Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum

Objectives

Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.

Methods

The participants were HIV‐1‐infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady‐state 12‐h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC_0–12) was ≥10th percentile NFV AUC_0–12 in non‐pregnant historical controls (18.5 μg h/mL).

Results

Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C_max), 12‐h post‐dose concentration (C₁₂) and AUC_0–12 were significantly lower during the third trimester compared to postpartum (P≤0.03). The metabolite hydroxyl‐tert‐butylamide (M8) AUC_0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC_0–12 exceeded the AUC_0–12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C_min) was above the suggested minimum trough concentration (0.8 μg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV‐1 RNA copies/mL in 81% of patients at delivery.

Conclusions

These results suggest that higher doses of NFV should be considered during pregnancy.     

Pharmacokinetics of oral zidovudine administered during labour: a preliminary study

OBJECTIVES: The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women. METHODS: ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. RESULTS: In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. CONCLUSIONS: While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.     

Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection

Summary.  Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA ≥ 1.2 × 10⁹ geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels ≥1.2 × 10⁹ geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial.     

Predictors of postpartum HIV care engagement for women enrolled in prevention of mother-to-child transmission (PMTCT) programs in Tanzania

Prevention of mother-to-child transmission of HIV (PMTCT) is a foundational component of a comprehensive HIV treatment program. In addition to preventing vertical transmission to children, PMTCT is an important catch-point for universal test-and-treat strategies that can reduce community viral load and slow the epidemic. However, systematic reviews suggest that care engagement in PMTCT programs is sub-optimal. This study enrolled a cohort of 200 women initiating PMTCT in Kilimanjaro, Tanzania, and followed them to assess HIV care engagement and associated factors. Six months after delivery, 42/200 (21%) of participants were identified as having poor care engagement, defined as HIV RNA >200?copies/mL or, if viral load was unavailable, being lost-to-follow-up in the clinical records or self-reporting being out of care. In a multivariable risk factor analysis, younger women were more likely to have poor postpartum care engagement; with each year of age, women were 7% less likely to have poor care engagement (aRR: 0.93; 95% CI: 0.89, 0.98). Additionally, women who had told at least one person about their HIV status were 47% less likely to have poor care engagement (aRR: .53; 95% CI: 0.29, 0.97). Among women who entered antenatal care with an established HIV diagnosis, those who were pregnant for the first time had increased risk of poor care engagement (aRR 4.16; 95% CI 1.53, 11.28). The findings suggest that care engagement remains a concern in PMTCT programs, and must be addressed to realize the goals of PMTCT. Comprehensive counseling on HIV disclosure, along with community-based stigma reduction programs to provide a supportive environment for people living with HIV, are crucial to address barriers to care engagement and support long-term treatment. Women presenting to antenatal care with an established HIV status require support for care engagement during the crucial period surrounding childbirth, particularly those pregnant for the first time.     

Clinical course of 161 untreated and tenofovir‐treated chronic hepatitis B pregnant patients in a low hepatitis B virus endemic region

Hepatitis B immunoprophylaxis failure is linked to high maternal viraemia. There is limited North American data on hepatitis B outcomes in pregnancy. Pregnant hepatitis B carriers were enrolled January 2011–December 2014 and offered tenofovir in the 3rd trimester if hepatitis B virus (HBV)‐DNA was >7‐log IU/mL. Outcomes were determined in treated vs untreated patients. In total, 161 women with 169 pregnancies (one twin, 170 infants; median age 32 years), 18% (29/161) HBeAg+ and median HBV‐DNA 2.51 log IU/mL (IQR 1.66–3.65; range 0.8–8.1) were studied. 14.3% (23/161) received tenofovir due to high viral load (16/23, median 74 days, IQR 59–110) or due to liver disease (7/23). In 10/16 treated due to high viraemia, with confirmed adherence, follow‐up HBV‐DNA showed a 5.49 log decline (P = 0.003). In treatment naïve mothers, median alanine aminotransferase (ALT) increased from 17 IU/L (IQR 12–24) to 29 (IQR 18–36) post‐partum (P = 1.5e‐7). In seven highly viraemic mothers who declined therapy (HBV‐DNA >8‐log IU/mL); median ALT increased ~3X from baseline (P < 0.01). 26% (44/169) had Caesarean section with no difference in treated vs untreated subjects. No tenofovir‐treated mothers had renal dysfunction. Data were available on 167/170 infants; in 50.8% (85/167) who completed immunoprophylaxis, 98.8% (84/85, including 12 exposed to tenofovir in utero) were HBV immune. One infant born to an HBeAg+ mother with HBV‐DNA >8‐log IU/mL failed immunoprophylaxis. In this prospective Canadian cohort study, most untreated mothers experienced mild HBV flares. Tenofovir in pregnancy is well tolerated and reduces viral load prior to parturition.     

Acceptability and feasibility of serial HIV antibody testing during pregnancy/postpartum and male partner testing in Tororo,Uganda

Our objective was to determine whether serial HIV testing during pregnancy and the postpartum period as well as male partner testing are acceptable and feasible in Tororo, Uganda. This was a prospective study of pregnant women at the Tororo District Hospital (TDH) Antenatal Clinic. Patients presenting for routine antenatal care were asked to participate in a serial HIV testing integrated into standard antenatal and postpartum/child immunization visits, and to invite their male partners for HIV testing. Serial testing was defined as ≥2 tests during pregnancy and ≥2 tests within 24 weeks postpartum. Of the 214 enrolled women, 80 (37%) completed serial testing, 176 (82%) had ≥2 tests, and 147 (69%) had ≥3 tests during the study period. One hundred eighty-two women (85%) accepted male partner testing, but only 19 men (10%) participated. One woman seroconverted during the study, for a cumulative HIV incidence of 0.5% (1/214). In multivariable logistic regression analysis, longer distance between home and clinic (aOR 0.87 [95% CI 0.79–0.97]) and not knowing household income (aOR 0.30 [95% CI 0.11–0.84]) were predictive of not completing serial testing. Higher level of education was associated with completing serial testing (linear trend p value = 0.05). In conclusion, partial serial HIV testing was highly acceptable and feasible, but completion of serial testing and male partner testing had poor uptake.     

Rapid point-of-care HIV testing in pregnant women: a systematic review and meta-analysis

Rapid, point-of-care human immunodeficiency virus (HIV) testing has the potential to enhance strategies to prevent mother-to-child transmission (MTCT) of HIV infection. Rapid tests need minimal laboratory infrastructure and can be performed by health workers with minimal training. In our systematic review and meta-analysis, we aimed to summarize the overall diagnostic accuracy of rapid HIV tests in pregnancy, and outcomes such as acceptability, patient preference, feasibility and impact of rapid testing. We searched four major databases, identified and screened 1377 citations, and included 17 studies that met our eligibility criteria. Analyses of these studies suggested that the overall sensitivity and specificity of blood-based rapid tests was high compared with oral rapid tests. A two-step testing strategy, particularly parallel testing, was found to be superior to single-test strategy in labour and delivery settings. Acceptability of rapid tests and patient preference was variable across studies. Overall, rapid HIV testing was highly accurate compared with conventional tests and offer a clear advantage of enabling the implementation of timely interventions to reduce MTCT of HIV. To improve diagnostic accuracy and to reduce false-positive results, it may be necessary to use two rapid tests during labour and delivery.     

HIV testing of male partners of pregnant women in Porto Alegre,Brazil: A potential strategy for reduction of HIV seroconversion during pregnancy

Pregnant women have a significantly higher risk of HIV acquisition during gestation than their non-pregnant counterparts due to behavioral and biological factors. Acute seroconversion during gestation results in increased HIV mother-to-child transmission rates and has been identified as a major public health challenge. In order to address potential HIV seroconversion in our pregnant patients, we conducted a prospective cohort study to evaluate the acceptability of offering HIV testing to sexual partners of HIV-negative pregnant women receiving antenatal care at two hospitals in Porto Alegre, Brazil. Over a 14-month study period, HIV-negative pregnant women at two hospital-based clinic sites were encouraged to bring their stable sexual partner for HIV voluntary counseling and testing during prenatal care. Women were re-interviewed following delivery to measure success of the intervention. Of the 1223 HIV-negative pregnant women enrolled in the study, 663 (54%) of their male sexual partners received HIV testing during antenatal care and 4 (0.6%) were diagnosed with HIV infection. A total of 645 women were interviewed at the time of delivery, with 620 (97%) confirming that HIV testing was suggested to their partner. The most common reason provided by women as to why partners did not come for testing was work (69%) and lack of perceived risk (14%). Independent predictors of successful partner testing included being white (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.18–2.12), married (OR 1.78, 95% CI 1.08–2.94), having an older age of sexual debut (OR 0.94, 95% CI 0.9–0.98), and being recruited at Hospital Conceiçao (OR 2.1, 95% CI 1.52–2.88). We conclude that HIV partner testing during prenatal care is acceptable, rendering this intervention attractive to public health programs targeting prevention of sexually transmitted infections.     

Comparison of the efficacy and safety of tenofovir and telbivudine in interrupting mother-to-child transmission of hepatitis B virus

The present study is aimed to evaluate and compare the efficacy and safety of tenofovir (TDF) and telbivudine (TBV) in interrupting hepatitis B virus (HBV) mother-to-child transmission (MTCT), and to provide evidence-based treatment options to clinicians and patients.Hepatitis B e-antigen (HBeAg)-positive pregnant women (644 in total) with high HBV DNA load (≥2 × 10⁵ IU/mL) and who received TDF (n = 214) or TBV (n = 380) in the second or third trimester, or received no treatment (n = 50) were included in this retrospective analysis.HBV DNA levels in mothers at delivery were significantly lower than baseline in the 2 treatment groups. HBV DNA levels in the TDF group were significantly different between the mothers receiving treatment in the second trimester and those receiving treatment in the third trimester; however, significant difference was not observed in the TBV group. The proportion of hepatitis B surface antigen (HBsAg)-positive infants at the age of 7 to 12 months in the TDF, TBV, and control groups were 0.00% (0/174), 0.30% (1/331), and 5.0% (2/40) with a significant difference between the treatment groups and the control group, but no difference between the TDF and TBV group (P > .05). However, no serious adverse events were observed in infants and mothers of all groups.TBV and TDF can effectively reduce the HBV DNA level and MTCT rate in pregnant women with high HBV DNA load (≥2 × 10⁵ IU/mL); both antiviral drugs are safe for infants and mothers. Since TDF was more effective in reducing HBV DNA levels during the second trimester, its use during the period is recommended to prevent HBV MTCT.     

HIV-related stigma in pregnancy and early postpartum of mothers living with HIV in Ontario,Canada

HIV-related stigma is associated with many psychological challenges; however, minimal research has explored how perceived HIV-related stigma intersects with psychosocial issues that mothers living with HIV may experience including depression, perceived stress and social isolation. The present study aims to describe the correlates and predictors of HIV-related stigma in a cohort of women living with HIV (WLWH) from across Ontario, Canada during pregnancy and early postpartum. From March 2011 to December 2012, WLWH?≥?18 years (n?=?77) completed a study instrument measuring independent variables including sociodemographic characteristics, perceived stress, depression symptoms, social isolation, social support and perceived racism in the third trimester and 3, 6 and 12 months postpartum. Multivariable linear regression was employed to explore the relationship between HIV-related stigma and multiple independent variables. HIV-related stigma generally increased from pregnancy to postpartum; however, there were no significant differences in HIV-related stigma across all study time points. In multivariable regression, depression symptoms and perceived racism were significant predictors of overall HIV-related stigma from pregnancy to postpartum. The present analysis contributes to our understanding of HIV-related stigma throughout the pregnancy–motherhood trajectory for WLWH including the interactional relationship between HIV-related stigma and other psychosocial variables, most notably, depression and racism.     

The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy

We report two cases in which osteomalacia developed in patients on tenofovir-containing highly active antiretroviral therapy (HAART) in the context of Fanconi syndrome with hypophosphataemia. Bone pain was the presenting feature and myopathy followed in one case. Disability was reversed with withdrawal of the drug and with mineral supplementation. The cases highlight the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir. A possible association with incipient acute renal failure, particularly during nonsteroidal anti-inflammatory drug (NSAID) use, needs further investigation.     

Loneliness and perceived social support in pregnancy and early postpartum of mothers living with HIV in Ontario,Canada

The HIV Mothering Study (n?=?72) was a prospective, observational, cohort study exploring psychosocial experiences and needs of WLWHIV in pregnancy and postpartum. We performed quantitative analysis of determinants of loneliness (UCLA Loneliness Scale) and lower perceived social support (SS) (Medical Outcomes Study-Social Support Survey). The hypothesized determinants included: age, years with HIV, racism (Everyday Discrimination Scale), depression (Edinburgh Postnatal Depression Scale [EPDS]), nadir CD4 (<200?cells/μL), tertiary vs. community HIV care, and marital status. The median age was 33 (IQR?=?30–37); 65.3% were African/Caribbean/Black. Multivariable analyses revealed associations between marital status and perceived social support (β?=??16.48, p?<?0.0001), and this association was also seen with change over time (p?=?0.02). Variables associated with SS that did not change over time were: income, EDS racism, EPDS score. Significant associations with loneliness were seen with the same variables associated with SS. Variables associated with loneliness that also changed over time were: EDS Racism (β?=?0.22, p?=?0.0005, and over time p?=?0.003), and EPDS score (β?=?0.74, p?<?0.0001), and over time (p?=?0.0211). Variables associated with loneliness but that did not change over time were: marital status and income. This analysis provides clinicians with prenatal risk factors which may be associated with increase loneliness and lower SS during pregnancy and postpartum: marital status, income, racism and depression.