Strengthening the Diagnosis and Treatment of Malnutrition Through Increased Nurse Involvement: A Quality Improvement Project From Pediatric Wards in Mozambique.

BACKGROUND: Childhood acute malnutrition continues to be a serious health problem in many low-resource settings in Africa. On pediatric wards in Mozambique, missed opportunities for timely diagnosis and treatment of malnutrition may lead to poor health outcomes. To improve inpatient nutritional care, a quality improvement (QI) project was implemented that aimed to engage pediatric nurses in inpatient malnutrition diagnosis and treatment. METHODS: In 2 Mozambican referral hospitals, for 6 months, the Plan-Do-Study-Act framework for QI was implemented to identify key drivers of the following measures: having complete anthropometric evaluation documented at admission, 3 or more weight measurements per hospitalization week, documentation of nutritional therapy for eligible patients, and documentation of referral for outpatient nutritional rehabilitation after discharge. Clinical data were abstracted from hospital charts and entered into an EpiInfo database, including a 3-month observation period after the project, and analyzed retrospectively. RESULTS: A total of 2,208 children from wards other than malnutrition were included in the analysis. Complete anthropometric evaluation at admission improved from 24.4% 2 months before the QI project to 80.1% during and 75.2% in the 3 months after the project (P<.001). The percentage of patients with 3 or more weight measurements per hospitalization week rose from 22.3% to 82.8% during and 75.0% after the project (P<.001). Documentation of nutritional therapy increased from 58.8% before to 67.1% during and 70.6% after the project (P=.54), and documentation of referral for outpatient nutritional rehabilitation after discharge decreased from 55.9% to 54.9% during and increased to 70.6% after the project, (P<.001). CONCLUSION: Nurse engagement may lead to important advancements in the diagnosis and treatment of acute malnutrition in pediatric wards other than malnutrition in Mozambique. Task-sharing, particularly nurse engagement, in combination with QI methodology, may be considered for wards in similar settings with a high burden of malnutrition.

Negative Rapid Serological Tests in an HIV-Infected Infant: A Call for Improved Inpatient Provider-Initiated Testing and Counseling Beginning With Breastfeeding Mothers.

Rapid serological tests are unreliable for the diagnosis of HIV exposure and infection in infants. This case reports an HIV-infected infant with a delayed diagnosis due to multiple negative serological tests, highlighting the importance of maternal testing for provider-initiated testing and counseling in hospitalized infants.

Inpatient Point-of-Care HIV Early Infant Diagnosis in Mozambique to Improve Case Identification and Linkage to Antiretroviral Therapy.

INTRODUCTION: Novel approaches to case identification and linkage to antiretroviral therapy (ART) are needed to close gaps in early infant diagnosis (EID) of HIV. Point-of-care (POC) EID is a recent innovation that eliminates the long turnaround times of conventional EID that limit patient management in the inpatient setting. The initial deployment of POC EID in Mozambique focused primarily on outpatient clinics; however, 2 high-volume tier-4 pediatric referral hospitals were also included. METHODS: To assess the impact of inpatient POC EID, a retrospective review of testing and care data from Hospital Central de Beira (HCB) and Hospital Central de Maputo (HCM) was performed for the period September 2017 to July 2018, with comparison to the 8-month pre-POC period when dried blood spots were used for conventional EID. RESULTS: Monthly testing volume increased from 8.5 tests pre-POC to 17.6 tests with POC (P<.001). Among 511 children with POC testing, the median age was 5 months, there was ongoing breastfeeding in 326 (63.8%), and 136 (26.6%) of mothers and 146 (28.6%) of infants had not received ART or antiretroviral prophylaxis, respectively. POC tests were positive in 152 (29.7%) infants, and 52 (37.5%) had a previous negative DNA polymerase chain reaction through the conventional outpatient EID program. Linkage to ART for infants with HIV-positive tests improved 64% during the POC period (P=.002). Inpatient mortality for infected infants during the POC period was 28.2%. Excluding these deaths, 61.2% of eligible infants initiated ART as inpatients, but only 29.8% of those discharged without ART were confirmed to have initiated as outpatients. CONCLUSIONS: Inpatient wards are a high-yield site for EID and ART initiation that have historically been overlooked in programming for prevention of mother-to-child transmission. POC platforms represent a transformative opportunity to increase inpatient testing, make definitive diagnoses, and improve timely linkage to ART. Scale-up plans should prioritize pediatric wards.

Compromise of Second-Line Antiretroviral Therapy Due to High Rates of Human Immunodeficiency Virus Drug Resistance in Mozambican Treatment-Experienced Children With Virologic Failure.

BACKGROUND: Virologic failure (VF) is highly prevalent in sub-Saharan African children on antiretroviral therapy (ART) and is often associated with human immunodeficiency virus drug resistance (DR). Most children still lack access to routine viral load (VL) monitoring for early identification of treatment failure, with implications for the efficacy of second-line ART. METHODS: Children aged 1 to 14 years on ART for ≥12 months at 6 public facilities in Maputo, Mozambique were consecutively enrolled after informed consent. Chart review and caregiver interviews were conducted. VL testing was performed, and specimens with ≥1000 copies/mL were genotyped. RESULTS: Of the 715 children included, the mean age was 103 months, 85.8% had no immunosuppression, 73.1% were taking stavudine/lamivudine/nevirapine, and 20.1% had a history prevention of mother-to-child transmission exposure. The mean time on ART was 60.0 months. VF was present in 259 patients (36.3%); 248 (95.8%) specimens were genotyped, and DR mutations were found in 238 (96.0%). Severe immunosuppression and nutritional decline were associated with DR. M184V and Y181C were the most common mutations. In the 238 patients with DR, standard second-line ART would have 0, 1, 2, and 3 effective antiretrovirals in 1 (0.4%), 74 (31.1%), 150 (63.0%), and 13 (5.5%) patients, respectively. CONCLUSION: This cohort had high rates of VF and DR with frequent compromise of second-line ART. There is urgent need to scale-up VL monitoring and heat-stable protease inhibitor formulations or integrase inhibitorsfor a more a durable first-line regimen that can feasibly be implemented in developing settings.

Temporal Trends in Patient Characteristics and Outcomes Among Children Enrolled in Mozambique's National Antiretroviral Therapy Program

During 2004-2009, >12,000 children (<15 years old) initiated antiretroviral therapy (ART) in Mozambique. Nationally representative outcomes and temporal trends in outcomes were investigated. Methods: Rates of death, loss to follow-up (LTFU) and attrition (death or LTFU) were evaluated in a nationally representative sample of 1054 children, who initiated ART during 2004-2009 at 25 facilities randomly selected using probability-proportional-to-size sampling. Results: At ART initiation during 2004-2009, 50% were male; median age was 3.3 years; median CD4% was 13%; median CD4 count was 375 cells/µL; median weight-for-age Z score was -2.1. During 2004-2009, median time from HIV diagnosis to care initiation declined from 33 to 0 days (P = 0.001); median time from care to ART declined from 93 to 62 days (P = 0.004); the percentage aged <2 at ART initiation increased from 16% to 48% (P = 0.021); the percentage of patients with prior tuberculosis declined from 50% to 10% (P = 0.009); and the percentage with prior lymphocytic interstitial pneumonia declined from 16% to 1% (P < 0.001). Over 2652 person-years of ART, 183 children became LTFU and 26 died. Twelve-month attrition was 11% overall but increased from 3% to 22% during 2004-2009, mainly because of increases in 12-month LTFU (from 3% to 18%). Conclusion: Declines in the prevalence of markers of advanced HIV disease at ART initiation probably reflect increasing ART access. However, 12-month LTFU increased during program expansion, and this negated any program improvements in outcomes that might have resulted from earlier ART initiation.

Temporal Trends in Patient Characteristics and Outcomes Among Children Enrolled in Mozambique's National Antiretroviral Therapy Program.

BACKGROUND: During 2004-2009, >12,000 children (<15 years old) initiated antiretroviral therapy (ART) in Mozambique. Nationally representative outcomes and temporal trends in outcomes were investigated. METHODS: Rates of death, loss to follow-up (LTFU) and attrition (death or LTFU) were evaluated in a nationally representative sample of 1054 children, who initiated ART during 2004-2009 at 25 facilities randomly selected using probability-proportional-to-size sampling. RESULTS: At ART initiation during 2004-2009, 50% were male; median age was 3.3 years; median CD4% was 13%; median CD4 count was 375 cells/µL; median weight-for-age Z score was -2.1. During 2004-2009, median time from HIV diagnosis to care initiation declined from 33 to 0 days (P = 0.001); median time from care to ART declined from 93 to 62 days (P = 0.004); the percentage aged <2 at ART initiation increased from 16% to 48% (P = 0.021); the percentage of patients with prior tuberculosis declined from 50% to 10% (P = 0.009); and the percentage with prior lymphocytic interstitial pneumonia declined from 16% to 1% (P < 0.001). Over 2652 person-years of ART, 183 children became LTFU and 26 died. Twelve-month attrition was 11% overall but increased from 3% to 22% during 2004-2009, mainly because of increases in 12-month LTFU (from 3% to 18%). CONCLUSION: Declines in the prevalence of markers of advanced HIV disease at ART initiation probably reflect increasing ART access. However, 12-month LTFU increased during program expansion, and this negated any program improvements in outcomes that might have resulted from earlier ART initiation.

Treatment of Kaposi sarcoma in human immunodeficiency virus-1-infected Mozambican children with antiretroviral drugs and chemotherapy.

AIDS-associated Kaposi sarcoma occurs in children, but treatment experience reports are very scarce. A retrospective analysis of 28 children treated with highly active antiretroviral therapy and monthly paclitaxel showed unexpected results with 19 children in complete and sustainable remission, including those with the most severe form. Tolerance and feasibility were good, despite a lack of skilled staff in a low-resource setting.

Absolute and percent CD4+ T-cell enumeration by flow cytometry using capillary blood.

INTRODUCTION: CD4+ T-cell counting is usually performed on whole blood obtained from standard venipuncture. Venipuncture requires expertise, results in discomfort and generates biological waste. Capillary blood could be used to measure the levels of CD4+ T-cell in children, elderly and very ill patients. We studied the agreement between CD4+ T-cell counts and percent generated using venous blood with those obtained with capillary blood in HIV-infected adults and children in a resource-limited tropical setting. METHODS: This cross-sectional study consecutively enrolled a total of 152 adult and pediatric HIV-positive patients attending two outpatient clinics in Maputo City, Mozambique. We recruited individuals presenting for their routine clinical follow-up that included the determination of CD4+ T-cell counts in peripheral blood. For each subject, peripheral blood specimens were obtained by both venipuncture and finger prick. Specimens were tested using two flow cytometers, the FACSCount and the FACSCalibur. RESULTS: Absolute CD4+ T-cell counts obtained using capillary blood were in close agreement with those from venous blood both on the FACSCalibur (absolute bias=+12.3 cells/mm³, limits of agreement: -259.2 to +283.9, R²=0.96) and the FACSCount (absolute bias=+16.1 cells/mm³, limits of agreement: -209.2 to +241.5, R²=0.97). Percent CD4+ T-cell counts were measured only on the FACSCalibur also showed a good agreement with a bias of +0.6% and limits of agreement of -3.1 to +4.3. CONCLUSIONS: Absolute CD4+ T-cell counts and percent generated using capillary blood are in close agreement with those from venous blood. Point-Of-Care assays and standard flow cytometers can be deployed in a tiered laboratory network where both venous and capillary blood collection can be used for CD4+ T-cell enumeration.

Nonvertical, nonsexual transmission of human immunodeficiency virus in children.

In a cohort of 450 human immunodeficiency virus (HIV)-infected children followed up in Maputo, Mozambique, 22 were born to HIV-uninfected mothers and had no history of sexual abuse. A case record review of these nonvertically, nonsexually infected children as well as a case-control study strongly suggests health care as possible source of infection for many of these children. This facet of the pediatric HIV epidemic should not be overlooked.

Risk of extended viral resistance in human immunodeficiency virus-1-infected Mozambican children after first-line treatment failure

Background: Resistant virus may be selected by sub-optimal control of HIV-1 replication during antiretroviral treatment. The incidence and profile of resistance in children receiving World Health Organization-recommended treatment remains to be evaluated on a large scale. Goals: Assessment of the frequency and profile of resistant virus in HIV-1-infected children, treated for at least 6 months with stavudine/zidovudine + lamivudine + nevirapine and presenting virological failure in a large access program in Maputo, Mozambique. Results: Cross-sectional evaluation of plasma HIV-1 viral load (VL) in 495 evaluable children among 512 treated for at least 6 months showed that 360 (72.7%) had a VL of <50 copies/mL of HIV-1 RNA. Genotypic resistance tests were performed in the 84 available samples from the 135 treated children with VL > or = 50 copies/mL: 92% of the viruses were resistant to lamivudine and/or nevirapine, and 15% were resistant to stavudine. Twenty children (24%) harbored virus with a extended spectrum of cross-resistance defined as resistance to the 3 drugs of the combination received by the child and/or at least 1 resistance to a drug to which the child had never been exposed (abacavir: 5%, tenofovir: 6%, didanosine: 3.5% and the new generation non nucleoside inhibitor, etravirine: 6%). The only factor identified by multivariate analysis as being associated with this extended resistance profile was the duration of treatment (aOR: 6.67 [95% CI: 1.24-35.93], P = 0.015 for treatment >24 months) with a per month increase of 1.09 (1.02-1.16) P = 0.007.

Risk of extended viral resistance in human immunodeficiency virus-1-infected Mozambican children after first-line treatment failure.

BACKGROUND: Resistant virus may be selected by sub-optimal control of HIV-1 replication during antiretroviral treatment. The incidence and profile of resistance in children receiving World Health Organization-recommended treatment remains to be evaluated on a large scale. GOALS: Assessment of the frequency and profile of resistant virus in HIV-1-infected children, treated for at least 6 months with stavudine/zidovudine + lamivudine + nevirapine and presenting virological failure in a large access program in Maputo, Mozambique. RESULTS: Cross-sectional evaluation of plasma HIV-1 viral load (VL) in 495 evaluable children among 512 treated for at least 6 months showed that 360 (72.7%) had a VL of <50 copies/mL of HIV-1 RNA. Genotypic resistance tests were performed in the 84 available samples from the 135 treated children with VL > or = 50 copies/mL: 92% of the viruses were resistant to lamivudine and/or nevirapine, and 15% were resistant to stavudine. Twenty children (24%) harbored virus with a extended spectrum of cross-resistance defined as resistance to the 3 drugs of the combination received by the child and/or at least 1 resistance to a drug to which the child had never been exposed (abacavir: 5%, tenofovir: 6%, didanosine: 3.5% and the new generation non nucleoside inhibitor, etravirine: 6%). The only factor identified by multivariate analysis as being associated with this extended resistance profile was the duration of treatment (aOR: 6.67 [95% CI: 1.24-35.93], P = 0.015 for treatment >24 months) with a per month increase of 1.09 (1.02-1.16) P = 0.007. CONCLUSIONS: Residual viral replication in children receiving stavudine/zidovudine + lamivudine + nevirapine treatment is associated with a time-dependent risk of acquiring cross-resistance, including resistance to drugs currently used for second-line treatment and also to the new generation of non nucleoside reverse transcriptase inhibitors.

Prevalence and risk factors associated with antiretroviral resistance in HIV-1-infected children.

In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated with resistance in this population. Prevalence of genotypic resistance was estimated retrospectively in treated children who experienced virologic failure (with HIV-1-RNA > 500 copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from 76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%, respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC status. In multivariate analysis, resistance to any drug remained associated independently with current low viral load and high lifetime number of past PI. Triple resistance was independently associated with the high lifetime number of past PI and with gender, particularly among children aged 11 years old or more with a prevalence seven times higher in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1-infected children and prevalence was similar with those observed in adult population in the same year period. However, adolescent boys seem to be at greater risk.

Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years.

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

Change to a once-daily combination including boosted atazanavir in HIV-1-infected children.

BACKGROUND: Pediatric experience with atazanavir combined with antiretroviral drugs administered once daily is very limited. OBJECTIVE: The objective of this prospective, single-center observation study was to evaluate efficacy and tolerance of once-a-day ritonavir-boosted atazanavir, including treatment. RESULTS: Antiretroviral treatment of 23 children and adolescents with a median age of 16 years (range, 10-19 years) was changed to a single daily dose of a combination of ritonavir-boosted atazanavir and 2 other nucleoside or nonnucleoside analogs. The single daily dosing was expected to improve adherence to treatment. The mean follow-up period was 12 months (range, 6-17 months). At the time of the treatment switch, the previous treatment had been effective in 11 children (plasma viral load [pVL] <50 copies/mL) and not effective in 12 (pVL >50 copies/mL). None of the viral genotypes had resistance to atazanavir. The susceptibility score for the drugs used in combination with atazanavir (GSS) was at least 1.5 in 12 of 20 children. The atazanavir dose was 300 mg per day for children weighing more than 50 kg and 200 mg per day for children weighing 30 to 50 kg, in all cases associated with 100 mg ritonavir. During follow up, the mean atazanavir plasma concentration at 12 to 15 hours was 2.18 +/- 1.19 mg/L. Tolerance was good in most patients, but 4 children chose to stop treatment because of icterus (n = 2) or persistent nausea and vomiting (n = 2). In 6 of the 12 children in whom treatment was not virologically effective before the switch, pVL was below 50 copies/mL after 1 to 3 months of treatment. Poor compliance and virologic failure persisted in the other 6 children. Seven of the 11 children with good virologic control before the switch continued to have undetectable pVL but 4 experienced virologic failure after 1, 1, 3 or 12 months of treatment despite good compliance. Insufficient antiviral potency of associated drugs could have been the cause of 2 of these 4 unexpected virologic failures. CONCLUSION: In these children with extensive previous treatment, the change to a once-daily treatment, including ritonavir-boosted atazanavir, was associated with a significant risk of virologic failure.

Characteristics of HIV-infected children recently diagnosed in Paris, France.

Pediatric HIV-1 infections are still being diagnosed in France, despite the efficacy of prophylactic treatment to prevent mother-to-child transmission. To describe the characteristics and mode of infection of these children, we retrospectively analysed data of 59 children diagnosed with the HIV-1 infection between January 2000 and June 2005 in a Parisian university hospital. Twenty of these children had been born in France, and none had received appropriate prophylaxis (insufficient, not taken or given too late). Six received no preventive treatment due to failures in screening: three mothers were HIV-seronegative at the start of pregnancy and no test was carried out for the other three. At diagnosis, four had a severe immune deficiency (CD4 cells <15%). The 39 children born abroad were diagnosed at a median age of 3 years (range: 3 months-16 years), sometimes several years after their arrival in France. The clinical, virological and immunological status of these children was poorer than that of the children born in France: 18 had less than 15% CD4 cells. In contrast, the response to treatment of the children born in France was not as good as that of the children born abroad. The HIV-1 screening and prevention programme for pregnant women could be improved. Some children infected following the failure of prevention are at high risk of subsequent treatment failure. HIV-1 infection should be taken into consideration in children born in countries with a high prevalence of HIV, even if they have been living in France for several years and present no symptoms.