Integrase Inhibitor Bictegravir Matches Dolutegravir for First-Line HIV Treatment

from CROI 2017

Bictegravir, an investigational integrase inhibitor from Gilead Sciences, was highly potent, well tolerated and worked as well as dolutegravir (Tivcay) in a Phase 2 clinical trial, according to study results presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle and published online in The Lancet HIV.

Integrase inhibitors, also known as integrase strand transfer inhibitors (INSTIs), are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but they could be applied to other retroviruses.

The discovery and development of integrase inhibitors led to the first integrase inhibitor approval by the U.S. Food and Drug Administration (FDA) on October 12, 2007, for raltegravir (brand name Isentress). Research results published in the New England Journal of Medicine on July 24, 2008, concluded that "raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks."

Since integrase inhibitors target a distinct step in the retroviral life cycle, they may be taken in combination with other types of HIV drugs to minimize adaptation by the virus. They are also useful in salvage therapy for patients whose virus has mutated and acquired resistance to other drugs.

Due to their high potency and good tolerability, integrase strand transfer inhibitors are an increasingly important part of initial antiretroviral therapy and are included in most recommended regimens for first-line treatment in U.S. and European HIV treatment guidelines.

Bictegravir (formerly GS-9883) is an investigational integrase inhibitor that can be taken once-daily and does not require a booster -- unlike Gilead's older integrase inhibitor elvitegravir, which must be boosted with cobicistat.

As previously reported, bictegravir demonstrated high potency against wild-type and resistant strains of HIV, favorable pharmacokinetics, and an improved resistance profile compared to older integrase inhibitors. In a 10-day monotherapy study, it rapidly reduced viral load by more than 2 login people with HIV.

At CROI Joseph Custodio from Gilead reported that bictegravir was safe and well-tolerated at doses ranging from 5 mg to 600mg in healthy volunteers. Bictegravir inhibits renal tubule transporters, which lowers creatinine levels and leads to a decline in estimated glomerular filtration rate, but it does not cause actual kidney function impairment, he explained.

Bictegravir is metabolized equally bythe CYP3A4 and UGT1A1 pathways. Custodio said it has low potential to be either a "victim" or "perpetrator" of drug-drug interactions. Bictegravir levels rose by more than 300% when administered with both CYP3A4 and UGT1A1 inhibitors, and fell by up to 75% when given with both CYP3A4 and UGT1A1 inducers. The drug had a half-life of approximately 18 hours, indicating it is suitable for once-daily dosing. Bictegravir had no effect on a common oral contraceptive or ledipasvir/sofosbuvir (Harvoni) for hepatitis C, and administering it 2 hours before or after minimises interactions with antacids.

Paul Sax of Brigham and Women's Hospital in Boston and colleagues conducted a Phase 2 placebo-controlled clinical trial comparing bictegravir to dolutegravir for initial HIV therapy.

The study included 98 previously untreated adults. Almost all were men, more than half were white, and the median age was about 32 years. They generally had asymptomatic HIV infectionwith a median CD4 T-cell count of approximately 450 cells/mm3 and a median viral load of about 4.4 log copies/mL at baseline. They had normal kidney function and people with hepatitis B or C coinfection were excluded.

Participants in this double-blind study were randomly assigned (2:1) to receive 75 mg bictegravir or 50 mg dolutegravir, each with matching placebos. Both drugs were combined with 25 mg tenofovir alafenamide (TAF) and 200 mg emtricitabine, taken once daily with or without food for 48 weeks. The primary endpoint was the proportion of people with HIV RNA below 50 copies/mL at 24 weeks.

Results

Both treatments were highly effective.

97% of participants in the bictegravir arm and 94% in the dolutegravir arm achieved viral suppression at 24 weeks.

97% and 91%, respectively, had undetectable HIV RNA at 48 weeks.

Given the small number of patients, these differences were not statistically significant and this study was not powered to determine full non-inferiority.

1 person in the bictegravir arm and 2 in the dolutegravir armhad HIV RNA >50 copies/mL, but no significant resistance was detected in either arm.

CD4 cell gains were 258 cells/mm3 in the bictegravir arm compared 192 cells/mm3 in the dolutegravir arm, not a significant difference.

Both regimens were generally safe and well-tolerated, with no treatment-related serious adverse events and no deaths.

The most frequent adverse events were diarrhea (12% in each arm) and nausea (8% with bictegravir and 12% with dolutegravir).

1 bictegravir recipient with a previous history of allergic dermatitis stopped treatment early due to hives after 24 weeks.

Estimated glomerular filtration rate declined by -7.0 mL/min in the bictegravir arm and -11.3 mL/min in the dolutegravir arm at week 48, but there were no discontinuations due to kidney-related adverse events and no cases of tubulopathy.

Bictegravir and dolutegravir taken with TAF and emtricitabine "both demonstrated high virologic response rates at week 24 that were maintained at week 48," the researchers concluded. "Both treatments were well tolerated, and no significant safety signal was detected in either arm."

These results were promising enough to proceed with Phase 3 trials using a single-tablet regimen of bictegravir, TAF, and emtricitabine. Custodio noted that optimising the formulation allowed for a lower 50 mg bictegravir dose in the coformulation.

Sax said that 4 Phase 3 studies are now fully enrolled; 2 of these are similar to the current study but will use the bictegravir single-tablet regimen rather than separate pills. Another is comparing the bictegravir single-tablet regimen against a coformulation of dolutegravir, abacavir, and lamivudine (Triumeq).

"The high virologic response rates seen in this study show that the pairing of bictegravir with [TAF/emtricitabine] could potentially offer patients and physicians a new HIV treatment option with pre-clinical data supporting few drug interactions and a high barrier to resistance," Sax said in a Gilead press release.

2/14/17

Sources

H Zhang, JM Custodio, X Wei, et al. Clinical Pharmacology of the HIV Integrase Strand Transfer Inhibitor Bictegravir. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 40.

P Sax, E DeJesus, G Crofoot, et al. Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for initial HIV therapy. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 41.

PE Sax, E DeJesus, G Crofoot, et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. The Lancet HIV. February 14, 2017 (online ahead of print).

Gilead Sciences. Gilead Presents New Phase 2 Data on Bictegravir, an Investigational Integrase Strand Transfer Inhibitor for the Treatment of HIV. Press release. February 13, 2017.

French ‘Vogue’ Has Its First Transgender Cover Model

Vogue Paris has its first transgender cover star, Brazilian Valentina Sampaio, the BBC reports:

“In her editorial column for next month’s issue, Emmanuelle Alt goes on to say the transgender model is the “absolute equal” of other iconic women in fashion. ‘Apart from one small detail, Valentina, the femme fatale, was born a boy,’ she adds. ‘It’s a detail one would prefer not to have to mention… but Valentina is on the cover of Vogue this month, not just for her looks or her sparkling personality, but because despite herself she embodies an age-old arduous struggle to be recognized and not to be perceived as something Other.'”

Adds American Vogue:

In her editor’s letter in the issue, Alt writes that when Sampaio turned up at a studio in London to be shot by Mert Alas and Marcus Piggott, she looked exactly like her idea of a typical French Vogue beauty, any Vogue beauty, no different from Daria Werbowy or Anna Ewers; it’s just that she happened to be born a boy. Alt goes on to say she felt it was important right now, crucial even, to celebrate those who are transgender, adding that when the day comes that a model like Sampaio can appear on a magazine cover without the publication needing to mention a model’s chosen gender identity, then victory really will have been achieved. 

The influential Monica Roberts leading African American blogger had a thing or two to say on this on her TransGriot blog:

" 'But only when a transgender person poses on the front cover of a fashion magazine and it is no longer necessary to write an editorial on the subject will we know that the battle is won.-Emmanuelle Alt, French Vogue editor

The French edition of Vogue magazine was founded in 1920, and despite the long list of stunning French trans women like Coccinelle, Marie-Pier Ysser, Marie-Pierre 'Bambi' Pruvot and most recently model Ines-Loan Rau, I was surprised to discover that Vogue Paris has never had a trans woman on the cover of their magazine until now.

The trans woman who has made that breakthrough fashion and French magazine history is Brazilian model Valentina Sampaio.  She recently graced the cover of Elle Brazil, and has starred in an ad campaign for L'oreal Paris.

"This month we are proud to celebrate transgender beauty and how models like Valentina Sampaio, who is posing for her first ever Vogue cover, are changing the face of fashion and deconstructing prejudice."said Vogue Paris on their Instagram account and pic of the historic cover."

The 21 year old Sampaio is also set to rip the runway for Saint Laurent soon, and will be on the March cover of Vogue Paris that hits newsstands on February 23.  It is the first time ever that a trans feminine woman has graced the cover of any French magazine. 

The translated French title from the cover reads:  Transgender beauty; How they're shaking up the world.

We most certainly are.  It's also just another day and another historic accomplishment checked off the list for my sisters here in the US and around the world who are part of the long stylish line of trans models.

Vogue Paris editor Emmanuelle Alt said,"Valentina is on the cover of Vogue this month, not just for her looks or her sparkling personality, but because despite herself she embodies an age-old arduous struggle to be recognised and not to be perceived as something Other.”

Good news on the business of transgender visibility and fashion in particular. 

also see:

Valentina Sampaio Appears On Cover Of Brazilian ELLE

The long stylish line of trans models has led the way in breaking ground for our community not only in the modeling world, but at times through their activism on behalf of themselves and this community. 

Proud to announce that for the first time in the 111 year history of the iconic Spiegel catalog, a girl like us will grace the cover of it.

Arisce Wanzer in October 2016, who recently appeared as one of the stars of the reality show Strut, is the model who will be making this inevitable breakthrough. 

Congratulations to her, and hope to continue seeing her do her thing in the modeling world.  It also proves once again if given an opportunity to do so, we (LGBT) can don anything and excel at it.

Peace & tolerance

H

Demisexual, emotional love ..............

In a follow up to a previous post on bisexual monogamy and a brief look at emotional connections some interesting reactions have been coming in via email. The business of emotional love within or outside of monogamous or polygamous and so on hence here is a post on demisexuality to gain some more insight.

Thanks for the feedback. 

What is Demisexuality?

Demisexuality is a sexual orientation in which someone feels sexual attraction only to people with whom they have an emotional bond. Most demisexuals feel sexual attraction rarely compared to the general population, and some have little to no interest in sexual activity. Keep reading to understand more about this orientation.

What is the emotional bond demisexuals need for sexual attraction?

It varies based on the demisexual’s personal experiences and is slightly different for everyone. Emotional intimacy is a main component, usually, so some demisexuals find themselves attracted to close friends or romantic partners. Other components may include familiarity with the person and knowledge about them (ex: learning about aspects of their personality).

However, forming an emotional bond doesn’t guarantee that sexual attraction will happen. It is just a prerequisite for it to occur at all. The length of time required to develop an emotional bond may vary. For some demisexuals, it’s after several years of being close friends with someone, and for others, it might be a short but intense experience, such as traveling abroad for a week with them.

Isn’t it normal to only want sex after getting to know someone?

There’s a difference between feeling sexually attracted to someone and wanting to have sex with them. Sexual attraction isn’t something you can control—either you have sexual feelings for someone or not. You can’t force it to happen and you can’t force it to go away, so you don’t have a choice in the matter. Sexual behavior, on the other hand, is something you can choose to participate in, or not.

Most people on the non-asexual side of the spectrum feel sexual attraction regardless of whether or not they have a close emotional bond with someone. They may have sexual feelings for attractive people on the street, classmates or coworkers they’ve barely spoken to, or celebrities. However, they may choose to wait to have sex for a variety of reasons: it might not be feasible or appropriate, they want to make sure the person is respectful and kind, it’s against their religious beliefs, they only want to have sex in a romantic relationship, etc. The difference is that demisexuals don’t start out with these sexual feelings at all.

How does demisexuality relate to asexuality and the asexual spectrum?

Asexuality is a sexual orientation in which one feels little to no sexual attraction or interest in sex (the former definition is more widely used, but some asexuals use the latter definition. Both are valid and accepted.) Demisexuals are considered to be on the asexual spectrum, meaning they are closely aligned with asexuality, but not quite asexual. The asexual spectrum has asexuality on one end and non-asexuality on the other end.

Demisexuals are considered part of the asexual community because for the most part, they don’t feel sexual attraction. Many demisexuals are only attracted to a handful of people in their lifetimes, or even just one person. Many demisexuals are also uninterested in sex, so they have a lot in common with asexuals.

The thing that makes them different from asexuals is that they are capable of feeling sexual attraction—it’s just that it only happens after they form a deep emotional bond with someone.

How do demisexuals feel about sex?

According to the 2014 AVEN Census, two thirds of demisexuals are uninterested in and/or repulsed by sex. However, there is a significant portion that enjoys it. Demisexuals have a variety of feelings about sex and other sexual activities, like masturbating and watching porn, so it’s hard to make statements about the group as a whole. All feelings about sex are valid in a demisexual identity: the only thing that defines demisexuals is that they only feel sexual attraction after forming an emotional bond.

Whether or not they feel sexually attracted to someone or not, they can choose to have sex too. They might want to have sex in order to get pregnant, to see what it’s like, or some other reason.

Why do demisexuals need a label?

The label helps demisexuals form a sense of community and a stronger sense of self. Through this label, they learn that there are others like them out there, and that there’s a community to support them. In this community, demisexuals can talk to others who share the same experiences, share advice on navigating a very sexual world, and find emotional support. The community unites around this label, which helps its members feel more secure in their identities.

Many demisexuals grow up feeling different from those around them. Most people have their first instance of sexual attraction in their preteen years. From that point on, sex becomes a topic of curiosity and interest for them, and they eventually look forward to pursuing it. For children and teens in school, there is a lot of talk about sex—what it’s like, what it’ll be like, etc. This becomes more prevalent as they approach college and early adulthood.

Demisexuals often feel alienated by these conversations because they aren’t interested in sex, they don’t find people sexually attractive, or both. When the conversation turns to hot celebrities, for example, demisexuals may feel confused, and wonder what it is their friends see and feel. They wonder if they will eventually feel it too, and some even end up feeling “broken.” Knowing that there are others like them helps demisexuals feel less alone.

More anon

Peace & tolerance

H