Factors associated with clinical, immunological and virological responses in protease-inhibitor-experienced Brazilian children receiving highly active … (original) (raw)
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Brazilian Journal of Infectious Diseases, 2007
This study evaluates clinical, virological and immunological responses to antiretroviral (ARV) therapy based on Lopinavir/ritonovir (LPV/r) in previously protease -inhibitor-experienced children. The study included 29 Brazilian children (median age = 5.91 years) who had failed previous ARV therapy and had begun a regimen based on LPV/r. At 12 months follow-up, a good virological response to LPV/r therapy was defined as achieving an undetectable viral load or as a decrease in plasma HIV RNA levels to ≥ ≥ ≥ ≥ ≥ 1 log. A good immunological response was defined as an increase in CD4 + cell count from baseline sufficient to attain a better CDC immune stage classification. The number of infectious episodes 12 months before and 12 months after beginning LPV/r was assessed. Sixteen (55.2%) and 19 (65.5%) of 29 patients exhibited good virological and immunological responses, respectively. Baseline CD4 + values (>500) predicted both virological and immunological responses (p<0.05). Older children were less likely to develop an immunological response (p<0.001) than younger children. Nine children receiving 3 ARV drugs plus LPV/r showed an immunological response (100%) compared to 10/20 (50%) children receiving 2 drugs plus LPV/r (p=0.01). A lower number (n<5) of infectious episodes was noted after 12 months follow-up in children using the LPV/r regimen (p=0.006). There was a positive correlation between children whose baseline CD4 + values were greater than 500 cells/mm 3 and virological responses. Although virological responses to therapy were seen in about half the children (55.2%), the use of HAART containing LPV/r provided clinical and immmunological benefits.
AIDS, 2011
a,c,e , on behalf of the HIV-NAT 077 Study Team Background: Monoboosted protease inhibitor is being evaluated as a strategy to simplify therapy in virologically suppressed patients who are on complex regimens. Methods: Children with two consecutive HIV-RNA below 50 copies/ml at least 3 months apart while on double boosted protease inhibitor (dPI) were switched to monoboosted lopinavir/r (mLPV/r). The previous dPI regimen was resumed within 4 weeks in children who experienced virological failure defined as two HIV-RNA at least 500 or three HIV-RNA at least 50 copies/ml. Primary endpoint was the proportion of children still on mLPV/r and having HIV-RNA less than 50 copies/ml at week 48. Results: Forty children on LPV/r þ saquinavir (90%) or LPV/r þ indinavir (10%) were enrolled, 50% were female, median [interquartile range (IQR)] age was 11.7 (10.2-13.5) years, and body weight was 29.4 (24.1-40.2 kg). The median (IQR) CD4% was 27 (23.5-29.5%). At 48 weeks, none had died or had HIV disease progression. Thirty-one children were on mLPV/r and 29 (72.5%) had HIV-RNA less than 50 copies/ml. Nine resumed dPI due to mLPV/r failure with four achieving undetectable HIV-RNA. Overall, 31 children (82.5%) had HIV-RNA suppression. Predicting factor for failing mLPV/r was baseline HIV-RNA at least 50 copies/ml. No major protease mutations were found. Conclusion: By simplifying second-line treatment from dPI to mLPV/r, the majority of children had sustained viral suppression at 48 weeks. Randomized study of simplified mono protease inhibitor therapy in children is warranted.
Pediatric Infectious Disease Journal, 2005
on behalf of the Spanish Collaborative Group on HIV Infection in Children Introduction. Many human immunodeficiency virus type 1 (HIV-1)-infected children have already failed treatment with 2 or even 3 classes of antiretrovirals. Coformulation of lopinavir with low dose ritonavir exhibits a potent antiretroviral effect. However, the data in heavily pretreated children are still scarce. This study evaluated the safety and effectiveness of combination therapy including lopinavir/ ritonavir in children with prior exposure to all classes of oral antiretrovirals. Methods. This was an open label multicenter observational study, in which data were reviewed according to a standardized protocol. The study population included all HIV-1-infected children with virologic failure (HIV-1 RNA Ͼ5000 copies/mL) followed in 12 Spanish hospitals for Ͼ12 months, experienced with the 3 classes of oral antiretrovirals, in whom a lopinavir/ritonavir-containing regimen was started. Results. By March 2003, 45 patients had been treated with lopinavir/ritonavir for a median of 18 months (range, 3-28). The median age at baseline was 9.7 years (range, 4.3-17.1). The median times of prior treatment were 88 months (range, 31-145) with nucleoside reverse transcription inhibitors and 42 months (range, 19-63) with protease inhibitors. Twenty-five patients were classified as Centers for Disease Control and Prevention clinical category C. Median values for absolute and percentage CD4 at baseline were 501 (range, 6-1512) and 19% (range, 0.5-49), respectively, and plasma HIV-RNA was 5.0 log 10 copies/mL (range, 4.1-6.1). During follow-up, 11 (24%) children switched from liquid to solid formulation. At 48 weeks, the median values for absolute and percentage CD4 increased by 199 cells/L and 3%, respectively, and median plasma viral load declined 1.75 log 10 copies/mL. Forty-two percent of children achieved a plasma RNA of Ͻ400 copies/mL (intent to treat analysis). Baseline genotypic resistance was available in 40 children. Nonresponders had 7.0 Ϯ 1.6 protease inhibitor-associated mutations at baseline compared with 4.8 Ϯ 1.7 in children achieving virologic suppression (P ϭ 0.06). Adverse events were described in 18 children. Three children permanently discontinued and 4 transiently withdrew lopinavir/ritonavir. At 12 months, there were mild but not significant increases in plasma cholesterol and triglycerides. Conclusions. Lopinavir/ritonavir when given as part of salvage regimen is well-tolerated, although switching to pills is frequently required. The regimen has a potent and durable antiretroviral activity in most heavily pretreated children, despite the presence of multiple mutations to all classes of oral antiretrovirals.
Mortality and Long-term Virologic Outcomes in Children and Infants Treated With Lopinavir/Ritonavir
The Pediatric Infectious Disease Journal, 2013
Background-There is scant data on young children receiving protease inhibitor (PI)-based therapy in real-life resource-limited settings and on the optimal timing of therapy among children who survive infancy. Our aim was to evaluate outcomes at the Hospital del Niño, Panama, where children have been routinely treated with lopinavir/ritonavir (LPV/r)-based therapy since 2002. Methods-Retrospective cohort analysis of all HIV-infected children enrolled in care between January 1, 1991 and June 1, 2011. Kaplan-Meier method and Cox proportional hazards regression were used to evaluate death, virologic suppression, and virologic rebound. Results-Of 399 children contributing 1,944 person-years of follow-up, 254 (63.7%) were treated with LPV/r and 94 (23.6%) were never treated with antiretrovirals (ARVs). Among infants, improved survival was associated with male gender (HR death 0.54, 95% CI 0.32-0.92) and treatment with highly active antiretroviral therapy (HAART) (HR death 0.32, 95% CI 0.12-0.83), while residence outside of Panama City was associated with poorer survival (HR death 1.72, 95% CI 1.01-2.94). Among children who survived to 1 year of age without exposure to ARVs, LPV/rbased therapy improved survival (HR death 0.07, 95% CI 0.01-0.33). Virologic suppression was achieved in 42.1%, 70.5%, and 85.1% by 12, 24 and 60 months of follow up among children treated with LPV/r. Virologic suppression was not associated with prior ARV exposure or age at initiation of therapy but was associated with residence outside of Panama City (HRsuppression 1.93, 95% CI 1.19-3.14). Patients with a baseline viral load > 100,000 copies/mL were less likely to achieve suppression (HRsuppression 0.37, 95% CI 0.21-0.66). No children who achieved virologic suppression after initiating LPV/r died. Conclusions-LPV/r-based therapy improved survival not only in infants but also in children over 1 year of age. Age at initiation of LPV/r-based therapy or prior ARVs did not impact virologic outcomes.
Long-term virological outcome in children receiving first-line antiretroviral therapy
AIDS Research and Therapy
Background: Studies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited. Methods: Perinatally HIV infected, ART-naive children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010-2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of > 1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure. Results: Three hundred and ninety-three ART-naïve children living with HIV [mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5-5.7) log 10 copies/ml] were enrolled into the study. At 48 weeks, significant improvement occurred in weight-forage and height-forage z-scores from baseline (all p < 0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4 + T cell count to more than 350 cells/mm 3. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported > 90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%-K103N and Y181C being the major NNRTI mutations-observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2-12), specificity 97% (92.4-98.9), PPV 44% (13.7-78.8) and NPV was 72% (65-77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment. Conclusions: Considerable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority.
Antimicrobial Agents and Chemotherapy, 2011
In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4 ؉ T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4 ؉ T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (C trough ) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P ؍ 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4 ؉ T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower C trough values and resulted in lower levels of virological control in these antiretroviral-experienced children.
Archives of Disease in Childhood, 2010
Aim To evaluate the long-term safety and effectiveness of lopinavir/ritonavir (LPV/r) in a population-based cohort of HIV-1-infected children. Methods All children enrolled in the Swiss Mother and Child HIV Cohort Study, treated with LPV/r-based combination antiretroviral treatment (cART) between November 2000 and October 2008, were included. Results 88 children (25 (28%) protease inhibitor (PI)-naive, 16 (18%) ART-naive) were analysed (251 patient-years on LPV/r). After 48 weeks on LPV/r, 70 children had a median (interquartile range (IQR)) decrease in HIV-1 viral load of 4.25 log (5.45-3.17; PI-naive, n=17) and 2.53 (3.68-1.38; PI-experienced, n=53). Median (IQR) increase in CD4 count was 429 (203-593; PI-naive) and 177 (21-331; PI-experienced) cells/µl. These effects remained stable throughout 192 weeks for 25 children. Treatment was stopped for viral rebound in seven and suspected toxicity in 12 children. Conclusion Long-term treatment with LPV/r-based cART is safe and effective in HIV-1-infected children.
Journal of Antimicrobial Chemotherapy, 2012
Objectives: Data on lopinavir/ritonavir tablets administered once daily in children are limited. We compared the pharmacokinetics (PK) of lopinavir/ritonavir twice daily versus once daily in virologically suppressed, HIVinfected children, and assessed the virological outcome, at 48 weeks, in children receiving the regimen of lopinavir/ritonavir once daily. Patients and methods: HIV-infected children receiving a twice-daily lopinavir/ritonavir-based regimen and with an HIV-1 RNA viral load (VL) ,40 copies/mL for at least 3 months were enrolled. Intensive steady-state 12 h blood sampling for PK assessment was performed at enrolment. Immediately afterwards, the lopinavir/ ritonavir dose was changed to once daily with the equivalent daily dose, and intensive steady-state 24 h blood sampling was repeated 2 weeks later. If the lopinavir C trough was ,1.0 mg/mL, the lopinavir/ritonavir dose was increased by 20%-30% and C trough measurement repeated. CD4 cell counts and VL were determined at baseline and at 12, 24 and 48 weeks. Results: Twelve children were enrolled. The median age was 13.1 years. Lopinavir AUC 0-24 following twice-daily and once-daily dosing was 169.7 (124.0-200.8) and 167.1 (95.1-228.1) mg. h/mL, respectively. Seven children, including all six concomitantly receiving efavirenz, had a C trough ,1.0 mg/mL with once-daily lopinavir/ritonavir dosing, and four of seven children had a C trough ,1.0 mg/mL after dose adjustment. All children maintained virological suppression throughout the 48 week period. Conclusions: Lopinavir/ritonavir-based once-daily regimens could simplify therapy in children/adolescents with virological control, but a lower lopinavir C trough was evident. Further efficacy studies of lopinavir/ritonavir once daily in children are necessary before routinely recommending this dosing strategy.
Long-term virological outcome in children on antiretroviral therapy in the UK and Ireland
AIDS, 2014
on behalf of the Collaborative HIV Paediatric Study Steering Committee Objective: To assess factors at the start of antiretroviral therapy (ART) associated with long-term virological response in children. Design: Multicentre national cohort. Methods: Factors associated with viral load below 400 copies/ml by 12 months and virologic failure among children starting 3/4-drug ART in the UK/Irish Collaborative HIV Paediatric Study were assessed using Poisson models. Results: Nine hundred and ninety-seven children started ART at a median age of 7.7 years (inter-quartile range 2.9-11.7), 251 (25%) below 3 years: 411 (41%) with efavirenz and two nucleoside reverse transcriptase inhibitors (EFV þ 2NRTIs), 264 (26%) with nevirapine and two NRTIs (NVP þ 2NRTIs), 119 (12%; 106 NVP, 13 EFV) with non-nucleoside reverse transcriptase inhibitor and three NRTIs (NNRTI þ 3NRTIs), and 203 (20%) with boosted protease inhibitor-based regimens. Median follow-up after ART initiation was 5.7 (3.0-8.8) years. Viral load was less than 400 copies/ml by 12 months in 92% [95% confidence interval (CI) 91-94%] of the children. Time to suppression was similar across regimens (P ¼ 0.10), but faster over calendar time, with older age and lower baseline viral load. Three hundred and thirtynine (34%) children experienced virological failure. Although progression to failure varied by regimen (P < 0.001) and was fastest for NVP þ 2NRTIs regimens, risk after 2 years on therapy was similar for EFV þ 2NRTIs and NVP þ 2NRTIs, and lowest for NNRTI þ 3NRTIs regimens (P-interaction ¼ 0.03). Older age, earlier calendar periods and maternal ART exposure were associated with increased failure risk. Early treatment discontinuation for toxicity occurred more frequently for NVP-based regimens, but 5-year cumulative incidence was similar: 6.1% (95% CI 3.9-8.9%) NVP, 8.3% (95% CI 5.6-11.6) EFV, and 9.8% (95% CI 5.7-15.3%) protease inhibitor-based regimens (P ¼ 0.48). Conclusion: Viral load suppression by 12 months was high with all regimens. NVP þ 3NRTIs regimens were particularly efficacious in the longer term and may be a good alternative to protease inhibitor-based ART in young children.