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

Evaluating Factors Associated with Tenofovir-Related Kidney Injury in HIV-Infected Women/nby/nSanjiv M. Baxi/nDoctor of Philosophy in Epidemiology/nUniversity of California, Berkeley/nProfessor Arthur L. Reingold, MD, Chair/nAntiretroviral 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./nThrough 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./nThese 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.

Advisor: Reingold, Arthur L