Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

BACKGROUND: Kaposi sarcoma (KS) is the most common HIV-associated malignancy in sub-Saharan Africa. The presentation and outcomes of pediatric KS are not well understood. PROCEDURE: We performed a retrospective cohort analysis of 81 HIV-infected children with KS at the Baylor Children's Clinical Centres of Excellence in Malawi and Botswana from March 2003 to October 2009. RESULTS: Eighty-one children with KS were identified whose median age was 8.0 (inter-quartile range 5.1-11.3) years. KS lesions were presented primarily on the skin (83%), lymph nodes (52%), and oral mucosa (41%). Occasionally disease was limited to the lymph nodes only (10%). Severe immunosuppression (70%), anemia (29%), and thrombocytopenia (17%) were common laboratory findings. Highly active antiretroviral therapy (HAART) was administered to 94% of children, including 77% who received HAART plus chemotherapy. KS immune reconstitution inflammatory syndrome (IRIS) occurred in 22%. Disease status 12 months after KS diagnosis was determined for 69 children: 43% were alive and 57% had died. Severe immunosuppression was independently associated with mortality in multivariate analysis (OR = 4.3; 95% CI 1.3-14.6; P = 0.02). CONCLUSION: KS occurs in a significant number of HIV infected children in sub-Saharan Africa. Pediatric KS is distinct from KS in adults. Lymph node involvement was a common manifestation of KS in children, and severe immunosuppression was associated with the highest mortality risk. Though overall mortality was high in children with KS, patients did achieve clinical remission in settings with limited diagnostic and therapeutic resources.

Routine inpatient provider-initiated HIV testing in Malawi, compared with client-initiated community-based testing, identifies younger children at higher risk of early mortality.

OBJECTIVE: To determine how routine inpatient provider-initiated HIV testing differs from traditional community-based client-initiated testing with respect to clinical characteristics of children identified and outcomes of outpatient HIV care. DESIGN: Prospective observational cohort. METHODS: Routine clinical data were collected from children identified as HIV-infected by either testing modality in Lilongwe, Malawi, in 2008. After 1 year of outpatient HIV care at the Baylor College of Medicine Clinical Center of Excellence, outcomes were assessed. RESULTS: Of 742 newly identified HIV-infected children enrolling into outpatient HIV care, 20.9% were identified by routine inpatient HIV testing. Compared with community-identified children, hospital-identified patients were younger (median 25.0 vs 53.5 months), with more severe disease (22.2% vs 7.8% WHO stage IV). Of 466 children with known outcomes, 15.0% died within the first year of HIV care; median time to death was 15.0 weeks for community-identified children vs 6.0 weeks for hospital-identified children. The strongest predictors of early mortality were severe malnutrition (hazard ratio, 4.3; 95% confidence interval, 2.2-8.3), moderate malnutrition (hazard ratio, 3.2; confidence interval, 1.6-6.6), age < 12 months (hazard ratio, 3.2; 95% confidence interval, 1.4-7.2), age 12 to 24 months (hazard ratio, 2.5; 95% confidence interval, 1.1-5.7), and WHO stage IV (hazard ratio, 2.2; 95% confidence interval, 1.1-4.6). After controlling for other variables, hospital identification did not independently predict mortality. CONCLUSIONS: Routine inpatient HIV testing identifies a subset of younger HIV-infected children with more severe, rapidly progressing disease that traditional community-based testing modalities are currently missing.

False-negative post-18-month confirmatory HIV tests in HIV DNA PCR-positive children: a retrospective analysis.

OBJECTIVE: The WHO guidelines for children less than 18 months old diagnosed with HIV based on presumptive clinical diagnosis or one virologic test recommend confirmatory HIV antibody testing after 18 months of age. This study describes post-18-month HIV test results following this WHO-recommended confirmatory testing strategy. DESIGN: Case series and retrospective review of routine program data. METHODS: Children enrolled at the Baylor Children's Clinical Center of Excellence, a pediatric and family HIV clinic in Maseru, Lesotho from December 2005 through January 2009 with a positive HIV DNA PCR at less than 18 months of age and HIV rapid test results after 18 months of age were included. Post-18-month confirmatory HIV test results are described. Factors associated with non-positive confirmatory rapid tests were determined using binary logistic regression. RESULTS: Of the 109 children meeting inclusion criteria, 22 (20.2%) had negative and 27 (24.8%) discordant confirmatory rapid tests. Forty-six of these 49 were on antiretroviral therapy (ART). Among these 49, 11 of 24 post-18-month HIV DNA PCRs were negative, whereas nine of 10 post-18-month HIV ELISAs were positive; 29 were definitively and 17 probably HIV-infected, two were uninfected, and one had undetermined status. Only age less than 9 months at ART initiation (odds ratio 4.25, P = 0.002) was associated with non-positive rapid tests. CONCLUSION: False-negative post-18-month confirmatory rapid tests and HIV DNA PCRs in children on ART are common, associated with early ART initiation, and may lead to inappropriate ART discontinuation and discharge from care of truly HIV-infected children.

Pneumonia and malnutrition are highly predictive of mortality among African children hospitalized with human immunodeficiency virus infection or exposure in the era of antiretroviral therapy.

OBJECTIVE: To identify clinical characteristics predicting death among inpatients who are infected with or exposed to human immunodeficiency virus (HIV) during a period of pediatric antiretroviral therapy scale-up in sub-Saharan Africa. STUDY DESIGN: Retrospective review of medical records from every child with HIV infection (n = 834) or exposure (n = 351) identified by routine inpatient testing in Kamuzu Central Hospital, Lilongwe, Malawi, September 2007 through December 2008. RESULTS: The inpatient mortality rate was high among children with HIV infection (16.6%) and exposure (13.4%). Clinically diagnosed Pneumocystis pneumonia or very severe pneumonia independently predicted death in inpatients with HIV infection (OR 14; 95% CI 8.2 to 23) or exposure (OR 21; CI 8.4 to 50). Severe acute malnutrition independently predicted death in children who are HIV infected (OR 2.2; CI 1.7 to 3.9) or exposed (OR 5.1; CI 2.3 to 11). Other independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and esophageal candidiasis for children infected with HIV, and meningitis and severe anemia for inpatients exposed to HIV. CONCLUSIONS: Severe respiratory tract infections and malnutrition are both highly prevalent and strongly associated with death among hospitalized children who are HIV infected or exposed. Novel programmatic and therapeutic strategies are urgently needed to reduce the high mortality rate among inpatients with HIV infection and HIV exposure in African pediatric hospitals.

Etiology of meningitis among patients admitted to a tertiary referral hospital in Botswana.

This retrospective review evaluated records of cerebrospinal fluid samples between 2000 and 2008 at Princess Marina Hospital in Gaborone, Botswana. Of the 7501 cerebrospinal fluid samples reviewed, Streptococcus pneumoniae (n = 125) and Haemophilus influenzae (n = 60) were the most common bacteria cultured. There were also 1018 cryptococcal and 44 tuberculous meningitis cases. Antimicrobial susceptibilities are described. Public health interventions could decrease the burden of meningitis in Botswana.

Routine inpatient human immunodeficiency virus testing system increases access to pediatric human immunodeficiency virus care in sub-Saharan Africa.

BACKGROUND: Routine Human Immunodeficiency Virus (HIV) testing, called provider-initiated opt-out HIV testing and counseling (PITC), is recommended in African countries with high HIV prevalence. However, it is unknown whether PITC increases access to pediatric HIV care. In 2008, the Baylor International Pediatric AIDS Initiative implemented PITC (BIPAI-PITC) at a Malawian hospital. We sought to evaluate the influence of BIPAI-PITC, compared with nonroutine HIV testing (NRT), on pediatric HIV care access. METHODS: Retrospective data from 7077 pediatric inpatients were collected during sequential 4-month periods of NRT and BIPAI-PITC. In-hospital and 1-year outcomes for 337 HIV-infected and HIV-exposed uninfected inpatients not previously enrolled in HIV care were analyzed to assess the clinical influence of each testing strategy. RESULTS: During BIPAI-PITC, a greater proportion of all hospitalized children received HIV testing (81.0% vs. 33.3%, P < 0.001), accessed inpatient HIV-trained care (7.5% vs. 2.4%, P < 0.001), enrolled into an outpatient HIV clinic after discharge (3.2% vs. 1.3%, P < 0.001), and initiated antiretroviral therapy (ART) after hospitalization (1.1% vs. 0.6%, P = 0.010) compared with NRT. Additionally, BIPAI-PITC increased the proportion of hospitalized HIV-infected and HIV-exposed uninfected children receiving DNA polymerase chain reaction testing (73.5% vs. 35.2%, P < 0.001), but did not improve outpatient enrollment or ART initiation of identified HIV-infected patients. CONCLUSIONS: BIPAI-PITC increases access to inpatient and outpatient pediatric HIV care for hospitalized children, including DNA polymerase chain reaction testing and ART. Broader implementation of BIPAI-PITC or similar approaches, along with more pediatric HIV-trained clinicians and improved defaulter-tracking methods, would improve pediatric HIV service utilization globally.

Pneumococcal endocarditis in children.

Endocarditis due to Streptococcus pneumoniae is unusual in children, accounting for 3%-7% of all cases of childhood endocarditis. The US Pediatric Multicenter Pneumococcal Surveillance Group has prospectively identified patients with invasive disease at 8 children's hospitals. During the period of 1 September 1993 through 28 February 2003, a total of 11 children with pneumococcal endocarditis were seen. Seven (64%) were 3-36 months old; 8 (73%) were boys. Ten (91%) had preexisting structural heart disease; 5 had undergone previous heart surgery. Concomitant sites of infection were noted in 6 patients (55%), including 3 patients with meningitis. One patient (9%) died during hospitalization, and 5 others (45%) experienced serious complications. Only 2 patients remained hospitalized for their entire course of parenteral antibiotic therapy. Eight of 10 pneumococcal isolates tested were vaccine or vaccine-related serotypes included in the currently licensed 7-valent conjugated pneumococcal vaccine. Pneumococcal endocarditis in children is unusual but often has serious complications.