Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study

Study Overview
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Brief Summary
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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

Detailed Description
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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: Likely widespread availability of generic DTG in the coming years. The manufacturer has indicated its willingness to make DTG available in low income countries, and is currently engaging with generic manufacturers. Estimates from the Clinton Foundation suggest that generic manufacture of DTG will make this drug affordable either as an alternative first line, or else second line agent (Hill 2013). Clinical guidelines from the US and Europe currently rank INSTIs such as raltegravir and elvitegravir alongside NNRTIs as preferred first line agents. INSTIs may replace NNRTIs in first line regimens due to their good safety and toxicity profile, lower propensity for drug interactions, and superior efficacy. Large phase III RCTs comparing raltegravir (Rockstroh, Dejesus et al. 2013), elvitegravir (Sax, DeJesus et al. 2012) and dolutegravir (van Lunzen, Maggiolo et al. 2012) against efavirenz-based therapy have shown superior virological outcome at 48 weeks, faster time to undetectable viral load, lower incidence of adverse events, and fewer treatment discontinuations, and these findings have recently been confirmed in a meta-analysis (Messiaen, Wensing et al. 2013). Low risk for serious drug-drug interactions. The potential for drug-drug interactions is significantly less for INSTIs compared with other antiretrovirals (relative risk compared with raltegravir: boosted protease inhibitors [RR = 4.96], non-nucleoside reverse transcriptase inhibitors [RR = 2.48](Patel, Abdelsayed et al. 2011). These are particularly important considerations for low/middle income country settings where adults with newly diagnosed HIV infection often present with tuberculosis, or during antenatal screening in late pregnancy. Here DTG may carry significant advantages over NNRTIs, and other INSTIs. In the absence of alternatives to rifampicin-based TB therapy, DTG and raltegravir exposures are only moderately reduced (Dooley, Sayre et al. 2013), compared to larger (50-90%) reductions in concentrations of boosted PIs, nevirapine and elvitegravir. Dolutegravir is metabolized by glucuronidation (UGT1A1) with some contribution from CYP3A. Rapid viral load drop potentially beneficial in late diagnosis during pregnancy. In Sub-Saharan Africa, pregnant mothers tend to engage with health services later in pregnancy compared with Europe, and new HIV diagnoses resulting from universal testing at ≥28w gestation are frequent. DTG results in a very rapid reduction in viral load; median time to undetectable viral load in the SINGLE study was 28 days vs. 84 days with Atripla (P<0.0001) (Walmsley, Antela et al. 2012). Use of DTG may lower risk of mother-to-child transmission of HIV in late presenters. Although meta-analysis shows no increase in birth defects with maternal efavirenz (Ford, Mofenson et al. 2010), there has been recent suspicion of neurological toxicity in a large French registry (Sibiude, Madelbrot et al. 2013) and neurodevelopmental delay in a South African cohort (Westreich, Rubel et al. 2010) Proven efficacy in patients with established drug resistance to other antiretrovirals. In most resource-poor settings, options for anti-retroviral therapy are limited (2011), and the emergence of HIV drug resistance gives cause for concern (Hedt, Wadonda-Kabondo et al. 2008; WHO 2012). In a cross-sectional study conducted among HIV-1 antiretroviral naïve patients in five African countries, the highest prevalence of transmitted resistance was observed in Kampala, Uganda 12.3% (22 of 179; 7.5-17.1) (Hamers, Wallis et al. 2011). In Malawi, the prevalence of primary drug resistance in new infections was 6.1% which is comparable with figures of  3% for South Africa (Manasa, Katzenstein et al. 2012), and 5.7% for Zambia (Hamers, Siwale et al. 2010), with over half of all mutations conferring resistance to non-nucleoside reverse transcriptases (NNRTI) (Wadonda-Kabondo, Banda et al. 2012). Studies across Africa have shown that treatment response to NNRTIs in mothers and children exposed to nevirapine (particularly single dose) during pregnancy is blunted (Musiime, Ssali et al. 2009). In this context, a novel class of ARV which is safe, affordable and effective is an urgent need Safety profile in pregnancy. DTG is classified as FDA pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, the manufacturer recommends that this drug should be used during pregnancy only if clearly needed (ViiV 2013). Necessity of investigating DTG PK in pregnant women. Alongside the clinical and humanitarian imperative to provide effective treatment for preventing HIV transmission in pregnant mothers with NNRTI-resistant HIV, there is an equally important ethical imperative to establish the safety, efficacy and pharmacokinetics of DTG in pregnant mothers and their breastfed infants in SSA, especially given the implementation of WHO Option B+, and the potential for widespread use of DTG in the forseeable future. Previous experience suggests it is universally the case that pregnant women in SSA receive new antiretrovirals (ARV) ahead of any proper evaluation, and clinical studies (if undertaken at all) occur at a much later stage after many mothers and infants have been exposed. Importance of undertaking the study in SSA. Any pivotal study if undertaken in developed countries would have limited generalizability to an African setting because i) ARVs tend to be initiated later in gestation in newly presenting pregnant women, ii) the standard of care across SSA is likely to be an efavirenz or nevirapine-based regimen iii) infant breastfeeding is recommended in the presence of ARVs ii) host factors such as BMI, ethnicity etc may impact on pharmacokinetics (PK) of ARVs. Continued administration of DTG for 2 weeks post-partum (whilst breastfeeding) to characterize PK in non-pregnant state. Under standard of care, the infant will receive 6 weeks of nevirapine syrup, and would be exposed to the NNRTI/NRTI/NRTI combination received by the mother under standard of care. In this study, infants will be exposed DTG via the breastmilk for a 2 week period following birth. We believe this risk to be acceptable given the potential benefits. Furthermore, the risk is unlikely to exceed any potential risk of in utero exposure to DTG. Drug-drug interactions between directly administered NVP and DTG ingested via the breastmilk are unlikely to have clinical significance, although we will study this. The potential risks of breastfeeding are fewer than those of giving formula feeding during the two week period that mothers continue to receive DTG postpartum. Replacement of breast feeding with formula feeding during the first two weeks post-partum would be unethical due to the loss of the immune benefits of colostrum to the neonate, risks intrinsic to formula feeding in low resource settings and increased risk of HIV transmission if mixed feeding occurs (Teasdale et al, 2011) The potential risks of low-level ARV causing drug-resistance in the infant should the PMTCT fail exist for the standard of care NNRTIs and NRTIs; it is not anticipated that DTG will carry a greater risk but nevertheless this is best monitored within a clinical trial setting before widespread uptake without monitoring. Study Design Open label randomized trial of DTG in late pregnancy. HIV+ pregnant women (untreated at ≥28w gestation will be randomized 1:1 to receive a DTG-based regimen compared with standard of care (regimen not containing INSTI).

Official Title
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Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study

Conditions
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HIV, Pregnancy

Intervention / Treatment
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* Drug: Dolutegravir 50mg od
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent Willing to participate, Women age 18 years and above Pregnant Untreated HIV infection in late pregnancy at ≥28 - 36 weeks gestation Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dolutegravir 50mg od<br>30 patients who will receive dolutegravir 50mg once daily plus the same NRTI backbone as the active comparator group (lamivudine and tenofovir) | Drug: Dolutegravir 50mg od<br>* Patients randomised to receive either Dolutegravir 50mg od or standard of care (Efavirenz 600mg od) plus Lamivudine 300mg od/ Tenofovir 300mg od<br>* Other names: GSK1349572;|
| Active Comparator: Standard of Care<br>Patients randomised to receive antiretroviral therapy as per Uganda national guidelines (Efavirenz 600mg od based plus Tenofovir 300mg od and Lamivudine 300mg od) | Drug: Standard of Care<br>* Patients are randomised 1:1 to receive either Dolutegravir 50mg once daily in combination with Lamivudine 300mg od and tenofovir 300mg od or standard of care (Efavirenz 600mg plus Lamivudine 300mg od and tenofovir 300mg od)<br>* Other names: Tenofovir 300mg od;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-24 of DTG in pregnant women in third trimester and 2 weeks postpartum | Rich PK with sampling at t0, 1, 2, 4, 6, 8 and 24 hours relative to drug dose | In 3rd trimester and 2 weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of DTG | Safety questionnaires at every scheduled and unscheduled study visit Infant safety questionnaires at all post-partum visits Self-reporting | Up to 6 months postpartum | 
| Proportion of women in each arm with VL < 50 copies/mL, and <400 copies/mL at delivery | HIV viral load will be measured at enrollment into the study and at delivery | At delivery | 
| Change in viral load over the first 4 weeks of therapy | HIV viral load will be measured at enrollment and after 4 weeks of antiretroviral therapy | 4 weeks after treatment started | 
| Cord:maternal plasma DTG ratio | A maternal blood sample and a cord blood sample will be taken at delivery to calculate the transplacental transfer of Dolutegravir | At delivery | 
| Maternal plasma: breastmilk DTG ratio | At the timepoints indicated, a single maternal blood sample and a sample of breast milk will be taken to measure Dolutegravir levels in both matrices and allow estimation of transmammary drug exposure | At 2 weeks postpartum, and after 1, 2 and 3 days after transfer back to standard of care medications | 
| Infant DTG levels | Infants from the Dolutegravir arm (N=30) will be randomised 1:1:1 to return for PK sampling 1, 2 or 3 days after the mother has discontinued Dolutegravir and changed to Standard of Care treatment. All infants will have a single capillary blood sample (heel prick) taken at 2 weeks postpartum, and then at the time point they have been randomised to. | At maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days after transfer to standard of care | 
| Incidence and severity of adverse events and laboratory abnormalities | Laboratory test measured routinely up until 3 days after change to standard of care. In addition, patients will remain under follow-up until 6 months postpartum, and laboratory tests will be performed if clinically indicated at any point. The routinely measured 'safety bloods' in this study are Full Blood Count, Urea and Electrolytes including eGFR, Liver Function Tests including Alanine Aminotransferase and Bilirubin | Up to 3 days after change to standard of care | 
| Absolute values and changes over time in laboratory parameters | Laboratory tests will be performed routinely until 3 days after change to standard of care regime, but the study will continue to follow the women until 6 months postpartum. Lab tests will be performed if clinically indicated at any time point | Until 3 days after change back to standard of care | 
| Proportion of subjects who discontinue treatment due to adverse events | Mothers will be switched to standard of care at 2 weeks postpartum | Until 2 weeks postpartum | 
| Proportion of mother to child transmission of HIV | Infant HIV testing by PCR will be undertaken at six weeks and six months of age, as per Uganda National Policy | 6 months postpartum | 
| Pharmacogenomic factors affecting DTG PK in pregnancy and transfer to infant via placenta or breastmilk | Blood sample for genomic testing will be taken at the same time as the rich PK sampling, either in the third trimester or at 2 weeks postpartum. A panel of known SNPs for the major drug metabolising enzymes known to alter the pharmacokinetics of efavirenz, lamivudine and tenofovir will be analysed (primarily SNPs affecting CYP2B6) | Single 5ml sample at rich PK visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Prevention of mother to child transmission, Africa, Uganda, Pharmacokinetics, Pregnancy, Breastfeeding