Antiretroviral Drug Levels During and After Pregnancy
Condition: Pharmacokinetics
Study type: Observational

Summary: 
      In HIV-infected women, the use of combination therapy with antiretrovirals (ARV) in pregnancy
      prevents HIV related morbidity and mortality and prevents mother-to-child transmission of the
      HIV virus.

      Specifically, suppression of the virus to an undetectable level is important during the
      delivery of the baby to minimize potential HIV exposure. In Sub-Saharan Africa, the use of
      ARV combinations containing nevirapine is the cornerstone of current HIV therapy, due to an
      affordable cost, availability in a fixed dose combination pill, and generic availability.
      Maintaining the efficacy and preventing development of resistance against this agent by the
      HIV virus is imperative, as second line therapies are often more difficult to obtain, are
      more expensive, and present more challenges in drug storage in clinics and in the community.

      Pregnancy adds another dimension to the challenge of treating women with HIV, as the
      physiologic and metabolic changes can affect levels of antiretroviral agents in the body.
      Though these changes are known to exist, few trials have evaluated the effect of these
      factors on the pharmacokinetics of antiretroviral agents and their impact has yet to be
      demonstrated.

      We wish to evaluate if the physiologic changes that occur during pregnancy impact the levels
      of stavudine, lamivudine, and nevirapine compared to those of a non-pregnant, HIV-infected
      Ugandan female. These data are imperative to ensure adequate suppression of the HIV virus
      throughout pregnancy.
    

Detailed description: 
      In HIV-infected women, the use of combination therapy with antiretrovirals (ARV) in pregnancy
      prevents HIV related morbidity and mortality and prevents mother-to-child transmission of the
      HIV virus.1 Specifically, suppression of the virus to an undetectable level is important
      during the delivery of the baby to minimize potential HIV exposure. Commonly prescribed ARV
      therapy in Ugandan pregnant women includes a combination of two NRTIs, along with a
      non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine. In Sub-Saharan Africa,
      the use of nevirapine containing regimens is the cornerstone of current ARV therapy, due to
      an affordable cost, availability in a fixed dose combination pill, and generic availability.
      Maintaining the efficacy and preventing development of resistance against this agent by the
      HIV virus is imperative, as second line therapies are often more difficult to obtain, are
      more expensive, and present more challenges in drug storage in clinics and in the community.

      Data have demonstrated that higher exposure to nevirapine is associated with a greater
      likelihood of achieving virologic control as well as maintaining virologic response over the
      long term, while sub-optimal drug levels may result in the development of viral resistance.2
      The use of combination therapy is important due to the development of resistance seen using
      single dose therapy with nevirapine at delivery.3 Resistance to nevirapine is particularly
      worrisome due to the cross-resistance between nevirapine and other NNRTIs, potentially
      eliminating one essential class of ARVs used to treat HIV. Evaluating nevirapine exposure is
      also important to avoid toxicities related to excess levels of nevirapine, which may
      compromise patient adherence to the regimen and put the woman at risk for virologic failure
      in addition to increased drug toxicity.4, 5

      To our knowledge, most studies to date have only evaluated the pharmacokinetics of first dose
      nevirapine in HIV-infected pregnant women during delivery.6,7 Other studies have had too few
      sampling times to fully characterize the pharmacokinetic parameters of nevirapine. However,
      previous studies have demonstrated that pharmacokinetic changes do occur with other ARVs
      metabolized by a metabolic path similar to nevirapine. For example, one published study
      demonstrated lower levels of nelfinavir and a disproportionate amount of the nelfinavir M8
      metabolite in pregnant women during their third trimester, possibly implicating alterations
      in the cytochrome P450 enzyme system responsible for both nelfinavir and nevirapine
      metabolism.8, 9 Given this evidence with similarly metabolized drugs, it is important to
      definitively characterize nevirapine pharmacokinetics to ensure the safe use of this drug
      during pregnancy.

      Data have also demonstrated a direct correlation between zidovudine intracellular
      triphosphate concentrations and change in CD4 cell count during therapy as well as a direct
      correlation between lamivudine intracellular triphosphate concentrations and decline in HIV
      RNA in plasma.10 Data have also shown that there is a wide inter-patient variability in the
      concentration of the NRTIs, and adjusting these concentrations based on therapeutic drug
      monitoring has resulted in improved virologic outcomes for patients.11, 12 No information is
      known about the intracellular triphosphorylated concentrations of the NRTIs in the pregnant
      female. We seek to establish if there is a necessity for further evaluation of intracellular
      levels of all NRTI agents in the pregnant population through this research.

      The available pharmacokinetic data to date, have primarily evaluated male populations in the
      western world. We are just beginning to understand the complex pharmacogenomic mechanisms
      that play a role in pharmacokinetics and pharmacodynamics. Efavirenz, also an NNRTI, and
      nevirapine have both been identified as having different pharmacokinetic properties in
      African patients as compared to American, European, and South American patients.13,14 These
      changes will play a significant role in the long term efficacy and toxicity of these agents
      as they are used on a more widespread basis in Sub-Saharan Africa. Evaluating these changes
      in African women during pregnancy is also essential as females represent the predominant
      gender impacted by HIV in Sub-Saharan Africa. These changes during pregnancy may impact the
      safety of these agents in pregnant females if the levels are higher than expected, and may
      also impact the mother-to-child transmission rate and long term use of these agents if the
      levels are lower than desired.

      Pregnancy adds another dimension to the challenge of treating women with HIV, as the
      physiologic and metabolic changes can impact the pharmacokinetics of antiretroviral agents.
      Proposed mechanisms include absorption changes due to prolonged gastric and intestinal
      emptying time, decreased gastric acid secretion, and increased mucus secretion; increased
      volume of distribution of drug caused by increased total body water and fat, and decreased
      plasma protein concentration; changes in elimination related to stimulation of hepatic
      microsomal enzymes and inhibition of microsomal oxidases; the effects of the fetus including
      compartmentalization of drugs in the fetus and placenta, biotransformation of drugs by the
      fetus and placenta, and additional elimination of drugs by the fetus.15,16 Though these
      physiologic and metabolic changes are known to exist, few trials have evaluated the effect of
      these factors on the pharmacokinetics of antiretroviral agents and their impact has yet to be
      demonstrated.

      Few pharmacokinetic studies have been undertaken to date in Sub-Saharan Africa, though it is
      becoming recognized that in order to support the antiretroviral rollout program, these
      studies are essential for the safe and effective long-term use of these agents. The
      University of Makerere, Infectious Diseases Institute, is establishing a strong foundation
      for pharmacokinetic work to take place in Uganda through the development of a pharmacokinetic
      laboratory which will become the leading resource for pharmacokinetic work in Sub-Saharan
      Africa. This makes the Makerere University the logical location for this essential
      evaluation. One of the first studies evaluating pharmacokinetic parameters in African
      patients was performed by our co-investigators at the Joint Clinical Research Center in
      Kampala, and established that pharmacokinetic evaluation of these drugs in an African
      population is both necessary and logistically feasible(22) .

      We wish to evaluate if the physiologic changes that occur during pregnancy impact the
      pharmacokinetics of stavudine, lamivudine, and nevirapine compared to those of a
      non-pregnant, HIV-infected Ugandan female. Evaluation of drug concentrations at steady state,
      instead of after a single dose is essential, as most patients are maintained on these
      medications throughout their pregnancy to ensure complete virologic suppression at the time
      of delivery. These data are imperative to ensure adequate viral suppression throughout
      pregnancy and to minimize the likelihood of the development of viral resistance engendered by
      inadequate drug concentrations
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        HIV positive women attending ante-natal care clinic at Mulago Hospital, Kampala Uganda
      
Biospecimen description: 
      Human plasma Red cell pellets
    
Keywords: Antiretroviral; Pharmacokinetics; Pregnancy