Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- AUC0-24 of DTG in Pregnant Women in Third Trimester and 2 Weeks Postpartum
研究概览
简要总结
Aim: To evaluate dolutegravir (DTG) pharmacokinetics in pregnant HIV-infected women
Rationale: In developing countries many women present with a new HIV diagnosis in late pregnancy, and are at high risk of transmitting infection during delivery. Moreover, women may acquire NNRTI resistance from primary transmission, or use of nevirapine (NVP) in previous pregnancies. In these circumstances, DTG is likely to be more effective in reducing mother to child transmission of HIV than NNRTI-based regimens.
Study design: HIV positive pregnant women presenting with untreated HIV infection in late (≥28 -36 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily) or standard of care (nevirapine or efavirenz) + 2 NRTIs. PK (0-24h) profile will be sampled in third trimester and post-partum.
Although this is primarily a PK study (and has been powered as such) randomisation is included to allow comparison of plasma HIV VL responses against standard of care (NVP or EFV) and is essential for evaluation of secondary endpoints of safety and efficacy of DTG in pregnancy.
Number recruited N=30 per group
详细描述
Antiretroviral therapy (ART) in pregnancy is able to effectively reduce mother-to-child transmission (MTCT) of HIV. If untreated, the risk of transmission is around 25% (greater with high viral loads) but ART administered optimally during pregnancy may reduce this risk to 1-2%. In order to successfully prevent infection, ART should be started in the first or second trimester, and should reduce maternal plasma viral load to undetectable levels. Unfortunately throughout low-middle income countries, MTCT rates are unacceptably high with an estimated 430 000 newborn children infected annually. The main causes for this are undiagnosed or late diagnosis of maternal infection, suboptimal adherence to therapy and drug resistance, particularly in mothers who have previously received single dose nevirapine.
In sub-Saharan Africa (SSA), women frequently engage with health services late in pregnancy, and new HIV diagnoses in the third trimester (≥28 weeks of pregnancy) are not uncommon. Risk of MTCT is high, especially as NNRTI-based therapy takes a median of 2 months to significantly reduce the HIV viral load, making it unlikely that commencement of these drugs in late pregnancy will offer protection of the infant from intrapartum transmission.
Vertical transmission of HIV remains a significant challenge in developing countries and antiretroviral prophylaxis for PMTCT is an important tool towards elimination of paediatric infections. Between 2009 and 2010, coverage of antiretroviral prophylaxis for prevention of mother to child transmission was 42% and an estimated 1.48 million infants were born to women living with HIV (WHO 2010). Global efforts are geared towards improving access to antiretrovirals for PMTCT by simplifying antiretroviral treatment protocols while ensuring optimal outcomes for HIV-infected women and their children (WHO 2010; WHO 2012).
Under consolidated antiretroviral guidelines issued by the WHO in 2013, efavirenz-based ART is now recommended the preferred NNRTI option for HIV-1 infected patients, including among women of childbearing age and pregnant women (WHO 2013). In 2012, Uganda adopted the Option B+ strategy for PMTCT of HIV. Under this strategy, lifelong ART is offered to all pregnant ART naïve women irrespective of CD4 count with efavirenz-based ART as the preferred treatment option. However, the effectiveness of this regimen could be compromised in the event of large populations of women who may have been either exposed to single dose nevirapine in the past or among women with transmitted NNRTI resistance.
The justification for studying DTG in pregnancy includes:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Able to provide informed consent
- •Willing to participate,
- •Women age 18 years and above
- •Untreated HIV infection in late pregnancy at ≥28 - 36 weeks gestation
排除标准
- •Received antiretroviral drugs in previous 6 months
- •Ever received integrase inhibitors
- •Serum haemoglobin < 8.0 g/dl
- •Elevations in serum levels of alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or ALT >3xULN and bilirubin >2xULN (with >35% direct bilirubin)
- •eGFR < 50ml/min
- •Active Hepatitis B infection, history or clinical suspicion of unstable liver disease, or subjects with severe liver disease (Class C by Childs-Hugh criteria)
- •Severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such as renal or liver abnormalities (e.g. grade 2 or above proteinuria, elevation in serum creatinine (above 2.5 x ULN), total bilirubin ALT or AST)
- •Paternal non-consent (where disclosure to male partner has been made)
- •Clinical depression or clinical judgement suggests increased risk of suicidality
研究组 & 干预措施
Dolutegravir 50mg od
30 patients who will receive dolutegravir 50mg once daily plus the same NRTI backbone as the active comparator group (lamivudine and tenofovir)
干预措施: Dolutegravir 50mg od (Drug)
Standard of Care
Patients randomised to receive antiretroviral therapy as per Uganda national guidelines (Efavirenz 600mg od based plus Tenofovir 300mg od and Lamivudine 300mg od)
干预措施: Standard of Care (Drug)
结局指标
主要结局
AUC0-24 of DTG in Pregnant Women in Third Trimester and 2 Weeks Postpartum
时间窗: In 3rd trimester and 2 weeks postpartum
Rich PK with sampling at t0, 1, 2, 4, 6, 8 and 24 hours relative to drug dose
Cmax of Dolutegravir
时间窗: After 2 weeks of starting dolutegravir, and again 2 weeks after delivery
Maximum plasma concentration of dolutegravir in pregnancy vs postpartum
Trough Concentration
时间窗: At 2 weeks after starting dolutegravir and again 2 weeks after delivery
Concentration at 24 hours after dose, immediately prior to next dose) of dolutegravir
次要结局
- Number of Participants Reporting Severe Adverse Events During Study Period(From 7 days after start of treatment to 6 months postpartum)
- Percentage of Women in Each Arm With VL < 50 Copies/mL, and <400 Copies/mL at Delivery(At delivery)
- Cord:Maternal Plasma DTG Ratio(At delivery)
- Maternal Plasma: Breastmilk DTG Ratio(At 2 weeks postpartum, and 24 hours after final maternal dose)
- Infant DTG Levels(At maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days after transfer to standard of care)
- Number and Severity of Adverse Events and Laboratory Abnormalities(Up to 3 days after change to standard of care, approximately 2 weeks after delivery)
- Percentage of Subjects Who Discontinue Treatment Due to Adverse Events(Until 2 weeks postpartum)
- Percentage of Mother to Child Transmission of HIV(6 months postpartum)
- Pharmacogenomic Factors Influencing Transplacental and Breast Milk Transfer of Drug(End of study)
研究者
Catriona Waitt
Site sub-investigator
University of Liverpool