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.

Combination Inhibitor BMS-986197 Demonstrates Good Anti-HIV Activity in Early Study

A long-acting bioengineered "combinectin" molecule with a triple mechanism of action demonstrated potent antiviral activity and worked against HIV that developed resistance to any of the 3 separate mechanisms in a laboratory study, and lowered viral load in humanized mice, according to research presented at theConference on Retroviruses and Opportunistic Infections (CROI 2016)last month in Boston.

Modern antiretroviral therapy is highly safe and effective for most people with HIV, but there is still room for more convenient agents that could help improve adherence, as well as drugs for people with highly resistant virus.

BMS-986197 is an injectable biologic agent which investigators think could potentially be self-administered as a long-acting subcutaneous injection; combining different modes of action in a single agent could avoid the need for multiple injections.

Mark Krystal, formerly of Bristol-Myers Squibb and now at ViiV Healthcare, presented findings from early laboratory and animal studies of BMS-986197, which is part of the portfolio of Bristol-Myers Squibb's investigational HIV agents recently acquired by ViiV.

BMS-986197 is made up of adnectins, small proteins with modifiable binding loops resembling certain antibody regions. Researchers combined adnectins targeting the CD4 cell surface receptor and HIV's gp41 protein subunit, along with a peptide fusion inhibitor, to build a so-called combinectin inhibitor that uses independent mechanisms to interfere with 3 routes of HIV entry. Finally, this combinectin was attached to human serum albumin to improve its pharmacokinetics.

The anti-CD4 adnectin appears to allow HIV's gp120 envelope protein to bind to the receptor, but prevents conformational changes needed for binding to co-receptors (CCR5 or CXCR4). The second adnectin attacks the N17 sequence of the HIV gp41 envelope protein subunit. The fusion inhibitor component works similarly to enfuvirtide (T20 or Fuzeon).

The EC50, or 50% effective concentration, of the anti-CD4 adnectin, the anti-gp41 adnectin, and the fusion inhibitor peptide were 8.5, 5.4, and 0.4 nM (nanoMolar), respectively. Linking these 3 inhibitors into a single molecule led to synergistic effects greater than the sum of the parts. The optimal combination of the 2 adnectins increased potency by more than 100-fold, while adding the fusion inhibitor appeared to increase the barrier to resistance. The addition of human serum albumin decreased potency but made the combinectin last longer in the body.

In the laboratory BMS-986197 demonstrated antiviral activity against a wide range of clinical virus isolates of different subtypes obtained from people with HIV. It retained potency against viruses that were resistant to any 1 of the 3 separate entry inhibition mechanisms and it showed no loss of potency in human blood serum.

In bio-engineered mice with humanized immune systems BMS-986197 produced dose-dependent decreases in viral load, and at the highest dose most became undetectable. Cell receptors remained occupied and pharmacokinetics were consistent over 36 days. In cynomologous monkeys a subcutaneous injection had a half-life of 30 hours and the researchers projected a half-life in humans of about 40 hours -- potentially adequate for once-weekly dosing.

"BMS-986197 is a long-acting (projected weekly dose) biologic molecule containing 3 individual inhibitors of HIV-1 entry that can be dosed subcutaneously," the researchers concluded. "BMS-986197 is effective at lowering viral loads in a mouse model of infection."

3/14/16

Reference

M Krystal, DWensel, Y Sun, et al. HIV-1 Combinectin BMS-986197: A Long-Acting Inhibitor With Multiple Modes of Action. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 97.

Transgender people are at high risk for HIV, but too little is known about prevention and treatment for this population

Tonia Poteat (you may remember her from the 'For The Bible Tells Me So' documentary)

Transgender women have among the highest rates of HIV infection but little is known about HIV prevalence among trans men, Tonia Poteat of Johns Hopkins Bloomberg School of Public Health said in a plenary lecture on transgender health and HIV at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston – the first ever on this population at CROI. A growing number of studies and prevention and treatment programmes are addressing transgender populations, but more research is needed.

Dr Poteat noted that while mainstream knowledge about transgender men and women is relatively new in the US and Europe, largely thanks to celebrities such as Chaz Bono and Caitlyn Jenner, people outside the male-female gender binary have long existed in many cultures, such as the hijra in India.

The size of the transgender population is uncertain, in part due to varying definitions. One estimate put the number of transgender people in the US at approximately 700,000, or 0.3% of the population. Estimates range from 0.1% to 0.5% in Europe, and from 0.7% to 2.9% in South Asia, where some countries legally recognise a ‘third gender’.

Traditional ‘one-step’ data collection approaches can make it difficult to accurately identify trans people in HIV research. Many investigators have categorised study participants according to either their current gender identity or their assigned sex at birth, both of which can result in misclassification. A ‘two-step’ method that asks about both initial sex assignment and current identity is more accurate and inclusive.

“The way you ask the question makes a big difference,” Dr Poteat stressed.

For example, the international iPrEx trial of tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) included transgender women in its population of 2499 men who have sex with men. The initial published iPrEx report said the study included just 29 trans women, but a later analysis used a broader definition – including people assigned male at birth who identified as women, trans or ‘travesti’, and those who identified as men but used feminising hormones – bringing the total up to 339.

HIV rates in trans populations

As Susan Buchbinder of the San Francisco Department of Public Health said in her introduction to the lecture, “There is probably no population that is both more heavily impacted [by HIV] and less discussed around the world than transgender people.”

Dr Poteat said that very little is known about HIV rates among transgender men. A recent systematic review found six US studies, including a self-report study with a prevalence of 0.4% and five studies based on laboratory testing with rates ranging from 0.5 to 4.3%, but actual numbers were small. Among non-US studies, three based on self-report found prevalence rates of 0.6 to 0.8%, while two based on lab tests had rates of 0 and 2.2%.

A bit more is known about trans women, who were the main focus of the talk. Trans women who have sex with men have one of the highest burdens of HIV infection among key affected populations, which also include gay and bisexual men and people who inject drugs.

One worldwide meta-analysis of 39 studies from 15 countries found that transgender women had an HIV prevalence rate of 19% – 49 times higher than that of the general population. In high-income countries the prevalence was 22%, with the highest rate among trans women of colour.

A more recent meta-analysis by Dr Poteat’s group looked at 49 new studies, which showed both an exponential increase in research and an ongoing high burden of HIV infection. Among the included studies based on lab testing, prevalence rates ranged from 2% among trans youth to 45% among trans sex workers. The three studies that estimated incidence, or new infections, reported rates of 1.2 to 3.6 per 100 person-years.

Even in countries where HIV prevalence in the general population is high, trans women still face a disproportionate burden. In Lesotho, for example, overall prevalence is estimated at 18% for all cisgender (non-transgender) men, 27% for all cisgender women and 28% for men who have sex with men, but rises to 60% for trans women.

Vulnerabilities affecting trans people

A number of factors may make transgender people more susceptible to HIV infection or less likely to use prevention methods or access treatment if they become infected.

Biological factors include hormone therapy, which has the potential to interact with PrEP or antiretroviral treatment (ART). While no clinically significant interactions have been confirmed between feminising hormones and tenofovir/emtricitabine PrEP or most antiretrovirals, many trans women worry about them and prioritise hormone use.

To date, no randomised clinical trials have looked specifically at PrEP for transgender women, but aniPrEx substudy led by Madeline Deutsch from the University of California at San Francisco’s Center of Excellence for Transgender Health found that Truvada appeared to protect trans women who took it consistently. No seroconversions occurred among trans women with tenofovir drug levels indicating they took at least four pills per week. However, their level of adherence was lower than that of gay men in the study, which Deutsch suggested could be due to concerns about PrEP and hormone interactions.

Prior studies have shown that tenofovir reaches higher levels in rectal tissue in men than in cervical or vaginal tissue in women. This could in part be related to hormonal differences between cisgender men and women, although some have found that tenofovir levels are lower in cervical-vaginal tissue samples than in matched rectal tissue samples obtained from the same women.

Some researchers hypothesise that exogenous or administered oestrogen may affect tenofovir pharmacokinetics, for example by interfering with creatine kinase phosphorylation of tenofovir disoproxil fumarate to its active form of tenofovir diphosphate. This could mean that trans women taking oestrogen and PrEP will have lower tenofovir levels in rectal tissue than cisgender men, and therefore may need higher doses – a prospect that requires further study.

Hormones could also potentially cause changes in rectal or vaginal mucosa that increase susceptibility to HIV. Further, sharing needles to inject hormones or fillers such as silicone can transmit HIV and hepatitis B or C. It is not known whether trans women who have genital sex reassignment or affirmation surgery are more vulnerable to HIV infection.

Social and structural factors

Social and structural factors that increase trans people’s vulnerability to HIV include stigma, fear of disclosure, sexual networks that include more people with HIV, poverty, lack of employment opportunities which leads many trans women to engage in sex work, homelessness or unstable housing, violence, lack of access to health care or insurance, substance use and mental health issues such as depression.

Although many transgender women are eligible for PrEP according to US Centers for Disease Control and Prevention (CDC) or World Health Organisation (WHO) guidelines, most are not yet using it and may not be aware of it. One study found that only about 14% of trans women in San Francisco – a city were PrEP awareness and use among gay and bisexual men are high – had heard of PrEP at the end of 2013.

Dr Poteat reported that among people with HIV using Ryan White HIV/AIDS services, transgender people were less likely than patients overall to remain in care (78 vs 80%) and to achieve viral suppression (74 vs 81%).

A survey of trans women with HIV conducted by the Transgender Law Center found that gender-affirming care and hormone therapy were their top priority, considered more urgent than HIV treatment. But trans women who had the same provider for both hormone therapy and HIV treatment were more likely to stay in care and have an undetectable viral load, demonstrating the benefit of integrated care.

“Transgender women have disproportionate HIV prevalence and incidence due to the interplay of biological and intersectional social factors,” Dr Poteat concluded. “Gender-affirming approaches are necessary to achieve optimal outcomes.”

To address barriers to care for trans women it is important to “reduce stigma and prevent secondary trauma including racism, transphobia, economic disadvantage and other structural factors,” she said. “HIV services we have available, mostly geared towards gay men, do not meet the needs of trans women.”

Resources for trans women and men

New resources for trans people have recently begun to appear, including the National Center for Innovation in HIV Care brief Transgender Women and Pre-Exposure Prophylaxis: What We Know and What We Still Need to Know and the booklet Transcending Barriers for Safer Pleasure from Project Inform and Outshine NW. Project Inform's booklet for men who have sex with men, Is Taking PrEP the Right Choice for You?, has also been updated with inclusive language and information for gay and bi transgender men.

In the United Kingdom ClinQ at 56 Dean Street, London, provides holistic sexual health and well-being services for trans people.

Reference

Poteat T HIV in transgender populations: charted and uncharted waters. Conference on Retroviruses and Opportunistic Infections (CROI), Boston, abstract 79, 2016.

View the abstract on the conference website.

View a webcast of this session on the conference website.

Gay Men and Trans Women Adhere Well to Rectal Gel As PrEP in Early US Study

A rectal gel containing 1 percent tenofovir showed promise as pre-exposure prophylaxis (PrEP) against HIV in a group of transgender women and men who have sex with men (MSM), who adhered well to the protocol for the gel’s use. The Phase II MTN-017 trial included 187 MSM and trans women in sites in the United States, (including Puerto Rico), Peru, Thailand and South Africa. Results were presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

Tenofovir-infused topical gel has protected non-human primates and successfully combats HIV in laboratory tests. Previous research has found that a vaginal formulation of 1 percent tenofovir was neither safe nor acceptable in the rectum. So the gel in this study was one that had been reformulated into a reduced glycerin formation of 1 percent tenofovir gel.

The participants for this study, all of whom reported receptive anal intercourse, were randomized so that each went through three phases of the trial, but in different orders. These phases included eight weeks each of the following (with a one-week “wash-out” period between each phase): the rectal 1 percent tenofovir gel with instructions to insert it into the rectum daily; the gel with instructions to use it rectally before and after anal intercourse, or at least twice weekly in the event of no receptive anal intercourse; or Truvada (tenofovir/emtricitabine) with instructions to take the tablet orally once daily. The study lasted for 27 weeks.

The participants, 12 percent of whom identified as women or transgender, made study visits every four weeks. The researchers measured the participants’ adherence to the various forms of PrEP through daily SMS texts as well as through returns of the product at each study visit (to see how much unused PrEP remained). They also tested study members’ plasma tenofovir levels at each study visit and gave them the results of that test at the subsequent visit. High adherence was defined as taking greater than 80 percent of expected doses.

There were no differences between the three versions of PrEP in terms of grade 2 adverse health problems. The researchers concluded that the rectal gel was safe in either of the dosing protocols.

Overall, the participants preferred the oral regimen to the two rectal application protocols, in particular the daily regimen. Ninety percent of individuals said they like liked the oral regimen, 80 percent liked the dosing protocol associated with sexual activity, and 70 percent liked the daily rectal gel protocol.

Adherence was generally high, and participants adhered similarly to administering the gel at least twice weekly and taking Truvada daily.

The researchers concluded that the trial supported further study of rectal microbicides in MSM and trans women, and that research should focus on convenient dosing regimens.

To read the conference abstract, click here.

HIV maturation inhibitor BMS-955176 looks promising in early study

A second-generation HIV maturation inhibitor, BMS-955176, demonstrated good safety and high potency, including activity against viral strains that were not susceptible to an earlier drug in this class, researchers reported yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2015), taking place this week in Seattle, USA.

Combination antiretroviral therapy consists of drugs that target different steps of the HIV lifecycle, but none of the currently approved agents act on viral assembly, maturation and release from host cells. Drugs that work in new ways could be particularly beneficial for highly treatment-experienced people with HIV who have extensive drug resistance.

As HIV replicates, it uses the cell's machinery to produce large polyproteins which are then cut up by protease enzymes and assembled into new virus particles. The final steps include forming a capsid around new viral RNA and budding out through the cell membrane, resulting in a mature virus surrounded by an outer envelope.

Maturation inhibitors like BMS-955176 interfere with protease cleavage between the p24 capsid protein and a smaller peptide in the Gag polyprotein, leading to the release of immature virus particles that cannot complete their lifecycle and are not infectious.

A company called Panacos, later acquired by Myriad Pharmaceuticals, previously worked on an older maturation inhibitor, bevirimat (also known as PA-457 or MPC-4326). Bevirimat showed promising antiviral activity in early studies, but it was hampered by formulation problems and more than half of study participants had virus with reduced susceptibility due to naturally occurring Gag variations. Myriad halted development of bevirimat in 2010.

Max Lataillade from Bristol-Myers Squibb and colleagues designed a phase 2a proof-of-concept study to evaluate BMS-955176, a second-generation maturation inhibitor that appears to overcome these difficulties.

Early studies showed that BMS-955176 binds tightly to the Gag polyprotein, has greater potency than bevirimat and remains active against HIV with a variety of Gag polymorphisms. It has a long half-life allowing for once-daily dosing and no significant safety issues have been identified so far.

This study, conducted in Germany, enrolled 60 previously untreated participants with HIV-1 subtype B, the most common type in Europe and the US (subtype C is more common in much of Africa and Asia, and is responsible for the worst global epidemics).

All participants were men, most were white and the median age was about 37 years. The median CD4 cell count was approximately 500 cells/mm3 and the median pre-treatment viral load was approximately 4 log10 copies/ml.

Participants were randomly assigned to receive BMS-955176 monotherapy at doses of 5, 10, 20, 40, 80 or 120mg, or else placebo, once daily for 10 days. They were then observed off treatment for an additional 14 days.

BMS-955176 produced median declines in HIV RNA levels from baseline through day 11 ranging from 0.15 to 1.36 log10 copies/ml across the BMS-955176 dose groups. Maximum median viral load declines ranged from 0.50 to 1.70 log10 copies/ml.

BMS-955176 demonstrated an overall dose-response relationship. While the 5mg dose was similar to placebo, potency then increased with doses up to 40mg, where it stabilised. The largest decline was seen in the 40mg dose group.

BMS-955176 was substantially more potent than bevirimat, and its antiviral activity was similar against wild-type HIV and virus with baseline Gag polymorphisms that led to failure of bevirimat.

A majority of participants still had viral load at least 1 log below the baseline level at one week after the end of BMS-955176 treatment, likely due to the drug's long half-life, Lataillade said.

BMS-955176 was generally safe and well-tolerated at all doses tested. There were no deaths, serious adverse events, study discontinuations due to adverse events, grade 3 or 4 drug-related side-effects or clinically relevant laboratory abnormalities.

"BMS-955176 is a potent, once-daily, second-generation maturation inhibitor with a maximum median decline in plasma HIV-1 RNA of 1.7 log10 copies/ml at the 40mg dose," the researchers concluded.

Based on these findings, a phase 2b study of BMS-955176 is expected to start in the second quarter of this year.

Lataillade said that BMS-955176 had overcome serum binding issues that were problematic for bevirimat and the new drug is suitable for use in coformulation – practically a necessity in the era of single-tablet regimens for HIV.

Reference

C Hwang et al (M Lataillade reporting). Antiviral activity/safety of a second-generation HIV-1 maturation inhibitor. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, USA, abstract 114LB, 2015.

View a webcast of this presentation.