Risk of cardiovascular events from current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study.

BackgroundThere is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates.MethodsUsing an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models.ResultsOver 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline.ConclusionCurrent, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors

Clinical Characteristics and Outcomes Among Individuals With Spinal Implant Infections: A Descriptive Study.

Little is known about the clinical presentation and outcomes associated with spinal implant infections. Here, we describe a single center's experience in a retrospective cohort of 109 individuals with spinal implant infections, including clinical, microbiological, therapeutic, and outcome data

Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of Uganda.

BackgroundRecently the use of indoor residual spraying of insecticide (IRS) has greatly increased in Africa; however, limited data exist on the quantitative impacts of IRS on health outcomes in highly malaria endemic areas.Methodology/principal findingsRoutine data were collected on more than 90,000 patient visits at a single health facility over a 56 month period covering five rounds of IRS using three different insecticides. Temporal associations between the timing of IRS and the probability of a patient referred for microscopy having laboratory confirmed malaria were estimated controlling for seasonality and age. Considering patients less than five years of age there was a modest decrease in the odds of malaria following the 1(st) round of IRS using DDT (OR = 0.76, p<0.001) and the 2(nd) round using alpha-cypermethrin (OR = 0.83, p = 0.002). Following rounds 3-5 using bendiocarb there was a much greater decrease in the odds of malaria (ORs 0.34, 0.16, 0.17 respectively, p<0.001 for all comparisons). Overall, the impact of IRS was less pronounced among patients 5 years or older.Conclusions/significanceIRS was associated with a reduction in malaria morbidity in an area of high transmission intensity in Uganda and the benefits appeared to be greatest after switching to a carbamate class of insecticide

Risk of cardiovascular events from current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study

Abstract Background There is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates. Methods Using an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models. Results Over 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline. Conclusion Current, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors

Evaluating Factors Associated with Tenofovir-Related Kidney Injury in HIV-Infected Women

Evaluating Factors Associated with Tenofovir-Related Kidney Injury in HIV-Infected WomenbySanjiv M. BaxiDoctor of Philosophy in EpidemiologyUniversity of California, BerkeleyProfessor Arthur L. Reingold, MD, ChairAntiretroviral drugs are used in the treatment of human immunodeficiency virus (HIV) infection, and the global development and availability of such medications has expanded dramatically over the last 15 years. Currently, HIV-infected individuals require lifelong antiretroviral therapy, but if taken as prescribed and relatively early in the course of infection, persons living with HIV can expect to have a virtually normal lifespan. Although antiretroviral drugs are generally well tolerated, some side effects from treatment can be irreversible. Side effects are particularly important in the current HIV treatment paradigm, where individuals will require lifelong antiretroviral therapy. Tenofovir, currently formulated as tenofovir disoproxil fumarate (TDF), is a nucleotide analogue reverse transcriptase inhibitor that is one of the most commonly used medications in the treatment and prevention of HIV infection. Tenofovir has few known side effects overall, but long-term use has been associated with the development of a chronic, irreversible decline in kidney function in a small proportion of individuals. Other than cumulative duration of exposure to tenofovir, little else is known about what factors increase an individual’s risk of developing kidney disease in the setting of chronic tenofovir use. As treatment for HIV infection has expanded in the developing world, with millions of people globally now taking tenofovir-containing products, understanding the factors that lead to a decline in kidney function in such individuals is fundamental to ensuring effective, yet safe, treatment and prevention of HIV. Through this dissertation, I conducted four studies that attempted to improve the understanding of the factors that contribute to tenofovir-associated kidney damage. To test the assumption that the magnitude of exposure to tenofovir (that is, the amount of drug experienced by an individual with a given dose) likely affects an individual’s risk of toxicity, an assumption that is frequently validated in pharmacodynamic studies of pharmacologic agents, I conducted three related studies. All three studies used a highly reliable measure of drug exposure – after taking a witnessed dose of tenofovir, study participants underwent serial blood sampling over 24 hours to draw a comprehensive exposure curve over a single day, yielding an area under the time-concentration curve (AUC) measure. The first study investigated the factors that contribute to elevated tenofovir exposure as measured by AUC. Interestingly, lower body weight, older age, pre-existing chronic kidney disease and simultaneous use of a protease-inhibitor antiretroviral called ritonavir, were all associated with large increases in tenofovir AUC. Taking this information, in the second study, I investigated whether exposure to elevated levels of tenofovir were associated with a decline in kidney function over time. We found that increasing exposure to tenofovir at a fixed point in time is associated with subsequent decline in kidney function, but that this process is heterogeneous, with tremendous variability, particularly in the group with the highest AUC at baseline. In the third study, I attempted to identify whether the presence of distinct single nucleotide polymorphisms was associated with an elevated AUC. We found one polymorphism that was associated with large increases in AUC. This same polymorphism has been implicated in diseases related to transport of other organic anions, particularly the condition of uric acid metabolism called gout. This group of three studies established novel factors, both clinical and genetic, that are associated with an elevated tenofovir AUC and have helped to clarify whether AUC is a predictor of the ultimate development of kidney dysfunction. In a fourth study, as a bridge to a future research program, I investigated the predictors of urinary biomarkers of kidney injury in women living with HIV. We identified distinct patterns of novel urinary biomarkers as a function of the degree of control of HIV through treatment, but these findings will require clarification in a longitudinal cohort study. Given that intensive pharmacokinetic analyses are impractical in the clinical setting, this latter study will provide the basis for understanding what urinary biomarkers can help identify early evidence of a propensity to develop kidney injury in persons living with HIV. All of these studies took place in a cohort of predominantly black and Hispanic women, a group that is typically under-represented in both HIV and pharmacological research. These four studies have improved our understanding of the factors that lead to the development of tenofovir-associated kidney disease in persons living with HIV. The findings have important implications for millions of people currently taking or planning to take tenofovir globally. As my career progresses, these studies have provided a framework that can be applied to studying drug toxicity in other settings or to delving more deeply into understanding the pharmacology of tenofovir and related compounds

Evaluating Factors Associated with Tenofovir-Related Kidney Injury in HIV-Infected Women

Antiretroviral drugs are used in the treatment of human immunodeficiency virus (HIV) infection, and the global development and availability of such medications has expanded dramatically over the last 15 years. Currently, HIV-infected individuals require lifelong antiretroviral therapy, but if taken as prescribed and relatively early in the course of infection, persons living with HIV can expect to have a virtually normal lifespan. Although antiretroviral drugs are generally well tolerated, some side effects from treatment can be irreversible. Side effects are particularly important in the current HIV treatment paradigm, where individuals will require lifelong antiretroviral therapy. Tenofovir, currently formulated as tenofovir disoproxil fumarate (TDF), is a nucleotide analogue reverse transcriptase inhibitor that is one of the most commonly used medications in the treatment and prevention of HIV infection. Tenofovir has few known side effects overall, but long-term use has been associated with the development of a chronic, irreversible decline in kidney function in a small proportion of individuals. Other than cumulative duration of exposure to tenofovir, little else is known about what factors increase an individual’s risk of developing kidney disease in the setting of chronic tenofovir use. As treatment for HIV infection has expanded in the developing world, with millions of people globally now taking tenofovir-containing products, understanding the factors that lead to a decline in kidney function in such individuals is fundamental to ensuring effective, yet safe, treatment and prevention of HIV. Through this dissertation, I conducted four studies that attempted to improve the understanding of the factors that contribute to tenofovir-associated kidney damage. To test the assumption that the magnitude of exposure to tenofovir (that is, the amount of drug experienced by an individual with a given dose) likely affects an individual’s risk of toxicity, an assumption that is frequently validated in pharmacodynamic studies of pharmacologic agents, I conducted three related studies. All three studies used a highly reliable measure of drug exposure—after taking a witnessed dose of tenofovir, study participants underwent serial blood sampling over 24 hours to draw a comprehensive exposure curve over a single day, yielding an area under the time-concentration curve (AUC) measure. The first study investigated the factors that contribute to elevated tenofovir exposure as measured by AUC. Interestingly, lower body weight, older age, pre-existing chronic kidney disease and simultaneous use of a protease-inhibitor antiretroviral called ritonavir, were all associated with large increases in tenofovir AUC. Taking this information, in the second study, I investigated whether exposure to elevated levels of tenofovir were associated with a decline in kidney function over time. We found that increasing exposure to tenofovir at a fixed point in time is associated with subsequent decline in kidney function, but that this process is heterogeneous, with tremendous variability, particularly in the group with the highest AUC at baseline. In the third study, I attempted to identify whether the presence of distinct single nucleotide polymorphisms was associated with an elevated AUC. We found one polymorphism that was associated with large increases in AUC. This same polymorphism has been implicated in diseases related to transport of other organic anions, particularly the condition of uric acid metabolism called gout. This group of three studies established novel factors, both clinical and genetic, that are associated with an elevated tenofovir AUC and have helped to clarify whether AUC is a predictor of the ultimate development of kidney dysfunction. In a fourth study, as a bridge to a future research program, I investigated the predictors of urinary biomarkers of kidney injury in women living with HIV. We identified distinct patterns of novel urinary biomarkers as a function of the degree of control of HIV through treatment, but these findings will require clarification in a longitudinal cohort study. Given that intensive pharmacokinetic analyses are impractical in the clinical setting, this latter study will provide the basis for understanding what urinary biomarkers can help identify early evidence of a propensity to develop kidney injury in persons living with HIV. All of these studies took place in a cohort of predominantly black and Hispanic women, a group that is typically under-represented in both HIV and pharmacological research. These four studies have improved our understanding of the factors that lead to the development of tenofovir-associated kidney disease in persons living with HIV. The findings have important implications for millions of people currently taking or planning to take tenofovir globally. As my career progresses, these studies have provided a framework that can be applied to studying drug toxicity in other settings or to delving more deeply into understanding the pharmacology of tenofovir and related compounds. (Abstract shortened by ProQuest.