Jennifer Jao

Antiretroviral Medications: Adverse Effects on the Kidney

The widespread introduction of highly active antiretroviral therapy (HAART) in the mid-1990s dramatically altered the course of human immunodeficiency virus (HIV) infection, with improvements in survival and reductions in the incidence of AIDS-defining illnesses. Although antiretroviral therapy has been shown to reduce the incidence of both AIDS-defining and non-AIDS conditions, long-term exposure to HAART may also be associated with significant toxicity. This article reviews the potential nephrotoxicity of specific antiretroviral agents and the impact of antiretroviral therapy on related metabolic disorders. The antiretroviral agents most strongly associated with direct nephrotoxicity include the nucleotide reverse transcriptase inhibitor, tenofovir, and the protease inhibitor indinavir, although other agents have been implicated less frequently. Tenofovir and related nucleotide analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir is known to cause nephrolithiasis, obstructive nephropathy, and interstitial nephritis. Kidney damage related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent, and nephrologists should be familiar with the potential toxicity of these agents to avoid delays in diagnosis.

Metabolic complications of in utero maternal HIV and antiretroviral exposure in HIV-exposed infants.

Background: Despite a wide body of literature supporting the use of antenatal antiretrovirals (ARV) for the prevention of mother-to-child transmission, there remains a need for continued monitoring as the intrauterine interval is a critical period during which fetal programming influences the future health and development of the child. Methods: We conducted a systematic review of the current literature addressing potential metabolic complications of in utero HIV and ARV exposure. We describe studies evaluating metabolic outcomes such as intrauterine and early postnatal growth, bone health and mitochondrial toxicity. Results: Overall, infants exposed to HIV/ARV do not appear to exhibit vastly compromised intrauterine or early postnatal growth. However, some studies on the effect of combination antiretroviral therapy on small for gestational age and low birth weight outcomes in low-middle income countries show a risk for small for gestational age/low birth weight while those in the United States do not. Postnatal growth to 1 year does not appear to be affected by intrauterine tenofovir exposure in African studies, but a US study found statistically significant differences in length for age z scores (LAZ) at 1 year. Little data exists on long-term bone health. Mitochondrial toxicity including abnormal mitochondrial morphology and DNA content, as well as neurologic deficits and death, have been demonstrated in HIV/ARV-exposed infants. Conclusion: Although gross measures of metabolic well-being appear to be reassuring, careful vigilance of even small risks for potential serious adverse effects to infants exposed to intrauterine HIV/ARVs is warranted as intrauterine fetal metabolic programming may substantially impact the future health of the child.

New academic partnerships in global health: innovations at Mount Sinai School of Medicine.

Global health has become an increasingly important focus of education, research, and clinical service in North American universities and academic health centers. Today there are at least 49 academically based global health programs in the United States and Canada, as compared with only one in 1999. A new academic society, the Consortium of Universities for Global Health, was established in 2008 and has grown significantly. This sharp expansion reflects convergence of 3 factors: (1) rapidly growing student and faculty interest in global health; (2) growing realization-powerfully catalyzed by the acquired immune deficiency syndrome epidemic, the emergence of other new infections, climate change, and globalization-that health problems are interconnected, cross national borders, and are global in nature; and (3) rapid expansion in resources for global health. This article examines the evolution of the concept of global health and describes the driving forces that have accelerated interest in the field. It traces the development of global health programs in academic health centers in the United States. It presents a blueprint for a new school-wide global health program at Mount Sinai School of Medicine. The mission of that program, Mount Sinai Global Health, is to enhance global health as an academic field of study within the Mount Sinai community and to improve the health of people around the world. Mount Sinai Global Health is uniting and building synergies among strong, existing global health programs within Mount Sinai; it is training the next generation of physicians and health scientists to be leaders in global health; it is making novel discoveries that translate into blueprints for improving health worldwide; and it builds on Mount Sinais long and proud tradition of providing medical and surgical care in places where need is great and resources few.

Factors associated with decreased kidney function in HIV-infected adults enrolled in the MTCT-Plus Initiative in sub-Saharan Africa.

Background:Pre-existing kidney disease in HIV-infected patients may necessitate dose modification of antiretroviral therapy (ART). Despite increasing ART availability, there are few prevalence studies of chronic kidney disease in HIV-infected individuals across multiple African countries. Methods:Routine laboratory data obtained before ART initiation were used to evaluate prevalence and predictors of decreased creatinine clearance (CrCl) in participants of the MTCT-Plus Initiative from 7 sub-Saharan countries. Cockcroft-Gault equation was used to estimate CrCl and logistic regression modeling to identify factors associated with CrCl <50 mL/min. Results:Of 2495 individuals evaluated, median age was 30 years (interquartile range: 27-35); 70% were women. Median CD4+ cell count was 295 (interquartile range: 173-450); 78% were World Health Organization stage 1/2. Median CrCl was 95 mL/min. Overall, 3.4% [95% confidence interval (CI): 2.7 to 4.1] of patients had a CrCl <50 mL/min. Age >30 years (odds ratio = 2.06; 95% CI: 1.23 to 3.45) and CD4+ count <50 cells per cubic millimeter (odds ratio = 5.4 for CD4+ <50, 95% CI: 2.5 to 11.9) were associated with CrCl <50 mL/min. Conclusions:The prevalence of clinically significant kidney disease was low in this relatively healthy population of HIV-infected adults, and few participants would have required ART dose reductions. These findings support recent World Health Organization guidelines to initiate ART without routine laboratory screening. Our findings suggest that available laboratory resources could be targeted to older persons and those with very low CD4+ cell count.

Severe pandemic (H1N1) 2009 influenza with false negative direct fluorescent antibody assay: case series.

Between May and June of 2009 we observed 4 patients that presented with severe influenza-like symptoms and respiratory failure. All cases tested negative for influenza A and B by direct fluorescent antibody assay. Further investigation revealed all cases to be positive for pandemic (H1N1) 2009 influenza virus by real-time RT-PCR. This article includes a description of these cases and the characteristics associated with them.

In-utero triple antiretroviral exposure associated with decreased growth among HIV-exposed uninfected infants in Botswana.

Objective:To assess associations between in-utero triple antiretrovirals (cART) versus zidovudine (ZDV) monotherapy exposure and growth among HIV-uninfected children of HIV-infected women in Botswana. Design:Secondary retrospective data analysis from two randomized intervention trials of mother-to-child HIV transmission prevention. Methods:The Mashi and Mma Bana studies enrolled HIV-infected pregnant women, following their children through 24 months of age. This analysis includes singleton, full-term, HIV-exposed uninfected children. Mothers received cART or ZDV at least 2 weeks predelivery, and breastfed up to 6 months. Weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) z-scores were derived. Mean z-scores were compared by exposure group at 24 months (t-test, linear regression). Results:Of 819 children, 303 were ZDV- and 516 cART-exposed in utero. Maternal median enrolment CD4+ was higher among ZDV versus cART-treated mothers (393 versus 324 cells/&mgr;l; P < 0.0001). Median duration of antepartum antiretroviral use was shorter among ZDV-treated women (5.7 versus 12.0 weeks; P < 0.0001). Median months breastfed were similar (5.9 and 6.0; P = 0.43). At 24 months, mean LAZ and WAZ were significantly lower among cART-exposed children (LAZ –1.01 versus –0.74; P = 0.003) (WAZ –0.53 versus –0.30; P = 0.002) in unadjusted analyses. Adjusting for maternal CD4+, viral load, enrolment site and maternal anthropometric measures, cART-exposed children had significantly lower LAZ and WAZ at 24 months (P = 0.0004 for both). Conclusion:At 24 months, in-utero cART-exposed children had significantly lower LAZ and WAZ. Poor growth impacts childhood and adult mortality. These findings raise concerns for potential lasting health impacts among HIV-exposed uninfected children with in-utero cART exposure.

In Utero Tenofovir Exposure Is Not Associated with Fetal Long Bone Growth

BACKGROUND Despite widespread use of tenofovir disoproxil fumarate (TDF) in pregnant and breastfeeding women, few data exist on fetal bone development after in utero TDF exposure. We evaluated fetal long bone growth in human immunodeficiency virus (HIV)-infected pregnant woman/fetus dyads in Cape Town, South Africa. METHODS Women were recruited from primary care antenatal services and underwent ultrasonography to determine femur (FLZ) and humerus (HLZ) length z scores. The duration of in utero TDF exposure was calculated in weeks. Linear regression models were applied to assess the associations between the duration of in utero TDF exposure and change in FLZ and HLZ. RESULTS A total of 646 woman/fetus dyads contributed 1376 ultrasonographic scans to this analysis: 132 dyads with ≥25 weeks, 326 with 10-24 weeks, and 188 with <10 weeks of TDF exposure. Women receiving TDF for ≥25 weeks were older than those receiving TDF for 10-24 or <10 weeks (median age, 31 vs 28 and 28 years, respectively; P < .01), and had lower HIV RNA levels (median log10 HIV RNA level, 1.59 vs 4.08 and 3.83, respectively; P < .01). Throughout gestation, overall median FLZ and HLZ were 0.30 (interquartile range, -0.03 to 0.63) and 0.22 (-0.26 to 0.59) respectively. In multivariate analysis, there was no association between duration of in utero TDF exposure per 1-week increment and change in FLZ (ß = .00; P = .51) or change in HLZ (ß = .00; P = .40). Results were similar using mixed-effects models. CONCLUSIONS Although longer follow-up is needed, these in utero data are reassuring and support the continued use of TDF in pregnancy.

Small for Gestational Age Birth Outcomes in Pregnant Women with Perinatally Acquired HIV

Objective:To compare small for gestational age (SGA) birth weight in children born to women with perinatally acquired HIV (PAH) vs. those with behaviorally acquired HIV (BAH). Design:Retrospective cohort study of HIV-infected pregnant women who received care and delivered a live born at a single hospital in New York City from January 2004 to April 2011. Methods:We collected data via chart review on demographics, behavioral risk factors, HIV clinical markers, antiretroviral therapy (ART), mode of HIV acquisition, and pregnancy outcomes on study participants. We compared rates of these exposures among participants by method of HIV acquisition. Generalized Estimating Equation was applied to evaluate the effect of HIV acquisition type on SGA birth weight, adjusting for potential confounders. Results:Of 87 live births evaluated, 17 were born to 14 women with PAH. Overall, 20 (23%) were SGA. Eight of these SGA neonates were born preterm. Live births to women with PAH were more likely to be born SGA in our unadjusted analysis [odds ratio (OR) = 4.13, 95% confidence interval (CI) = 1.38–12.41). After adjusting for mothers age, substance use during pregnancy, nadir CD4 cell count during pregnancy, viral suppression at delivery, and second-line ART use during pregnancy, this relationship persisted with an adjusted OR of 5.7 (95% CI = 1.03–31.61). Conclusion:In comparison to infants born to women with BAH, infants born to women with PAH were at high risk for compromised intrauterine growth. Future studies are warranted to determine possible causal mechanisms.

Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis.

Introduction:Cotrimoxazole is widely prescribed to treat a range of infections, and for HIV-infected individuals it is administered as prophylaxis to protect against opportunistic infections. Some reports suggest that fetuses exposed to cotrimoxazole during early pregnancy may have an increased risk of congenital anomalies. We carried out this systematic review to update the evidence of cotrimoxazole safety in pregnancy. Methods:Three databases and 1 conference abstract site were searched in duplicate up to October 31, 2013, for studies reporting adverse maternal and infant outcomes among women receiving cotrimoxazole during pregnancy. This search was updated in MEDLINE via PubMed to April 28, 2014. Studies were included irrespective of HIV infection status or the presence of other coinfections. Our primary outcome was birth defects of any kind. Secondary outcomes included spontaneous abortions, terminations of pregnancy, stillbirths, preterm deliveries, and drug-associated toxicity. Results:Twenty-four studies were included for review. There were 232 infants with congenital anomalies among 4196 women receiving cotrimoxazole during pregnancy, giving an overall pooled prevalence of 3.5% (95% confidence interval: 1.8% to 5.1%; &tgr;2 = 0.03). Three studies reported 31 infants with neural tube defects associated with first trimester exposure to cotrimoxazole, giving a crude prevalence of 0.7% (95% confidence interval: 0.5% to 1.0%) with most data (29 neural tube defects) coming from a single study. The majority of adverse drug reactions were mild. The quality of the evidence was very low. Conclusions:The findings of this review support continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women. It is critical to improve data collection on maternal and infant outcomes.

Lower preprandial insulin and altered fuel use in HIV/antiretroviral-exposed infants in Cameroon.

CONTEXT Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants. OBJECTIVE The objective of the study was to understand the relationship(s) between mitochondrial fuel use (assessed via acylcarnitines and branched chain amino acids) and preprandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine or nevirapine compared with HIV/ARV-unexposed uninfected (HUU) infants. DESIGN This was a prospective cohort study with the following three groups: 1) intrauterine HIV/ARV/postnatal zidovudine-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal nevirapine-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between in utero HIV/ARV exposure and infant insulin. SETTING The study was conducted at Cameroonian urban antenatal centers. PARTICIPANTS HIV-infected and -uninfected pregnant woman/infant dyads participated in the study. MAIN OUTCOME Preprandial insulin was the main outcome measured. RESULTS Of 366 infants, 38 were HEU-A, 118 HEU-N. Forty intermediary metabolites were consolidated into seven principal components. In a multivariate analysis, both HEU-A (β = -.116, P= .012) and HEU-N (β = -.070, P= .022) demonstrated lower insulin compared with HUU infants. However, at high levels of plasma metabolites, HEU-A (β = .027, P= .050) exhibited higher insulin levels than HEU-N or HUU infants. A unique array of short-chain acylcarnitines (β = .044, P= .001) and branched-chain amino acids (β = .033, P= .012) was associated with insulin. CONCLUSION HEU-A and HEU-N infants have lower preprandial insulin levels at 6 weeks of age and appear to use metabolic fuel substrates differently than HUU infants. Future studies are warranted to determine whether observed differences have lasting metabolic implications, such as later insulin resistance.