HIV/AIDS Topics CROI 2016: On-Demand Rectal Microbicide Gel Has Reasonable Acceptability -- Daily Less So
- Details
- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Monday, 29 February 2016 00:00
- Written by Gus Cairns
Results from the MTN-017 study of 1% tenofovir gel as a rectal microbicide were presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston. The study compares the safety and acceptability of oral tenofovir/emtricitabine (Truvada) PrEP with the rectal gel either in daily use or used before and after the participant has anal sex as the receptive partner.
[Produced in collaboration with Aidsmap.com]
The study found that the rate of adverse events of any severity was exactly the same as for oral PrEP for daily use, and somewhat lower during occasional use. However, though participants rated the gel as almost as easy to use as oral PrEP, and said that they would be willing to use the gel again during sex (though not daily), there was no disguising the fact that, if offered the choice between the gel and the pill as the one PrEP method they could use, most participants would choose the pill.
The encouraging safety and adherence results, however, may help this product move further towards a full acceptability study.
The MTN-017 Study
MTN017 was conducted between 2013 and 2015 at 8 sites in 4 countries: Pittsburgh, Boston, and San Francisco, as well as San Juan, Puerto Rico, in the U.S.; Bangkok and Chiang Mai in Thailand; Lima, Peru; and Cape Town, South Africa.
The study had a so-called crossover design, meaning that every participant used all 3 PrEP regimens in turn. After a screening visit, participants used one of the 3 methods (oral PrEP, daily gel, or gel before and after sex) for 8 weeks, with clinic visits on day 1, after 4 weeks, and after 8 weeks. They then waited for a week before using the second method for 8 weeks, then waited another week and used the third method.
The researchers selected 195 participants from 349 who were screened for the study. The most common reason for not being selected were ineligible lab results (such as poor kidney function), but 8 people were found to already have HIV (2.3%) and 3 were screened out for possible acute HIV symptoms.
Adherence was measured by product returns and by participants responding to SMS text reminders, but free drug levels were also measured in blood, rectal fluid, and rectal biopsies, and intracellular drug levels were assessed in rectal tissue and in T-lymphocytes.
The average age of the 195 participants was 31.1 years, and the average age at individual sites ranged from 22.8 in Cape Town to 35.9 in San Francisco. On average 80% had a college education or were attending college (apart from at Cape Town, where it was 27%).
Notably, this study managed to enroll a significant proportion of trans women. While 73% of participants defined themselves as gay or bisexual men, there were 4 cisgender women (2%), 19 people who defined themselves as trans women, and another 30 who described themselves as "other" or declined to define their gender. So this study included somewhere between 10% and 25% trans people.
Safety, Acceptability, Adherence, and HIV Infections
In terms of safety, the rectal gels were at least as safe as the Truvada pill. The percentage of participants who experienced adverse events of grade 2 or above (i.e., more than "mild") was 34% among oral pill users, 33% among daily rectal gel users, and 30% among sex-associated gel users.
In terms of subjective acceptability, however, the oral pill was more popular than the gel. Scores from 1 (dislike) to 10 (like) for general impression of the product, ease of use, and intention to use it again if it became available were added up. If the score for oral Truvada was regarded as 100%, then the score for generally liking the product was only 28% for daily-use gel and 37% for before-and-after sex gel.
The gel’s scores for ease of use were better, with a score of 56% for the daily gel (again compared with 100% for oral Truvada) and 76% for before-and-after sex use. For intention to use in the future, the score was 38% for daily gel and 70% for before-and-after sex. The 70% and 76% scores did not differ, statistically speaking, from the Truvada scores.
Adherence was defined as the proportion of participants who used the pill or gel more than 80% of the time. In terms of self-report and product returns, 94% of pill users and 93% of before-and-after sex gel users achieved at least 80% adherence, but only 83% of those using gel daily.
Drug level measurements confirmed the self-reports: the percentage of participants with detectable tenofovir in plasma and issues was 94% for oral Truvada and 80% for the daily gel. Levels were not given for the before-and-after-sex gel, as these would vary with use.
There were 4 HIV infections during the study, 3 of them in Cape Town, though 1 of these was diagnosed 82 days after his last product use. The other 3 infections were distributed 1:1:1 in terms of the regimen the participant was allocated to at the probable time of infection. Of these, 2 participants had HIV resistance mutations to the NNRTI class of drugs, which could not be PrEP-related as the PrEP regimen did not include NNRTIs.
Tenofovir gel is not the only one being evaluated as a possible rectal microbicide. A study of gel containing the drug dapivirine, which was also used in the vaginal ring studies presented at CROI, is underway.
Presenter Ross Cranston of the University of Pittsburgh told the conference, "These results support further study of 1% rectal gel tenofovir as a microbicide for HIV prevention in men who have sex with men and transgender women."
2/29/16
Reference
R Cranston, J Lama, BA Richardson, et al. MTN-017: Rectal Phase 2 Extended Safety and Acceptability Study of 1% Tenofovir Gel
.Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 108LB.
Coverage of the 2016 Conference on Retroviruses and Opportunistic Infections
- Details
- Category: HIV Treatment
- Published on Friday, 26 February 2016 00:00
- Written by HIVandHepatitis.com
HIVandHepatitis.com coverage of the 2016 Conference on Retroviruses and Opportunistic infections (CROI 2016), February 22-25, 2016, in Boston.
HIVandHepatitis.com coverage by topic
2/26/16
CROI 2016: TAF PrEP Protects Monkeys, But Levels in Humans May Be Too Low
- Details
- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Wednesday, 24 February 2016 00:00
- Written by Liz Highleyman
A proof-of-concept study showed that the new tenofovir alafenamide (TAF) plus emtricitabine (FTC) protects macaque monkeys from infection with an HIV-like virus, with a degree of protection similar to that previously seen with the older tenofovir disoproxil fumarate (TDF), researchers reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)this week in Boston. But another study looking at TAF concentrations in rectal and genital tissue samples from women found lower than expected levels, which could mean it won't be as effective as TDF/FTC (Truvada) for pre-exposure prophylaxis, or PrEP.
Gilead Sciences' Truvada is currently the only agent approved for HIV prevention in the U.S., France, and a few other countries. Studies have shown that it dramatically reduces the risk of HIV infection when used consistently, with around 90% or better efficacy among gay men. TDF is generally considered safe and well-tolerated, but it can cause modest bone loss and kidney problems in susceptible individuals.
TAF is a new tenofovir pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. TAF produces high intracellular drug levels with a 10-fold lower dose than TDF (25 mg vs 300 mg), which means about 90% lower drug concentrations in the blood plasma and less exposure for the kidneys, bones, and other organs and tissues.
Gilead has requested approval of a dual coformulation of TAF/FTC, which could be a successor to Truvada (to be marketed as Descovy). Several studies -- including one presented this week at CROI -- found that antiretroviral regimens containing TAF/FTC maintain viral suppression as well as those containing TDF/FTC when used for HIV treatment, but with less detrimental effects on kidney function and bone density.
Kidney and bone side effects among HIV-negative people using TDF/FTC for PrEP are not fully understood. Most clinical trials -- which excluded people with pre-existing kidney problems -- did not see significant kidney toxicity or bone loss, but these have been reported in PrEP demonstration projects and "real world" clinical use.
Some researchers and advocates have suggested that TAF could potentially be a safer alternative to TDF for PrEP, but it is not yet known whether it will be equally effective, given that it is distributed differently in the body.
TAF/FTC Protects Monkeys
Gerardo Garcia-Lerma from the U..S Centers for Disease Control and Prevention (CDC) presented findings from a study evaluating whether TAF/FTC would prevent rectal infection in macaques exposed to an HIV-like virus called SHIV. Garcia-Lerma's team previously conducted much of the animal research showing that TDF/FTC is effective for PrEP.
The study consisted of 2 parts. In the first part, Indian rhesus macaques were given a single dose of TAF to determine a human-equivalent dose. TAF was administered orally at 3 different doses -- 0.5, 1.5 and 4.5 mg/kg -- to 4 animals per dose. Tenofovir and tenofovir diphosphate (TFV-DP) concentrations were then measured in blood plasma, peripheral blood mononuclear cells such as T-cells (PBMCs), and rectal biopsy samples.
The researchers found that a 1.5 mg/kg TAF dose produced TFV-DP levels in PBMCs that were within the range achieved with 25 mg once-daily dosing in humans. As seen in humans, a low 1.5 mg/kg TAF dose (about one-tenth the TDF dose) produces about 90% lower plasma tenofovir exposure. Biopsies suggested that TFV-DP levels were lower in rectal tissue with TAF than with TDF.
In the second part of the study 6 macaques were treated with TAF/FTC (1.5 and 20 mg/kg) while another 6 received a placebo. After 1 to 24 hours the animals were exposed to rectally administered SHIV (strain SHIV162p3), with repeated weekly exposures for up to 19 weeks to simulate people at high risk for HIV infection.
Garcia-Lerma said the study design and procedures were the same as those previously used to demonstrate the effectiveness of TDF/FTC in monkeys in a prior study that showed 5 of 6 animals were protected after 14 SHIV exposures, for an efficacy of 94%.
In the current study none of the TAF/FTC-treated macaques became infected after 19 SHIV exposures. In contrast, all the placebo-treated monkeys were eventually infected after 1 to 10 exposures.
"We show that [TAF/FTC] prevents rectal SHIV infection in macaques to a degree similar to that previously found with [TDF/FTC] but with a substantially reduced TAF dose," the researchers concluded. "High protection [was] achieved despite lower rectal TFV-DP exposure with TAF than with TDF."
These findings, they added, "suggest that [TAF/FTC] may be a feasible alternative to [TDF/FTC] for PrEP against rectal HIV infection, and support the clinical development of [TAF/FTC] as a PrEP agent."
TAF Levels in Human Tissue
A second study, however, gives reason for caution about whether these promising animal findings will apply to humans.
Katy Garrett from the University of North Carolina at Chapel Hill and colleagues from Gilead analysed tenofovir and TFV-DP concentrations in genital and rectal tissue and fluid samples obtained from 8 healthy women. Most were white and the median age was 27.5 years. Although all participants were cisgender women, the rectal tissue results may also hold for men (and the vaginal results for trans men).
As background, Garrett noted that the efficacy of oral TDF/FTC PrEP has been low in clinical trials of women compared with the high levels of protection seen in studies of men who have sex with men. Social and cultural factors play a role, especially regarding adherence, but biological factors also appear to be important.
TFV-DP concentrations with TDF are lower in the female genital tract than in rectal tissue and the protective effect does not last as long. One analysis suggested that while rectal protection could be achieved with just 2 doses of TDF/FTC per week -- though the usual recommended minimum for gay men is 4 doses -- female genital tract protection would require 7 doses.
In this study women were treated with a single 25 mg dose of TAF, and tenofovir and TFV-DP concentrations were measured in cervical tissue, vaginal tissue, cervicovaginal fluid, and colorectal tissue over 14 days.
Since a 25 mg dose of TAF produces TFV-DP levels 7-fold higher in PBMCs than a 300 mg dose of TDF, the researchers hypothesised that TFV-DP concentrations in cervical, vaginal, and rectal mucosal tissue would also be 7 times higher with TAF than with TDF.
Instead, they found that drug concentrations were lower in genital and rectal tissue than predicted, even though levels in plasma and cells were consistent with prior studies. Tenofovir levels in plasma were 19-fold lower with TAF than with TDF, while TFV-DP levels in PBMCs were 9-fold higher.
But tenofovir levels in genital tissue (cervical and vaginal combined) were about 2-fold lower with TAF than with TDF. Levels peaked at 12 hours after dosing and became undetectable by day 10. TFV-DP levels were below the level of detection in 75% of the genital samples after TAF dosing compared with 25% of samples after TDF dosing. Tenofovir levels in cervicovaginal fluid were about 11-fold lower with TAF.
Tenofovir concentrations in rectal tissue were about 10-fold lower with TAF than with TDF. Here, levels peaked by day 3 and remained detectable through the end of the 14-day study period. TFV-DP levels were undetectable in 63% of the rectal samples after TAF dosing but always detectable after TDF dosing.
"Over 48 hours, tenofovir exposure in mucosal tissues was 2-10 fold lower after TAF than TDF" and "TFV-DP exposure was 13-fold lower in rectal tissue and 1-fold lower in the female genital tract," the researchers summarized.
Garrett said additional research is needed to better understand the pharmacology of TAF in mucosal tissues and to determine pharmacological targets or surrogate markers that consistently predict what drug levels confer adequate protection against HIV infection.
In addition, we still do not know whether protection depends on tenofovir or TFV-DP levels in plasma, in genital or rectal tissues, or both.
Until more is known, both Garrett and Garcia-Lerma stressed that TAF should not be used for PrEP until clinical trials are complete and it is approved for this indication.
If TAF/FTC for HIV treatment is approved in the U.S. in the coming months, as expected, it will be important to educate potential users that they should not substitute the new coformulation for Truvada on an off-label basis.
2/24/16
References
I Massud, J Mitchell, D Babusis, G Garcia-Lerma, et al. Chemoprophylaxis with Oral FTC/TAF Protects Macaques from Rectal SHIV Infection. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 107.
KL Garrett, ML Cottrell, HM Price, et al. Concentrations of TFV and TFVdp in Female Mucosal Tissues after a Single Dose of TAF. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 102LB.
CROI 2016: Almost-Certain Case of Truvada PrEP Failure Due to Drug Resistance Reported
- Details
- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Thursday, 25 February 2016 00:00
- Written by Gus Cairns
A case report of a man in Toronto who became infected with a multidrug-resistant strain of HIV despite apparently very consistent adherence to PrEP using tenofovir/emtricitabine (Truvada) was presented at the 2016 Conference on Retroviruses and Opportunistic Infections this week in Boston.
CROI 2016: Vaginal Rings Containing Dapivirine Moderately Effective in Preventing HIV
- Details
- Category: HIV Prevention
- Published on Monday, 22 February 2016 00:00
- Written by Gus Cairns
The results of 2 studies announced today at the annual Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston show that vaginal rings impregnated with an anti-HIV drug are effective at cutting the HIV infection rate in women. However, the overall effectiveness seen was only moderate, preventing less than a third of infections -- and the primary reason for this was that the rings had no effect at all in the youngest trial participants, aged 18-21, who also had the highest rates of HIV infection. The rings were more effective in older women with almost two-thirds of infections prevented in women over age 25 in the ASPIRE trial.
[Produced in collaboration with Aidsmap.com]
Researchers are still teasing out why the vaginal rings did not work for the youngest women. Some of the low effectiveness seen was undoubtedly due to poor adherence, but drug level tests did not suggest adherence rates so low as to produce zero effectiveness. The results could be caused by a combination of intrinsic efficacy of less than 100% for the rings, intermittent use among participants, and greater vulnerability to HIV infection among young women.
Whether these are the reasons, or others, for the relatively low levels of adherence and lack of effect seen in young women remains to be seen. The same is true of whether these results will be enough for the ring to be licensed as a protection method.
The Studies
The 2 trials, the ASPIRE study and the Ring study, jointly enrolled 4588 HIV-negative women aged 18-45 at 22 sites in South Africa, Uganda, Malawi, and Zimbabwe. ASPIRE enrolled 2629 women at 15 sites and the Ring study 1959 at seven sites.
The findings from ASPIRE were published in the February 22 online edition of New England Journal of Medicine. Only interim results from the Ring study were presented at a press conference today. Both studies will present fuller findings at CROI on Wednesday
Both studies had the same design: the women were given a silicone polymer ring designed to be worn inside the vagina for 1 month and then changed for another one. Half the rings were impregnated with 25 milligrams (mg) of a non-nucleoside reverse transcriptase inhibitor (NNRTI) anti-HIV drug called dapivirine, which was never licensed as an oral drug due to poor systemic absorption. Previous studies indicated that these rings should be able to deliver enough drug throughout a month to prevent HIV infection.
The vaginal ring technology is not new -- it is already used to deliver hormonal contraceptives, though in that case the rings are not worn during the period of menstruation.
The ASPIRE study, run primarily by the Microbicides Trials Network (MTN), is fully complete; the Ring study, run primarily by the International Partnership for Microbicides (IPM), was still proceeding when the ASPIRE results became known, and all women on the placebo arm were offered a ring containing active drug.
Adherence has been shown to be the primary influence on whether oral pre-exposure prophylaxis (PrEP) and microbicides work, so the women in both trials were given regular drug level tests. Dapivirine is to some extent systemically absorbed, and a dapivirine level in the blood of more than 95 picograms per milliliter (pg/ml) indicated that the ring had been in place for more than 8 hours before the drug level measurement. However, this measure was only able to establish that the women wore the ring on the day of the blood test. So a year into ASPIRE, researchers also started measuring drug levels in returned rings: if there was less than 23.5 mg of drug left in the ring after a month’s use -- i.e., if at least 1.5 mg had leached out -- then the women were deemed to be adherent.
ASPIRE Study -- Details
In ASPIRE, at enrollment, the average age of participants was 26; 41% were married and 85% had had at least some secondary education. Virtually all had 1 primary sexual partner, but 17% had had more than 1 partner in the previous 3 months. 57% said they had used a condom last time they had sex, 6% had engaged in transactional sex in the last 3 months, and 2% reported anal sex. Nearly two-thirds (64%) said their partners knew they were in the study.
More details of ASPIRE participants are given in this Aidsmap.com report from last year. Nearly 4 in every 100 participants became pregnant per year (annual pregnancy incidence 3.95%). Women were suspended from the study while pregnant or breastfeeding.
Retention was good, with more than 85% of women remaining in the study and on average staying in the study for 1.6 years, with 39% staying in the study for more than 2 years.
ASPIRE: Effectiveness and Adherence
There were 168 HIV infections among ASPIRE participants: 71 using dapirivine rings and 97 using placebo rings. This translates to an effectiveness of 27%, i.e., slightly more than 1 in 4 HIV infections that would otherwise have happened was prevented.
This is disappointingly low. But there was a very strong interaction between effectiveness and age. There was zero effectiveness among women aged 18-21. In women over 21, effectiveness was 56% -- i.e., more than half of all infections prevented -- and in women over 25 it was 61%.
ASPIRE also had a specific difficulty in that it became clear early on that 2 out of the 15 sites were having problems with recruiting and monitoring participants. These 2 sites and their participants were excluded from the rest of the study apart from follow-up HIV testing. When these 2 sites were excluded, effectiveness in the other 13 was 37%.
In women whose partners knew they were in the study, effectiveness was 44%, and in those whose partners did not know it was 29%, although this was not a statistically significant difference.
The drug level tests found dapivirine in 82% of blood samples, though as noted above all this meant was that the participant had used the ring that day. However, in 84% of returned rings, drug levels indicated consistent if not constant use through the month. In 9% of samples test results were discordant, with high levels of dapivirine in blood, but very little drug having left the ring -- this might indicate "white coat dosing" or women only inserting the ring on the day they went to the clinic.
Interestingly, there was no indication of a decrease in adherence as time went on -- rather the opposite. Adherence seemed to improve after the first month and also after the first year, and the difference in infection rates between dapivirine and placebo arms only became apparent in most age groups after a year. This seems to be a technology that women have to get used to.
The Ring Study: Preliminary Effectiveness and Incidence
Preliminary efficacy results were also announced from the Ring study at the conference. The overall efficacy seen in the Ring study was 31% (compared with 27% in ASPIRE). The same relationship with age was seen, though not as strongly; efficacy in women over 21 was 37%, compared with 56% in ASPIRE.
The Ring researchers also gave a figure for the HIV incidence rates among women in the placebo arms of both studies. It was 8.2% per year for women under 21, 7.3% for women age 21-25, and 4.3% for women over 25, again showing that it is young women under 21 who are in greatest need of a prevention method that can truly protect them.
Next Steps and Comments
The Ring researchers said that despite the fact that only moderate effectiveness was demonstrated, plans were underway for a follow-up open-label study for Ring participants, and possibly ASPIRE participants too, starting in April 2016. The rationale for this is that in some PrEP studies, adherence and effectiveness have been higher in participants when they know they are all using the active drug. If results are promising, then there would be an application for a product license from early 2017.
Zeda Rosenberg, founding chief executive officer of IPM, said, "IPM will seek regulatory approval for the monthly dapivirine ring and work with partners to determine its role in strengthening HIV prevention efforts. We are also hopeful we can learn more about how to help women who want to use the ring do so consistently. A follow-on study would help answer key questions about how women could use the ring when they are aware it can safely offer protection."
Jared Baeten, who co-led the ASPIRE study, said, "Women -- especially in sub-Saharan Africa -- need multiple options for HIV prevention. The ASPIRE study was an important step towards determining whether the dapivirine ring could become one such option."
Anthony Fauci, Director of the U.S. National Institute of Allergy and Infectious Diseases, the primary funder of the ASPIRE study, said, "Women need a discreet, long-acting form of HIV prevention that they control and want to use. This ring confers partial protection, [but]…further research is needed to understand the age-related disparities in the observed level of protection."
Questions to be Answered
Why were the results of these studies relatively disappointing? First, the ring technology probably does not have the same intrinsic efficacy as oral PrEP: one researcher told Aidsmap that 100% adherence probably implied an efficacy of about 70%.
Second, however, it has become clear from qualitative studies that what women might like in a vaginal ring was not necessarily on offer from these particular ones. A recent study investigated the characteristics thought more and less desirable by women who used contraceptive rings and found that women would prefer a ring that was a little more pliable and thinner than the HIV prevention one.
In addition, women preferred to be able to take the rings out and clean them, did not like wearing them during menstruation, and some preferred to take them out even during sex (which might not inevitably mean loss of efficacy as long as they were immediately replaced). This was also the case in a previous acceptability trial of another HIV ring: while women were reassured about safety, some participants could not rid themselves of the feeling that retaining the ring felt "dirty," especially during their menstrual period, and they remained aware of wearing it, rather than forgetting it was there except when it needed to be changed.
One reason Rosenberg thinks is unlikely to apply is any biological difference between the youngest women and others. "There's not a lot of difference between 19 and 21 year olds," she told Aidsmap.
Whether any of these are the reasons, or others (such as fear of discovery or inconvenience), for the relatively low levels of adherence and lack of effect in young women remains to be seen. The same is true of whether these results or the ones from an open-label trial will be enough for the ring to be licensed as an HIV protection method.
2/22/16
References
JM Baeten, TPalanee-Phillips, ER Brown, et al. A Phase III Trial of the Dapivirine Vaginal Ring for HIV-1 Prevention in Women. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 109LB.
JM Baeten, TPalanee-Phillips, ER Brown, et al. Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. New England Journal of Medicine. February 22, 2016 (epub ahead of print).
A Nel, SKapiga, L-G Bekker, et al. Safety and Efficacy of Dapivirine Vaginal Ring for HIV-1 Prevention in African Women
. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 110LB.
Web Design and Development by