for nelfinavir of 0.627 mg/l, 2.39 mg/l, 30.6 mg*h/l and 4.2 liters/h/kg, respectively. When normalized for a daily dose of nelfinavir of 150 mg/kg/day, 16.7% of C(max) and 27.8% of AUC(0-24 h) values were below the tenth percentile for adult values. During the first year of life, nelfinavir requirement is much higher than in older children and adults to obtain similar drug exposure. The mechanisms underlying such differences may involve higher first past metabolism and/or drug interactions or might be related to feeding conditions.

Reviews, 1996

In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS... more In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiate ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to switch or interrupt therapy. This review aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 2 years of age. To evaluate 1) when to start ART in young children; 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and PI-based regimens; and 3) whether and when ART should be stopped or switched from a PI-based regimen to an NNRTI-based regimen. We searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform). We identified RCTs that recruited perinatally HIV-infected children under 2 years of age without restriction of setting. We rejected trials that did not include children less than 2 years of age, or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy. Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes. Of 1921 records retrieved, 5 studies were eligible for inclusion in the review, addressing when to start treatment (n=2), what to start (n=2) and whether to switch regimen (n=1). Three ongoing studies that address the question of treatment interruption were also identified.Early infant treatment was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller trial,median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure was 2.01 (95%CI 1.47, 2.77) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) with no clear difference in effect by age group. The hazard for virological failure was overall 2.28 (95%CI 1.55, 3.34) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0005) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life. By contrast, increases in weight z-score (MD=0.37, 95%CI 0.08, 0.65, p=0.01) and height z-score (MD=0.23, 95%CI 0.04, 0.42, p=0.02) were larger in the NVP arm compared to the LPV/r arm .Infants starting on a LPV/r regimen but who then switched to a NVP-based regimen after a median time of 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 copies/mL) was higher among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002). Immediate ART reduces morbidity and mortality among infants and may improve neurodevelopmental outcome. However It remains unclear whether all children diagnosed with HIV infection between 1-2 years of age should start ART, as has been recommended by the World Health Organization on practical grounds.The available evidence suggests that a LPV/r-based first-line regimen is more potent than NVP, regardless of PMTCT exposure status. However, this finding provides a dilemma to policy-makers because higher cost, poor palatability, inconvenient formulation and cold chain requirements make LPV/r a more costly and challenging first-line regimen. An alternative approach to long-term LPV/r is switching to NVP (maintaining the NRTI backbone) once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of VL testing. Ongoing trials are exploring the possibility of starting early ART and interrupting treatment beyond the…

Clinical Pharmacology & Therapeutics, 2011

The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study... more The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dosenormalized area under curve (AUC) 0-12 and peak concentration (C max ) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC 0-12 were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC 0-12 dnGMR = 1.58 (1.37-1.81), C max dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations. P Nahirya-Ntege, M aber, fN Kaggwa, P Kaleebu,R Katuramu, JH Kyarimpa, J Lutaakome, L Matama, M Musinguzi, G Nabulime,

Antiviral therapy, 2006

To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children wi... more To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing (n = 87) or no testing (n = 83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classe...

Expert Opinion on Pharmacotherapy, 2007

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field ar... more The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations.

AIDS research and therapy, 2014

Increasing numbers of HIV-infected patients in sub-Saharan Africa are exposed to antiretroviral t... more Increasing numbers of HIV-infected patients in sub-Saharan Africa are exposed to antiretroviral therapy (ART), but there are few data on lipid changes on first-line ART, and even fewer on second-line. DART was a randomized trial comparing monitoring strategies in Ugandan/Zimbabwean adults initiating first-line ART and switching to second-line at clinical/immunological failure. We evaluated fasting lipid profiles at second-line initiation and ≥48 weeks subsequently in stored samples from Zimbabwean patients switching before 18 September 2006. Of 91 patients switched to second-line ART, 65(73%) had fasting samples at switch and ≥48 weeks, 14(15%) died or were lost <48 weeks, 10(11%) interrupted ART for >14 days and 2(2%) had no samples available. 56/65(86%) received ZDV/d4T + 3TC + TDF first-line, 6(9%) ZDV/d4T + 3TC + NVP and 3(5%) ZDV + 3TC with TDF and NVP. Initial second-line regimens were LPV/r + NNRTI in 27(41%), LPV/r + NNRTI + ddI in 33(50%) and LPV/r + TDF + ddI/3TC/ZDV...

PLoS ONE, 2014

In contrast to resource-rich countries, most HIV-infected patients in resource-limited countries ... more In contrast to resource-rich countries, most HIV-infected patients in resource-limited countries receive treatment without virological monitoring. There are few long-term data, in this setting, on rates of viral suppression or switch to second-line antiretroviral therapy. The DART trial compared clinically driven monitoring (CDM) versus routine laboratory (CD4

The Pediatric Infectious Disease Journal, 1996

Recurrent bacterial sepsis is common in pediatric HIV infection and immunization against Haemophi... more Recurrent bacterial sepsis is common in pediatric HIV infection and immunization against Haemophilus influenzae type b (Hib) is recommended. Long term persistence of anti-Hib antibody and the need for, or timing of, a booster dose has not been adequately studied. Immunogenicity during a 12-month period following immunization with Hib-tetanus conjugate vaccine (ACT-HIB; Merieux) was evaluated in 48 vertically HIV-infected children and 36 uninfected children, born to HIV-positive mothers. A titer of anti-Hib polysaccharide antibody of > or = 0.15 microgram/ml was considered to indicate short term and > or = 1 microgram/ml long term protection. At 1 month postvaccination 36 (100%) uninfected and 42 (88%) HIV-infected children achieved titers of > or = 1 microgram/ml. However, by 1 year titers had dropped below this value in 18 (43%) infected compared with only 4 (11%) uninfected children (chi square, 9.7; P = 0.002). Although the rate of fall of antibody titer was greater in uninfected than in infected children, this was no longer the case after adjustment for the 1-month postimmunization titer. The rate of antibody titer decline was not significantly related to HIV disease status or to either the age-related CD4 count at the time of immunization or the change in age-adjusted CD4 count during the 12 months after immunization. Not only was the initial antibody response to Hib conjugate vaccine decreased in children with HIV infection and AIDS but also 1 year later only 57% of the initial responders had persisting titers above the level associated with long term protection. The need for reimmunization of children with HIV infection against Hib requires further evaluation.

PLoS ONE, 2011

Introduction: A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-S... more Introduction: A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-Saharan Africa is necessary to develop interventions to sustain high levels of adherence.

Retrovirology, 2008

Objective: In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of ... more Objective: In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants.

Retrovirology, 2011

The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced... more The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced susceptibility to all nucleoside reverse transcriptase inhibitors (NRTIs) excluding tenofovir (TDF). This pathway emerges after long term failure of therapy, and is increasingly observed in the resource poor world, where antiretroviral therapy is rarely accompanied by intensive virological monitoring. In this study we examined the genotypic, phenotypic and fitness correlates associated with the development of Q151M MDR in the absence of viral load monitoring. Single-genome sequencing (SGS) of full-length RT was carried out on sequential samples from an HIV-infected individual enrolled in ART rollout. The emergence of Q151M MDR occurred in the order A62V, V75I, and finally Q151M on the same genome at 4, 17 and 37 months after initiation of therapy, respectively. This was accompanied by a parallel cumulative acquisition of mutations at 20 other codon positions; seven of which were located in the connection subdomain. We established that fourteen of these mutations are also observed in Q151M-containing sequences submitted to the Stanford University HIV database. Phenotypic drug susceptibility testing demonstrated that the Q151M-containing RT had reduced susceptibility to all NRTIs except for TDF. RT domain-swapping of patient and wild-type RTs showed that patient-derived connection subdomains were not associated with reduced NRTI susceptibility. However, the virus expressing patient-derived Q151M RT at 37 months demonstrated ~44% replicative capacity of that at 4 months. This was further reduced to ~22% when the Q151M-containing DNA pol domain was expressed with wild-type C-terminal domain, but was then fully compensated by coexpression of the coevolved connection subdomain. We demonstrate a complex interplay between drug susceptibility and replicative fitness in the acquisition Q151M MDR with serious implications for second-line regimen options. The acquisition of the Q151M pathway occurred sequentially over a long period of failing NRTI therapy, and was associated with mutations in multiple RT domains.

PLoS Medicine, 2010

Background: Survival to older childhood with untreated, vertically acquired HIV infection, which ... more Background: Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated.

PLoS Medicine, 2008

The advent of highly active antiretroviral therapy (HAART) dramatically improved the prognosis fo... more The advent of highly active antiretroviral therapy (HAART) dramatically improved the prognosis for both adults and children infected with HIV who had access to treatment. However, the optimal timing for initiating treatment remains controversial, particularly in children. This debate lays out the case for deferred treatment against the case for early initiation of HAART in children.

PharmacoEconomics, 2000

In the absence of interventions, 20% of infants born to women infected with HIV acquire infection... more In the absence of interventions, 20% of infants born to women infected with HIV acquire infection from their mother at or before delivery. A further 15% are infected through breast feeding. Prenatal testing for HIV allows infected women to be reliably identified so that they can receive antiretroviral therapy and, in countries with safe water supplies, be advised not to breast feed. These and other interventions can reduce the risk of transmission to 5% or less. Economic evaluations of prenatal testing for HIV are reviewed and compared in this article, and future research priorities outlined. These studies set the costs of testing and intervention against the averted lifetime costs of paediatric infection, and generate estimates of the HIV prevalence threshold above which there would be a net cost saving, or calculate the cost per life-year saved given a particular prevalence. In the developed world, prenatal testing has been adopted in many countries, and recent economic analyses broadly support this. Future research is likely to focus on the incremental benefits of different antiretroviral regimens in lowering transmission rates still further, with or without elective caesarean section, and the possibility that some may lead to adverse effects in uninfected infants exposed to them in utero. Some earlier assessments in resource-poor settings concluded that prenatal testing was unaffordable or of doubtful cost effectiveness. This negative conclusion appears to be the result of very low estimates of the lifetime costs of paediatric HIV infection, together with developed world conceptions of pre-test counselling. The demonstration that nevirapine reduces transmission risk at a low cost has transformed the outlook, and there is hope that antiretrovirals can act prophylactically to prevent infection of the breast-fed child. However, to achieve a sustained reduction in vertical transmission there may be a need to evaluate the need for a strengthened infrastructure to deliver prenatal HIV testing and treatment, as well as programmes to reduce HIV incidence in adults.