Susan D. Emmett

Predicting Virologic Failure Among HIV-1-Infected Children Receiving Antiretroviral Therapy in Tanzania: a Cross-Sectional Study

Background:Many HIV care and treatment programs in resource-limited settings rely on clinical and immunologic monitoring of antiretroviral therapy (ART), but accuracy of this strategy to detect virologic failure (VF) among children has not been evaluated. Methods:A cross-sectional sample of HIV-infected children aged 1-16 years on ART ≥6 months receiving care at a Tanzanian referral center underwent clinical staging, CD4 lymphocyte measurement, plasma HIV-1 RNA level, and complete blood count. Associations with VF (HIV-1 RNA ≥400 copies/mL) were determined utilizing bivariable and multivariate analyses; accuracy of current clinical and immunologic guidelines in identifying children with VF was assessed. Findings:Of 206 children (median age 8.7 years, ART duration 2.4 years), 65 (31.6%) demonstrated VF at enrollment. Clinical and immunological criteria identified 2 (3.5%) of 57 children with VF on first-line therapy, exhibiting 3.5% sensitivity and 100% specificity. VF was associated with younger age, receipt of nevirapine vs. efavirenz-based regimen, CD4% < 25%, and physician documentation of maladherence (P < 0.05 on bivariable analysis); the latter 2 factors remained significant on multivariate logistic regression. Interpretation:This study demonstrates poor performance of clinical and immunologic criteria in identifying children with virologic failure. Affordable techniques for measuring HIV-1 RNA level applicable in resource-limited settings are urgently needed.

The socioeconomic impact of hearing loss in U.S. adults.

Objective To evaluate the associations between hearing loss and educational attainment, income, and unemployment/underemployment in U.S. adults. Study Design National cross-sectional survey. Setting Ambulatory examination centers. Patients Adults aged 20 to 69 years who participated in the 1999 to 2002 cycles of the NHANES (National Health and Nutrition Examination Survey) audiometric evaluation and income questionnaire (N = 3,379). Intervention(s) Pure-tone audiometry, with hearing loss defined by World Health Organization criteria of bilateral pure-tone average of more than 25 dB (0.5, 1, 2, 4 kHz). Main Outcome Measure(s) Low educational attainment, defined as not completing high school; low income, defined as family income less than

GDP matters: cost effectiveness of cochlear implantation and deaf education in sub-Saharan Africa

20,000 per year; and unemployment or underemployment, defined as not having a job or working less than 35 hours per week. Results Individuals with hearing loss had 3.21 times higher odds of low educational attainment (95% confidence interval [95% CI], 2.20–4.68) compared with normal-hearing individuals. Controlling for education, age, sex, and race, individuals with hearing loss had 1.58 times higher odds of low income (95% CI, 1.16–2.15) and 1.98 times higher odds of being unemployed or underemployed (95% CI, 1.38–2.85) compared with normal-hearing individuals. Conclusion Hearing loss is associated with low educational attainment in U.S. adults. Even after controlling for education and important demographic factors, hearing loss is independently associated with economic hardship, including both low income and unemployment/underemployment. The societal impact of hearing loss is profound in this nationally representative study and should be further evaluated with longitudinal cohorts. Received institutional review board approval (National Center for Health Statistics Institutional Review Board Protocol no. 98-12).

Gestational vitamin A deficiency: a novel cause of sensorineural hearing loss in the developing world?

Hypothesis Cochlear implantation and deaf education are cost effective in Sub-Saharan Africa. Background Cost effectiveness of pediatric cochlear implantation has been well established in developed countries but is unknown in low resource settings, where access to the technology has traditionally been limited. With incidence of severe-to-profound congenital sensorineural hearing loss 5 to 6 times higher in low/middle-income countries than the United States and Europe, developing cost-effective management strategies in these settings is critical. Methods Costs were obtained from experts in Nigeria, South Africa, Kenya, Rwanda, Uganda, and Malawi using known costs and published data, with estimation when necessary. A disability adjusted life years (DALY) model was applied using 3% discounting and 10-year length of analysis. Sensitivity analysis was performed to evaluate the effect of device cost, professional salaries, annual number of implants, and probability of device failure. Cost effectiveness was determined using the WHO standard of cost-effectiveness ratio/gross domestic product per capita (CER/GDP) less than 3. Results Cochlear implantation was cost effective in South Africa and Nigeria, with CER/GDP of 1.03 and 2.05, respectively. Deaf education was cost effective in all countries investigated, with CER/GDP ranging from 0.55 to 1.56. The most influential factor in the sensitivity analysis was device cost, with the cost-effective threshold reached in all countries using discounted device costs that varied directly with GDP. Conclusion Cochlear implantation and deaf education are equally cost effective in lower-middle and upper-middle income economies of Nigeria and South Africa. Device cost may have greater impact in the emerging economies of Kenya, Uganda, Rwanda, and Malawi.

Bilateral hearing loss is associated with decreased nonverbal intelligence in US children aged 6 to 16 years.

Hearing loss is a substantial public health problem with profound social and economic consequences in the developing world. The World Health Organization (WHO) estimates that there are 360 million people living with disabling hearing loss globally, and 80% of these individuals are from low- and middle-income countries. The epidemiology of hearing impairment remains poorly defined in most impoverished societies. Middle ear infections in childhood are a key determinant; however, congenital anomalies may also comprise an important etiology and may arise from gestational malnutrition. While evidence exists that preventable vitamin A deficiency exacerbates the severity of ear infections and, consequently, hearing loss, antenatal vitamin A deficiency during sensitive periods of fetal development may represent an etiologically distinct and virtually unexplored causal pathway. Evidence from multiple animal systems clearly shows that fetal inner ear development requires adequate vitamin A nutriture to proceed normally. Inner ear malformations occur in experimentally imposed maternal vitamin A deficiency in multiple species in a dose-response manner. These anomalies are likely due to the loss of retinoic acid-dependent regulation of both hindbrain development and otic morphogenic processes. Based on in vivo evidence in experimental animals, we hypothesize that preventable gestational vitamin A deficiency, especially during early stages of fetal development, may predispose offspring to inner ear malformations and sensorineural hearing loss. As vitamin A deficiency affects an estimated 20 million pregnant women globally, we hypothesize that, in undernourished settings, routine provision of supplemental vitamin A at the recommended allowance throughout pregnancy may promote normal inner ear development and reduce risk of an as yet unknown fraction of sensorineural hearing loss. If our hypothesis proves correct, gestational vitamin A deficiency would represent a potentially preventable etiology of sensorineural hearing loss of substantial public health significance.

Moving Beyond GDP: Cost Effectiveness of Cochlear Implantation and Deaf Education in Latin America.

To evaluate the association between hearing loss and nonverbal intelligence in US children.

Nutrition and hearing loss: a neglected cause and global health burden

Hypothesis: Cochlear implantation (CI) and deaf education are cost effective management strategies of childhood profound sensorineural hearing loss in Latin America. Background: CI has been widely established as cost effective in North America and Europe and is considered standard of care in those regions, yet cost effectiveness in other economic environments has not been explored. With 80% of the global hearing loss burden existing in low- and middle-income countries, developing cost effective management strategies in these settings is essential. This analysis represents the continuation of a global assessment of CI and deaf education cost effectiveness. Methods: Brazil, Colombia, Ecuador, Guatemala, Paraguay, Trinidad and Tobago, and Venezuela participated in the study. A Disability Adjusted Life Years model was applied with 3% discounting and 10-year length of analysis. Experts from each country supplied cost estimates from known costs and published data. Sensitivity analysis was performed to evaluate the effect of device cost, professional salaries, annual number of implants, and probability of device failure. Cost effectiveness was determined using the World Health Organization standard of cost effectiveness ratio/gross domestic product per capita (CER/GDP)<3. Results: Deaf education was very cost effective in all countries (CER/GDP 0.07–0.93). CI was cost effective in all countries (CER/GDP 0.69–2.96), with borderline cost effectiveness in the Guatemalan sensitivity analysis (Max CER/GDP 3.21). Conclusion: Both cochlear implantation and deaf education are widely cost effective in Latin America. In the lower-middle income economy of Guatemala, implant cost may have a larger impact. GDP is less influential in the middle- and high-income economies included in this study.

Hearing Loss is Associated with Decreased Nonverbal Intelligence in Rural Nepal

Hearing loss is a neglected public health problem that affects an estimated 360 (1) to 554 (2) million adults and children in the world. Although the difference in magnitude depends in part on the hearing threshold adopted, available estimates ignore milder, yet consequential, hearing loss. The estimates, however, reveal a disability that appears early in life, increases several-fold over the life span, and affects all societies. The prevalence of hearing loss is disproportionately high in low-resource settings, especially in South Asia and sub-Saharan Africa (2), the reasons for which remain uncertain. Hearing loss has profound health, social, and economic consequences (3). Affected children are likely to experience speech, language, and cognitive delays and poor school performance (4), whereas adults face higher risks of unemployment or low earnings (3), cognitive decline, and dementia (5). Social isolation accompanies daily life of the hearing impaired (6). Major causes of this burden vary across the life stages and include congenital disorders; otitis media; vaccine-preventable infections such as measles, mumps, and rubella; noise exposure; ototoxic drugs; and age (1). Surprisingly, only severe prenatal iodine deficiency (7) is listed by the WHO as a nutritional cause of hearing loss (1), leaving the broad roles of diet and nutrition within its complex set of etiologies yet to be defined. In high-income countries, large-population studies in adults have reported protective risk ratios against hearing loss with higher dietary intakes of fish, long-chain PUFAs, folate, b-carotene, and vitamins A, E, and C. Although findings across studies are inconsistent, animal evidence exists to support roles for each of these studied nutrients in regulating redox stress, protecting cochlear function, and enabling hearing. Interestingly, dietary exposure to potentially ototoxic heavy metals (e.g., cadmium, lead), a high BMI and waist circumference (i.e., obesity), and reduced physical activity have also been linked to hearing loss (8), which implies that systemic stress from a chronically unhealthy diet, lifestyle, and environment may carry consequences for ear health and hearing. In low-income countries, where undernutrition remains widespread, limited research has identified micronutrient deficiencies (e.g., of vitamin A and zinc) as risk factors for otitis media (9), the leading acquired cause of childhood hearing loss (10). In one trial cohort, preschool vitamin A supplementation was shown to reduce hearing loss attributed to childhood purulent ear infection (11). Animal evidence suggests that vitamin A deficiency may also lead to hearing loss through an entirely separate, developmental pathway (12). Nonetheless, few studies have reported other nutritionally sensitive mechanisms to explain the high prevalence of hearing loss in low-income countries (9), which reveals a formidable research gap to define roles for malnutrition in the etiology of this global disability. In this issue of the Journal, studies by Curhan et al. (13) and Choudhury et al. (14) reinforce the likely importance of micronutrient imbalance or deficiency as determinants of hearing loss for 2 very different life stages, populations, environments, and causal pathways: the Nurses’ Health Study cohort in the United States (13) and a study in infants born at 34 wk of gestation in New Delhi, India (14). Curhan et al. prospectively assessed diets of 65,521 nurses by a validated food-frequency questionnaire every 4 y from 1991 to 2009, at the end of which the occurrence and year of onset of a hearing problem, inferred as hearing loss, was obtained by self-report. Although no effect of vitamin A was observed, perhaps reflecting its homeostatic control in a well-nourished population, the authors reported higher intakes of b-carotene, b-cryptoxanthin, and folate to be protective against incident hearing loss. Oxidative stress and impaired homocysteine metabolism appear to contribute to inner-ear dysfunction, effects that adequate carotenoid and folate nutriture may attenuate by postulated scavenging of free radicals (13) and maintenance of antioxidant enzyme homeostasis (15), respectively, although other mechanisms likely exist. Paradoxically, the risk of hearing loss was increased in subjects who reported an increased intake of vitamin C, also an established antioxidant, at amounts that exceeded the Recommended Dietary Allowance (i.e.,.75–90 mg/d) but that fell well below the Tolerable Upper Intake Level (,2000 mg/d) of the Dietary Reference Intakes, suggesting that poorly understood, organ-specific nutrient interactions may exist. A limitation of the Nurses’ Health Study was its reliance on self-report of incident hearing loss, because audiometric testing is necessary to quantify severity and extent of hearing loss and to differentiate sensorineural, or inner-ear, from conductive or middleear pathologies. Conventional audiometry has required permanent equipment in a sound-proof room. In the United States, NHANES overcame this limitation by using audiometric booths fit onto

Early childhood undernutrition increases risk of hearing loss in young adulthood in rural Nepal

Objective To evaluate the association between adolescent and young-adult hearing loss and nonverbal intelligence in rural Nepal. Study design Cross-sectional assessment of hearing loss among a population cohort of adolescents and young adults. Setting Sarlahi District, southern Nepal. Patients Seven hundred sixty-four individuals aged 14 to 23 years. Intervention Evaluation of hearing loss, defined by World Health Organization criteria of pure-tone average greater than 25 decibels (0.5, 1, 2, 4 kHz), unilaterally and bilaterally. Main outcome measure Nonverbal intelligence, as measured by the Test of Nonverbal Intelligence, 3rd Edition standardized score (mean, 100; standard deviation, 15). Results Nonverbal intelligence scores differed between participants with normal hearing and those with bilateral (p = 0.04) but not unilateral (p = 0.74) hearing loss. Demographic and socioeconomic factors including male sex; higher caste; literacy; education level; occupation reported as student; and ownership of a bicycle, watch, and latrine were strongly associated with higher nonverbal intelligence scores (all p < 0.001). Subjects with bilateral hearing loss scored an average of 3.16 points lower (95% confidence interval, −5.56 to −0.75; p = 0.01) than subjects with normal hearing after controlling for socioeconomic factors. There was no difference in nonverbal intelligence score based on unilateral hearing loss (0.97; 95% confidence interval, −1.67 to 3.61; p = 0.47). Conclusion Nonverbal intelligence is adversely affected by bilateral hearing loss even at mild hearing loss levels. Socio economic well-being appears compromised in individuals with lower nonverbal intelligence test scores.

Global Hearing Loss Prevention

ABSTRACT Background Prevalence of young adult hearing loss is high in low-resource societies; the reasons for this are likely complex but could involve early childhood undernutrition. Objective We evaluated preschool childhood stunting, wasting, and underweight as risk factors for hearing loss in young adulthood in Sarlahi District, southern Nepal. Design Ear health was assessed in 2006–2008 in a cohort of 2193 subjects aged 16–23 y, who as children <60 mo of age participated in a 16-mo placebo-controlled, randomized vitamin A supplementation trial from 1989 to 1991. At each of five 4-mo assessments, field staff measured childrens weight, height, and mid-upper arm circumference (MUAC) and recorded validated parental history of ear discharge in the previous 7 d. Children were classified as stunted [<–2 z score height-for-age (HAZ)], underweight [<–2 z score weight-for-age (WAZ)], or wasted [<–2 z score MUAC-for-age (MUACAZ) or body mass index-for-age (BMIAZ)]. At follow-up, hearing was tested by audiometry and tympanometry, with hearing loss defined as pure-tone average >30dB in the worse ear (0.5, 1, 2, 4 kHz) and middle-ear dysfunction as abnormal tympanometric peak height (<0.3 or >1.4 mmho) or width (<50 or >110 daPa). Results Hearing loss, present in 5.9% (95% CI: 5.01%, 7.00%) of subjects, was associated with early childhood stunting (OR: 1.64; 95% CI: 1.10, 1.45), underweight (OR: 1.70; 95% CI: 1.18, 2.44) and wasting by BMIAZ (OR: 1.88; 95% CI: 1.19, 2.97) and MUACAZ (OR: 2.14; 95% CI: 1.47, 3.12). Abnormal tympanometry, affecting 16.6% (95% CI: 15.06%, 18.18%), was associated with underweight (OR: 1.46; 95% CI: 1.16, 1.84) and wasting by BMIAZ (OR: 1.80; 95% CI: 1.32, 2.46) and MUACAZ (OR: 1.42; 95% CI: 1.10, 1.84), but not stunting (OR: 1.18; 95% CI: 0.93, 1.49) in early childhood. Highest ORs were observed for subjects with both hearing loss and abnormal tympanometry, ranging from 1.87 to 2.24 (all lower 95% CI >1.00). Conclusions Early childhood undernutrition is a modifiable risk factor for early adulthood hearing loss.