Graham Taylor

The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women

Objective:To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum. Design:A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. Methods:HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4–6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0. Results:Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71–0.83) for TDF area under the curve (AUC0–24 h); 0.81 (0.68–0.96) for TDF Cmax and 0.79 (0.70–0.90) for TDF C24 h and 0.75 (0.68–0.82) for FTC AUC0–24 h; and 0.87 (0.77–0.99) for FTC Cmax and 0.77 (0.52–1.12) for FTC C24 h. The viral load close to delivery was less than 200 copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported. Conclusion:Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.

A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK

Background The natural history of HTLV-1-associated myelopathy (HAM) has been mainly described in HTLV-1 endemic countries such as Japan, Brazil and Martinique. Objectives The authors describe the natural history of the largest cohort of patients with HAM living in the UK from 1993 to 2007. Methods Prospective, longitudinal study comparing clinical and virological outcome between first and last clinical visit. Incidence and cause of death were documented and the mortality calculated. Results 48 patients were included: 79.2% were female, 79.2% were of Afro-Caribbean origin, and 83.3% acquired HTLV-1 through breastfeeding or unprotected heterosexual intercourse. The mean age of onset was 46 years. The median durations from onset of symptoms to diagnosis and to last follow-up were 2 and 11.6 years. The median time of follow-up was 3.8 years. The most common first recalled symptom was unilateral leg weakness. The median times from onset to unilateral, bilateral walking aid and frame or a wheelchair were 11, 11.2, 11.3 and 18 years. The overall average deterioration in timed walk in patients whose need for aid did not change was 2 s/10 m/year. Three patients progressed rapidly and were unable to walk within 2 years. Six patients were slow/non-progressors. The mortality was 2.4/100 person year follow-up. The median HTLV-1 viral load remained unchanged at 14%. Conclusions HAM is a slowly progressing chronic disease. Timed walk deteriorates by 2 s/10 m/year, and patients remain ambulant for 10 years but become wheelchair-dependent a decade later. HTLV-1 viral load remains high and unchanged over time regardless of clinical progression.

Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women

OBJECTIVES To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum. PATIENTS AND METHODS This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929. RESULTS Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported. CONCLUSIONS Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.

Raltegravir in HIV-1–Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy

BACKGROUND The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION NCT00825929.

HTLV-1 and HTLV-2 Prevalence in the United States

During the 1980s and early 1990s, there was considerable interest in the seroepidemiology of human T-lymphotropic virus (HTLV) types 1 and 2. The limitations of these studies included a focus on areas of described high prevalence, distinct ancient populations, or high-risk groups through social behavior and the use of diagnostic assays that lacked specificity. However, based on these data, de Thé and Bomford could make a crude estimate of 10–20 million HTLV-1 infections in their review of the need for an HTLV-1 vaccine [1]. This was followed by a period of relative epidemiological inactivity, during which the global population increased by approximately 1 billion. The burden of this population growth has been in many of the regions that are endemic for HTLV-1 infection. Gessain et al [2] recently published a revised estimate of 5–10 million infections but took care to note that this was based on only 1.5 billion of the world’s 7 billion inhabitants. Furthermore, Hlela et al [3] found only 17 published studies on the prevalence of HTLV infections in general populations, and none from Europe or North America. Although it does not completely fill this gap, the article by Chang et al [4] in this issue of The Journal is an extremely welcome addition to the literature. It is the first detailed study of HTLV-1 and HTLV-2 prevalence in new blood donors within the United States for more than a decade. It not only provides contemporary data from 2000–2009, which are sufficient to look in detail at trends over time, but also provides the opportunity for comparison with data from the same risk population during the early to mid1990s [5]. Chang et al [4] show that HTLVs remain prevalent in the United States, withHTLV-2more common thanHTLV1, and an overall prevalence of 22/ 100 000 population. As the authors clearly highlight, these data will underestimate the prevalence of infections in the general population because the aim of screening questionnaires is to identify and exclude high risk populations from blood donation. The authors suggest that this may underestimate the true prevalence of these bloodborne viruses in the general population by 3–5-fold. In data from Europe based on unselected antenatal clinic attendees, an imperfect surrogate, as the comparator, a 6-fold difference was observed in a multinational study despite widely differing prevalence rates [6]. Comparisons with the general population are further complicated because the prevalence of HTLV infection rises with age, most dramatically among women. However, applying this assumption to the data from Chang et al [4] suggests an overall general population prevalence in the United States of 0.1%–0.2%. Importantly, the authors have identified significant variation in HTLV prevalence by region and have reported that the pockets of high prevalence differ for HTLV-1 and HTLV-2. These are mapped only in the counties in which >5000 first -donors had been tested; thus, the extent of such pockets remains to be fully elucidated. Notable absentees are counties in New York and Florida, where patients commonly present with HTLV-related diseases are. Conversely, the data identify some counties that have a high prevalence among blood donors, but are less well recognized for a high incidence of HTLV-1–associated diseases. Further work is needed to complete this important mapping exercise. As reported in endemic regions, HTLV prevalence among the blood donors is highly age dependent, increasing from 1.3 to 9.3 per 100 000 for HTLV-1 and from 3.6 to 27 per 100 000 for HTLV-2 either side of age 30 years. The peak in HTLV-2 infection among women in the 40–49-year age cohort observed in the 1990–1996 data was attributed to a period during the 1960s and 1970s when injecting drug use was more widespread; this use later tailed off, presumably owing to health concerns related to human immunodeficiency virus. An alternative explanation may have been that HTLV-2 causes premature death. This seemed unlikely in the absence, apart from rare cases of HTLV-2–associated myelopathy, of clear disease associations with HTLV-2, particularly a lack of associated malignancy. However, data from the HTLV Outcomes Study study [7] have pointed to an increase in all-cause and Received 11 October 2013; accepted 16 October 2013. Correspondence: Graham P. Taylor MD, Section of Infectious Diseases, Faculty of Medicine, Imperial College, Norfolk Place, London, W2 1PG, UK (g.p.taylor@imperial.ac.uk). The Journal of Infectious Diseases

Atazanavir exposure is effective during pregnancy regardless of tenofovir use

BACKGROUND We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir. METHODS This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional. RESULTS 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected. CONCLUSIONS Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effective concentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis.
 ClinicalTrials.gov number NCT00825929.

Evidence of Brain Inflammation in Patients with Human T-Lymphotropic Virus Type 1-Associated Myelopathy (HAM): A Pilot, Multimodal Imaging Study Using 11C-PBR28 PET, MR T1-Weighted, and Diffusion-Weighted Imaging

HTLV-1–associated myelopathy (HAM; HTLV-1 is human T-lymphotropic virus type 1) is a chronic debilitating neuroinflammatory disease with a predilection for the thoracic cord. Tissue damage is attributed to the cellular immune response to HTLV-1–infected lymphocytes. The brains of HTLV-1–infected patients, with and without HAM but no clinical evidence of brain involvement, were examined using a specific 18-kDa translocator protein ligand, 11C-PBR28, and T1-weighted and diffusion-weighted MRI. Methods: Five subjects with HAM and 2 HTLV-1 asymptomatic carriers were studied. All underwent clinical neurologic assessment including cognitive function and objective measures of gait, quantification of HTLV-1 proviral load in peripheral blood mononuclear cells, and human leukocyte antigen–antigen D related expression on circulating CD8+ lymphocytes. 11C-PBR28 PET and MRI were performed on the same day. 11C-PBR28 PET total volume of distribution and distribution volume ratio (DVR) were estimated using 2-tissue-compartment modeling. MRI data were processed using tools from the FMRIB Software Library to estimate mean diffusivity (MD) and gray matter (GM) fraction changes. The results were compared with data from age-matched healthy volunteers. Results: Across the whole brain, the total volume of distribution for the subjects with HAM (5.44 ± 0.84) was significantly greater than that of asymptomatic carriers (3.44 ± 0.80). The DVR of the thalamus in patients with severe and moderate HAM was higher than that in the healthy volunteers, suggesting increased translocator protein binding (z > 4.72). Subjects with more severe myelopathy and with high DR expression on CD8+ lymphocytes had increased DVR and MD (near-significant correlation found for the right thalamus MD: P = 0.06). On the T1-weighted MRI scans, the GM fraction of the brain stem was reduced in all HTLV-1–infected patients compared with controls (P < 0.001), whereas the thalamus GM fraction was decreased in patients with HAM and correlated with the disease severity. There was no correlation between neurocognitive function and these markers of central nervous system inflammation. Conclusion: This pilot study suggests that some patients with HAM have asymptomatic inflammation in the brain, which can be detected and monitored by 11C-PBR28 PET together with structural and diffusion-weighted MRI.

Etravirine pharmacokinetics in HIV-infected pregnant women

Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred. Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. Clinical Trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa.

Human T‐lymphotropic virus (HTLV)‐1 causes T‐cell leukaemia and myelopathy. Together with HTLV‐2, it is endemic in some African nations. Seroprevalence data from Malawi are scarce, with no reports on associated disease incidence. HTLV seroprevalence and type were tested in 418 healthy mothers from Malawi. In addition, we tested the sera of 534 children to investigate mother‐to‐child transmission. To provide context, we conducted a systematic review and meta‐analysis of HTLV seroprevalence in African women and children.

HTLV-1 and bronchiectasis in a UK cohort, report and review

Background Associations between HTLV-1 and pulmonary disease have been reported but causality and risk have not been confirmed. Pulmonary function tests have been routinely offered to new patients attending the UK HTLV service whilst a retrospective case review has been conducted to determine the prevalence of diagnosed bronchiectasis.