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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2013)

Though efavirenz is an effective antiretroviral therapy for the treatment of HIV, its use is associated with pronounced interindividual variability in plasma concentration (exposure) and toxicity, increasing the risk of adverse events or therapy failure. Both genetic and non-genetic factors contribute to efavirenz exposure variability. This dissertation research contributes to our understanding of this phenomenon by modeling the influence of genetic and non-genetic factors on efavirenz exposure and describing a broad spectrum of symptoms and side effects and their association with genotypes that influence efavirenz exposure. A total of 182 SNPs and 45 haplotypes in 9 genes were analyzed with previously identified non-genetic factors in relationship to efavirenz drug exposure in 111 women on efavirenz who had undergone 24-hour blood sampling following a witnessed dose under routine conditions. Area-under-the-time curves (AUC) were calculated. We observed three alleles from two genes associated with an increase in efavirenz exposure: CYP2B6 (rs3745274); CYP2B6 (rs28399499), ABCB1 Haplotype A1 (rs27779562 and rs4148745). Of all the non-genetic factors assessed only orange juice consumption and increases in alanine aminotransferase remained statistically significant when genetic factors were included in the final multivariate model. CYP2B6 rs3745274 and rs28399499 can be combined into the CYP2B6 Metabolizer diplotype. Metabolizer diplotype was associated with an increase in efavirenz exposure for both slow and intermediate metabolizers. Risk alleles associated with increased efavirenz exposure were evaluated for associations with a broad spectrum of symptoms and side effects. Variation in CYP2B6 rs28399499 was associated with a perceived change in the amount of fat in the buttocks and change in buttock fat. Variability in CYP2B6 rs3745274 was associated with report of dietary changes to influence body shape. SNPs in the ADME pathway are associated not only with efavirenz exposure but also side effects. Pharmacogenetic testing may improve efavirenz outcomes and reduce symptoms and side effects associated with efavirenz exposure variability.

Key Words: ADME pharmacogenetics, adverse events, antiretroviral therapy, ATP-binding cassette (ABC) B1 haplotype, body habitus changes, cytochrome P450 (CYP) 2B6 single nucleotide polymorphisms (SNPs), CYP2B6 metabolizer diplotype, drug exposure, efavirenz, gene variations, HIV, plasma concentration, side effects and symptoms.

    Cover page: The Pharmacogenetics of Efavirenz and its Side Effects
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2017)
    Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain.
      Cover page: Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2024)
        Cover page: MITOCHONDRIAL HOMEOSTASIS IN SCHWANN CELLS IS LINKED TO C-FIBER NEUROENERGETICS AND NEUROPATHIC PAINCreative Commons 'BY' version 4.0 license
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2018)
        We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (∼70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals.
          Cover page: Effect of antiretroviral therapy on allele-associated Lp(a) level in women with HIV in the Women's Interagency HIV Study
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2017)

          Objective

          In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)-related elevated cardiovascular disease risk remain unclear.

          Approach and results

          The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima-media thickness.

          Conclusions

          Lp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.
            Cover page: Lipoprotein(a) and HIV
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2022)

            Background

            At the start of the COVID-19 pandemic, HIV experts suggested that an increase in mental health diagnoses and substance use among people living with HIV (PLHIV) may be an unintended consequence of COVID-19 mitigation efforts (e.g., limiting social contact). We evaluated short-term trajectories in binge drinking, marijuana, and recreational drug use in a prospective cohort of PLHIV.

            Methods

            Data (N = 2121 PLHIV) consist of survey responses on substance use behaviors from two pre-COVID-19 (October 2018-September 2019) and one COVID-19-era (April 2020-September 2020) timepoints within the MACS/WIHS Combined Cohort Study (MWCCS). We conducted group-based trajectory models, triangulated with generalized linear mixed models, to assess changes in binge drinking, daily marijuana use, and recreational drug use at the start of the pandemic. Controlling for age and race/ethnicity, we tested whether trajectories differed by sex and early-pandemic depressive symptoms, loneliness, and social support.

            Results

            Group-based trajectory models yielded two trajectory groups for binge drinking (none vs. any), marijuana (none/infrequent vs. daily), and recreational drug use (none vs. any). Binge drinking and recreational drug use decreased at the beginning of the pandemic. Generalized linear mixed model supported these trends. Consistent with prior research, male sex and having depressive symptoms early pandemic were positively associated with each substance use outcomes. Social support was inversely associated with recreational drug use.

            Conclusions

            Contrary to hypotheses, problematic substance use behaviors decreased from pre-pandemic to the post-pandemic follow-up in our sample of PLHIV. Ongoing surveillance is needed to assess whether this pattern persists as the pandemic continues.
              Cover page: Short-term binge drinking, marijuana, and recreational drug use trajectories in a prospective cohort of people living with HIV at the start of COVID-19 mitigation efforts in the United States
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