Study of Pharmacokinetics in HIV-infected Women
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Observational

Summary: 
      Women represent an increasing proportion of HIV cases globally and in Canada, yet are
      underrepresented in clinic trials. It is therefore critical to conduct this study on
      antiretroviral (ARV) pharmacokinetics (PK) in women to obtain additional information on ARV
      drug levels in women and their relation to adverse events (AEs).

      The hypothesis for this study is three-fold:

        1. that the mean drug levels (Cmin and Cmax) of ARVs will be significantly higher in our
           female population as compared to the mean drug levels in the historical HIV population
           (which is primarily men)

        2. that ARV drug levels, particularly Cmin, are associated with body weight in women

        3. that higher ARV drug levels, particularly Cmax, are associated with higher frequency and
           severity of AEs.

      The objectives of this study are as follows:

      Primary objectives:

        1. To demonstrate that levels of Protease Inhibitors (PIs) and Non-Nucleoside Reverse
           Transcriptase Inhibitors (NNRTIs) are significantly higher in our female population as
           compared to the mean drug levels in the historical general population (which is
           primarily men).

        2. To determine the association between PI and NNRTI minimum concentration (Cmin) and body
           weight in our female population.

      Secondary objectives

        1. To determine the association between maximum concentration (Cmax) and the frequency and
           severity of AEs as measured by the proportion of patients with grade 2 or higher
           laboratory or clinical AEs and the Symptom Index Score in women.

        2. To determine the association between ARV drug levels and age, race, height, body mass
           index, adherence, hormonal levels and therapy, menstruation history, duration of HIV
           infection, duration on ARV therapy, baseline viral load, baseline CD4 count, present CD4
           count, hepatitis B or C infection, class of ARVs, presence of ritonavir and other
           medications.
    

Detailed description: 
      Predictors of antiretroviral pharmacokinetics in HIV-infected women with virologic
      suppression on combination antiretroviral therapy

      Background

      Women in Canada constitute the fastest growing population groups at risk for infection with
      HIV and AIDS. Women now represent approximately 40% of all AIDS cases worldwide and
      approximately 20% of cases in Canada. Although the AIDS epidemic has been ongoing for more
      than 20 years, surprisingly little is known about the differential efficacy and toxicity of
      various antiretroviral (ARV) drugs in women as compared to men. This gap in knowledge is a
      result of the initial exclusion of and continued underrepresentation of women in ARV clinical
      trials. Many studies suggest that HIV-infected women taking ARV treatment (ART) have more
      adverse events (AEs) than men, especially in relationship to systemic symptoms like diarrhea,
      as well as organ toxicity, including hepatotoxicity, lactic acidosis, peripheral neuropathy
      and, notably, lipodystrophy. Currently, the occurrence and management of AEs is the most
      important issue in the treatment of HIV. Understanding the reasons for the differences of AEs
      in HIV-infected women is critical and has yet to be evaluated within a large cohort. It is
      unknown whether these differences relate to hormonal influences, drug metabolism, adherence,
      fat distribution, body size or other factors. Some small studies have found that drug levels
      (e.g. Cmin, Cmax, AUC) are higher in women and are associated with increased toxicity.
      Ultimately, we plan to conduct a randomized clinical trial (RCT) to assess the utility of
      therapeutic drug monitoring (TDM) and ARV drug dose adjustment on the frequency of AEs in
      women. Prior to conducting this RCT, it is critical to conduct this study on ARV
      pharmacokinetics (PK) in women to obtain additional information on ARV drug levels in women
      and their relation to AEs.

      Hypothesis

      The hypothesis for this study is three-fold:

        1. that the mean drug levels (Cmin and Cmax) of ARVs will be significantly higher in our
           female population as compared to the mean drug levels in the historical HIV population
           (which is primarily men)

        2. that ARV drug levels, particularly Cmin, are associated with body weight in women

        3. that higher ARV drug levels, particularly Cmax, are associated with higher frequency and
           severity of AEs.

      Patient population

      Eighty HIV-infected women from 8 Canadian sites who have been on their first combination ART
      regimen containing either a PI or an NNRTI (since these are the ARV agents eligible for PK
      analysis) for at least three months and who have evidence of full virologic suppression (HIV
      RNA VL less than 50 copies/mL) on at least two occasions at least one month apart.

      Objectives Primary objectives

        1. To demonstrate that the Cmin and Cmax of PIs and NNRTIs are significantly higher in our
           female population as compared to the mean drug levels in the historical general
           population (which is primarily men).

        2. To determine the association between PI and NNRTI Cmin and body weight in our female
           population.

      Secondary objectives

        1. To determine the association between Cmax and the frequency and severity of AEs as
           measured by the proportion of patients with grade 2 or higher laboratory or clinical AEs
           and the Symptom index score in women.

        2. To determine the association between ARV drug levels and age, race, height, body mass
           index, adherence, hormonal levels and therapy, menstruation history, duration of HIV
           infection, duration on ARV therapy, baseline VL, baseline CD4 count, present CD4 count,
           hepatitis B or C infection, class of ARVs, presence of ritonavir and other medications.

      Study design

      The study will be a cross-sectional study with ARV drug levels (Cmin and Cmax) measured
      weekly for three weeks Three samples will be taken from each subject to reduce variability
      due to both technologic and biologic sources. Data will be collected on demographic
      characteristics, clinical disease and ARV history and on clinical toxicities at the first
      visit. Blood work will be carried out on the first visit to assess for laboratory toxicity
      and hormonal levels.

      Data analysis

      Drug levels will be summarized with the mean of the 3 values for Cmin and Cmax for each woman
      for their PI or NNRTI and compared to the mean values of the general HIV population. Cmin and
      Cmax will be classified into high and low levels with a high level defined as less than or
      equal to 1.5 X arithmetic population mean for each drug. Characteristics of patients with
      high drug levels will be compared to those of patients with low drug levels. Univariate and
      multivariate logistic regression models will be used to identify independent associations of
      patient characteristics with high drug levels. The proportions of patients with AEs and the
      median number of AEs per patient will be compared between patients with high Cmax and
      patients with low Cmax.
    

Intervention name(s): antiretroviral treatment
Intervention type(s): Drug
Intervention description(s): These antiretroviral drugs are a part of the participant's current drug regimen.
Intervention MeSH terms: Anti-Retroviral Agents
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The patient population will consist of 80 HIV-infected women (who are on their first cART
        regimen containing either a PI or an NNRTI for at least three months and who have evidence
        of full virologic suppression (HIV RNA VL < 50 copies/mL) on at least two occasions at
        least one month apart. The first cART regimen can include ARV switches as long as these
        switches are not due to virologic failure. The patient population is being limited to women
        who have full virologic suppression to avoid inclusion of women with difficulty with drug
        adherence.
      
Biospecimen description: 
      Blood samples will be drawn before and after antiretroviral drugs are taken for visits 1-3.
    
Keywords: Anti-HIV agents; Physiological Effects of Drugs; ARV-associated Adverse Events; HAART; Pharmacokinetics; Protease Inhibitors; Non-nucleoside Reverse Transcriptase Inhibitors; Women