Lee Fairlie

Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents

Three decades into the HIV/AIDS epidemic there is a growing cohort of perinatally HIV‐infected adolescents globally. Their survival into adolescence and beyond represent one of the major successes in the battle against the disease that has claimed the lives of millions of children. This population is diverse and there are unique issues related to antiretroviral treatment and management. Drawing from the literature and experience, this paper discusses several broad areas related to antiretroviral management, including: 1) diverse presentation of HIV, (2) use of combination antiretroviral therapy including in the setting of co‐morbidities and rapid growth and development, (3) challenges of cART, including nonadherence, resistance, and management of the highly treatment‐experienced adolescent patient, (4) additional unique concerns and management issues related to PHIV‐infected adolescents, including the consequences of longterm inflammation, risk of transmission, and transitions to adult care. In each section, the experience in both resource‐rich and limited settings are discussed with the aim of highlighting the differences and importantly the similarities, to share lessons learnt and provide insight into the multi‐faceted approaches that may be needed to address the challenges faced by this unique and resilient population.

High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study

BackgroundThere are limited data on the prevalence of multi-drug resistant tuberculosis (MDR-TB), estimated at 0.6-6.7%, in African children with tuberculosis. We undertook a retrospective analysis of the prevalence of MDR-TB in children with Mycobacterium tuberculosis (MTB) at two hospitals in Johannesburg, South Africa.MethodsCulture-confirmed cases of MTB in children under 14 years, attending two academic hospitals in Johannesburg, South Africa during 2008 were identified and hospital records of children diagnosed with drug-resistant TB were reviewed, including clinical and radiological outcomes at 6 and 12 months post-diagnosis. Culture of Mycobacterium tuberculosis complex (MTB) was performed using the automated liquid broth MGIT™ 960 method. Drug susceptibility testing (DST) was performed using the MGIT™ 960 method for both first and second-line anti-TB drugs.Results1317 children were treated for tuberculosis in 2008 between the two hospitals where the study was conducted. Drug susceptibility testing was undertaken in 148 (72.5%) of the 204 children who had culture-confirmed tuberculosis. The prevalence of isoniazid-resistance was 14.2% (n = 21) (95%CI, 9.0-20.9%) and the prevalence of MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%). The prevalence of HIV co-infection was 52.1% in children with drug susceptible-TB and 53.9% in children with MDR-TB. Ten (76.9%) of the 13 children with MDR-TB received appropriate treatment and four (30.8%) died at a median of 2.8 months (range 0.1-4.0 months) after the date of tuberculosis investigation.ConclusionsThere is a high prevalence of drug-resistant tuberculosis in children in Johannesburg in a setting with a high prevalence of HIV co-infection, although no association between HIV infection and MDR-TB was found in this study. Routine HIV and drug-susceptibility testing is warranted to optimize the management of childhood tuberculosis in settings such as ours.

Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis.

BACKGROUND Coadministration of rifampicin dramatically reduces the concentrations of protease inhibitors. A pharmacokinetic study in healthy adults showed that doubling the dose of coformulated lopinavir/ritonavir was able to overcome the inducing effect of rifampicin. We evaluated this strategy in children treated with rifampicin-based antituberculosis therapy attending antiretroviral clinics in South Africa. METHODS Plasma concentrations of lopinavir were measured in children (aged 0.64-2.43 years) established on antituberculosis treatment who commenced antiretroviral therapy comprising double the usual recommended dose of lopinavir/ritonavir oral solution (460/115 mg/m(2) twice daily) plus two nucleoside reverse transcriptase inhibitors. Control children (0.57-4.23 years old) without tuberculosis received standard doses of lopinavir/ritonavir (230/57.5 mg/m(2) twice daily). RESULTS Pre-dose lopinavir concentrations were reduced by >80% in children with tuberculosis (median 0.7 mg/l, IQR 0.1-2.0) compared with controls (4.2 mg/l, IQR 3.4-8.1; P<0.001) and were below the minimum recommended concentration of 1 mg/l in 12 of 20 (60%) children with tuberculosis versus 2 of 24 (8%) controls (P<0.001). CONCLUSIONS Double doses of coformulated lopinavir/ritonavir results in inadequate lopinavir concentrations in young children treated concurrently with rifampicin. Suitable regimens are urgently needed for treating young children with HIV-associated tuberculosis.

Providing comprehensive health services for young key populations: needs, barriers and gaps

Adolescence is a time of physical, emotional and social transitions that have implications for health. In addition to being at high risk for HIV, young key populations (YKP) may experience other health problems attributable to high‐risk behaviour or their developmental stage, or a combination of both.

Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment

Background Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir. Methods and Findings A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6–24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29). Conclusion Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation.

Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa

Introduction:Stavudine is a commonly used drug in paediatric antiretroviral treatment (ART) regimens. Due to toxicity concerns, however, the drug abacavir has replaced stavudine in first-line paediatric regimens in many countries. We describe the frequency of stavudine toxicity in children receiving ART at a treatment clinic in Soweto, South Africa. Methods:Data on patient characteristics and outcomes of ART were collected from a cohort of 2222 HIV-infected children initiating ART between 2004 and 2008 when stavudine-containing regimens were routinely recommended. At several time-points after treatment initiation, we estimate the proportion of children where an attending clinician discontinued stavudine due to lipodystrophy, pancreatitis, lactic acidosis or peripheral neuropathy. Factors associated with stavudine-related toxicities were identified. Results:At ART initiation, most children had advanced disease. The majority initiated an efavirenz/lamivudine/stavudine regimen (n = 1422), and 76% of children remained on their initial ART regimen after a median 19.9 months of ART. Replacement of stavudine due to drug toxicity occurred at a rate of 28.8 per 1000 child years on treatment (95% confidence interval = 23.6–35.2). Rates of toxicity increased with treatment duration (in their first year of ART stavudine was replaced in 0.5% of children, but after 3 years stavudine had been changed to abacavir in 12.6% of children). Toxicity was more common in older children and in girls. Lipodystrophy accounted for 87 of 96 toxic events. Conclusion:Stavudine-associated toxicity resulting in single-drug substitution was uncommon in this cohort, though its frequency increased steadily with ART duration, especially with lipodystrophy. Where drug options are limited, stavudine remains a relatively well tolerated and effective option for children.

Cost and outcomes of paediatric antiretroviral treatment in South Africa

Objective:Little is known about the cost of paediatric antiretroviral treatment (ART) in low-income and middle-income countries. We analysed the average cost of providing paediatric ART in South Africa during the first 2 years after ART initiation, stratified by patient outcomes. Methods:We collected data on outpatient resource use and treatment outcomes of 288 children in two Johannesburg public clinics, Empilweni Services and Research Unit (ESRU) and Harriet Shezi Childrens Clinic (HSCC) from 2005 to 2009. Patient-level resource use was estimated from patient records. Unit cost data came from site accounts and public-sector sources. Patient outcomes at month 12 and 24 after initiation were defined based on patients’ weight CD4 cell counts/percentages, viral loads, and the presence of new WHO stage 3/4 conditions. Results:Median age/CD4 percentage at initiation was 4.03 years/12.40% in ESRU and 5.84 years/14.05% in HSCC, respectively. Sixty-two and 91% of patients remained in care and responding to treatment at month 12 in ESRU and HSCC, respectively, and 68 and 80% at month 24. The average cost per patient in care and responding was US

Predictors of loss to follow-up among children in the first and second years of antiretroviral treatment in Johannesburg, South Africa

830 in year 1 and US

OUTCOMES OF INFANTS STARTING ANTIRETROVIRAL THERAPY IN SOUTHERN AFRICA, 2004-2012

717 in year 2 in ESRU and US

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

678 and US