Added Value of Next Generation over Sanger Sequencing in Kenyan Youth with Extensive HIV-1 Drug Resistance.

HIV-1 drug resistance testing in children and adolescents in low-resource settings is both important and challenging. New (more sensitive) drug resistance testing technologies may improve clinical care, but evaluation of their added value is limited. We assessed the potential added value of using next-generation sequencing (NGS) over Sanger sequencing for detecting nucleoside reverse transcriptase inhibitor (NRTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRMs). Participants included 132 treatment-experienced Kenyan children and adolescents with diverse HIV-1 subtypes and with already high levels of drug resistance detected by Sanger sequencing. We examined overall and DRM-specific resistance and its predicted impact on antiretroviral therapy and evaluated the discrepancy between Sanger sequencing and six NGS thresholds (1%, 2%, 5%, 10%, 15%, and 20%). Depending on the NGS threshold, agreement between the two technologies was 62% to 88% for any DRM, 83% to 92% for NRTI DRMs, and 73% to 94% for NNRTI DRMs, with more DRMs detected at low NGS thresholds. NGS identified 96% to 100% of DRMs detected by Sanger sequencing, while Sanger identified 83% to 99% of DRMs detected by NGS. Higher discrepancy between technologies was associated with higher DRM prevalence. Even in this resistance-saturated cohort, 12% of participants had higher, potentially clinically relevant predicted resistance detected only by NGS. These findings, in a young, vulnerable Kenyan population with diverse HIV-1 subtypes and already high resistance levels, suggest potential benefits of more sensitive NGS over existing technology. Good agreement between technologies at high NGS thresholds supports their interchangeable use; however, the significance of DRMs identified at lower thresholds to patient care should be explored further. IMPORTANCE HIV-1 drug resistance in children and adolescents remains a significant problem in countries facing the highest burden of the HIV epidemic. Surveillance of HIV-1 drug resistance in children and adolescents is an important public health strategy, particularly in resource-limited settings, and yet, it is limited due mostly to cost and infrastructure constraints. Whether newer and more sensitive next-generation sequencing (NGS) adds substantial value beyond traditional Sanger sequencing in detecting HIV-1 drug resistance in real life settings remains an open and debatable question. In this paper, we attempt to address this issue by performing a comprehensive comparison of drug resistance identified by Sanger sequencing and six NGS thresholds. We conducted this study in a well-characterized, vulnerable cohort of children and adolescents living with diverse HIV-1 subtypes in Kenya and, importantly, failing antiretroviral therapy (ART) with already extensive drug resistance. Our findings suggest a potential added value of NGS over Sanger even in this unique cohort.

Two overlooked contributors to abandonment of childhood cancer treatment in Kenya: parents' social network and experiences with hospital retention policies.

BACKGROUND: The principal reason for childhood cancer treatment failure in low-income countries is treatment abandonment, the most severe form of nonadherence. Two often neglected factors that may contribute to treatment abandonment are as follows: (a) lack of information and guidance by doctors, along with the negative beliefs of family and friends advising parents, which contributes to misconceptions regarding cancer and its treatment, and (b) a widespread policy in public hospitals by which children are retained after doctor's discharge until medical bills are settled. OBJECTIVE: This study explored parents' experiences with hospital retention policies in a Kenyan academic hospital and the impact of attitudes of family and friends on parents' decisions about continuing cancer treatment for their child. METHODS: Home visits were conducted to interview parents of childhood cancer patients who had been diagnosed between 2007 and 2009 and who had abandoned cancer treatment. RESULTS: Retrospective chart review revealed 98 children diagnosed between 2007 and 2009 whose parents had made the decisions to abandon treatment. During 2011-2012, 53 families (54%) could be reached, and 46 (87%) of these agreed to be interviewed. Parents reported the attitudes of community members (grandparents, relatives, friends, villagers, and church members); 61% believed that the child had been bewitched by some individual, and 74% advised parents to seek alternative treatment or advised them to stop medical treatment (54%). Parents also reported that they were influenced by discussions with other parents who had a child being treated, including that their child's life was in God's hands (87%), the trauma to the child and family of forced hospital stays (84%), the importance of completing treatment (81%), the financial burden of treatment (77%), and the incurability of cancer (74%). These discussions influenced their perceptions of cancer treatment and its usefulness (65%). Thirty-six families (78%) had no health insurance, and 19 of these parents (53%) could not pay their medical bills and were not allowed to take their child home when treatment ended. Parents reported feelings of desperation (95%), powerlessness (95%), and sadness (84%) and that their child has been imprisoned (80%), during the period of retention. The majority of parents (87%) felt that hospital retention of children must cease. CONCLUSIONS: The attitudes and beliefs of parents of children with cancer are impacted by those close to them and their community and may influence their perceptions of cancer treatment and decisions to stop treatment. Hospital retention policies are highly distressing for parents and may contribute to both treatment delays and treatment abandonment. These factors jeopardize treatment outcomes for young patients and require attention and modification.

Abandonment of childhood cancer treatment in Western Kenya.

BACKGROUND: The most important reason for childhood cancer treatment failure in low-income countries is treatment abandonment. OBJECTIVE: The aim of this study was to explore reasons for childhood cancer treatment abandonment and assess the clinical condition of these children. DESIGN: This was a descriptive study using semistructured questionnaires. Home visits were conducted to interview families of childhood cancer patients, diagnosed between January 2007 and January 2009, who had abandoned treatment at the Moi Teaching and Referral Hospital (MTRH). RESULTS: Between January 2007 and January 2009, 222 children were newly diagnosed with a malignancy at MTRH. Treatment outcome was documented in 180 patients. Of these 180 patients, 98 (54%) children abandoned treatment. From December 2011 until August 2012, 53 (54%) of the 98 families were contacted. Due to lack of contact information, 45 families were untraceable. From 53 contacted families, 46 (87%) families agreed to be interviewed. Reasons for abandonment were reported by 26 families, and they were diverse. Most common reasons were financial difficulties (46%), inadequate access to health insurance (27%) and transportation difficulties (23%). Most patients (72%) abandoned treatment after the first 3 months had been completed. Of the 46 children who abandoned treatment, 9 (20%) were still alive: 6 (67%) of these children looked healthy and 3 (33%) ill. The remaining 37 (80%) children had passed away. CONCLUSIONS: Prevention of childhood cancer treatment abandonment requires improved access to health insurance, financial or transportation support, proper parental education, psychosocial guidance and ameliorated communication skills of healthcare providers.

Influence of health-insurance access and hospital retention policies on childhood cancer treatment in Kenya.

BACKGROUND: Kenyan national policies for public hospitals dictate that patients are retained on hospital wards until their hospital bills are paid, but this payment process differs for patients with or without access to National Hospital Insurance Fund (NHIF) at diagnosis. Whether these differences impact treatment outcomes has not been described. Our study explores whether childhood cancer treatment outcomes in Kenya are influenced by health-insurance status and hospital retention policies. PROCEDURE: This study combined retrospective review of medical records with an illustrative case report. We identified children diagnosed with malignancies at a large Kenyan academic hospital between 2007 and 2009, their treatment outcomes, and health-insurance status at diagnosis. RESULTS: Between 2007 and 2009, 222 children were diagnosed with malignancies. Among 180 patients with documented treatment outcome, 54% abandoned treatment, 22% had treatment-related death, 4% progressive/relapsed disease, and 19% event-free survival. Health-insurance status at diagnosis was recorded in 148 children: 23% had NHIF and 77% had no NHIF. For children whose families had NHIF compared with those who did not, the relative risk for treatment abandonment relative to event-free survival was significantly smaller (relative-risk ratio = 0.31, 95% CI = 0.12-0.81, P = 0.016). The case report illustrates difficulties that Kenyan families might face when their child is diagnosed with cancer, has no NHIF, and is retained in hospital. CONCLUSIONS: Children with NHIF at diagnosis had significantly lower chance of abandoning treatment and higher chance of survival. Childhood cancer treatment outcomes could be improved by interventions that prevent treatment abandonment and improve access to NHIF. Hospital retention of patients over unpaid medical bills must stop.

Physical and sexual abuse in orphaned compared to non-orphaned children in sub-Saharan Africa: a systematic review and meta-analysis.

This systematic review assessed the quantitative literature to determine whether orphans are more likely to experience physical and/or sexual abuse compared to non-orphans in sub-Saharan Africa (SSA). It also evaluated the quality of evidence and identified research gaps. Our search identified 10 studies, all published after 2005, from Zimbabwe, South Africa, Kenya and Uganda. The studies consisted of a total 17,336 participants (51% female and 58% non-orphans). Of those classified as orphans (n=7,315), 73% were single orphans, and 27% were double orphans. The majority of single orphans were paternal orphans (74%). Quality assessment revealed significant variability in the quality of the studies, although most scored higher for general design than dimensions specific to the domain of orphans and abuse. Combined estimates of data suggested that, compared to non-orphans, orphans are not more likely to experience physical abuse (combined OR=0.96, 95% CI [0.79, 1.16]) or sexual abuse (combined OR=1.25, 95% CI [0.88, 1.78]). These data suggest that orphans are not systematically at higher risk of experiencing physical or sexual abuse compared to non-orphans in sub-Saharan Africa. However, because of inconsistent quality of data and reporting, these findings should be interpreted with caution. Several recommendations are made for improving data quality and reporting consistency on this important issue.

Factors Underlying Taking a Child to HIV Care: Implications for Reducing Loss to Follow-up among HIV-Infected and Exposed Children

Objective: With the aim of reducing pediatric loss to follow-up (LTFU) from HIV clinical care programs in sub-Saharan Africa; we sought to understand the personal and socio-cultural factors associated with the behavior of caregivers taking HIV-infected and -exposed children for care in western Kenya.Methods: Between Mayand August; 2010; in-depth interviews were conducted with 26 purposively sampled caregivers caring for HIVinfected(7); HIV-exposed (17) and HIV-unknown status (2) children; documented as LTFU from an urban and rural HIV care clinic. All were women with a majority (77) being biological parents. Interviews were audio-recorded; transcribed and content analyzed.Results: Thematic content analysis of the women's perceptions revealed that their decision about routinely taking their children to HIV care involved multiple levels of factors including: (1) intrapersonal: transport costs; food availability; time constraints due to work commitment; disclosure of HIV status for both mother and child; perception that child is healthy and religious beliefs; (2) interpersonal: unsupportive male partner; stigma by the family and family conflicts; (3) community: cultural norms; changing community dynamics and perceived stigma; (4) health care system: clinic location; lack of patient-centered care; delays at the clinic and different appointment schedules (mother and child). Furthermore; the factors across these different levels interacted with each other in a complex way; illustrating the challenges women face in taking their children to HIV care.Conclusion: The complexity and interconnectedness of the factors underlying retention of children in HIV care perceived by these women caregivers suggests that interventions to reduce pediatric LTFU need to be holistic and address multiple socio-ecological levels. Patient-centered care that integrates a family-centered approach to HIV pediatric care is recommended

Characteristics of HIV-infected children seen in Western Kenya.

OBJECTIVES: To describe the characteristics and outcomes of children registered for care in a large HIV care programme in Western Kenya. DESIGN: A retrospective descriptive study. SETTING: USAID-AMPATH HIV clinics in health centres; district and sub-district hospitals; Moi Teaching and Referral Hospital in Western Kenya. SUBJECTS: HIV-infected children below age of 15 years seen in a network of 18 clinics in Western Kenya. INTERVENTIONS: Paediatric HIV diagnosis and care including treatment and prevention of opportunistic infections and provision of combination antiretroviral therapy (CART). MAIN OUTCOME MEASURES: Diagnosis, clinical stage and immune status at enrollment and follow-up; hospitalisation and death. Descriptive statistical analyses and chi square tests were performed. RESULTS: Four thousand and seventeen HIV-infected children seen between June 2002 and April 2008. Median age at enrollment was four years (0-14.2 years), 51% girls, 25% paternal orphans, 10% total orphans and 13% maternal orphans. At enrollment, 25% had weight-for-Age Z scores (WAZ) > or = -1 and 21% had WAZ scores < or = 3. Orphaned children had worse WAZ scores (p=0.0001). Twenty five per cent of children were classified as WHO clinical stage 3 and 4, 56% were WHO clinical stages 1 and 2 with 19% missing clinical staging at enrollment. Cough (25%), gastroenteritis (21%), fever (15%), pneumonia (10%) were the commonest presenting features. Twenty six per cent had been diagnosed with tuberculosis and only 25% started on cotrimoxazole preventive therapy (CPT). Median CD4% at enrollment was 16% (0-64%); latest recorded values were 22% (0-64). Sixty four per cent were on cART (cART+), median age at start was 5.4 (014.4 years). The median initial CD4% among cART+ was 13 (0-62) compared to 24 (0-64) for those not on ART (cART-). Median CD4% for cART+ improved to 22% (0-59); whereas cART- was 23% (0-64) at last appointment. During the period of follow-up, one fifth (19%) of children on cART were lost to follow-up compared to slightly over one third (37%) for those not on cART. Thirty four percent were hospitalised; 41% diagnosed with pneumonia. Six per cent of 4017 were confirmed dead. CONCLUSIONS: HIV-infected children were enrolled in care early in childhood. Orphanhood was prevalent in these children as were gastroenteritis, fever, pneumonia and advanced immuno-suppression. Orphans were more likely to be severely malnourished. Only a quarter of children were put on cotrimoxazole preventive therapy. Children commenced on cART late but responded well to treatment. Loss to follow-up was less prevalent among those on cART.