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The Pediatric Antiretroviral Pipeline
By Polly Clayden
The big news since the 2014 Pipeline Report is that there is finally a solid form of lopinavir/ritonavir (LPV/r) suitable for infants and young children.
On 21 May 2015, the United States Food and Drug Administration (FDA) tentatively approved LPV/r pellets, manufactured by Cipla, for infants and young children less than three years old.1, 2
A few months before, in December 2014, the Medicine Patent Pool (MPP) signed a licensing agreement with AbbVie – that holds the patent for LPV/r. This agreement will help to make the new formulation available for children in low- and middle-income countries. The next hurdles will be getting it approved by regulatory agencies and used in programs in these countries.3
There has not been a lot of activity in the pediatric pipeline over the last year. This year's chapter confirms (again) the need for priority generic products and highlights the ones to watch in the originator pipeline. It also includes a few new ones: the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine, and long acting formulations cabotegravir and rilpivirine.
Lopinavir/Ritonavir Pellets Tentatively Approved
The World Health Organization (WHO) recommends LPV/r-based regimens as preferred for infants and young children.4 Compliance with the recommendation has been hard as this boosted protease inhibitor was previously only available as syrups, which are too complicated to use for most programs in low- and middle-income countries. The new formulation consists of a finite number of LPV/r 40/10 mg pellets in a capsule, which is opened and sprinkled on soft food.
Although it is quite a step forward from syrup, the new formulation of LPV/r is still not ideal. The pellets are much easier to transport and store (no cold chain), and for this reason programs are keen to start using them. But acceptability data from the CHAPAS-2 trial5 – that showed similar LPV/r exposure with pellets and syrups – revealed that pellets were not more acceptable than syrups by 48 weeks.6 For infants and young children overall, the trial found pellets were more acceptable than syrups at week 12 but not by week 48. The main problem was taste.
Infants less than three months old have not yet been treated with the pellets. As they cannot be stirred, dissolved/dispersed or crushed in liquids it is important to make sure that infants can swallow them. For the youngest infants (three to six months old) in CHAPAS-2, the pellets were either added to a small amount of expressed breast milk in a spoon and given to the infant, or put on the infant's tongue before breastfeeding.
DNDi is waiting for the production of the clinical batch of the pellets to begin the LIVING study (implementation study using the new formulation) in Kenya.7 All the necessary local regulatory approvals are in place to start the study.
DNDi is also working on an improved taste masked granule formulation of LPV/r (as part of a fixed dose combination [FDC] 4-in-1 regimen).
WHO Recommendations and Current Priority Formulations
WHO 2013 guideline recommendations for adults are simple: two preferred first line regimens and two alternatives. Recommendations for children are more complicated (see Table 1). Only one regimen, AZT plus 3TC plus nevirapine (NVP) is currently available as an FDC. There is still some way to go with formulations and regimens appropriate to children. Despite some advances in the last few years, innovation and access in antiretrovirals for children still lags behind that for adults.
Table 1: 2013 WHO Guidelines Pediatric Recommendations
First-line
<3 years old
LPV/r-based regimens regardless of previous NNRTI exposure. If LPV/r is not feasible, NVP-based.
Consider substituting LPV/r with an NNRTI after sustained virological suppression (defined as viral load less than 400 copies/mL at six months, confirmed at 12 months from starting treatment).
Children who develop active TB while on LPV/r- or NVP-based regimens should be switched to ABC + 3TC + AZT during TB treatment. They should switch back to the original regimen when their treatment for TB is completed.
The NRTI backbone should be one of the following (in order of preference): ABC or AZT + 3TC; d4T + 3TC.
EFV preferred and NVP alternative.
< 12 years or weighing less than 35 kg, backbone (in order of preference): ABC+3TC; AZT or TDF + 3TC or FTC.
>12 years
Adolescents 12 years (weighing more than 35 kg) should align with adults, the backbone: TDF+ 3TC or FTC; ABC or AZT + 3TC.
Second-line
After first-line NNRTI failure, a LPV/r regimen is preferred.
After LPV/r failure, children <3 years should remain on the regimen with improved adherence support.
After failure of first-line regimen containing ABC or TDF + 3TC or FTC, the preferred backbone is AZT + 3TC.
After failure of first-line regimen containing AZT or d4T + 3TC or FTC, the preferred backbone is ABC or TDF + 3TC or FTC.
ABC, abacavir; AZT, zidovudine; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NVP, nevirapine;
TDF, tenofovir disoproxil fumarate, 3TC, lamivudine.
NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor;
TB, tuberculosis
Missing Pediatric Formulations
Several gaps remain in available products for children that need to be filled before the 2013 WHO guidelines (and the 2015 ones that are on the way) can be implemented in most low- and middle-income settings.
Where possible these should be FDC dispersible tablets. For compounds that cannot be formulated in this way (large and/or insoluble molecules) granules are preferable to liquids. Liquid formulations are expensive, have short shelf lives, and often require a cold chain, making them hard to store and transport and inappropriate for most low- and middle-income countries.8
The WHO 2014 supplement to the 2013 guidelines include a pediatric chapter: Optimizing Antiretroviral Drugs for Children: Medium- and Long-Term Priorities.9 WHO highlights two priority formulations needed to treat children according to the 2013 guidelines:
AZT or abacavir (ABC) plus 3TC plus LPV/r. These formulations are in development and are needed to make it possible to give FDCs to children younger than three. Better solid forms could overcome palatability issues with the currently available nasty tasting LPV/r syrup (although taste masking is complicated and can limit drug absorption and the recently approved solid form still needs improving). Many barriers with supply chain – transport, storage and distribution – could be addressed by these formulations.
Supported by UNITAID, DNDi is working on a more palatable version of LPV/r – which will be produced in combined 4-in-1 granule formulations (finer than the newly approved 0.8mm pellets and more sand-like in texture).10 The plan is to have the optimized 4-in-1 LPV/r-based FDCs by 2016.
ABC plus 3TC plus efavirenz (EFV). Currently this regimen can only be given by using ABC/3TC co-formulated tablets with EFV tablets. A one-pill, once-daily regimen for children aged three to 10 years (less than 35 kg) would be useful. There is some discussion as to what dosing ratios for the FDC best facilitate recommendations for the individual agents across weight bands. Optimal doses need to avoid under- and overdosing of children at either end of each weight band, as far as possible, and be most suitable from a regulatory standpoint.
These two formulations have been a priority for some time now and are still unavailable.
Recommendations From the Second Pediatric Drug Optimization Meeting
The first Pediatric Antiretroviral Drug Optimization (PADO1) meeting, held in Dakar in 2013, brought together researchers, clinicians, activists and other experts to identify medium- and long-term priority drugs and formulations for children. The recommendations from this meeting were summarized in the WHO 2014 supplement,11 and continue to inform formulation development.
The Second Pediatric Antiretroviral Drug Optimization (PADO2) meeting,12 held in December 2014 was conducted to build on the PADO1 agenda and provide technical advice to the WHO 2015 guidelines development group. Among the topics discussed at the meeting were the needs for children at both ends of the age spectrum: newborns and adolescents.
For newborns, less than four weeks, the participants noted that there was currently no alternative to NVP plus 3TC plus AZT. Although very early treatment is being explored for infants, data for this very young age group are scarce. See Table 2. Some missing data will be provided by ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) trials:
P1026s – phase IV, prospective, pharmacokinetic study in pregnancy and post partum, that obtains infant antiretroviral washout data.13
P1093 – phase I/II, open label, non-comparative, intensive pharmacokinetics and safety study of dolutegravir (DTG) down to four weeks.14
P1097 – washout pharmacokinetic study of raltegravir (RAL) including in low birth weight (<2500 g) infants.15
P1106 – phase IV prospective pharmacokinetic study in low birth weight infants receiving NVP prophylaxis, tuberculosis (TB) prophylaxis or treatment and/or LPV/r-containing ART.16
P1110 – phase I open label, non-comparative pharmacokinetic dose-finding study of RAL in high risk, HIV-exposed neonates.17
P1115 – phase I/II proof of concept study of very early intensive antiretroviral therapy (ART) in infants to achieve HIV remission.18
Table 2: Newborn Treatment Options (including ongoing and planned IMPAACT trials)
Nucleos(t)ide Reverse Transcriptase Inhibitor
P1106 < 2500 g
P1026s washout
Non-nucleoside Reverse Transcriptase Inhibitor
Doravirine
EFV
P1115 >34 weeks GA
P1106 <2500 g
P1093 dosing
(in development)
P1097 washout
CCR5 Receptor Antagonist
Adapted from Ruel T. IMPAACT 2015.
ABC, abacavir; ATV, atazanavir; AZT, zidovudine; ddI, didanosine; DTG, dolutegravir; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; ETR, etravirine; LPV/r, lopinavir/ritonavir; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; 3TC, lamivudine. GA, gestational age.
For infants two weeks and above, the immediate priority first-line is still LPV/r-based regimens and for older children EFV-based FDCs. An alternative to the liquid formulation of ritonavir (RTV) is needed to make double boosting (adding extra RTV to overcome pharmacokinetic interactions with TB drugs during co-treatment) easier with LPV/r.
For second-line treatment a generic, co-formulated, heat stable version of darunavir/ritonavir (DRV/r) was prioritized. Children who fail on LPV/r-based first-line regimens particularly need a robust option second-line. Current dosing recommendations for DRV/r (approved by regulators in the United States and Europe) need to be simplified to reduce the number of different formulations and minimize pill burden for children in low- and middle-income countries. A 240/40 mg DRV/r tablet for twice daily dosing is a priority for children in weight bands 10 kg and above. DRV/r is not approved for children less than three years old and will not be investigated in this age group due to toxic levels in pre-clinical studies.
Discussion about adolescents focused on adherence and more tolerable alternatives to EFV.
The priority antiretrovirals in the medium-term (five years) are: DTG, RAL and tenofovir alafenamide fumarate (TAF). Although the PADO2 participants did not expect RAL to be used widely when DTG comes to the market (and it has not been identified as a priority for adults) a better formulation of RAL might offer an alternative for infants.
Pediatric investigation plans (PIPs) will be in place or under discussion for all compounds in early phases of development by originator manufacturers (described in the adult antiretroviral chapter). Although a generic company and DNDi are developing the LPV/r-based 4-in-1 FDC, the list of pipeline pediatric drugs and combinations also includes this.
There are considerable incentives and/or penalties from regulatory agencies to ensure that any new drug that might benefit children must be studied in this population. Pediatric research and development of new drugs is mandatory. The European Medicines Agency (EMA) enforces penalties for companies that do not provide a PIP as part of their application (or request a waiver). The FDA also extends six month patent protection to companies that perform the requested pediatric studies – though companies are not required to do this.
A PIP can be waived for specific drugs or classes of drugs that are likely to be ineffective or unsafe in all or some pediatric age groups. A waiver can also be obtained for products that are intended for conditions that only occur in adults, or that do not represent a benefit over existing pediatric treatments. In some cases, studies can be deferred until after the adult studies have been conducted.
Manufacturers must include pharmacokinetic data for all age groups of children, efficacy, tolerability, and differences in side effects. They must have stability and palatability data for formulations and demonstrate that they are able to achieve pharmacokinetic targets associated with efficacy in adults.
Studies are conducted in children as soon as there are sufficient data from those in adults. Most pediatric development programs take a staggered approach, starting with the older cohorts of children and working in de-escalated age bands: 12 to 18 years; six to 12 years; two to six years; six months to two years and less than six months. Data are required in the youngest age groups – down to newborns – unless a regulatory waiver is obtained. As the youngest age group is last to be studied and approved there are considerable delays in availability of new drugs for this population.
Whether this process could be accelerated and age groups studied simultaneously, where possible, has been discussed for some time. It would be interesting to see if doses for younger children have changed dramatically from predicted milligrams per kilogram ones due to pharmacokinetic data from older cohorts.
The current pediatric antiretroviral pipeline is shown in Table 3.
Table 3. The Pediatric Antiretroviral Pipeline
Formulation/s and dose
Status and comments
Nucleotide reverse transcriptase inhibitor and combinations
Tenofovir alafenamide fumarate (TAF)/ /emtricitabine (FTC) elvitegravir (EVG)/cobicistat (COBI)
(E/C/F/TAF)
Reduced dose FDC tablets in development
Phase II/III single arm, open label E/C/F/TAF treatment-naive children and adolescents 6 to <18 years
PK within adult range at 24 weeks in 12 to <18 years
Waiver <6 years
FTC/TAF
(F/TAF)
Reduced dose, co-formulated tablets and non-solid formulation in development
Switch study in children and adolescents stable on FTC/TDF plus 3rd agent
Study in infants and children 4 weeks to <6 years planned
Rilpivirine (RPV)/FTC/TAF
Gilead/Janssen
Reduced dose, FDC tablets planned
Dependent on development of RPV and F/TAF
Initial indication adolescents >12 years
Non-nucleoside reverse transcriptase inhibitors
Etravirine
(ETR)
Dispersible tablets 25 (scored), 100 mg
FDA/EMA approval for children and adolescents 6 to <18 years
Phase I /II treatment-experienced infants and children 2 months to <6 years and treatment-naive 2 months to <2 years enrolling
Waiver <2 months
Rilpivirine
(RPV)
Tablet 25mg
Granules 2.5 mg /g
Submitted to FDA and EMA for adolescents 12 and above with viral load < 100,000 copies/mL
2 to <12 years planned
Single agent and FDC with TDF/3TC planned
Pediatric plans under discussion with EMA and FDA
Protease inhibitor and combinations
Lopinavir/ritonavir/lamivudine/abacavir or zidovudine (LPV/r/3TC/ABC or AZT)
DNDi/Cipla
4-in-1 FDC granules
Formulation work ongoing
(COBI)
75 mg tablets
20 mg dispersible tablets for oral suspension
Booster with ATV, DRV and as part of E/C/F/TDF and E/C/F/TAF
Atazanavir/cobicistat
(ATV/c)
Gilead/BMS
Reduced dose and dispersible tablets planned
Phase II/III treatment experienced children 3 months to <18 years (ATV/c)
3 to < 18 years (DRV/c)
Darunavir/cobicistat
(DRV/c)
Gilead/ Janssen
Integrase inhibitors and combinations
(RAL)
Granules for suspension 6mg/kg (100 mg sachet)
FDA-approval for use in children 4 weeks and older
Passive PK study ongoing: neonates born to women who received RAL in pregnancy and during labor
Neonates PK and safety study for prophylaxis ongoing in high-risk HIV-exposed neonates from birth to six weeks
(EVG)
Reduced dose tablets and suspension in development
EVG PK completed, RTV boosted 12 to <18 years
RTV-boosted EVG to be studied in all age groups
E/C/F/TDF
(Stribild)
Reduced dose tablets in development
Studies underway in treatment-naive 12 to <18 years
E/C/F/TAF
See TAF above
Studies underway in treatment naive 12 to <18 years
(DTG)
Granule formulation
(for studies)
Dispersible tablets in development
10 mg and 25 mg tablets
Approved for adolescents 12 to <18 years weighing >40kg in US and EU
Phase I/II study, 6 weeks to <18 years treatment-naive and -experienced children, ongoing
In a PK study, exposures from granules were moderately higher than with tablets and highest with formula milk
DTG/ABC/3TC
(572-Trii)
ViiV
Pediatric formulation development planned
FDA/EMA approval for adolescents >12 years and >40 kg
Dependent on ongoing studies confirming DTG dose in children and ability to establish appropriate dosing ratios for components
DTG/RPV
ViiV/Jansen
Reduced dose
co-formulation
PIP in development
Studies planned in children and adolescents 6 to <18 years
Cabotegravir/RPV long acting (LA)
ViiV/Janssen
Age appropriate liquid formulation for induction
Intramuscular nanosuspension as for adults
PIP approved October 2014 (to be completed by 2018)
Deferral 2 to <18 years
(MVC)
Suspension 20 mg/mL
Treatment-experienced CCR5 tropic 2 to <18 years
NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR
Tenofovir Alafenamide Fumarate
TAF is considered to be a priority for future generic FDCs for children. Early data in adults suggests that it might have a better safety profile than TDF. This has yet to be confirmed in children. TAF also has a low milligram dose: 25 mg without a boosting agent and 10 mg boosted.
For children TAF might be an alternative to ABC. It could help to harmonize pediatric and adult ART regimens, particularly if it could be co-formulated with DTG and 3TC or FTC.
The originator company Gilead Sciences is not developing TAF as a single agent for adults or children. The development of an FDC of elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF (E/C/F/TAF) is the company's priority.
As with adults, Gilead is also investigating a co-formulation with FTC (F/TAF), which hopefully will provide data to inform the dose of TAF as part of future un-boosted generic regimens.
E/C/F/TAF and F/TAF are currently under regulatory review for adults.19, 20, 21
F/TAF
TAF is being investigated co-formulated with FTC in a phase II/III switch study will enroll children down to six years of age.22
Adolescents aged 12 to 18 years will switch their current two nucleoside reverse transcriptase inhibitor (NRTI) containing regimen to F/TAF (while continuing on their third antiretroviral agent) for 96 weeks. After review of the pharmacokinetic and safety data from the older cohort, children aged six to 12 years will be randomized to receive either F/TAF or FTC/TDF (continuing on their third agent) for 96 weeks.
A study in infants and children aged four weeks to six years is planned. Reduced dose tablets and a non-solid formulation are in development. As with the pediatric formulation of TDF, the taste of TAF is bitter and will need masking. Because of TAF's low milligram dose, taste masking might be easier than it was for TDF.
A phase II/III, single arm, open label study of once-daily E/C/F/TAF in treatment-naive children and adolescents aged six to18 years is ongoing.23 There is a waiver for children less than six years old.
Data were recently presented from the phase II/III for 48 treatment-naive 12 to 18 year olds with a median age of 15 years receiving E/C/F/TAF for 24 weeks.24
Steady-state pharmacokinetic parameters of EVG, COBI, FTC, TAF and tenofovir (TFV) were compared to adult exposures. The study found TAF (as well as TFV, EVG, COBI, and FTC) pharmacokinetic parameters in adolescents to be consistent with those associated with safety and efficacy in adults.
A scored 25 mg etravirine (ETR) tablet with dosing recommendations for treatment-experienced children and adolescents aged six to 18 years and weighing at least 16 kg is currently approved.25 The recommended dose is based on 5.2 mg/kg twice daily.
IMPAACT P1090 is evaluating the drug in treatment-naive and -experienced children aged two months to six years.26 Phase I/II studies in the younger age groups are currently enrolling treatment-experienced children. There is a waiver for infants less than two months.
Rilpivirine (RPV) is approved for treatment of adults 18 years old and above with viral load less than 100,000 copies/mL. The originator company Janssen has submitted applications for an adolescent indication (12 to 18 years) to the FDA and EMA.
PAINT (Pediatric study in Adolescents Investigating a New NNRTI TMC278), is an ongoing, open label, 48-week phase II trial looking at RPV pharmacokinetics, safety and efficacy in treatment-naive adolescents aged 12 to 18 years.27
Based on pharmacokinetics, tolerability and efficacy data at four weeks, a dose of 25mg RPV once daily with food was selected28 – providing comparable exposure to that in adults. This dose was effective and generally well tolerated over 24 weeks for the treatment of ART-naive adolescents with viral load less than 100,000 copies/mL.29 PAINT is ongoing.
IMPAACT P1111 is planned in children from two weeks to less than 12 years of age.30 A granule formulation of RPV is in development.
RPV is also being developed as an intramuscular long acting formulation for treatment and prevention (see cabotegravir below).
Once-daily 100 mg doravirine looks promising in adults (see antiretroviral pipeline chapter).
The originator company Merck has submitted pediatric plans to FDA and EMA for doravirine as a single agent and as an FDC: doravirine plus TDF plus 3TC. The plans are being discussed with the regulatory agencies. The current aim is to enroll populations similar to those in adult phase III studies: treatment-naive and stable experienced patients for switch studies.
PROTEASE INHIBITOR
Lopinavir/ritonavir
As described above, the FDA has recently tentatively approved LPV/r pellets for young children. DNDi and Cipla are now developing a more palatable version of LPV/r granules in 4-in-1 FDCs with two NRTIs, ABC or AZT, plus 3TC. The granule formulation of LPV/r will be tested in HIV-negative adults very soon. The plan is to have the 4-in-1 by 2016.
RAL is approved for infants and children from four weeks of age.31 For the youngest age group (four weeks to less than two year olds, weighing 3 kg to 20 kg) it is formulated as an oral suspension. This comes in single-use packets of banana-flavored granules containing 100 mg of RAL, which is suspended in 5 mL of water giving a final concentration of 20 mg/mL.
For older children there is an orange-banana flavored, chewable pediatric formulation. Because the formulations are not bioequivalent, chewable tablets and the oral suspension are not interchangeable and have specific guidance.
The pediatric program is ongoing including in neonates below four weeks of age (both HIV-infected and exposed) infants. 32,33, 34, 35, 36, 37
Elvitegravir (EVG) is an integrase inhibitor given with a booster and mostly used for adults in the FDC containing EVG/COBI/FTC/TDF (E/C/F/TDF). It is also being developed as part of E/C/F/TAF.
Exposures in adolescents 12 to 18 years old receiving 150 mg once daily EVG plus a RTV-boosted protease inhibitor-optimized background regimen, showed comparable exposures to those seen in adults.38
Two pediatric formulations are in development: a 50 mg tablet and a 5 mg/mL suspension. Single-dose pharmacokinetics evaluations compared two formulations to the 150 mg adult formulation (all boosted by RTV) in a crossover study in HIV-negative adults.39
In this study, both pediatric formulations were bioequivalent to the adult formulation. The RTV-boosted formulations are being evaluated in children in an ongoing phase II/III study in children aged 4 weeks to 18 years of age.40
PENTA 17 will evaluate EVG with DRV/r in stable, virologically suppressed children.
EVG is also being studied in treatment-naive adolescents aged 12 to 18 years as part of the adult FDC, E/C/F/TDF containing EVG 150 mg, COBI150 mg, FTC 200 mg and TDF 300 mg.41 Early data has shown similar exposures of all the individual agents to adults and good virologic suppression.42 Study of E/C/F/TDF in adolescents and children continues.
DTG is manufactured by ViiV and is approved for adults and children aged 12 years and above. It is currently under investigation for use in all age groups from birth. DTG has shown good safety, efficacy and tolerability so far, does not require boosting and has a low milligram dose. There is a lot of interest in this drug as an option for adults and children for first- and second-line regimens.
It is being evaluated for children in IMPAACT P1093 – an ongoing, phase I/II, open label pharmacokinetic, safety and efficacy study in children and adolescents in age de-escalated cohorts. 43 Preliminary (24 week) data from the first cohort of the study were included with the adult regulatory submissions and led to the recent approvals.
Twenty-four week data have been presented for children aged 6 to 12 years and 48-week data for children and adolescents aged 12 to 18 years.
Treatment-experienced but integrase inhibitor-naive children (n=11) with viral load greater than 1000 copies/mL were enrolled in an intensive pharmacokinetic evaluation.44
Participants received DTG tablets (10, 25, 50mg) dosed at 1 mg/kg once daily (based on weight bands) added to a stable, failing ART regimen, with optimized background therapy added after the pharmacokinetic evaluation performed between days 5 and 10.
Children were a median age of 10 years, had received prior ART for a median duration of about nine years, and just over half were triple-class experienced.
The dose of 1 mg/kg once a day achieved adequate DTG exposure. Adolescents aged 12 to 18 had also previously achieved exposures comparable to those in adults with the pediatric weight band dose.45 Both age groups showed good short-term safety and tolerability.
In a safety and efficacy evaluation of the older age group, at 48 weeks, 74% of adolescents (n=23), a median of 15 years, achieved virologic suppression to less than 400 copies/mL and 61% less than 50 copies/mL. There were no serious adverse events.46
Reduced-strength 10 mg and 25 mg tablets have been developed for children.
A granule formulation is being used for early studies. In a phase I pharmacokinetic study in healthy adult volunteers the granules were given with and without 30 mL of various liquids and compared to the current tablet formulation given with 240 mL of tap water.47
Participants received a single dose of DTG as a 50 mg tablet (adult formulation) and as 10 g of granule given: with no liquid; with purified water; with mineral water; or with infant-formula milk.
DTG exposures of the granule formulation were all moderately higher than those of the tablet formulation, with or without liquids. Exposure was highest when the granule formulation was given with formula milk.
The granule formulation is currently being evaluated in the six to 12 years of age cohort of IMPAACT P1093. It will be used in the two to six years of age cohort that has begun screening.
The company is developing a dispersible tablet formulation that will be used in future studies and marketed. The granules will not be available commercially.
A treatment strategy trial ODYSSEY (PENTA 20) of DTG in all age groups of children is also planned.
Dolutegravir timeline:
Dispersible tablet formulation end 2015
Pharmacokinetic data from IMPAACT P1093
from 2 to 6 years mid 2017
from 4 weeks to 2 years mid 2019
Comparative efficacy
ODYSSEY (PENTA 20) opens early 2016
Development of a pediatric formulation of the FDC of DTG/ABC/3TC,– currently approved for adults and adolescents aged 12 years and above 48, 49 - is also planned.
The DTG/ABC/3TC PIP requires data from IMPAACT P1093 in two to 12 year old children to inform DTG dosing. Results from the ARROW trial50 (that found once-daily dosing of ABC and 3TC non-inferior to twice-daily in children) will provide data for ABC/3TC once-daily dosing.
The investigation plan also requires the completion of a DTG/ABC/3TC FDC pediatric study in two to 12 year olds. This will be an open-label, switch design and enroll children who are fully suppressed on ART and integrase inhibitor-naive.
The current plan for a pediatric DTG/RPV FDC is as a maintenance regimen in children and adolescents aged six to 18 years and virologically suppressed.
Data from planned adult phase III studies and existing adolescent data from single agents will be used for the 12 to 18 years age group. Providing the adult data supports the maintenance strategy, dosing studies and pediatric FDC development will then go ahead in the 6 to 12 age group.
Cabotegravir and Rilpivirine Long-Acting
Cabotegravir is under investigation as a long-acting formulation with RPV. An age appropriate formulation will be developed for induction and the intramuscular nanosuspension will be the same as for adults.
The final PIP was approved October 2014 and includes pharmacokinetics, safety, tolerability, durability, acceptability and maintenance of cabotegravir and rilpivirine in two to 18 year olds.
There is a waiver for children less than two and a deferral for two to 18 year olds. The PIP will be completed by 2018, so although the idea of long acting formulations might be appealing for children and adolescents, it is some way off.
PHARMACOKINETIC BOOSTER
COBI is a CYP3A inhibitor with no antiretroviral activity. COBI 150 mg is approved for adults as a booster of atazanavir (ATV) 300 mg or DRV 800 mg, including in co-formulated tablets.51, 52 It is also under investigation for children and adolescents aged at least six years as a part of the FDCs: E/C/F/TDF and E/C/F/TAF.
A 50 mg pediatric immediate-release tablet and a 20 mg pediatric dispersible tablet are in development.
COBI is being studied in treatment-experienced children aged three months to 18 years who are suppressed and on RTV boosted ATV- or DRV-containing regimens.53 The study will switch children from RTV to COBI and look at steady state pharmacokinetics and confirm the dose. It will also evaluate the safety, tolerability, and efficacy of ATV/COBI or DRV/COBI. Reduced dose co-formulations are planned.
The pediatric maraviroc (MVC) study is still ongoing in children aged two to 18 years who are infected with CCR5-tropic virus (virus variants that use the CCR5 receptor for entry). This drug will not work for people with CXCR4-tropic virus or in dual- or mixed-virus (CCR5/CXCR4) populations.54
Dosing of MVC is complex and determined by body surface area and concomitant medications. 55 Wide use of MVC is not expected.
What Needs to be Done?
With a few modifications, most of the recommendations from previous years remain:
Implement WHO recommendations. As simpler formulations identified to implement the guidelines become available (most topically this year LPV/r pellets), countries must ensure that they are swiftly approved and distributed, with appropriate training for health workers.
Ensure that patents are not an obstacle. The MPP is putting a lot of emphasis on pediatric antiretrovirals and has now negotiated patent sharing agreements with ViiV, Gilead, Bristol-Myers Squibb, Merck/MSD and Abbvie – which takes care of the priority products in most low- and middle-income countries with large pediatric HIV epidemics. Licenses for the drugs in development need to make it easy to transfer patent agreements from one age band to another as approval is gained.
Speed up approval. The gap needs to be narrowed between approval of new drugs for adults, children, and neonates. An evidence base to support not always taking a de-escalated age band approach when studying new drugs is needed. Harmonization of regulatory requirements (including age categories and weight bands) between stringent authorities, WHO prequalification, and national authorities is needed to help speed up approval.
Coordinate procurement. Guidance on optimal formulations needs to be easily available to countries and updated as better ones become available. Companies need to be informed of the priority formulations. Donors need to ensure the availability of low volume products in a diminishing market.
All links last accessed 12 June 2015.
CROI – Conference on Retroviruses and Opportunistic Infections
IAS – International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
Food and Drug Administration (US). Tentative Approval letter. 21 May 2015. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.pdf
Food and Drug Administration (US). Approved and Tentatively Approved Antiretrovirals in association with the President's Emergency Plan. http://www.fda.gov/InternationalPrograms/PEPFAR/ucm119231.htm
Medicines Patent Pool. Press release. The Medicines Patent Pool (MPP) signs licensing agreement with Abbvie for pediatric formulations of lopinavir and ritonavir. 1 December 2014. http://www.medicinespatentpool.org/mpp-signs-licensing-agreement-with-abbvie-for-hiv-paediatric-formulations-of-lopinavir-and-ritonavir/
World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 30 June 2013.http://www.who.int/hiv/pub/guidelines/arv2013/download/en/
Musiime V, Fillekes Q, Kekitiinwa A, et al. The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in African HIV-infected children. JAIDS 2014; 66(2): 148-154. http://journals.lww.com/jaids/Citation/2014/06010/The_Pharmacokinetics_and_Acceptability_of.6.aspx
Kekitiinwa A, Musiime V, Thomason M, et al. Acceptability of lopinavir/r minitabs, tablets and syrups in HIV-infected children. CROI 2015. 23-26 February 2015. Seattle, WA. Poster abstract 955. http://www.croiconference.org/sites/default/files/posters-2015/955.pdf
National Institutes of Health (US). Prospective study of Lopinavir Based ART for HIV Infected childreN Globally (LIVING Study). https://clinicaltrials.gov/ct2/show/NCT02346487
American Academy of Pediatrics. Increasing antiretroviral drug access for children with HIV infection. Pediatrics 2007; 119 (4): 838-845. http://pediatrics.aappublications.org/content/119/4/838.full
World Health Organization. March 2014 Supplement to the 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/
Drugs for Neglected Diseases initiative. Press Release. DNDi is awarded USD 17.3 million from UNITAID to bolster development and delivery of child-adapted antiretroviral (ARV) formulation. http://www.dndi.org/media-centre/press-releases/1514-grant-unitaid-arv.html
Pediatric Antiretroviral Drug Optimization 2 Meeting Report. Forthcoming.
National Institutes of Health (US). Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy. https://clinicaltrials.gov/ct2/show/NCT00042289
National Institutes of Health (US). Safety of and immune response to dolutegravir (GSK1349572) in HIV-1 infected infants, children, and adolescents. https://clinicaltrials.gov/ct2/show/NCT01302847
National Institutes of Health (US). Evaluating the safety and pharmacokinetics of raltegravir in infants. https://clinicaltrials.gov/ct2/show/NCT01828073
National Institutes of Health (US). IMPAACT P1106: Pharmacokinetic characteristics of antiretrovirals and tuberculosis medicines in low birth weight infants. https://clinicaltrials.gov/ct2/show/NCT02383849
National Institutes of Health (US). Safety and pharmacokinetics of raltegravir in HIV-1-exposed newborn infants at high risk of acquiring HIV-1 infection. https://clinicaltrials.gov/ct2/show/NCT01780831
National Institutes of Health (US). IMPAACT P1115: Very early intensive treatment of HIV-infected infants to achieve HIV remission. https://clinicaltrials.gov/ct2/show/NCT02140255
Gilead Sciences. Press Release. Gilead submits new drug application to U.S. Food and Drug Administration for tenofovir alafenamide (TAF)-based single tablet regimen for HIV. 6 November 2014. https://gilead.com/news/press-releases/2014/11/gilead-submits-new-drug-application-to-us-food-and-drug-administration-for-tenofovir-alafenamide-tafbased-single-tablet-regimen-for-hiv
Gilead Sciences. Press Release. Gilead submits new drug application to U.S. Food and Drug Administration for fixed-dose combination of emtricitabine/tenofovir alafenamide for HIV treatment. 7 April 2015. https://www.gilead.com/news/press-releases/2015/4/gilead-submits-new-drug-application-to-us-food-and-drug-administration-for-fixeddose-combination-of-emtricitabinetenofovir-alafenamide-for-hiv-treatment
Gilead Sciences. Press Release. European Medicines Agency validates Gilead's marketing application for fixed-dose combination of emtricitabine and tenofovir alafenamide for HIV treatment. 28 May 2015. http://www.gilead.com/news/press-releases/2015/5/european-medicines-agency-validates-gileads-marketing-application-for-fixeddose-combination-of-emtricitabine-and-tenofovir-alafenamide-for-hiv-treatment?
National Institutes of Health (US). Emtricitabine/tenofovir alafenamide (F/TAF) in HIV-1 Infected Children and Adolescents Virologically Suppressed on a 2-NRTI-Containing Regimen https://clinicaltrials.gov/ct2/show/NCT02285114
National Institutes of Health (US). Pharmacokinetics, safety, and antiviral activity of the elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (E/C/F/TAF) single tablet regimen (STR) in HIV-1 infected antiretroviral treatment-naive adolescents. http://clinicaltrials.gov/show/NCT01854775
Lawson E, Shao Y, Sean Bennett S, et al. Week-24 data from a phase 3 clinical trial of E/C/F/TAF in HIV-infected adolescents. CROI 2015, 23-26 February 2015. Seattle, WA. Poster abstract 953.
http://www.croiconference.org/sessions/week-24-data-phase-3-clinical-trial-ecftaf-hiv-infected-adolescents
Food and Drug Administration (US). Intelence (etravirine): pediatric dosing recommendations and new scored 25 mg tablet for pediatric dosing. 26 March 2012.
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm297471.htm
National Institutes of Health (US). Evaluating the safety and tolerability of etravirine in HIV-1 infected infants and children. http://clinicaltrials.gov/ct2/show/NCT01504841
National Institutes of Health (US). TMC278-TiDP38-C213 (PAINT): an open label trial to evaluate the pharmacokinetics, safety, tolerability and antiviral efficacy of TMC278 in antiretroviral naive HIV-1 infected adolescents. http://clinicaltrials.gov/ct2/show/NCT00799864
Crauwels H, Hoogstoel A, Vanveggel S, et al. Rilpivirine pharmacokinetics in HIV-1-infected adolescents: A substudy of PAINT (phase II trial). CROI 2014, 3-6 March 2014, Boston, MA. Poster abstract 900. http://croiconference.org/sites/all/abstracts/900.pdf
Lombaard J, Bunupuradah T, Flynn P, et al. Safety and efficacy of a rilpivirine-based regimen in HIV-infected treatment-naive adolescents: week 24 primary analysis of the PAINT phase II trial. 6th International Workshop on HIV Pediatrics, 18-19 July 2014, Melbourne, Australia. Oral abstract O_05. http://regist2.virology-education.com/2014/6thHIVped/10_Lombaard.pdf
National Institutes of Health (US). Safety, tolerability, drug Interactions, and antiviral activity of rilpivirine in antiretroviral-naive HIV-infected children less than 12 years of age. https://clinicaltrials.gov/ct2/show/NCT01975012
Food and Drug Administration (US). New Isentress (raltegravir) dosage form: oral suspension. December 20, 2014. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm379632.htm
National Institutes of Health (U.S.). Safety and effectiveness of raltegravir in HIV-infected children and adolescents. http://clinicaltrials.gov/show/NCT00485264
Teppler H, Homony B, Welebob C, et al. Raltegravir paediatric development: new options for treating the youngest children with HIV. 6th International Workshop on HIV Pediatrics, 18-19 July 2014, Melbourne, Australia. Poster abstract P_10. http://www.infectiousdiseasesonline.com/wp-content/uploads/2014/07/abstracts_6th-HIVPed_final.pdf
National Institutes of Health (U.S.). Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants. http://clinicaltrials.gov/show/NCT01828073
Clarke DF, Acosta E, Bryson Y,et al. Raltegravir (RAL) pharmacokinetics (PK) and safety in neonates: washout PK of transplacental RAL (IMPAACT P1097) (Abstract O_22). Paper presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012 March 16–18; Barcelona, Spain. http://regist2.virology-education.com/2012/13hivpk/docs/39_Clarke.pdf
Clarke D, Acosta E, Rizk M, et al. Raltegravir pharmacokinetics and safety in neonates (IMPAACT P1097). (Abstract 974). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections: 2013 March 3-6; Atlanta, GA. http://www.retroconference.org/2013b/Abstracts/47397.htm
National Institutes of Health (U.S.). Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at High Risk of Acquiring HIV-1 Infection. https://clinicaltrials.gov/ct2/show/NCT01780831?term=IMPAACT+P1110&rank=1
Gaur A, Abadi J, Wiznia A, et al. Pharmacokinetics and safety of Once-daily Elvitegravir in HIV-infected Adolescents. 17th CROI. February 2010. San Francisco, CA. Abstract 874.
Custodio JM, Liu Y, Graham H, et al. Bioequivalence of two pediatric formulations vs adult tablet formulation of elvitegravir. 21st CROI. 3-6 March 2014. Boston, MA. Poster abstract 902. http://www.croiconference.org/sites/all/abstracts/902.pdf
National Institutes of Health (US). Two part study to study pharmacokinetics, safety, and antiviral activity of elvitegravir (EVG) administered with a PI/r background regimen for ARV treatment-experienced pediatric subjects. https://clinicaltrials.gov/ct2/show/NCT01923311?term=elvitegravir+children&rank=1
National Institutes of Health (US). Pharmacokinetics, safety, and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet regimen (STR) in adolescents.
https://clinicaltrials.gov/ct2/show/NCT01721109?term=elvitegravir+children&rank=3
Chokephaibulkit K, Gaur A, Fourie J, et al. Safety, efficacy and pharmacokinetics of the integrase inhibitor-based Stribild single-tablet regimen in HIV-infected treatment-naïve adolescents through 24 weeks. 6th International Workshop on HIV Pediatrics. 18-19 July 2014. Melbourne, Australia. Oral abstract O_06. http://www.infectiousdiseasesonline.com/6th-hivpediatrics-online-program/
National Institutes of Health (US). Safety of and immune Response to dolutegravir (GSK1349572) in HIV-1 infected infants, children, and adolescents. https://clinicaltrials.gov/ct2/show/NCT01302847?term=dolutegravir+children&rank=1
Viani RM, Alvero C, Fenton T et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children. 21st CROI. 3-6 March 2014. Boston, MA. Poster abstract 901. http://croiconference.org/sites/all/abstracts/901.pdf
Hazra R, Viani R, Acosta E, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093. 19th International AIDS Conference. July 22-27 July 2012. Washington DC. Poster abstract 2UAB0204. http://pag.aids2012.org/session.aspx?s=236#3
Viani RM, Alvero C, Fenton T, et al. Safety and efficacy of dolutegravir in HIV treatment-experienced adolescents: 48-week results. CROI 2014. 3-6 March 2014, Boston, MA. Poster abstract 906LB.
http://croiconference.org/sites/all/abstracts/906LB.pdf
Patel P, Song I, Borland J, et al. Pharmacokinetics of a dolutegravir pediatric granule formulation in healthy adult subjects. 19th CROI. March 5–8 2012. Seattle, WA. Poster abstract 985.
ViiV Healthcare. ViiV Healthcare receives FDA approval for Triumeq. 22 August 2014. http://www.viivhealthcare.com/media/press-releases/2014/august/viiv-healthcare-receives-fda-approval-for-triumeq.aspx
ViiV Healthcare. Triumeq® (dolutegravir/abacavir/lamivudine) single-tablet regimen receives positive CHMP opinion in Europe for the treatment of HIV. 27 June 2014. http://www.viivhealthcare.com/media/press-releases/2014/june/triumeq®-dolutegravirabacavirlamivudine-single-tablet-regimen-receives-positive-chmp-opinion-in-europe-for-the-treatment-of-hiv.aspx
Musiime V, Kasirye P, Naidoo-James B, et al. Randomized comparison of once- vs twice-daily abacavir and lamivudine among 669 HIV+ children in the AntiRetroviral Research for Watoto Trial. (Poster Abstract 977). 20th CROI. 3-6 March 2013. Atlanta, GA, USA.
Janssen. Press release. Prezcobix (darunavir/cobicistat) approved in the US for the treatment of adults living with HIV-1. 29 January 2015.
http://www.janssentherapeutics.com/news-center
BMS Press release. U.S. Food and Drug Administration approves Bristol-Myers Squibb's Evotaz (atazanavir and cobicistat) for the treatment of HIV-1 infection in adults. 29 January 2015.
http://www.bms.com/News/press_releases/pages/default.aspx
National Institutes of Health (US). Pharmacokinetics, safety, and efficacy of cobicistat-boosted atazanavir or cobicistat-boosted darunavir in HIV-1 infected, treatment-experienced, virologically suppressed pediatric subjects.
https://clinicaltrials.gov/ct2/show/NCT02016924?term=cobicistat+children&rank=3
National Institutes of Health (US). An open label pharmacokinetic, safety and efficacy study of maraviroc in combination with background therapy for the treatment of HIV-1 infected, CCR5-tropic children.
http://clinicaltrials.gov/ct2/show/NCT00791700?
Vourvahis M, McFadyen L, Checchio T, et al. Update from Study A4001031: maraviroc pharmacokinetics in CCR5-tropic HIV-1-infected children aged 2 to <18 years. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 30 June – 3 July 2013. Kuala Lumpur, Malaysia.
Poster abstract MOPE044. http://pag.ias2013.org/abstracts.aspx?aid=544


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» Why Do Married Men Cheat
Why Do Married Men Cheat
/ Surviving Infidelity
/ By Daniel Dashnaw
Why Do Married Men Cheat?
Revised 1/6/20
Wives I see in intensive couples therapy want to know "Why do married men cheat?"
When I researched this question, I discovered lots of useless opinions and dubious surveys.
But there is higher quality social science research coming out of our universities about why married men cheat.
Research tells us that there can be many reasons. The following causes are numbered but not ranked in order of importance. However, each reason has some clinical research behind it. It's not just opinion.
Reason #1 Why Married Men Don't Stay Faithful: Men have a Stronger Sex Drive.
Yeah, sounds like an excuse …doesn't it?
A recent study published in Personality and Social Psychology Bulletin suggests that "men are more likely to give in to sexual temptations because they tend to have stronger sexual impulse strength than women do."
So says Natasha Tidwell, lead author of this study conducted at the Department of Psychology at Texas A&M University.
"Men have plenty of self-control — just as much as women…However if men fail to use self-control, their sexual impulses can be quite strong. This is often the situation when cheating occurs."
This is as a comment on how powerful the male sex drive is, not an excuse for poor impulse control. Men who cheat have as much willpower as women, but, according to this study, the temptation to stray in inherently greater.
Self-control, from an evolutionary biology perspective, is one of the new kids on the cognitive block. Tidwell and her team see infidelity, in part, an impulse control issue.
Reason #2 Why Married Men Are Unfaithful: Desire…Frustration…Disconnection
Julia Omarzu is a psychologist at Loras College. She conducted a study of people who were either currently, or very recently, having an extra-marital affair.
This research examined how the participants described their emotional experiences during and after their infidelity.
Unfortunately, the participants weren't acquired from a random source, so the results cannot reliably be generalized to the broader population of the unfaithful.
And this study wasn't just limited to men. Researchers may one day revisit the Omarzu study and credit it for helping to clarify where more research is needed. Omarzu is a helpful new addition to our understanding of the emotional context of infidelity.
Reason #3 Why Married Men Have Affairs: Lack of Sexual Satisfaction in the Marriage.
The Omarzu study suggests that marital sexual unhappiness may draw some men into affairs.
Some men are comfortable compartmentalizing their sexual desires, but describe their marriage as an otherwise "happy" one. These "happily" married men are often distressed in couples therapy when they realized that their marriage and family were in jeopardy because of their behavior.
Power, privilege, and a sense entitlement also have a role to play with these otherwise "happy" husbands. This is backed up by other research which suggests that the greater the income disparity between a couple, the greater the likelihood of infidelity.
Reason #4 Why Married Men Cheat: Lack of Emotional Intimacy in Marriage.
I found some arguments and pseudo-research that claimed that this was the number one reason for men, but I could see little credible academic research to back it up.
Lack of emotional intimacy is, however, more of an issue for unhappily married women. But it is also true for some men.
Overall, men are reporting somewhat more emotional involvement with their affair partners than 30 years ago, but it's still not a dominant factor. There's a difference between enjoying attention and flattery, which is a very common feature, and deep emotional involvement, which is not.
Reason #5 Why Married Men Wander: Validation Vulnerability.
Men hunger for appreciation. While this is a profound emotional need, it lacks the bi-directionality of intimacy.
Men often get drawn into workplace affairs because they become addicted to the approval and validation they feel from their affair partner.
Validation, admiration, and appreciation are some of the well-worn tools of the workplace mate-poacher.
Reason #6 Why Married Men Cheat: Restlessness, Pursuit of Novelty, and Desire for Autonomy.
This research finding was similar to research by Allen and Baucom (2004). That study found that men with a Dismissive-Avoidant attachment style would cheat as a way to distance from their spouse. Attachment science is helping us to learn more about infidelity.
Other research by Del Giudice (2011) and Feeney (1999) demonstrated that men are more likely to develop a Dismissive-Avoidant attachment style, while women tend to acquire an Anxious-Avoidant Attachment style.
Less Common Reasons Why Married Men Cheat From the Omarzu Study
Reason #7 Why Married Men Cheat: I'm Not in Love…You'll Wait a Long Time For Me.
In the Omarzu study, relatively few men reported that they cheated because they fell out of love with their spouse.
Also less common are married men who cheat because they fall in love with their affair partners, but it does happen.
Numerous studies indicate that the reasons why married men cheat have little to do with a feeling that they are "out of love" with their partner. The reason why married men cheat has less to do with love or limerence. Because a Dismissive-Avoidant attachment is so prevalent among men, they tend to be much more casual and superficial in their infidelities than women.
Reason #8 Why Married Men Cheat: Limerence.
This finding surprised me, and I would like to see more research on affairs and limerence. Limerence is a peculiar phenomenon of "love-sickness" which tends to fade after 18 months or so. Very few Men in the Ormazu study reported that they had become infatuated or obsessed with their affair partner. Sexual satisfaction, validation, and to a somewhat lesser extent, emotional intimacy were more commonly reported reasons why married men cheat than limerence.
Payback Affairs. Getting even with a cheating partner is a familiar theme in Hollywood movies, but it rarely plays out that way in real life. It does happen…just not that often.
Why Do Married Men Cheat? Attachment Science is Providing New Answers
The individual attachment styles of men are a template for understanding their sexual behavior.
Men may use their sexual behavior a tool to achieve an optimal "comfort zone" for whatever degree of intimacy they can tolerate in their marriage.
According to Cooper (2006), securely attached men are more likely to confine their sex life to their committed relationship, and securely attached couples are less likely to grapple with extra-marital affairs.
As this research begins to inform clinical practice, science-based couples therapy will become even more successful in treating infidelity by helping distressed couples to develop a secure attachment.
Heal from an Affair in a Science-Based Couples Retreat.
Call us for more information at 844-926-8753 to reach Cindy at extension 2.
Allen, E.S. & Baucom, D.H. (2004) Adult attachment and patterns of extra-dyadic involvement. Family Process,43, 467-488.
Cooper, M.L. Pioli, M., Levitt, A., Telly, A. E., Micheas & Collins, N .L. (2006). Attachment styles, sex motives, and sexual behavior. In M. Mikulincer & G.S. Goodman (Eds.) Dynamics of Romantic Love: Attachment, caregiving, and sex (pp. 243-274) New York, NY: Guilford Press.
N. D. Tidwell, P. W. Eastwick. Sex Differences in Succumbing to Sexual Temptations: A Function of Impulse or Control? Personality and Social Psychology Bulletin, 2013.
Omarzu, J., Miller, A. N., Schultz, C., & Timmerman, A. (2012). Motivations and emotional consequences related to engaging in extramarital relationships. International Journal Of Sexual Health, 24(2), 154-162.
About the Author Daniel Dashnaw
Daniel is a Marriage and Family Therapist. He currently sees couples at Couples Therapy Inc. in Boston, Massachusetts, three seasons in Cummington (at the foothills of the Berkshires...) and in Miami during joint retreats with his wife, Dr. Kathy McMahon. He uses EFT, Gottman Method, Solution-focused and the Developmental Model in his approaches.
8 Predictable Issues in Leaving Your Marriage for Your Affair Partner
Should You Confront Your Husband's Affair Partner?
9 Essential Pathways to Rebuilding Trust With Your Betrayed Spouse
Stages of Mid-Life Crisis Affairs
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A calm and overcast Florida afternoon was the perfect setting for this active, sports loving couple. Kemonte a lover of sports was calm and collected throughout the day. Danielle, who coaches volleyball, was a stunning bride. The wedding and reception was held at Delray Beach Golf Club. The venue was packed with more guests than anticipated. The couple committed their lives to one another in a sweet and light hearted ceremony. After the ceremony, Danielle and Kemonte celebrated with family and friends inside the venue. The passion and love between these two was noticed by all who attended.
Danielle was born and raised in Florida with a passion for sports, especially volleyball. She loves to use her creativity to make beautiful art and her style was evident throughout the ceremony. Kemonte, a Tennessee native loves gaming and even played baseball during college. When Kemonte met Danielle at Bryan College in Tennessee five years ago, he immediately knew she was the woman he was meant to be with forever. Danielle was attracted to Kemonte's calm demeanor and great sense of humor. The couple bonded over their shared love of sports, gaming and even baking! They are a dynamic duo for sure.
The day was made even more special by starting at Danielle's Family home. The lake backdrop made for a stunning first look where the couple had a brief moment to themselves. Danielle and her bridesmaids enjoyed a few mimosas on the deck to relax before the ceremony began. The ceremony at Delray Beach Golf Club was serene and the venue was packed. A large crowd of guests watched Danielle walk down the aisle in a gown by Alfred Angelo. As requested during ceremony, the pastor made a few jokes to keep the mood lite. Shortly before sunset the couple exchanged vows and committed their lives to one another. The moment was powerful.
Not to risk their reception to the ever-changing Florida weather the couple decided to have the reception indoors. The couple joined family and friends at the Delray Beach Golf Club to dance the night away. Danielle and Kemonte selected "Thinking About You" by Ed Sheeran as the song for their first dance. Guests enjoyed a photo booth and delicious food and drinks that lasted all evening. As Danielle and Kemonte left the ceremony they were sent off in style by the large crowd and were anxious to start their honeymoon!
Danielle and Kemonte were thrilled to start their honeymoon as newlyweds. The couple took a cruise through Key West, Florida and then onto Cozumel, Mexico. They enjoyed relaxing after a stressful season of wedding planning. As an active fun loving couple, their marriage is sure to be an adventure!
See all the images from the wedding here.
Photographic Team Members: Vanessa and Diego Velez, Lenisse Komatsu and Kristen Browning.


Paris Saint-Germain manager Thomas Tuchel is rumored to be interested in Maximilian Eggestein and Arne Maier.
Ligue 1 kicked off this weekend, and the champions from PSG were off to a flying start, beating Caen 3-0 at home.
However, not all seems to be going well at the club as central midfielder Adrien Rabiot is said to be refusing an extension on his contract and is looking for a move away from the French capital.
The former Dortmund manager Thomas Tuchel could be looking towards the Bundesliga for options to replace the Frenchman in the shape of Werder Bremen's Maximilian Eggestein and Hertha Berlin's Arne Maier, French media outlet Paris United understands.
Maier and Eggestein are both young midfielders coming off good seasons for their respective teams, and Tuchel is said to have taken a liking to the players.
As PSG have already sold Javier Pastore earlier in the summer, options at central midfield are looking slim which could signify that Tuchel sees the Germans as more than just squad depth.


Some Secrets of Hex Nut Fasteners - Haiyan Julong Standard Part Co., Ltd.
Hex Nut fasteners are the female part of the hardware family. These are used along with their male mate i.e. the bolts in order to join the physically separable things. Let us take an example of an automobile. In this, various systems are assembled together. These systems are developed separately and perform various functions. So, to assemble different systems nut & bolt fasteners are used. There are numerous other examples that prove that how significant are the industrial fasteners for various industries. Industries like automobile, aircraft, manufacturing, production, construction, instrumentation, etc., all use these extensively for various applications.


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16 December 2021 21 December 2021 Felpham Sailing Club
You probably already know that most cruise ships have always had casinos. But did you know that casino gaming was only allowed when the ship was sailing in most parts of the world? The reason for this was to avoid going against the gambling laws where the vessels docked.
Gambling when sailing makes a lot of sense because, just like sailing, gambling involves testing unknown waters. That is why it is the perfect thing to have sailing-themed games in modern casinos.
The idea has been best exemplified in online casinos like mfortune-freespins.co.uk, making it easy to create numerous games. Sailing lovers can now enjoy such games in their favourite casinos.
Sailor-Themed Slots
Slots allow users to use their creativity more than with other casino games. Unlike roulette, where the wheel has definite characteristics, slots allow the developer to play with features like the number of reels, scatter symbols, and reward coins.
Sailor-themed slots use the same principle as ordinary slots but then use things that sailors encounter as symbols. These include boats/yachts, sailor hats and clothes and water creatures. Playing these slots feels like navigating the waters and exploring the unknown.
Some of the best slots for lovers of sailing include Ocean Princess, Lucky Blue, Sails of Gold, Mermaid Millions, Lord of the Ocean, Maritime Maidens and Queen of the Atlantis. You can also sample Ocean Rush, Dolphin's Pearl, Orca, Ariana, Cash Wave and Lucky Fishing.
The list is long, and the names are particularly creative. You can play some of these games for free and others for real money.
In slot gaming, the theme plays a huge role in the player's satisfaction. Having a sailor theme alone should make these games fun for sailing lovers. The winning then comes as an impressive bonus!
28 August 2021 Felpham Sailing Club
Sailing lovers in the UK are spoilt for choice when it comes to sailing clubs. People...


Isaac Bledsoe was born in Culpepper County, Virginia, but as a young man settled with his brother Anthony on the Holston River a few miles west of Bristol. After serving with British colonial troops in Lord Dunmore's War, he hunted and explored extensively along the Cumberland River. In 1772 he discovered Bledsoe's Lick and Bledsoe's Creek in an area of North Carolina that later became Sumner County, Tennessee. He was a captain in Colonel William Christian's Cherokee expedition in 1776; the next year he commanded a company to protect the border settlements. During the autumn of 1779, Commissioners Thomas Walker and Daniel Smith chose him for the party to survey the Virginia-North Carolina state line. They selected him for his firsthand knowledge of the western country, but he went in order to select a site for the stockaded fort he had agreed to build near Bledsoe's Lick as part of the proposed Cumberland settlements. One of the court of triers of the original Cumberland Association, Bledsoe was a justice of the peace in the first Davidson County Quarterly Court in 1783, first major of the county militia, and a guard for the surveyors of the North Carolina Military Reservation. When Sumner County was created from eastern Davidson County in 1786, Bledsoe served in the first Sumner County Quarterly Court, was first major of the county militia, and became lieutenant colonel commandant in April 1788.
In 1772 Isaac Bledsoe married Katherine Montgomery, a sister of the veteran frontiersman Colonel John Montgomery. The Bledsoe family lived at Mansker's fort in 1782-83, but moved into Bledsoe's fort about 1784. They had eight children. Indians shot and killed Isaac Bledsoe while he was working in a field near his fort on April 9, 1793. Eleven months later, his son Anthony fell mortally wounded in an Indian attack near Daniel Smith's Rock Castle home.


For the footy loving parents and bub, this premium fun gift hamper featuring plush first footy, quality bib, cute kicker socks, muslin wrap and bottle of Moet will no doubt bring lots of footy fun! A quality gift that has a serious cute factor and will be remembered!Gift also comes in a personalised gift box with baby's name on the box.
Bubba Blue Muslin Wrap - beautiful muslin wrap that is great for swaddling, play rug or simply to keep bub nice and warm.
Tippy Toes Kicker Socks - Set of 6 - Simply adorable these oh so cute socks will complete any outfit.
Moet & Chandon 750ml - beautiful bottle of French Moet and Chandon for mum and dad to enjoy. Presented in a stunning gift box.
Gorgeous gift card with your personal message.


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Q: AngularJS no output I've started learning AngularJS using some tutorials on youtube.
In a tutorial there's this code but when I coded it , the browser won't show the properties.
How to solve it?
This is my index.html
<!DOCTYPE html>

<meta charset="utf-8"/>
    <title>

    </title>

            First Name : {{ employee.firstName }}

            Last Name : {{ employee.lastName }}

            Age : {{ employee.age }}

And this is my script.js file
var myApp = angular.module("myModule",[]);
myApp.controller('myController', function($scope){

        var employee = {
            firstName : "abcd",
            lastName : "efgh",
            age : 24
        };

        $scope.employee = employee;
    });

In the browser it displays like this
 First Name :
 Last Name :
 Age :

Why don't it show the property details ? I mean "abcd" as the first name and so on ?
EDIT :
Still having the same problem when I'm trying to insert an image. It workds on Codepen.io and here's the link
http://codepen.io/speco92/pen/jAQdAv
But when I checked it on my pc (localhost)image file won't load. Other object properties loads.
Here it's included screenshots of my TestMyAngular.html , script.js and the result in the browser as well !
https://postimg.org/gallery/2g08oma4q/
How to solve it?

A: Can you please tell how you are running your angular app??
are you directly opening the pages in browser??
angular application cannot be opened by the filepath on the local machine because ofcross origin domain errors. You need to use some server like http-server

A: Your code is working.
Given that you are starting to learn AngularJS you may not know that you cannot simply double-click on your index.html to see the results.
If your default browser is Google Chrome, it will not work because google chrome does not allow javascripts to be run from file system.
You can open your index.html with Firefox for example.
If you still want to use Google Chrome your should use a webserver

redpajama_set_name: RedPajamaStackExchange


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You are here: Home / Europe / UK / Bristol
Mini-Guide To Bristol
Much of what goes on in Bristol centres around the newly redeveloped harbour area with much of the nightlife, shops and restaurants located there. The region's largest IMAX cinema is based there along with a planetarium and botanical gardens. The City has an award winning Zoo which was voted Zoo of the Year in 2004. The underwater areas housing seals and penguins and also the rainforest zone's are spectacular and well worth a visit.
Local Airports In Bristol
Bristol International Airport, UK, Europe
Bristol is well located with the M4 giving access to London and Cardiff via the new Severn Bridge and the M5 making Devon and Birmingham accessible with an a short drive. By train, Bath is just over 10 minutes away and the Cotswolds, Somerset and Cardiff being a short journey away. Getting around the city is easy, and free maps of the city can be downloaded from the official tourism website. Most locations in the city centre are within walking distance – including the Harbour side and Old City areas – and there are various pleasant routes along the quaysides and pedestrianised roads. The city's bus service is regular and reliable, and the purchase of a day ticket will allow you to ride them with in the city centre with no extra charge for the rest of the day. There is plenty of parking available within the city centre, so if you arrive by car there are various options, including the three park and ride stations outside the city. There is plenty to do in the city as well: - The SS Great Britain is preserved in dry-dock by the floating harbour. It was the first steam-powered passenger liner, built by Brunel in 1843. - @Bristol is the city's science centre and planetarium, with hundreds of interactive displays. - Castle Park and St Peter's Church, which contains the excavated ruins of Bristol Castle and the remains of the church which was destroyed during the bombing of WWII. It was left to stand as a memorial to those who had died. - Clifton Suspension Bridge, which offers a fantastic view of the Avon Gorge and the surrounding area.
Who flies to Bristol?
Air France Book online now...
bmibaby Link
Eastern Airways Click to book
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Thomsonfly Book online now...


The architecture of Nextcloud is a classic Web Application architecture. I picked this architecture 7.5 years ago because it is very well known and is proven to be scaled relatively easily. This usually works with off the shelf technologies like http load balancers, clusters of Linux webservers and clustered databases.
But for many years users and customers asked for ways to distribute a single instance over several datacenters. A lot of users and customers run organizations that are not in one office or sometimes not even in one country or on one continent. So how can the service run distributed over different hosting centers on different continents?
Until now there was no good answer for this requirement.
Over the years I talked with users who experimented with different approaches. Unfortunately, they all didn't work.
If you talk to storage people how to solve this challenge they say: No problem. Just use a distributed storage system like Gluster, Ceph, Hadoop or other.
If you talk to database people and how to do this they say: No problem! Just use one of the cluster and replication systems for Oracle, MySQL, MariaDB and others.
The challenge is how this all works together. If a user changes a file in Nextcloud then it is necessary that the file is changed, potential encryption keys are updated, log files are written, database tables are changed, email notification are sent, external workflow scripts are executed and a lot of other things happen. All these operations that are triggered by a single file change have to happen in an atomic way. It happens completely or not at all. Using database replication and storage replication independently will lead to a broken state and data loss. Additional problems are that you need the full bandwidth and storage in all data centers. So there is a lot of overhead.
The Global Scale architecture, that we designed, is currently the only solution, as far as I know, which solves this challenge.
Additional benefits are that the storage and database and overall operational costs decreases because simpler, commodity and more standard components can be used.
Another benefit is that the locality of data can be controlled. So if it is a legal requirement that certain files never leave a certain jurisdiction then this can be guaranteed with the right GS Balancer and File Access Control settings.
So far I only talk about the benefit that GS breaks a service down into several data centers. This is only half of the truth. Nextcloud Global Scale can be used in an even more radical way. You could stop using clustered Nextcloud instances in general. Killing all central storage boxes and databases and move completely to commodity hardware. Using only local storage and local databases and local caching. This changes the world completely and makes big storages, SAN, NFS and object store boxes completely obsolete.
The Global Scale architecture idea and implementation were developed over the last year with feedback and ideas from many different people. Storage experts, Database vendors, Linux distribution people, container and orchestration experts for easy automatic deployment and several big customers and users of Nextcloud.
The main inspiration came out of long discussions with the people at DeiC are running the National Research and Education Network of Denmark. DeiC was doing successful experiments with a similar architecture for a while already.
At Nextcloud we are committed to develop everything we do as open source. This includes this feature. Also, if you want to contribute to this architecture then no Contributer License Agreement is needed and you don't need to transfer any rights to the Nextcloud company.
I have a wide spread Family, all with their own Internet Provider, router and sometimes really slow internet connection.
If I setup a RaspberryPi for every accommodation, could I create with Nextcloud a distributed Backup solution that guarantee that the Families hold backups from each other?
The Idea is also that I have one little public php Webhost with a Domain. This Nextcloud instance do not store any data but act as node which connect all other RaspberryPi Nextcloud and handle their dynamic DNS.


HIGH POINT, N.C., Feb. 1, 2019 – Today, High Point University contributed $1 million to Bennett College to support Bennett and rally others to help the college reach their $5 million fundraising goal.
View the social media announcement here.
PHOTO ABOVE – Bennett College President Dr. Phyllis Worthy Dawkins gives High Point University President Dr. Nido Qubein a thumbs up as they speak to a crowd of Bennett College and High Point University students inside HPU's Hayworth Chapel, where Qubein made the $1 million contribution announcement. HPU is contributing $1 million to inspire others to support Bennett in reaching their final $5 million campaign goal. The $5 million will allow Bennett to make an appeal to the Southern Association of Colleges and Schools Commission on Colleges (SACSCOC) to reinstate its accreditation.


First of all, if you've been reading along but haven't played the game, go do it before reading this arc. This is the point of no return. Much of this game is the mystery, and this route lays all the cards on the table, so enter at your own risk.
Also, the gutsyness of this being called the "Massacre Arc" when every other arc has ended in the death of the entire cast is amazing. What could this arc possibly do to be more of a massacre than everything before it?


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Home » Tablets » Huawei MediaPad 7 Vogue Now Official, Provides Calling and 3G Function...
Huawei MediaPad 7 Vogue Now Official, Provides Calling and 3G Functionality | TechTree.com
Huawei MediaPad 7 Vogue Now Official, Provides Calling and 3G Functionality
Huawei's new MediaPad tablet weighs in at 335g, and has a 4100mAh battery.
13:00 25th Jun, 2013
Huawei has made its new tablet, the MediaPad 7 Vogue official. The MediaPad Vogue 7 would be available both in 3G and Wi-Fi only variants, and supports voice calling. Huawei's new slate runs on a quad-core processor, and as its name suggests, the tablet has a 7-inch IPS touch screen. With its 1GB RAM and the 1.2 GHz quad-core processor combination, running certain (not all) high-end games is also possible, in the Huawei MediaPad 7 Vogue.
This 7-inch slate with its calling functionality can be expected to compete most prominently with Samsung's recent GALAXY Tab 3. Asus' Intel powered offering, the Fonepad, also has the potential to be a likely adversary to the Huawei MediaPad 7 Vogue, when brand reputation (in India) and high-end nature are taken into consideration.
As of now, the pricing of the Huawei Vogue slate is not known, but what is known is that the device would initially be released in China, after which other markets would receive the tablet. Technical specifications of Huawei's MediaPad 7 Vogue are:
7-inch multi-touch screen, IPS panel, 1024x600 pixels
SIM-card support for calls
Android 4.1 (Jelly Bean) operating system
1.2GHz quad-core processor, and a 16-core GPU
8GB internal storage
MicroSD card slot for expansion up to 32GB
3 MP rear camera, and a VGA front camera
3G, Wi-Fi and Bluetooth 4.0 connectivity
4100 mAh Li-Ion battery that is claimed to provide 20 hrs continuous calling on a single charge
Weighs 335 grams
Huawei says that users can expect an integration of Facebook, YouTube, GPS Navigation and word processor, within the MediaPad 7 Vogue tablet device. Huawei has also built-in its Emotion User Interface that is present in the company's Ascend P6 smartphone (touted as the "World's slimmest smartphone") offering. The new MediaPad's USP is its 4100mAh battery, apart from its calling and 3G functionality. That battery places the device in the league of the Asus Nexus 7 that comes with a 4325 mAh battery that is expected to provide a backup time of 9 hrs.
Buyers of this product can always hope that Huawei would provide an upgrade to the Android 4.2 platform.
TAGS: Huawei, Tablets, Android, jellybean


can someone help me out with some poppy seeds?
I've got some Miner's Ghost you can have.
miners ghost?? p.m me man...!
in which somniferum variation are you interested in ?
seedring could maybe help you, or i could also send you seeds with pleasure.
I'm only several days away from a super-fresh batch of backyard Tassie seeds, if you after any.
I have a couple of types if your interested.
I also have some selfed and backcrossed seeds from my Paoeny/Persian white cross that I did last year.
hey,hey Garret ! :D how are you ?
i remember this beautifull pink flower ! and if my remembering is well only one of your pods gave you white seeds ?! do i have a chance getting some of these particular one ?
Hey reshroomed - can you tell me what miners ghosts are??
some said they are from asia, in a particular located place and some other said they are from Izmir farm and are only a taz/giant cross.
anyway i always see the same pict and i am really curious to see more differents one to understood the strain(i mean variation...) traits.


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TWICE's "Likey" MV Beats Their Personal Record For Most Views In 24 Hours
by J. K
TWICE's latest MV was watched more in its first day than their previous hits!
On October 30 at 6 p.m. KST, TWICE released their music video for "Likey," which is the fun title track off their new album "Twicetagram."
As of October 31 at 6 p.m. KST, the MV had reached 10,767,044 views on YouTube!
TWICE's "Knock Knock" previously set the group's personal record for highest views in 24 hours when it was viewed 9,857,751 times in its first day back in February.
"Likey" is now the K-pop group MV with the fourth highest views in the first 24 hours. The top three spots are held by BTS's "DNA," BLACKPINK's "As If It's Your Last," and BTS's "Not Today."
Congratulations to TWICE!
MV Record


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Aster-Obit: Betty White
Just as the year 2021 came to its close, so did the life of Betty White, one of the most beloved entertainers in America. Fate was oftentimes a friend to Betty throughout her long life, but unkind to her at its end – she expired barely two weeks before her 100th birthday. Just days before her passing, she had tweeted her eager anticipation of the star-studded celebrations planned to commemorate her centennial.
White, who enjoyed the longest career of any female entertainer, was an actor and singer noted for her comedic talents. From the sugar-spiked sexpot Sue Ann Nivens in "The Mary Tyler Moore Show", to the naïve sexagenarian ingenue Rose Nylund of "The Golden Girls" and the acerbic house caretaker Elka Ostrovsky on "Hot in Cleveland", White continued to delight TV audiences for over seven decades with her unique brand of charm and humor.
Born 17 January 1922 at 6:38 PM CST in Oak Park, Illinois (Rodden Rating AA), White's comedic chops were celestially supported, in spades! Asteroid Thalia at 0 Scorpio, named for the Greek Muse of Comedy, is in an out-of-Sign square with the 27 Capricorn Sun, broadly squared Mercury at 10 Aquarius as well. Thalia is also involved in a Grand Trine with Uranus at 7 Pisces and Pluto at 8 Cancer, reflecting her unique style (Uranus) and the deeply transformative influence (Pluto) which comedy (Thalia) would be on her life. This pattern becomes a Kite with the addition of asteroid White at 8 Virgo, opposing Uranus, at its "string", further personalizing its potential to her and guiding the Grand Trine's manifestation.
A memorial grows at Betty White's star on the Hollywood Walk of Fame; with asteroid Thalia, named for the Muse of Comedy, in square to her Sun, and asteroid Hilaritas, the root of our word "hilarity", at station, White had a genius for making people laugh
As well, asteroid Hilaritas, named for the Roman term for merriment and cheerfulness, and root of our word "hilarity", appears at station, making it an embedded factor in White's character and biography. Turning direct just six days after her birth, Hilaritas at 7 Gemini participates in a Grand Trine with Saturn at 7 Libra and Mercury at 10 Aquarius, depicting the comedic (Hilaritas) timing (Saturn/Mercury) for which she was famed. A second Kite is formed by Hilaritas' opposition to asteroid Actor at 10 Sagittarius, identifying her as a professional (Saturn) comedic (Hilaritas) actress (Actor), best known for her work in television (Uranus).
White, identified early in her career as "non photogenic", cut her teeth in radio, but quickly proved her skeptics wrong, eventually being referred to as "the First Lady of Television." But her contributions to the industry didn't end when the cameras stopped rolling. She was among the first women to exert control in front of and behind the camera, and the first woman to produce a sitcom ("Life with Elizabeth", in 1953), a true pioneer who garnered eight Emmy Awards in various categories, three American Comedy Awards, three Screen Actors Guild Awards, and a Grammy Award, with a Guinness World Record as the longest-working performer in television.
A variety of small parts (some unpaid) and supporting roles was followed by Variety TV work (which she hosted and in which she frequently sang) and short-lived series where she starred, supplemented with frequent game show appearances, which together dominated her career in the '50s and '60s. But she struck comedy gold in 1973 when she joined the cast of the smash hit, "The Mary Tyler Moore Show", at first in a guest role, later integrated into the ensemble cast. White made her mark nationally as Sue Ann Nivens, the faux-saccharin, man-hungry host of "The Happy Homemaker", a cooking show filmed at the same station as the newsroom which centered the series. White's Nivens made an art of the double entendre and the backstabbing aside, a master of slopping sugar while she verbally cut one to the quick.
Happy Homemaker Sue Ann Nivens on "The Mary Tyler Moore Show" was White's breakout role; asteroid Niven conjunct career-minded Saturn and celebrity-generating Jupiter tells the tale
A cosmic marker of the importance of this role to her career and fame is seen as asteroids Niven (for character Sue Ann Nivens) at 16 Libra and Mary (for "The Mary Tyler Moore Show") at 13 Libra, which punctuate the zone between natal Saturn (career) at 7 Libra and Jupiter (celebrity) at 18 Libra. These oppose asteroid Moore at 14 Aries with asteroid Betti (alternate spelling of Betty) at 7 Aries, further linking White to the show that made her famous.
When White first appeared on MTM, on 15 September 1973, asteroids Tyler and White conjoined Uranus at 17, 18 and 21 Libra respectively, topping the natal cluster and energizing its potential, and binding the actress to the show. The Sun at 22 Virgo was fast approaching her natal Moon at 28 Virgo, and anchoring a T-Square of asteroids Mary at 24 Gemini, Betti at 24 Sagittarius, and Hilaritas at 25 Sag, once again linking White with the series. Asteroid Niven at 12 Sagittarius conjoined Neptune at 4 Sag, opposed asteroid Moore at 6 Gemini, for the breakout acting (Neptune) role (Niven) on TV's most popular sitcom (Moore). A combination of Thalia at 10 Scorpio with Venus at 2 Scorpio, T-Squared Mars at 9 Taurus and Jupiter at 2 Aquarius on the fulcrum, defines sexuality (Mars) as the characteristic which would propel the female (Venus) comedian (Thalia) to fame and celebrity (Jupiter).
When MTM folded four years later, White was rolled immediately into her own eponymous series, "The Betty White Show", which had the bad luck to be slated opposite Monday Night Football, and failed due to poor ratings after one season. White filled most of the next decade as Ellen Harper Jackson on "Mama's Family", reprising a role she had originated as a guest in sketches on "The Carol Burnett Show" in the '70s. But lightning struck again in 1985 when she was cast in "The Golden Girls", with Rue McClanahan and Bea Arthur.
McClanahan had appeared with White in "Mama's Family", and Arthur and McClanahan had also worked together before, in "Maude." Arthur's role as the daughter of octogenarian Estelle Getty was the show's anchor, flanked by White, originally typecast as the southern sexpot Blanche Devereaux, descending from her Sue Ann Nivens days; and McClanahan, cast as the ditzy ingenue Rose Nylund, based on her passive, homemaker role in "Maude". The ladies took one look at the script, and said, "We want to switch!", and comedy gold was born. The series ran from 1985 through 1992, and White was nominated for an Emmy as "Outstanding Actress in a Comedy Series" every year, winning once. (White was Emmy-nominated a total of 24 times throughout her career, being honored with a Lifetime Achievement Award in 2015.)
Betty White (right) as Rose Nylund on "The Golden Girls", with series co-stars Bea Arthur and Rue McClanahan; asteroid Rosa (closest to Rose) is in a Grand Cross with Saturn (career), Pluto (transformation) and asteroid Betti, for the role that became the zenith of her career
Again, the show's impact on White's biography can be gleaned from her birth chart. Asteroid Golden at 15 Gemini conjoins Hilaritas at 7 Gemini, forming part of the Kite pattern which includes Saturn and Mercury, and is also sesquiquadrate the Sun. Asteroid Rosa (closest to Rose) at 11 Capricorn lies squared to Betti at 7 Aries, allowing White to fully embody the role with a personal connection, and is in a Grand Cross with Saturn at 7 Libra and Pluto at 8 Capricorn, for the transformative (Pluto) part which would catapult her to the zenith of her career (Saturn). (Rosa had already proved a powerful draw on White's legacy, long before GG: in the 1950s, White began a nineteen-year run as hostess and commentator on the annual Rose Parade broadcast on NBC, in essence its public face; in 1975, NBC replaced her as commentator hostess of the Tournament of Roses Parade, feeling that she identified too heavily with rival network CBS's "The Mary Tyler Moore Show".)
When "The Golden Girls" premiered on 14 September 1985 (note, just one day prior to her 1973 entrance into MTM, with a full Jupiter cycle between them), Betti and Hilaritas are once again conjunct, at 2 and 7 Pisces (and activating her natal Kite). These oppose a cluster of Mars with asteroids Golden and Thalia, and Mercury, at 2, 6, 8 and 14 Virgo respectively, for the series that, more than any other, focused on "talking sex" (Mercury/Mars) from women entering their golden years (Golden), with comedy (Thalia, Hilaritas) and grace. In its day, GG was groundbreaking, not only for its frank portrayal of senior sex appetites, but also for its inclusion of gay and lesbian characters and highlighting sensitive issues such as drug abuse, domestic violence, Alzheimer's and HIV/AIDS. Betti/Hilaritas also appears at the Apex of a Yod, or Finger of Destiny, with inconjunct aspects to Golden/Thalia and asteroid Rosa at 3 Libra, again granting White a personal connection to the role that she seemed destined to play.
A well-received Super Bowl XLIV commercial for Snickers in 2010 revived White's career; within six months she was starring in a new series
"The Golden Girls" ended in 1992 with Bea Arthur's departure; at 70, Betty White was at an age when many would be seriously considering retirement. A spinoff, "The Golden Palace", reunited the remaining cast, but, sans Arthur, lacked the punch of their original interplay, and lasted only one season.
But White had one more hit show in her. In 2010, just shy of her 89th birthday, she was cast as Elka Ostrovsky in TV Land's first original series, "Hot in Cleveland", along with Valerie Bertinelli, Jane Leeves, and Wendie Malick, three forty-something friends renting a house for which White was caretaker. The show lasted six seasons, and White received another Emmy nomination as Supporting Actress.
Once again, we find the cosmos supportive of her efforts. Asteroid Cleveland (for "Hot in Cleveland") at 21 Taurus is sesquiquadrate Saturn (career) at 7 Libra, semisquare Betti at 7 Aries; asteroid Elko (closest to Elka) at 12 Aquarius is angular, on the 19 Aquarius Descendant, conjoined Mercury and sextile Betti, trine Saturn; asteroid Ostrovskij (alternate spelling) at 25 Gemini is squared the 28 Virgo Moon and inconjunct the 27 Capricorn Sun, all of which granted White that personal connection to the part which is so pivotal for a successful performance.
White as Elka Ostrovsky in "Hot in Cleveland", her final series role; asteroid Elko (closest to Elka) is conjoined the Descendant, trine Saturn and sextile Betti
When "Hot in Cleveland" premiered on 16 June 2010, the Sun at 25 Gemini was an exact match for natal Ostrovskij, in a T-Square with a Hilaritas/Saturn conjunction at 24 and 28 Virgo (atop White's natal Moon) and a Uranus/Jupiter conjunction at 0 and 1 Aries, affirming the spotlight (Sun) placed on the comedy career (Hilaritas/Saturn) of a TV celebrity (Uranus/Jupiter). Asteroid White at 7 Gemini was an exact match for natal Hilaritas, while a Pluto/Ostrovskij pairing at 4 and 6 Capricorn feeds directly into her Saturn/Betti opposition, again activating White's career. Incredibly, an exact triple conjunction of asteroids Actor, Thalia and Elko, all at 29 Taurus, reiterates this latest comedic (Thalia) acting (Actor) role (Elko).
We can't memorialize Betty White without mention of her eternal passion for animal welfare. A tireless advocate for both domestic pets and wildlife, White worked with several welfare and conservation organizations including the Los Angeles Zoo Commission, The Morris Animal Foundation (where she served as a trustee of the organization since 1971), African Wildlife Foundation, and Actors and Others for Animals. She was a member of the board of directors of the Greater Los Angeles Zoo Association since 1974, shortly after producing and hosting a syndicated series, "The Pet Set", where she introduced viewers first to pets, and then to their celebrity owners!
White's humanitarian and conservation instincts towards animals can be traced to her 10 Aquarius Mercury's opposition to Neptune at 15 Leo, which straddles the Ascendant/Descendant axis at 19 Leo/Aquarius, and formed such a large part of her public image. Mercury rules pets, while Neptune rules rescuing, saving and altruistic endeavors. In addition, asteroids Katz (German for "cat" and a phonetic match) and Kitty exactly conjoin each other at 22 Capricorn, conjoined the Sun at 27 Cap, making pets in general, and felines in particular, self-identifying factors for her.
A young Betty White showcases her love of animals; animal welfare and rescue was a passion for her, with Mercury (ruling pets) opposed Neptune (altruism, rescue and saving)
When Betty White died on 31 December 2021, the skies reflected her passing. Asteroid White at 27 Sagittarius opposed asteroid Rip at 25 Gemini (a death indicator in the form of the acronym "RIP", "Rest In Peace", a common tombstone inscription), T-Squared with asteroid Anubis (named for the ancient Egyptian deity governing funerary rites) at 20 Virgo. White also conjoined asteroid Lachesis at 2 Capricorn, named for the mythic Greek Fate who determines the span of life.
Anubis was at station, as it was at her birth, preparing to turn retrograde on January 12th (in 1922, it also stationed on the 12th, moving direct). Anubis' natal placement at 28 Taurus had been ignited by the Lunar Eclipse of November 19th at 27 Taurus, signaling her potential demise, and was opposed at her death by transit asteroid Betti, at 21 Scorpio, which also conjoined natal asteroids Lachesis, Atropos (her sister, who severs the thread of life at death) and Rip, at 14, 23 and 26 Scorpio. Transit Betti and natal Anubis formed a T-Square with transit Damocles, the doom hanging unseen overhead, at 25 Aquarius when she unexpectedly died.
Asteroid Actor at 5 Taurus was also at station (it turned direct the day prior), conjoined Uranus at 10 Taurus and asteroid Osiris (named for the Egyptian god of the dead) at 29 Aries, again suggesting the sudden, unexpected nature (Uranus) of her passing (Osiris). Transit asteroid Requiem (named for the funeral mass for the dead) was at station at 9 Virgo, turning retrograde the day after, and with transit Atropos at 7 Scorpio formed the base of a Yod, with natal asteroid Betti on its Apex at 7 Aries, seeming to suggest a fated ending.
A grassroots campaign from fans in 2010 prompted producers to invite Betty White to host "Saturday Night Live" at age 88; she remains the show's oldest host
The transit Sun at 10 Capricorn was highlighting natal asteroid Rosa at 11 Cap, recalling her most famous role, and formed a Grand Cross with natal Saturn at 7 Libra, the ancient lord of death, natal Pluto at 8 Cancer, the modern lord of death, and natal asteroid Betti at 7 Aries, bringing this energy home directly to White.
Betty White will live in our hearts (and in syndication) forever, bringing smiles to faces for many generations to come.
January 3rd, 2022 at 09:21am
Laurien
So sad that she died before her 100th birthday celebrations. This is a nice tribute to her though and as usual, the asteroid connections are amazing. Thanks Alex!
Betty White cut across all social ties and generations with her epic comedic gold and football goal in the Snickers Ad 2010. I just loved the commercial where she delivers the line about "That's not what your girlfriend said", pure Betty White! She stood for equality way before others did, represented women in all of their complexities, and like Doris Day always took up for animals. RIP, BETTY.