PrEP News Coverage
Contents HIV Infection Despite PrEP: 6 Things You Need to Know ...... 2 The BodyPRO ...... 2 Maraviroc-Containing Regimens Safe, Tolerable When Taken for HIV Prevention ...... 5 NIAID/NIH ...... 5 Maraviroc drug safe, well-tolerated when taken as PrEP to prevent HIV infection ...... 7 News Medical ...... 7 First Man to Become HIV-Positive While on PrEP Is Rare Exception ...... 9 Advocate ...... 9 AHF: PrEP Patient’s Drug-resistant HIV Infection; Bone Loss, Fractures in Others, Suggest Caution ...... 10 Business Wire ...... 10 Panic Over HIV Infection While on PrEP Is Not Necessary ...... 11 TheBody ...... 11 PrEP Is Not Magic—and Treating It That Way Undermines Its Incredible Power ...... 12 Slate ...... 12 Almost-certain case of PrEP failure due to drug resistance reported at CROI 2016 ...... 14 Aidsmap ...... 14 The first case of HIV contraction while taking preventative drugs has been documented ...... 17 AOL News ...... 17 Man on Daily PrEP Regimen Contracts HIV, According to Study ...... 17 Gawker ...... 17 Case report details gay man becoming HIV+ while on PrEP ...... 19 Metro Weekly ...... 19 Gay Man Taking PrEP Daily Has Tested Positive For HIV ...... 20 Queerty ...... 20 Gay man taking daily HIV prevention pills contracts resistant strain of the virus - in first recorded case of PrEP failing ...... 22 DailyMail ...... 22 Researchers Report First Man to Contract HIV While Using Truvada as PrEP Daily ...... 23 Frontiers Media ...... 23 Modest kidney function decline in people taking Truvada for PrEP supports need for monitoring ...... 25 Aidsmap ...... 25 PrEP News Coverage TAF/emtricitabine maintains viral suppression as well as TDF regimens with less bone and kidney toxicity ...... 28 Aidsmap ...... 28 NIH-funded Study Finds Effect of PrEP on Bone Density Is Reversible ...... 30 NIH Press Release ...... 30 Switching to Emtricitabine/Tenofovir Alafenamide (F/TAF) Maintains Viral Suppression With Better Bone and Kidney Safety ...... 31 TheBodyPro.com ...... 31 Bone density recovers quickly after stopping PrEP ...... 32 Aidsmap ...... 32 Halting Truvada restores BMD ...... 34 Healio ...... 34 The Kidney Report - CROI 2016 ...... 35 NATAP ...... 35 ViiV and Janssen take long-acting HIV regimen into phase III ...... 38 PMLive ...... 38 Injected Long-Acting Cabotegravir Protects Macaques From Injected SIV ...... 39 NATAP ...... 39 CROI 2016: Long-Acting Cabotegravir PrEP Injection Tolerable and Acceptable, but Dose Adjustment Needed ...... 41 HIV&Hepatitis ...... 41 Injectable PrEP Given Every 8 Weeks Passes Safety Test ...... 43 HIVEqual ...... 43 CROI 2016: Long-Acting Injectable Cabotegravir + Rilpivirine Works Well as HIV Maintenance Therapy . 44 HIV&Hepatitis ...... 44 The Possibility of PrEP that's Not Truvada ...... 46 HIVEqual ...... 46
HIV Infection Despite PrEP: 6 Things You Need to Know The BodyPRO Damon Jacobs 26 February 2016 PrEP News Coverage
A thorough case study has revealed the likely acquisition of HIV by a 43-year-old gay man in Toronto who was adherent to pre-exposure prophylaxis (PrEP). Presented at CROI 2016 on Feb. 25, this is the first documented case of "PrEP failure," and it is spurring a lot of community and scientific discussion. "PrEP works when taken. Very rarely, PrEP with FTC/TDF [emtricitabine/tenofovir, Truvada] may fail to provide full protection against rare multidrug resistant viruses," said noted PrEP and HIV prevention researcher Robert Grant in an interview with BETA. "If that happens, HIV treatment is highly effective and prolongs life to normal levels and makes people less infectious."
It's not surprising that HIV community members, educators and care providers have many questions and concerns when they learn about this particular case. Let's break down the information to address some of the top questions we're likely to hear from people who are on PrEP, considering PrEP use or living with HIV.
Why didn't PrEP prevent HIV infection in this person? PrEP did not prevent infection in this instance because the person was exposed to a strain of HIV that had become resistant to several antiretroviral medications. These medications included (but were not limited to) tenofovir and emtricitabine, the two antiretrovirals in Truvada, which is currently the only PrEP regimen approved in the U.S.
It is estimated that well below 1% of people living with HIV are resistant to these two medications; even fewer also have a detectable viral load. Even if a person had this rare strain, if their viral load were undetectable, it would be extremely unlikely -- borderline impossible, research has found -- that he or she could transmit the virus to anyone.
Nonetheless, based on this new case, it is now known that consistent adherence to PrEP might not be enough to protect people from exposure to this particular HIV strain.
Does this mean that PrEP is not as effective as previously thought? No, PrEP is still as effective as we thought it was. It's very effective. Knowledgeable HIV doctors and educators generally use a "99% effective" estimate when explaining how well PrEP works. Experts knew that as PrEP implementation expanded, it was possible we would see "outliers." So the 99% figure still applies.
Again, it is believed that less than 1% of individuals living with HIV carry this rare strain, and only a subset of those are likely to have a detectable viral load. If it were easy to transmit these particular drug- resistant mutations, there would likely be a lot more people testing HIV positive with them, but that has not happened.
There are approximately 40,000 individuals using PrEP in the U.S., and this type of transmission has never been seen before.
Now that this person has HIV, will HIV treatment work for him? According to the study, yes. The person was prescribed HIV treatment quickly and achieved an undetectable viral load less than a month after being diagnosed with HIV.
Initially, the man's level of HIV drug resistance was unknown, so when he was first diagnosed, doctors maintained his tenofovir/emtricitabine prescription and added two additional active antiretrovirals -- PrEP News Coverage raltegravir (Isentress) and ritonavir (Norvir)-boosted darunavir (Prezista) -- to form a complete treatment regimen. After testing revealed that his strain of HIV had developed at least some level of resistance to several HIV drugs across multiple classes (including integrase inhibitors), he was switched to a more unusual regimen: dolutegravir (Tivicay), darunavir/cobicistat (Prezcobix) and rilpivirine (Edurant).
In the 12 weeks since beginning his new regimen, the man's HIV viral load has remained undetectable.
Are there ways for people with HIV to find out if PrEP would not work for their partners, due to the possibility that they may have this type of resistant virus? When people are newly diagnosed with HIV, care providers are expected to perform a genotypic resistance test in order to make sure they do not prescribe antiretrovirals that the person is already resistant to. That test would reveal if the person has resistance to tenofovir/emtricitabine. But keep in mind, this strain is rare. If people with HIV have this strain, it is most likely that their clinician would have informed them already. Even if they do have this strain, they can eliminate nearly all risk of HIV transmission to any negative partner, with or without PrEP, by adhering to their HIV medications and maintaining an undetectable viral load.
In the Toronto case, it is believed that the person from whom the PrEP user acquired HIV had not complied with treatment, and that is how his strain became resistant. That can't be confirmed at this time, however, because when the case was presented it was unknown exactly whom the PrEP user acquired HIV from. But we know it's extremely unlikely for people who are adherent to their HIV medications to become resistant to them.
Will there be other kinds of PrEP that could block this type of resistant virus? There are many kinds of PrEP currently being studied -- for instance, PrEP using different medications (such as maraviroc [Selzentry, Celsentri]), as well as different modes of administration such as gels and injectables. It's difficult to say at this time whether these new forms will offer adequate protection from this rare strain, or from other strains that are resistant to the drugs or drug classes used for those particular forms of PrEP.
Where can I see the actual research related to this case? You can watch the case study presentation at CROI 2016 via archived webcast.
PrEP News Coverage
Maraviroc-Containing Regimens Safe, Tolerable When Taken for HIV Prevention NIAID/NIH 24 February 2016 http://www.niaid.nih.gov/news/newsreleases/2016/Pages/CROI-HPTN069.aspx
An analysis of condom use in the placebo-controlled phase of the French IPERGAY trial of intermittent PrEP, presented at the CROI 2016 conference, found that just over half of the participants had high levels of PrEP use but rarely used condoms, and about a quarter were “belt-and-braces” users who had high levels of both PrEP and condom use.
However this left about one in six trial participants who had low levels of use of both PrEP and condoms. While their condom use did not change, in a minority of this group their PrEP use declined significantly during the study.
In this randomised phase of the study, participants did not know if they were taking PrEP or placebo. A second presentation of results from the open-label phase of the study, when all participants knew they were on PrEP, found that the use of condoms where the participant was the receptive partner declined slightly but significantly, with a relative fall from previous condom use rates of about 15-20%.
About IPERGAY The IPERGAY trial of intermittent PrEP stopped its randomised phase in October 2014 and at the subsequent CROI conference in February 2015 it was announced that there were 86% fewer HIV infections in participants allocated to PrEP than to placebo. Its full results were published last December. Details can be found in these reports but in brief the innovative regimen that IPERGAY offered participants was that they take two tenofovir/emtricitabine (Truvada) pills in the 24 hours before they anticipated having sex, and if they did, then to continue daily PrEP if they continued sex, and to take one pill on both of the two days after sex if they stopped having it.
The presentation on PrEP and condom use confirms that PrEP use as measured by pharmacy refills and returned bottles was generally high. Adherence, defined as the proportion of cases on anal sex covered by at least the double dose beforehand, two doses afterwards, or both, was also high. PrEP and condom use in the placebo-controlled trial
The researchers, further analysing the data, discovered that participants fell into four fairly distinct patterns of PrEP use.
Nearly 40% of trial participants were consistent users who used PrEP 95% to 100% of the time they had sex. In fact after the third month of the trial, usage was 100% in this group.
Slightly over 30% of users were high-level but inconsistent users. Their coverage of sex with PrEP varied between 70% and 90% over the course of the trial but did not significantly increase or decline over time. While one reason for this variation could have been poor adherence, another could be that they changed their PrEP status according to the known or perceived HIV or viral load status of partners. PrEP News Coverage
Another group, forming 16% of participants, only used PrEP to cover sex occasionally. During the first 16 months of the trial their PrEP use fell from about 20% to zero, rallying slightly in the last eight months, though numbers of participants were small by this time and these changes were not statistically significant.
In the smallest of the four groups, forming 13% of participants, PrEP use declined significantly during the trial. These participants started off with 90% use on average in the first two months but usage had fallen to 50% by month ten. It rallied slightly at their one-year visit but had fallen to pretty much zero by month 16.
As for condom use, participants fell into two groups. A majority – 70% - were low-level users whose use of condoms during anal sex varied between 10% and 25% during the trial. The remaining 30% were higher-level users, though on average their condom adherence varied between 80% and 45%, so this is a relative term. Their adherence had a tendency to fall during the trial, from 78% at month one to 45% at month 18, though it increased to 71% at month 24.
Combining the figures for PrEP and condom use, the researchers found that: • 54% of trial participants were consistent or high-level users of PrEP but did not often use condoms • 23.5% had high levels of both PrEP and condom use • 6.5% had high levels of condom use but used PrEP only rarely • 16% rarely used either PrEP or condoms.
It is of course this latter group who are of greatest concern. If compared to the most-protected 23.5%, this group included more frequently older participants (50% more likely to belong to this group for every ten years older). They were also twice as likely to not have had college education, twice as likely to say they were dissatisfied with their sex lives and – worryingly – were nearly three times more likely to have had sex with partners they did not know. They were also somewhat more likely (p=0.08) to be the active partners in anal sex.
Qualitative studies from IPERGAY will elucidate further why individuals chose particular PrEP and condom use strategies.
Data from the open-label trial Another presentation gave data from the open-label phase of the trial when, from November 2014, all participants were given the option to use Truvada PrEP.
Among the 400 participants initially enrolled in IPERGAY, 336 were eligible to join the open-label study (the remainder having dropped out of the study for various reasons) and all but three joined. Another 29 new participants were enrolled, making 362. All but one transgender woman were gay men. The data shown at this conference was for the ten months up till the end of September 2015 and the cumulative follow-up time was 248 participant-years. Study retention was good with only 13 participants discontinuing follow-up (3.6%).
Their average age was 35 and 84% were of French or European origin. At the start of the open-label phase 10% had had no anal intercourse in the previous month and the average number of partners in the previous two months was seven. PrEP News Coverage
During the open-label phase, one person became HIV positive. Like the two people allocated to PrEP who were infected during the randomised phase, he had stopped using PrEP. He was in the randomised trial for eight months and was diagnosed one month and ten days into the open-label study. By self- report he had not used PrEP since starting the open-label study had had no drug detectable in in his blood. His HIV had no drug resistance mutations.
Lumping together HIV incidence in the randomised and open label phases, HIV incidence as 0.4% a year in people allocated to PrEP. This compared with 0.91% in people allocated to PrEP in the randomised phase alone and to 6.6% in people allocated to placebo; it implies 94% fewer HIV infections in those given PrEP versus those given placebo.
Participants used an average of 18 pills a month according to pharmacy returns but this is probably an overestimate, because after the results from the randomised study were announced, participants became reluctant to return their PrEP bottles in case PrEP became unavailable after the trial (in fact, fully-reimbursable PrEP became available in France from the beginning of this year.)
During the open-label study a third of participants were diagnosed with a new sexually transmitted infection. Of these 38% were diagnosed with gonorrhoea, 42% with chlamydia and 21% with syphilis. Three individuals (1%) were diagnosed with hepatitis C.
There was no significant change between the randomised phase and the open-label phase in the median number of occasions of sex or sexual partners. But there was a significant decrease in condom use for receptive anal intercourse Condom use as the receptive partnervaried between 40% and 25% during the randomised study. During the open-label study, it varied between 20% and 30%.
Safety was good with a low rate of serious adverse events (4%). One participant discontinued PrEP because of a decrease in creatinine clearance, but more as a precaution as high actual relative loss in kidney function was slight: his creatinine clearance was 81 millilitres per minute at the start of the open label study and 76 at discontinuation.
Drug-related gastrointestinal adverse events were fairly common. Diarrhoea was reported by 10% of patients, nausea by 11%, abdominal pain by 8% and other gastrointestinal symptoms. The only life- threatening diverse event was a stroke, in a participant who already had a cerebral aneurysm (blood vessel dilation).This was not regarded as drug-related.
Further data will be forthcoming from IPERGAY and the French health ministry has made the collection of behavioural and safety data a requirement for joining the rollout programme.
Maraviroc drug safe, well-tolerated when taken as PrEP to prevent HIV infection News Medical 25 February 2016 PrEP News Coverage http://www.news-medical.net/news/20160225/Maraviroc-drug-safe-well-tolerated-when-taken-as- PrEP-to-prevent-HIV-infection.aspx
Maraviroc, an oral drug used to treat HIV infection, is safe and well-tolerated when taken daily as pre- exposure prophylaxis (PrEP) to prevent HIV infection by HIV-uninfected men who have sex with men (MSM) at increased risk for acquiring HIV. These findings from the Phase 2 HPTN 069/ACTG 5305 trial were presented today at the Conference on Retroviruses and Opportunistic Infections in Boston. The trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIH-funded HIV Prevention Trials Network, in collaboration with the AIDS Clinical Trials Group.
A daily pill called Truvada containing the antiretroviral drugs tenofovir disoproxil fumarate (TDF) and emtricitabine currently is the only PrEP regimen approved by the Food and Drug Administration. TDF and emtricitabine interfere with viral replication after HIV has entered cells. Maraviroc blocks HIV from entering cells and concentrates in the rectum and genital tract.
In the study, 406 MSM in the United States and Puerto Rico were randomly assigned to take either once- daily maraviroc alone, maraviroc plus TDF, maraviroc plus emtricitabine, or TDF and emtricitabine. Investigators found that the maraviroc-containing regimens were as safe and well-tolerated as TDF and emtricitabine. Five participants became infected with HIV during the study. These participants had low, variable or undetectable drug levels, likely indicating they were not consistently using PrEP.
The researchers also reported results from a substudy evaluating the impact of these PrEP regimens on colorectal tissue samples from 55 participants. Previous work in HIV-infected people had suggested that maraviroc may increase immune T-cell activation in rectal tissue, which potentially could increase susceptibility to HIV infection. However, the researchers did not observe increased T-cell activation in the samples. Viral suppression experiments with tissue samples taken from study volunteers provided a preliminary indication that maraviroc alone may be less effective at preventing HIV infection than combination PrEP regimens.
PrEP News Coverage First Man to Become HIV-Positive While on PrEP Is Rare Exception Advocate 26 February 2016 http://www.advocate.com/hiv-aids/2016/2/26/first-man-become-hiv-positive-while-prep-rare- exception
It’s been nearly two years since the Centers for Disease Control and Prevention issued historic guidelines recommending that thousands of Americans — particularly gay and bi men, transgender women, injection drug users, and partners of HIV-positive people — start taking Truvada as pre-exposure prophylaxis (or PrEP) to prevent HIV infection.
The prevention method has shown to be 99 percent effective at preventing HIV transmission among those who take it daily as prescribed and, as was reported at the Conference on Retroviruses and Opportunistic Infections this week, it’s even 86 percent effective among those using it “on demand” (essentially one dose two to 24 hours before sex, and then twice more the two days following sex).
Truvada as PrEP has had its critics from the get-go, notably Michael Weinstein, the head of AIDS Healthcare Foundation, who has led what some activists called a moral crusade against the drug. But many scientists, doctors, public health experts, and activists have heralded the prevention method as part of the necessary one-two punch needed to get HIV and AIDS numbers lowered in the U.S. (The other part is treatment as prevention—TasP — in which people who are HIV-positive take medication to reach viral suppression so they can no longer transmit HIV to others). The CDC’s own study, reported this week at CROI, in fact, says that PrEP has the potential to reduce new HIV infections by at least 70 percent in the United States.
But Weinstein and naysayers finally got the tiniest bit of ammunition in the culture war over PrEP. Researchers reported the first documented case of HIV infection this week of a man who appears to have been using the treatment regularly and as recommended. Dr. David C. Knox, a physician at Toronto’s Maple Leaf Medical Clinic and the lead author of the study presented at CROI, says that a 43- year-old Canadian man is believed to have been taking PrEP for two years when he seroconverted to a multidrug-resistant strain of HIV, despite “clinical and pharmacokinetic data suggesting long-term adherence” to PrEP.
The man’s virus was found to be resistant to multiple drugs, including emtricitabine and tenofovir, the two main ingredients in Truvada. When researchers from Maple Leaf, St. Michael's Hospital (also in Toronto), the British Columbia Centre for Excellence in HIV/AIDS in Vancouver, and the University of Colorado — all coauthors of the CROI study — did standard and deep sequencing of the virus from day 7, it revealed CCR5-tropic clade B HIV-1 with mutations conferring resistance to several classes of HIV drugs, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and integrase inhibitors.
Phylogenetic analysis revealed a very narrow range of sequence diversity, consistent with infection from a single source, which led researchers to believe that the HIV was transmitted from a single individual, rather than something the man got through an acquired resistance to the drugs he was taking.
The vast pool of resistance mutations means the strain of HIV in question is resistant to many of the most common HIV medications, including Isentress (raltegravir), Vitekta (elvitegravir), Tivicay PrEP News Coverage (dolutegravir), Ziagen (abacavir), Viread (tenofovir), Epivir (lamivudine), and Emtriva (emtricitabine). However, Poz’s Benjamin Ryan reported that “despite all these resistance mutations, the man in the case study is currently on successful HIV treatment, with a fully suppressed viral load. He is taking Tivicay (dolutegravir), Prezcobix (darunavir/cobicistat), and Edurant (rilpivirine).”
So how do we know the man was really adherent to PrEP guidelines? Researchers gathered his pharmacy records, which showed he had consistent prescription refills. Liquid chromatography–mass spectrometry “was performed on the untimed plasma sample from day 0” to determine the quantities of each medication in his system. Dried blood spot testing collected on day 16 showed consistent dose- taking in the preceding one to two months, thus overlapping with the time period when he would have seroconverted to HIV-positive.
In addition, standard population sequencing and deep sequencing to 2 percent of the viral population was completed on day 7, as was phenotypic testing for resistance to integrase inhibitors, and “phylogenetic analysis of the V3 loop of envelope protein gp120” to characterize the “founder virus.”
Knox and his fellow researchers told conference attendees that “to our knowledge, this is the first reported case of breakthrough HIV infection with evidence of long-term adherence to [Truvada as PrEP].”
There is further testing this individual could undergo. But further analysis seems unwarranted after the litany of tests the newly-poz man has already undergone. Moreover, if PrEP is 99 percent effective, this guy could indeed be that 1 percent. While none of the nearly 10,000 people in the famed iPrEx study of PrEP among gay and bi men and trans women acquired HIV — and mutation like this wasn’t seen among the participants — scientists have always argued there could be a very small possibility of such.
While resistance to tenofovir is cited as a main concern among people living with HIV who are resistant to treatment worldwide, tenofovir-resistant strains of HIV only account for about 1 percent of all cases. Resistance to Truvada’s other active ingredient, emtricitabine, is more common, but the strain that managed to bypass the safety of PrEP and infect the man in this study involved a mutation that was resistant to both medications, an exceedingly rare occurrence.
While this case proves that there is no 100 percent guarantee when PrEP is concerned, most experts, including those in this study, say that cases such as this will likely remain rare.
AHF: PrEP Patient’s Drug-resistant HIV Infection; Bone Loss, Fractures in Others, Suggest Caution Business Wire 25 February 2016 http://www.businesswire.com/news/home/20160225006800/en/AHF-PrEP-Patient%E2%80%99s-Drug- resistant-HIV-Infection-Bone
An article in POZ Magazine today reported that for the first time, an individual on the HIV-prevention protocol pre-exposure prophylaxis, or PrEP, for over two years not only became infected with HIV, but PrEP News Coverage became infected with a drug resistant strain of the virus. In a case presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, researchers found that a 43 year-old man whose blood serum levels suggested had been adherent to the medication portion of the HIV prevention regimen nevertheless became infected with HIV and that “… his drug resistance had been transmitted from another person, rather than acquired post-transmission.
There was no mention of condom use—as FDA guidelines for PrEP indicate—in the report on the case at CROI.
In addition, a day earlier at CROI, other presentations documented bone fractures among HIV patients taking tenofovir and bone loss—albeit reversible—associated with the use of tenofovir in pre-exposure prophylaxis (PrEP).
“Due to issues surrounding medication adherence with PrEP, AHF has always been concerned about the potential for overall spread of the virus as well as other STDs for which PrEP offers no protection,” said Michael Weinstein, President of AIDS Healthcare Foundation, which has criticized and cautioned against the widespread deployment of PrEP as a community wide public health strategy, such as the CDC’s recommendation that 1.2 million Americans be put on PrEP, but supports its use on a case-by-case basis decided upon between a medical provider and his or her patient. “Now, on the heels of this drug resistant infection found in one individual who appeared to be adherent with the drug portion of his PrEP regimen, a larger concern is about the potential for a more drug resistant strain of HIV entering the community-at-large.”
In November 2015, the CDC recommended that 1.2 million high-risk Americans go on PrEP. At the time, USA Today reported that the Centers for Disease Control (CDC) confirmed that three years after the FDA first approved the use of Gilead Sciences’ successful HIV/AIDS treatment medication, Truvada, for pre- exposure prophylaxis to prevent HIV transmission in uninfected individuals, just 21,000 people were on PrEP today in the U.S.
AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and/or services to over 594,000 individuals in 35 countries worldwide in the US, Africa, Latin America/Caribbean, the Asia/Pacific Region and Eastern Europe. To learn more about AHF, please visit our website: www.aidshealth.org, find us on Facebook: www.facebook.com/aidshealth and follow us on Twitter: @aidshealthcare and Instagram: @aidshealthcare
Panic Over HIV Infection While on PrEP Is Not Necessary TheBody Aaron Laxton 26 February 2016 http://www.thebody.com/content/77162/panic-over-hiv-infection-while-on-prep-is-not-nece.html
Social media has been abuzz today, with people sharing the news that a gay man who was taking Truvada as PrEP (pre-exposure prophylaxis) has contracted a drug-resistant strain of HIV. I can only PrEP News Coverage imagine that this is the news that Michael Weinstein has been wringing his troll-ish hands in gleeful anticipation since 2012. There is only one small problem that people are failing to recognize -- this is not surprising.
It was only a matter of time before a person who was taking PrEP contracted the virus. Those of us who work in the field or are advocates are not surprised by this. I would simply caution everyone to get your facts from people who are knowledgeable about PrEP and the science behind it; rather than individuals who have never had a good thing to say about PrEP. They probably were biased against PrEP long before this study. These are the same people who will exaggerate the side effects (which most people will never experience) or the cost (which most people will get for free or through insurance) or kidney damage (which is reversible once the patient stops taking the medication) however they never tell the full story.
Below are a few things that came to mind as I was reading the results of the study:
1. Truvada is not 100% effective in preventing HIV. It is around 96% effective; advocates have never portrayed it as being 100% effective. 2. There are currently around 44,000 people prescribed Truvada; this is one person of 44,000. Statistically, that is around 0.00002% which is of no statistical value, ask any statistician. 3. Drug-resistant strain, well that does not necessarily have anything to do with PrEP since when a person contracts HIV, they contract the mutated virus (if it is mutated) from that other person. 4. All medications, no matter what it is, will have a certain amount of failure. Think about it. 5. If anything, this study goes to support the fact that PrEP works. For 44,000 other individuals, we have only now heard of one person. That is awesome that it is only one. 6. So for all you Michael Weinstein's out there, crawl back into your little troll cave. PrEP works, and as advocates have always said, it is part of the prevention toolbox that each and every person has at their disposal. A person and a couple need to negotiate what works for them.
Those who are on PrEP need to know that PrEP is still up to 96% effective in preventing HIV. Those who are considering PrEP need to know that for the first time in history they now have the opportunity to protect themselves and it is completely up to the top.
PrEP Is Not Magic—and Treating It That Way Undermines Its Incredible Power Slate J Bryan Lowder 26 February 2016 http://www.slate.com/blogs/outward/2016/02/26/hiv_transmission_on_prep_is_possible_but_very_ra re_according_to_new_study.html
PrEP News Coverage It’s been a confusing week with regard to PrEP—an HIV-prevention strategy which currently consists of taking a daily pill (Truvada) to prevent infection if one is exposed to the virus.
At a major conference for HIV research—the Conference on Retroviruses and Opportunistic Infections— the CDC revealed that, if deployed widely alongside pushes for more HIV testing and treatment, PrEP has the potential to help reduce new infections in the U.S. by 70 percent, preventing an estimated 185,000 new cases by 2020. Specifically, suppressing the virus to “undetectable”—and therefore essentially nontransmissible—levels in HIV-positive people could prevent 168,000 infections, while an expansion of access to PrEP to negative individuals could forestall 17,000 new cases.
Those numbers add to the promise of PrEP, which has been shown to be 99 percent effective at preventing HIV transmission if taken daily as directed. But of course, that statistic leaves a 1 percent chance of infection open—and, unfortunately, an instance of that 1 percent also showed up at the conference.
David C. Knox, a physican and researcher from Toronto, presented a case study of a patient who, according to the doctor, represents “the first reported case of breakthrough HIV infection with evidence of long-term adherence to PrEP.” The patient, a 43-year-old man, had been on PrEP for about two years (testing negative for HIV seven times as part of the regular checkups required for the regimen) when he seroconverted. Importantly, pharmacy records and further medical investigations confirmed his claim that he had been taking the medication as prescribed. (Cases of infection in PrEP patients who had not kept up with the daily pill have been reported; this is the first time an apparently compliant individual has seroconverted.) The patient reported multiple instances of anal sex without condoms in the period before testing positive. While PrEP’s protection rates are actually higher than those for condoms, it is currently recommended that individuals on the program continue to use them, as condoms help protect against other STIs and enhance coverage for HIV.
To the scientific community, this is an intriguing—though rare—case of HIV multi-drug resistance. The patient’s particular viral pool showed varying levels of resistance to a host of drugs, including those that make up Truvada—though he is now on a customized regimen rendering him undetectable. In the presentation (which is streamable online), Knox suggested that the patient was likely infected by an HIV- positive partner whose own treatment on the drug cocktail Stribild was “failing,” or losing efficacy, as sometimes happens for various reasons over the long term.
It’s important to note that the resistance of this particular instance of the virus is extremely uncommon. Speaking to Betablog, Dr. Robert Grant, a noted HIV/AIDS researcher, provided some helpful context:
The prevalence of this kind of virus among recently infected persons is less than 1%. Maybe much less. If PrEP is not fully effective against viruses that are HIGHLY resistant to both drugs in FTC/TDF PrEP, the efficacy of PrEP when taken may decrease from 99% to 98%. Or from 99.9% to 98.9%. Or from 100% to 99%. The decimal points are not certain. My point is that one chooses whether to focus on the glass 99% full or 1% empty. Still, the news has caused a great deal of consternation among gay/bi men and the wider PrEP constituency, both among advocates who fear a scientifically unfounded “told-you-so” reaction from PrEP opponents like the AIDS Healthcare Foundation, and among individuals currently taking or curious about PrEP and unsure of what to make of such an unsettling report. The latter anxiety is understandable, but ultimately unwarranted—such a case was essentially guaranteed to surface at some point. All that’s changed is that a percentage point has unfortunately become a person. PrEP News Coverage
That shift does not negate PrEP’s efficacy or importance as an HIV prevention tool. In fact, it just confirms what we already knew about its limitations—limitations that remain, well, amazingly limited. But it does offer two useful takeaways.
The first is rather obvious: PrEP is powerful, but, as a series of ads on buses and trains in New York are currently putting it, “PrEP + condoms” is even more powerful. While there’s no way of being certain, that double-up strategy might have helped this patient avoid his seroconversion, and it undoubtedly could help prevent similar situations for others. In a certain sense, it’s an embarrassment of riches to have two incredibly effective methods for preventing HIV transmission (and three if you count treatment-as-prevention) at our disposal. Yes, sex is complicated, condomless sex isn’t inherently “bad” (though nor is it inherently transcendent), and we all should feel empowered to make decisions appropriate to the situation. But if this dispatch from the 1 percent gives you pause, using both is probably a good idea.
But more important, the heated response to this news has revealed a fundamental problem in the way many of us, from advocates to detractors, have been thinking and talking about PrEP. It has taken on an aura of the magical. For some skeptics, the pill is a cursed object, capable of turning gay men into irresponsible “sluts” or “partiers” and vexing the fragile recovery the community achieved after the initial AIDS crisis was quieted. And for some supporters, it’s an amulet, imbuing the holder with imperviousness and warding off fear, even the sort that might be healthy. These twin responses make sense for a community that suffers from group trauma—discovering sex and death in bed together isn’t an experience you easily shake. But they are both ultimately inaccurate, as all magical thinking must be. Truvada is not a hex or a charm; it’s a drug. It is not magic; it’s medicine.
Medicines work, and medicines fail—we usually understand this, cheering the former and mourning the latter. That we find PrEP’s exhibition of the same behavior to be some kind of betrayal or portent suggests we’ve lost sight of that logic in this case. Let’s use this opportunity to get it back. Let’s discuss PrEP with nuance, fighting for those who need it while avoiding the allure of generalization. Let’s ask smart questions about its impact on the community in a way that embraces the complexity of reality rather than retreating into the ease of the metaphysical. The awesome is always intimidating, regardless of whether it’s beautiful or terrible, and intimidation is not what we need right now. PrEP was never going to save us, not entirely, nor was it going to end us—but what good it can do will be hampered by freighting it with powers it does not possess and responsibilities it cannot bear.
Almost-certain case of PrEP failure due to drug resistance reported at CROI 2016 Aidsmap Gus Cairns 25 February 2016 http://www.aidsmap.com/Almost-certain-case-of-PrEP-failure-due-to-drug-resistance-reported-at- CROI-conference/page/3039748/ PrEP News Coverage
A case report of a man in Toronto who became infected with a multi-drug-resistant strain of HIV despite apparently very consistent adherence to PrEP was presented at the Conference on Retroviruses and Opportunistic Infection (CROI 2016) conference in Boston today.
Dr David Knox, a doctor at Toronto’s Maple Leaf Medical Clinic, said the patient was a 43-year-old gay man who had been on PrEP for two years. He had an HIV-positive partner who was undetectable on antiretroviral therapy, but also had casual sex contacts involving the risk of HIV exposure.
He was a regular attender at the clinic and tested for HIV on average every three months. It was suggested to him that he start Truvada PrEP in April 2013 and he appeared to have good adherence to it on the basis of the frequency of pharmacy refills.
Two years later in April 2015 he started having symptoms after a period of exposure to HIV with multiple partners. The symptoms were not classic HIV seroconversion symptoms but involved an episode of fever with abdominal pain severe enough for him to go for hospital investigation, where a scan revealed an inflamed colon.
During this time he came in for his regular HIV test and this showed he had acute HIV infection, with a negative test for HIV antibodies but a positive test for the HIV p24 antigen, which shows up sooner. His HIV viral load three days later was 28,000 copies/ml – rather low for acute HIV infection and suggestive that either his PrEP had ‘blunted’ viral replication without stopping infection, or that the highly drug- resistant virus was replicating weakly.
The patient was adamant that he maintained excellent adherence to PrEP so Dr Knox, by now concerned that he might be seeing a case of genuine PrEP failure, ordered more tests. One was a resistance test, for all antiretroviral drug classes, for his patient’s virus, from a sample taken a week after his HIV diagnosis.
The other needs explanation. The patient was treated within a cash-poor public health setting and his old blood samples had not been saved. So there was no way to directly prove that he had drug levels consistent with high adherence around the time of HIV exposure.
There was an indirect way, however. Dr Knox analysed a so-called Dried Blood Spot (DBS) from the patient taken 20 days after he was diagnosed. The point of a DBS test is that it measures drug levels inside red blood cells, rather than inside the white blood cells HIV infects, or in blood plasma. Drug levels rise much more slowly inside red blood cells, taking 17 days to reach half of their steady-state levels, and a full eight weeks to reach the drug-saturated steady state completely. Drug levels also rise steadily and are less susceptible to short-term peaks and troughs. Drug levels in the patient’s DBS were actually 47% higher than the average figure, suggesting consistent PrEP adherence for most of the period covering his exposure to HIV. If he had only been taking the drugs since he learned his diagnosis, the drug levels would only be 47% of the average steady state level or 31% of their actual level in this patient.
This is an indirect way of measuring drug levels. Given that the onset of symptoms occurred four weeks before the patient’s HIV diagnosis and the dried blood test was taken over three weeks after, and that the period of risk according to the patient started two weeks before the onset of symptoms, thus leaving nine weeks for the drug to accumulate, this test did not entirely rule out the possibility that he PrEP News Coverage had been off PrEP at the time he took a risk and that this had prompted him to start taking it again. However, the patient insists this is not the case.
There was a small blood sample left over from his diagnostic test, taken three days before the patient learned he had HIV. This revealed high levels of tenofovir and levels of emtricitabine so high they were above the test’s limit of quantification. However this was not a test of long-term drug levels and again cannot completely rule out the possibility that he had had a lapse in adherence around the time he was exposed to HIV.
The resistance test showed that the patient had HIV that had no significant resistance to the protease inhibitor class of antiretrovirals. He had one resistance mutation to the first generation NNRTI drug nevirapine, and complete resistance to emtricitabine. He also had extensive resistance to the first- generation NRTI drugs like zidovudine (AZT) and stavudine (d4T), and these mutations also confer some resistance to tenofovir. However he did not have the so-called K65R mutation that confers high-level resistance to tenofovir, and it was estimated that the resistance pattern he did have only confers 1.3- fold resistance to tenofovir, meaning that drug levels 30% higher than those needed for non-resistant virus should have been enough to prevent infection – and he had much higher drug levels than this in the tests. Resistance, however is a complex process and some combinations of mutations can catalyse higher levels of resistance than they would produce alone.
Not relevant to the apparent PrEP failure, but to the spread of drug resistance, was the fact that this patient also had two resistance mutations to the integrase inhibitor drugs and complete resistance to the drug elvitegravir.
Transmission of HIV with integrase inhibitor resistance is very rare, and especially resistance to drugs other than raltegravir, the first integrase inhibitor. The pattern of resistance observed is compatible with the unnamed person who passed on the virus being on a failing regimen of Stribild (the two-class, four- drug combination pill of tenofovir, emtricitabine, elvitegravir and cobicistat). Given that four out of the five first-line HIV drug regimens recommended by the US Department of Health and Human Services are integrase inhibitor-based, and that this drug class is being investigated for use as PrEP, it would be of concern if more integrase inhibitor-resistant virus started to circulate.
The patient himself was put on a potent three-class regimen of dolutegravir, rilpivirine and boosted darunavir and became virally undetectable only three weeks after starting it.
In conclusion, this is probably not an absolutely clinching case – one would need drug level samples taken at the time of infection for that. But on the balance of probabilities, with three different measures all supporting the patient’s self-report, this is probably the first documented case of the failure of Truvada PrEP despite high adherence and more-than-adequate drug levels though recently two cases on solo tenofovir were published.
It is not unexpected that there would be occasional cases of PrEP failure; but the fact that this is the first case report among the tens of thousands of people now taking PrEP shows that it is very rare.
PrEP News Coverage The first case of HIV contraction while taking preventative drugs has been documented AOL News 25 February 2016 http://www.aol.com/article/2016/02/25/the-first-case-of-hiv-contraction-while-taking-preventative- drug/21318772/
According to a case that has been documented and presented by David Knox, MD, an HIV specialist at the Maple Leaf Medical Clinic: Evidence suggests that the individual in question, a 43-year-old man who has sex with men, adhered well to PrEP over the long-term. Nevertheless, after 24 months on Truvada he tested positive for HIV. Initial tests indicated that he was acutely (very recently) infected: He tested positive for the p24 antigen, which appears within about three weeks of HIV infection and disappears a few weeks afterward; and at that time he tested negative for HIV antibodies, which typically appear two to eight weeks after infection.
In light of this new information, scientists have concluded that it is, in fact, possible for individuals who are adherent to PrEP to contract HIV when they are exposed to a particular virus that is resistant to drugs.
"After 32 years of experience with HIV research, I have learned never to say 'never'," said Robert M. Grant, MD, MPH, a professor at the University of California, San Francisco.
However, there is still more than a silver lining when it comes to HIV preventative medication.
Despite this case of infection while adhering to the regimen, research still suggests that gay men who take Truvada at least four times a week are still more than 99 percent protected against HIV, though CDC guidelines advise taking Truvada daily for maximum protection.
According to an article from Poz, "real-world use of Truvada as HIV prevention has suggested it is indeed highly effective." For example, none of the more than 1,400 generally high-risk individuals taking PrEP through the Kaiser Permanente San Francisco PrEP program have contracted HIV to date, despite their very high rate of other sexually transmitted infections, including hepatitis C virus (HCV) in two of them.
So anyone on the PrEP regimen can breathe a sigh of relief -- while this one case is definitely concerning, experts in the PrEP field suggest that such failures will likely remain rare.
Man on Daily PrEP Regimen Contracts HIV, According to Study Gawker Rich Juzwak 24 February 2016 http://gawker.com/man-on-daily-prep-regimen-contracts-hiv-according-to-s-1761282343 PrEP News Coverage
The first case of HIV contraction in a person taking PrEP (pre-exposure prophylaxis, or a antiretroviral drug cocktail used to protect people from contracting HIV) daily has been documented and presented by David Knox, MD, an HIV specialist at the Maple Leaf Medical Clinic, at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, according to Benjamin Ryan at Poz. Ryan reports:
Evidence suggests that the individual in question, a 43-year-old man who has sex with men, adhered well to PrEP over the long-term. Nevertheless, after 24 months on Truvada he tested positive for HIV. Initial tests indicated that he was acutely (very recently) infected: He tested positive for the p24 antigen, which appears within about three weeks of HIV infection and disappears a few weeks afterward; and at that time he tested negative for HIV antibodies, which typically appear two to eight weeks after infection.
And furthermore:
“After 32 years of experience with HIV research, I have learned never to say ‘never’,” said Robert M. Grant, MD, MPH, a professor at the University of California, San Francisco, who was the head of the iPrEx trial that first proved PrEP’s effectiveness among MSM and transgender women in 2010. “Yet I also think that gay men benefit from feeling safer during sex, and I am grateful that PrEP affords that feeling.”
Pharmacy records indicated that the man in the case study had consistently filled his Truvada prescription on schedule. Dried blood-spot testing on a sample taken 16 days after he tested positive for HIV indicated that he had adhered well to Truvada during the previous one to two months, a period that overlapped with the estimated time when he contracted the virus.
“This person claims he was taking PrEP every day and I believe him,” said Grant. The man tested positive for a strain of the virus that was resistant to multiple drugs, including emtricitabine and tenofovir, which make up Gilead’s Truvada, the current antiretroviral cocktail on the market that’s used as PrEP. Poz adds, “Despite all these resistance mutations, the man in the case study is currently taking HIV treatment and has a fully suppressed viral load.” And also:
What is more rare is a virus that is highly resistant to both tenofovir and emtricitabine, as in this new case report. Indeed, according to Grant, among more than 9,200 participants in the clinical trials of PrEP, such a virus that was highly resistant to both components of Truvada was never seen. The takeaway is that PrEP is not 100 percent effective, as many hoped it was. That doesn’t mean that it’s ineffective (its efficacy has been estimated by some to be as high as 99 percent), it just means that like virtually everything, it is not the perfect, absolute solution to the HIV epidemic. Antiretrovirals are incredibly powerful tools in curbing the spread of HIV—a study of hundreds of sero-different couples amounting to tens of thousands of condomless sexual encounters found not one instance of transmission of HIV from the positive partner to the negative.
Also presented at the conference was the CDC’s estimation that the combination of PrEP, alsong with expanded HIV testing and treatment has the potential to reduce new infections in the United States by 70 percent by 2020, according to another report for Poz by Ryan.
And while this PrEP news is sobering, it’s far from the most sobering HIV-related headline of the week. That honor goes to the CDC’s estimation that if rates continue as they are, one in two black men who PrEP News Coverage have sex with men will contract HIV in his lifetime. Fifty percent. For a variety of reasons, that population is particularly underserved when it comes PrEP and HIV treatment as a whole.
Case report details gay man becoming HIV+ while on PrEP Metro Weekly 26 February 2016 http://www.metroweekly.com/2016/02/report-claims-gay-man-becoming-hiv-while-using-prep/
Is there a strain of HIV that is resistant to PrEP? That’s the question being asked following a presentation by Dr. David C. Knox, of the Maple Leaf Medical Clinic in Toronto, Ontario.
Knox told an audience at the Conference on Retroviruses and Opportunistic Infections about his clinic’s study of one gay man who seroconverted to become HIV-positive while adhering to a prescription drug regimen designed to prevent HIV, known as pre-exposure prophylaxis,or PrEP.
In his presentation, Knox detailed the story of what he believes is a rare incidence of “multi-class resistance” leading to HIV infection, calling attention to a 43-year-old man who had sex with men and seroconverted to HIV-1 after two years of being on PrEP. Blood tests indicated he had levels of PrEP in his blood suggesting he had been regularly adherent. Knox also noted that no other case of “breakthrough HIV infection” had been documented in a study to date.
The patient had reportedly been taking medications for “depression, anxiety and herpes labialis [cold sores]” but presented “no evidence of STIs” and “had no history of substance abuse.” He first tested negative for HIV in Feb. 2013, and two months later began taking PrEP. Over the course of two years, the patient had seven more HIV tests that all came back negative. However, a screening in May of 2015 showed positive signs of HIV.
Knox also presented information about the man’s sexual history and symptoms before the final positive tests. Prior to his diagnosis, the man reported that he had engaged in multiple acts of receptive, condomless sex with different partners.
“At this point, as the treating provider, I became concerned that this could be a true breakthrough HIV infection, in the context of PrEP, because my patient was adamant that he was adhering to his PrEP over the preceding 24 months,” Knox said.
Knox said the clinic investigated the patient’s claim, including the examination of his pharmacy dispensing records, collection of dried blood spots, and testing of TDF & FTC concentrations in his plasma. He stated that “phylogenetic analysis indicated infection from a single source,” and that the drug resistance appeared to have been “transmitted rather than acquired.” Evidence indicated that the patient “was exposed to somebody who was failing a regimen of…Stribild [an antiretroviral treatment consisting of FTC, TDF, elvitegravir (ELF) and cobicstat (COBI)].”
The patient has since been put on a combination of Prezcobix, Tivicay and Edurant and achieved viral suppression within 21 days, remaining undetectable to date. PrEP News Coverage
“The clinical history, pharmacy records, the mass spec results consistent with recent dosing, the dried blood spots consistent with long-term dosing of FTC/TDV suggest that HIV infections is possible despite adherence to daily oral PrEP,” Knox said during his presentation. “To our knowledge, this is the first reported case of breakthrough HIV infection with evidence of long-term adherence to PrEP. Failure of PrEP in this case was likely due to the transmission of a PrEP-resistant, multi-class resistant strain of HIV- 1.”
Megan Coleman, a family nurse practitioner and director of community research at Whitman-Walker Health, says that while this case appears to be the first of its kind, this particular form of resistant virus is quite uncommon.
“In medicine, we’ve learned never to say anything is 100 percent,” Coleman says. “This particular virus, which is very, very rare, had a lot of mutations and a very complicated interplay of mutations that seemed to make it resistant to Truvada.”
Coleman cautions against widespread panic — particularly since the patient was infected with an already drug-resistant strain, as opposed to developing resistance to PrEP internally — and says medical providers will continue to make scientific-based recommendations to their patients, including prescribing PrEP as one of several HIV prevention strategies.
“When I counsel patients about Truvada for PrEP, my message won’t change,” Coleman says. “It’s to continue to encourage people to take it daily…. We can say, with authority, that PrEP is over 90 percent effective. And the other information, which is based on modeling data, ranges anywhere from 92 to 99 percent effective. So one out of tens of thousands of individuals still translates to 99 percent effective.”
Gay Man Taking PrEP Daily Has Tested Positive For HIV Queerty 25 February 2016 https://www.queerty.com/gay-man-taking-prep-daily-has-tested-positive-for-hiv-20160225
For the first time, researchers have documented a case in which an individual has contracted a multi- drug resistant strain of HIV.
He claims that at the time he was adhering to a daily regiment of Truvada (tenofovir/emtricitabine) as pre-exposure prophylaxis (PrEP).
POZ reports that scientists have come to the conclusion that it’s indeed possible to contract HIV even when adhering to PrEP, when exposed to a strain of the virus that’s resistant to both drugs included in Truvada.
While it’s concerning, experts are suggesting failures like these will be rare.
PrEP News Coverage David Knox, MD is an HIV specialist at the Maple Leaf Medical Clinic and the head author of the case study.
The findings were first presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.
The 43-year-old man had sex with men while taking PrEP once a day.
But after 2 years on Truvada, he tested HIV-positive.
Preliminary tests suggest he was acutely infected.
The man tested positive for the p24 antigen, which surfaces within roughly three weeks of HIV infection and disappears several weeks later.
It was then that he tested negative for HIV antibodies, which typically appear two to eight weeks after infection.
According to POZ: Research suggests that men who have sex with men (MSM) who take Truvada at least four times a week are more than 99 percent protected against HIV. (CDC guidelines advise taking Truvada daily for maximum protection, but the drug apparently has a good amount of dosing “forgiveness.”) Real-world use of Truvada as HIV prevention has suggested it is indeed highly effective. For example, none of the more than 1,400 generally high-risk individuals taking PrEP through the Kaiser Permanente San Francisco PrEP program have contracted HIV to date, despite their very high rate of other sexually transmitted infections, including hepatitis C virus (HCV) in two of them.
All of PrEP’s power to curb HIV notwithstanding, this new case study underlines the fact that in science there is, unfortunately, no 100 percent guarantee.”
Robert M. Grant, MD, MPH, a professor at the University of California, says, “After 32 years of experience with HIV research, I have learned never to say ‘never’… yet I also think that gay men benefit from feeling safer during sex, and I am grateful that PrEP affords that feeling.”
Pharmacy records demonstrate the man did indeed fill his Truvada prescription regularly.
“This person claims he was taking PrEP every day and I believe him,” said Grant.
Tests suggest the man contracted the virus from a single individual, and while his virus was resistant to multiple drugs, he’s continuing HIV treatment and has a fully suppressed viral load.
Research indicates that resistance to tenofovir, the most commonly prescribed ARV in the world, is increasing. What’s rare is a virus that’s resistant to both tenofovir and emtricitabine, as in this particular case report.
According to Richard Harrigan, PhD, director of the lab program at the British Columbia Center for Excellence in HIV/AIDS in Vancouver, Canada, who was one of the researchers on this case study, “I PrEP News Coverage think we would assume that the efficacy of PrEP would be lower if there is exposure to virus which is resistant to either drug, and lowered further if there is exposure to virus resistant to both drugs.”
“I certainly don’t think that this is a situation which calls for panic. It is an example that demonstrates that PrEP can sometimes be ineffective in the face of drug resistant virus, in the same way that treatment itself can sometimes be ineffective in the face of drug resistant virus.”
“This case demonstrates that while PrEP is beneficial, we can’t rely on it to be an infallible magic bullet.”
Gay man taking daily HIV prevention pills contracts resistant strain of the virus - in first recorded case of PrEP failing DailyMail 25 February 2016 http://www.dailymail.co.uk/health/article-3464517/Gay-man-taking-daily-HIV-prevention-pills- contracts-resistant-strain-virus-recorded-case-PrEP-failing.html
A once-a-day HIV prevention pill failed to protect a gay man from a drug-resistant strain of the virus, doctors have revealed.
The 43-year-old man had been taking Truvada – pre-exposure prophylaxis medication (PrEP) - pills every day for two years.
However, the man recently tested positive for a drug-resistant HIV strain, reported the HIV/AIDS website PoZ.
Blood tests indicate the man was infected 'very recently'.
He tested positive for the p24 antigen – which appears within three weeks of HIV infection and disappears a few weeks afterwards.
Additionally, the man tested negative for HIV antibodies – which usually appear two to eight weeks after infection.
The report suggests PrEP may not be as effective on drug-resistant strains, experts warn.
The study was presented by Dr David Knox, a HIV specialist at the Maple Leaf Medical Center, at the 2016 Conference on Retroviruses and Opportunistic Infections in Boston.
Truvada, manufactured by Gilead, is a combination of two drugs - known as tenofovir and emtricitabine - and was approved by the Food and Drug Administration in 2012, as PrEP to prevent HIV infections. Initial trials last year found it to be 90 per cent effective in preventing HIV infections among gay and bisexual men and transgender women who consistently took the daily pill.
PrEP News Coverage Pharmacy records of the individual at the heart of the case study showed that he had consistently filled his Truvada prescription on time.
Doctors conducted dried blood-spot testing on a sample that was taken 16 days after his positive HIV results.
That test indicated that he had adhered well to Truvada during the previous one to two months. However, that time period overlaps with when doctors estimate he contracted HIV.
Dr Robert Grant, of University of California, San Francisco, who was head of a trial that first proved PrEP’s effectiveness, told PoZ: ‘This person claims he was taking PrEP every day and I believe him.’
Doctors conducted additional tests on samples taken a week after the man received his positive results. Those tests found that the virus contained many drug-resistant mutations.
However, the man is currently undergoing HIV treatment and has a fully suppressed viral load.
Dr Richard Harrigan, of the British Columbia Center for Excellence in HIV/AIDS, told PoZ: ‘I certainly don't think that this is a situation which calls for panic.
‘It is an example that demonstrates that PrEP can sometimes be ineffective in the face of drug resistant virus, in the same way that treatment itself can sometimes be ineffective in the face of drug resistant virus.’
Researchers Report First Man to Contract HIV While Using Truvada as PrEP Daily Frontiers Media 26 February 2016 https://www.frontiersmedia.com/frontiers-blog/2016/02/26/researchers-report-first-man-to-contract- hiv-while-using-truvada-as-prep-daily/
Researchers have documented the first reported case of a man who contracted HIV despite a daily regimen Truvada as pre-exposure prophylaxis (PrEP).
The unidentified 43-year-old tested positive for HIV after using Truvada every day for two years, with no evidence that he had slipped in his adherence to a daily regimen of the drug.
While research suggests that Truvada is more than 99% effective in preventing infection when taken daily, there can never be guarantees, and this individual was unlucky enough to come across a rare strain of the virus that was resistant to both tenofovir and emtricitabine, the two main components of Truvada.
PrEP News Coverage Since his diagnosis, the man is on a successful HIV treatment program, with a fully suppressed viral load thanks to other drug treatments.
Researchers were quick to downplay the risk to other PrEP users, insisting that multi-drug resistant strains like this are very rare. Among over 9,200 participants in Truvada clinical trials, such a virus that was highly resistant to both components of Truvada was never seen.
“I certainly don’t think that this is a situation which calls for panic,” Dr. Richard Harrigan, one of the researchers on the study, told Poz. “It is an example that demonstrates that PrEP can sometimes be ineffective in the face of drug resistant virus, in the same way that treatment itself can sometimes be ineffective in the face of drug resistant virus.”
“This case demonstrates that while PrEP is beneficial, we can’t rely on it to be an infallible magic bullet.”
PrEP News Coverage Modest kidney function decline in people taking Truvada for PrEP supports need for monitoring Aidsmap 2 March 2016 http://www.aidsmap.com/page/3040983/
Participants taking tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) in two major studies experienced modest declines in kidney function that were associated with higher tenofovir drug levels and older age, according to studies presented in a poster discussion session entitled “It’s complicated: renal function and STIs in PrEP users” at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston. Together, these findings indicate that while Truvada PrEP is safe for most people, ongoing kidney function monitoring is important to promptly catch any problems that may occur.
Tenofovir disoproxil (Viread, also in the Atripla, Eviplera or Complera, and Stribild single-tablet regimens) has been used in HIV treatment for more than a decade and is generally considered safe and well- tolerated, but it can cause kidney damage and bone loss in some people.
For this reason, regular kidney function tests are recommended for people taking Truvada for PrEP and those with pre-existing kidney problems are advised not to use it. The US product label for Truvada states that it should not be used for PrEP in people with creatinine clearance below 60 ml/min, and if a decrease is observed providers should “evaluate potential causes and re-assess potential risks and benefits of continued use.”
Reports to date from PrEP clinical trials – which tried to exclude people with known kidney impairment – have not revealed notable kidney problems. But sometimes uncommon toxicities only show up after many more people are using a drug.
Renal function in iPrEx
Monica Gandhi from the University of California at San Francisco presented follow-up findings on kidney function in the pivotal iPrEx trial, the first to show that once-daily Truvada PrEP was highly effective for gay and bisexual men and transgender women who took it consistently. In an open-label extension (iPrEx OLE), in which everyone knew they were taking active Truvada, no one who took the pills at least four times a week became infected with HIV.
The iPrEx team looked at the relationship between tenofovir and emtricitabine concentrations in hair samples – which reflect cumulative drug exposure – and kidney function over time in iPrEx OLE. Hair samples were collected, serum creatinine (an indicator of kidney function) was measured and estimated glomerular filtration rate (eGFR, an indicator of creatinine clearance) was calculated every 12 weeks.
Of the more than 1000 iPrEx OLE participants, hair drug levels and creatinine measurements were available for 220 people. A majority of participants in this international study were Latino or mixed race/ethnicity and the median age was 29 years (range 19-70). At baseline, the mean creatinine level was 0.89 mg/dl (0.6 to 1.3 is considered normal) and the median estimated eGFR was 112 ml/min (>90 is normal, 60 is a moderate decrease and <30 is a severe decrease). PrEP News Coverage
While creatinine clearance for participants on Truvada decreased slightly overall – by 2.5% over 18 months – there was a consistent and statistically significant relationship between percentage eGFR decline and increasing levels of tenofovir or emtricitabine in hair samples. Among people in the highest quartile of hair drug levels, indicating they took all seven doses a week, the eGFR decrease was 5.6%.
Older participants were more likely to see their eGFR fall below 70 ml/min, considered a clinically significant decrease. Among people older than 50, the proportion with eGFR below this threshold rose from 6% in the lowest hair level quartile (indicating about two doses a week) to 24% in the highest quartile. Among participants under age 40, however, the proportion never rose above 5% even with daily dosing. People with slightly low eGFR (<90 ml/min) at baseline were also more likely to fall below 70 ml/min, with 27% doing so.
Establishing thresholds of tenofovir/emtricitabine exposure that minimise adverse events while maximizing efficacy “are essential to the real-world roll-out of PrEP,” the researchers wrote.
PrEP Demo Project
Albert Liu of the San Francisco Department of Public Health then presented findings on changes in kidney function among participants in the US Demo Project.
The Demo Project enrolled more than 500 gay and bisexual men and transgender women at risk for HIV at sexual health clinics and community health centers in San Francisco, Miami and Washington, DC. All received once-daily Truvada PrEP on an open-label basis for a year.
Nearly half of participants were white, about 7% were black, the median age was 35 years (range 18-65) and 12% had hypertension or diabetes. To be eligible, participants had to have baseline creatinine clearance of at least 60 ml/min, most had at least 70 ml/min and the median was 97 ml/min.
In this study, tenofovir diphosphate (the metabolised form of the drug in the body) was measured in dried blood spots from a subset of participants, and kidney function was again monitored every 12 weeks; 82% of participants had tenofovir diphosphate levels consistent with taking at least four Truvada doses a week.
Overall, eGFR declined by an average of 2.8% from baseline to week 12 – similar to the proportion in iPrEx OLE – and then remained stable through the end of the study at week 48. Only a small number (11 people or 2.4%) had their creatinine clearance fall by 10% or more and their serum creatinine rise by 0.2 mg/dl or more on more than two occasions. Three people did have their Truvada suspended due to an elevated creatinine reading, but these were not confirmed with repeat testing and all restarted PrEP with no further interruptions.
Higher tenofovir diphosphate levels in blood spots were associated with significantly greater declines in eGFR. Again, kidney function decline was associated with older age and a lower baseline level. Among people with baseline eGFR <90 ml/min, the proportion falling below 70 ml/min ranged from about 6% in the 26-35 age group to about 30% of those older than 45. But among people who started with an eGFR of 90 ml/min or higher, less than 5% fell below 70 ml/min in any age group.
Kidney damage in Partners PrEP PrEP News Coverage
Finally, Kenneth Mugwanya of the University of Washington in Seattle presented findings on the occurrence of more serious kidney problems among participants in the Partners PrEP trial, which tested once-daily Truvada or tenofovir alone as PrEP for HIV-negative partners in serodiscordant heterosexual couples in Africa.
This study looked at proximal tubulopathy, which occurs when proximal tubule cells in the kidneys are unable to reabsorb substances such as glucose, salts, minerals and bicarbonate. Sometimes this is sub- clinical and detected by protein or glucose in the urine, but more serious conditions such as Fanconi syndrome can lead to disruption of the body’s pH balance and bone loss. Drugs like tenofovir that are excreted by the kidneys can build up and cause tubule damage, usually in people who have a genetic predisposition or other risk factors. Mugwanya noted that proximal tubulopathy can sometimes occur without an accompanying severe decline in GFR.
This analysis included 776 people randomised to Truvada and 773 randomly assigned to a placebo. Two- thirds were men and the median age was 37 years. Proximal tubulopathy was defined as having any two of the following: protein in the urine, glucose in the urine, increased urinary phosphate or uric acid excretion.
The frequency of proximal tubulopathy was 1.7% (13 people) in the Truvada arm compared with 1.3% (10 people) in the placebo arm, not a statistically significant difference. Protein in the urine alone was seen in 7.3 vs 4.0%, respectively, and this was statistically significant.
A related case-control analysis revealed that two of the 52 people (3.8%) who experienced at least a 25% decline in eGFR developed tubulopathy, compared with three of 208 people (1.4%) who did not, again not a statistically significant difference.
There was “no significant association between tubulopathy and clinically relevant decline in eGFR,” the researchers concluded, suggesting that “using routine markers of proximal dysfunction will not be an efficient approach to predict the rare events of kidney toxicity in persons using PrEP.”
Implications
Taken together, these studies indicate that Truvada is safe and well-tolerated for most people using it for PrEP, but kidney problems – usually mild or moderate – may occur in a small proportion of people, especially if they have other risk factors.
“It is often said that these declines are so low it doesn’t matter, but PrEP studies have not monitored people as long as treatment studies,” Gandhi said at a CROI press conference. She noted that even minor toxicities can be a concern in a healthy population.
These findings support the US Centers for Disease Control and Prevention (CDC) recommendation that creatinine clearance should be monitored at least every six months, with more frequent monitoring and additional tests for people with other kidney safety risk factors such as high blood pressure or diabetes.
Gandhi and Liu agreed that monitoring more often may be appropriate for older people and those who start PrEP with an eGFR <90 ml/min. Conversely, Gandhi also suggested that maybe less frequent monitoring could be considered for people under age 40 with good baseline creatinine clearance. PrEP News Coverage
TAF/emtricitabine maintains viral suppression as well as TDF regimens with less bone and kidney toxicity Aidsmap Liz Highleyman 25 February 2016 http://www.aidsmap.com/TAFemtricitabine-maintains-viral-suppression-as-well-as-TDF-regimens-with- less-bone-and-kidney-toxicity/page/3039254/
A fixed-dose coformulation of tenofovir alafenamide (TAF) and emtricitabine (FTC, Emtriva), combined with a variety of third antiretroviral agents, maintained undetectable viral load in people who switched from similar regimens containing the older tenofovir disoproxil fumarate (TDF), according to a study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston. The study also showed improvements in kidney function biomarkers and bone density gains in the group taking TAF/emtricitabine.
Gilead Sciences’ tenofovir disoproxil fumarate (Viread) plus emtricitabine is one of the most widely used nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) ‘backbones’ of antiretroviral therapy. These drugs make up the Truvada coformulation – used for both HIV treatment and pre-exposure prophylaxis (PrEP) – and are included in the single-tablet regimens Atripla, Eviplera or Complera, and Stribild. TDF is generally considered safe and well-tolerated, but it can cause modest bone loss and lead to 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 adequate intracellular drug levels with a 10-fold lower dose, which means about 90% lower drug concentrations in the blood plasma and less exposure for the kidneys, bones and other organs and tissues.
A single-tablet regimen containing TAF, emtricitabine, elvitegravir and the cobicistat booster (Genvoya) was recently approved in the US and is under regulatory review in Europe. Studies presented last year showed that people who switched from a similar coformulation containing TDF (Stribild) to the TAF- containing combination maintained viral suppression and saw improvements in kidney function and bone density.
Gilead has also requested approval of a dual coformulation of TAF/emtricitabine, which could be a successor to TDF/emtricitabine or Truvada. Joel Gallant from the Southwest Care Center in Santa Fe, New Mexico, presented findings from a phase 3 randomised clinical trial comparing TAF/emtricitabine versus TDF/emtricitabine when used in triple antiretroviral regimens with various third drugs.
This analysis included 663 participants with undetectable HIV viral load (<50 copies/ml) at study entry. About 85% were men, 75% were white, 20% were black, the median age was 49 years and the median baseline CD4 cell count was approximately 650 cells/mm3. At baseline they had near-normal kidney function with an estimated GFR (eGFR) of at least 50 and a median of 100 ml/min.
PrEP News Coverage Study participants were randomly assigned to either switch to TAF/emtricitabine or remain on TDF/emtricitabine, both taken once daily, while staying on the same third drug. Just under half were using boosted protease inhibitors while the rest were on unboosted third agents including NNRTIs and integrase inhibitors. The TAF dose was 10mg if taken with boosted protease inhibitors or 25mg with unboosted third agents; the TDF dose was 300mg.
Participants were followed for 96 weeks and the primary endpoint was continued viral suppression (HIV RNA <50 copies/ml) at 48 weeks.
At week 48, most people in both study arms maintained undetectable viral load – 94% in the TAF/emtricitabine group and 93% in the TDF/emtricitabine group – demonstrating the non-inferiority of the TAF-containing combination.
The likelihood of continued viral suppression did not vary significantly according to age, sex or race/ethnicity. Treatment response was also similar regardless of whether participants used a boosted protease inhibitor or an unboosted third agent (92 vs 93%, respectively).
Only a small number of participants experienced virological failure (0.3 and 1.5%, respectively). Among the few people who underwent resistance testing, the emergence of resistance mutations was rare – a single M184V seen in a TAF/emtricitabine recipient with poor adherence.
Treatment was generally safe and well-tolerated; 6% in each arm discontinued the study for any reason. Drug-related serious adverse events were rare, with none occurring in more than one person, and few people stopped treatment due to adverse events (7 vs 3, respectively).
Kidney function improved in people who switched to TAF/emtricitabine. Median eGFR improved by +8.4 ml/min in the TAF/emtricitabine group and by +2.8 ml/ min in the TDF/emtricitabine group, a statistically significant difference. Proteinuria (protein in the urine) and other renal biomarkers improved in the TAF/emtricitabine group but worsened in the TDF/emtricitabine group. A few people had glycosuria (sugar in the urine), but most were diabetic and this was not considered related to kidney damage. There were no cases of proximal renal tubulopathy or Fanconi syndrome, types of serious kidney damage, in either group.
Bone mineral density also improved in people who switched to TAF/emtricitabine. Bone density rose by +1.1% at the hip and by +1.5% at the spine in the TAF/emtricitabine arm, while falling by -0.2 at both sites in the TDF/emtricitabine arm; these differences were also significant. More people who switched saw at least a 3% improvement in bone density over 48 weeks: 17% and 30% at the hip and spine in the TAF/emtricitabine arm compared to 9% and 14% in the TDF/emtricitabine group. Dr Gallant said that while these bone density changes are relatively small, they could have more clinical significance in older people already experiencing bone loss.
Tenofovir is known to lower blood lipids, and because it reaches lower levels in the blood this effect is not as great with TAF. People taking TAF/emtricitabine had higher total and LDL cholesterol and triglyceride levels than those on TDF/emtricitabine, and their total-to-HDL ratio rose slightly, but there was no difference in the proportion who started lipid-lowering therapy (4%). Dr Gallant said the clinical significance of these small differences is “questionable”.
PrEP News Coverage “[TAF/emtricitabine] was non-inferior to [TDF/emtricitabine] in maintaining virologic suppression in combination with a variety of third agents” and showed “significant improvements in multiple measures of renal and bone safety after switching from [TDF/emtricitabine] to [TAF/emtricitabine],” the researchers concluded. “These data support that [TAF/emtricitabine] is an important NRTI backbone for antiretroviral treatment with safety benefits over [TDF/emtricitabine].”
Gilead is developing two other TAF-containing single-tablet regimens, one with the NNRTI rilpivirine and the other with the HIV protease inhibitor darunavir. Stand-alone TAF is being studied as a treatment for hepatitis B. The company is also studying TAF in combination with GS-9883, an experimental integrase inhibitor that does not require boosting.
Given the kidney and bone benefits of TAF/emtricitabine, some have suggested that it could potentially be a good alternative to Truvada for PrEP, but lower tenofovir levels in body tissues might be a concern. Data from animal and early human studies of TAF for HIV prevention are being presented this week at CROI. Investigators for these studies stress that TAF should not be used as PrEP until clinical trials are complete.
NIH-funded Study Finds Effect of PrEP on Bone Density Is Reversible NIH Press Release 24 February 2016 http://www.sciencenewsline.com/news/2016022416270045.html
The slight loss in bone mineral density associated with HIV pre-exposure prophylaxis (PrEP) antiretroviral use is reversible in young adult patients who stop taking the drugs, according to findings presented by researchers today at the 23rd Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. PrEP is an HIV prevention strategy in which at-risk HIV-negative people take a daily pill of Truvada, which contains the antiretroviral drugs tenofovir and emtricitabine, to prevent them from becoming infected.
The findings result from a bone mineral density substudy of two large clinical trials, iPrEx and iPrEx OLE, funded by the National Institute of Allergy and Infectious Diseases (NIAID). Data from the substudy presented today illustrate that bone mineral density decreased a measurable but clinically insignificant amount over the course of a year in young adult males and transgender participants with an average age of 24 taking a protective amount of PrEP. However, six months after stopping the regimen, bone mineral density levels in the spines of these individuals increased to levels consistent with study participants of the same age who took a placebo. Hip bone mineral densities also increased in the first six months after stopping PrEP and returned to normal levels by a median follow-up time of 73 weeks.
Previous studies using sensitive scans have shown that HIV medications containing tenofovir slightly reduce bone mineral density, though not to a degree at which patients experience complications. This is the first study to show that this effect is reversible when a patient can stop PrEP, such as when an individual enters into a mutually monogamous relationship with another HIV-negative individual.
Overall, the new findings indicate that Truvada-based oral PrEP does not pose an irreversible effect on bone mineral density and support using PrEP to prevent HIV infection in at-risk young adults. PrEP News Coverage
Switching to Emtricitabine/Tenofovir Alafenamide (F/TAF) Maintains Viral Suppression With Better Bone and Kidney Safety TheBodyPro.com Warren Tong 24 February 2016 http://www.thebodypro.com/content/77131/switching-to-emtricitabinetenofovir-alafenamide-ft.html
Switching from treatment regimens containing tenofovir/emtricitabine (Truvada, F/TDF) to regimens containing emtricitabine/tenofovir alafenamide (F/TAF) maintains undetectable viral loads and improves renal and bone safety, according to 48-week study results presented at CROI 2016 in Boston. Although elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) has already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV, tenofovir alafenamide (TAF) by itself -- or in this case, combined with emtricitabine (FTC, Emtriva) -- has not yet been approved and continues to be investigated.
The popular coformulation F/TDF is a part of many recommended first-line treatment regimens and is also approved for pre-exposure prophylaxis (PrEP), However, tenofovir disoproxil fumarate (TDF, Viread) has been associated with kidney and bone toxicities. TAF is a much-discussed improved version of tenofovir, which has shown better kidney and bone safety when used in Genvoya.
Baseline Characteristics
The study, which was presented by Joel Gallant, M.D., M.P.H., followed 663 HIV-positive individuals who were already on a regimen containing F/TDF, had achieved undetectable viral loads (< 50 copies/mL) and had an eGFR (estimated glomerular filtration rate -- a measure of kidney health) ≥ 50 mL/min.
At baseline, the median age was 49, 85% were male, and the median eGFR was 100 mL/min (over 90 is considered healthy and below 60 is abnormal). As for treatment, 46% were on regimens containing a boosted protease inhibitor, 28% on regimens containing an integrase inhibitor and 25% were on regimens with a non-nucleoside reverse transcriptase inhibitor (NNRTI).
After randomization, 333 were switched to regimens containing F/TAF and 330 stayed on regimens containing F/TDF.
Virologic Suppression Differences
After 48 weeks, 94.3% of those in the F/TAF group maintained an undetectable viral load compared with 93% in the F/TDF group.
Viral suppression numbers remained similar for both regimens when stratifying by age, race and sex, but with a discrepancy in females, which Gallant attributed to low sample size and administrative difference. PrEP News Coverage Resistance and drug-related adverse events were rare (well below 1% for each group), while drug discontinuation due to adverse events was low (2.1% for F/TAF versus 0.9% for F/TDF). No cases of proximal renal tubulopathy were observed in either group.
Kidney Safety Differences
The median eGFR increased by 8.4 mL/min in the F/TAF group, compared with an increase of 2.8 mL/min in the F/TDF group (P < .0001). Measures of proteinuria (indicators of kidney damage) improved in the F/TAF group but not the F/TDF group, with all differences being statistically significant (P < .001).
Bone Safety Differences
On average, bone mineral density (BMD) increased for the F/TAF group but decreased for the F/TDF group: in the hip +1.14% versus -0.15% (P < .001) and in the spine: +1.53% versus -0.21% (P < .001). Additionally, more patients in the F/TAF group had greater than 3% increase in BMD at week 48: in the hip 17% versus 9% (P = .003) and in the spine 30% versus 14% (P < .001).
Lipid Differences
Participants in the F/TAF group had a higher median increase in lipids, with statistically significant differences for total cholesterol, LDL (low-density lipoprotein) cholesterol and triglycerides. However, Gallant noted that the differences were relatively small, with questionable clinical significance. Gallant also noted that there was no statistical significance between the two groups for total cholesterol/HDL (high-density lipoprotein) ratio, nor was there a difference between groups for participants who started lipid-lowering medications during the study.
Going Forward
These 48-week snapshot results are consistent with results seen in studies of Genvoya. The study is expected to continue through 96 weeks. F/TAF is currently being reviewed by the FDA in two different doses for combination with other antiretrovirals, as well as in an updated version of rilpivirine/tenofovir/emtricitabine (Complera).
Bone density recovers quickly after stopping PrEP Aidsmap Keith Alcorn 24 Februray 2016 http://www.aidsmap.com/Bone-density-recovers-quickly-after-stopping-PrEP/page/3038620/
PrEP News Coverage Bone mineral density recovers within six months of stopping pre-exposure prophylaxis (PrEP) containing tenofovir, Bob Grant of the University of California, San Francisco reported on behalf of the iPrEx study on Tuesday at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.
The study investigators were reporting further results from a sub-study of the iPrEx trial which measured bone mineral density in 498 people enrolled in the international study of pre-exposure prophylaxis using tenofovir/emtricitabine (Truvada) in men who have sex with men and transgender women.
Tenofovir is known to affect bone mineral density in people who take the drug as part of antiretroviral treatment. The drug also had a modest effect on bone mineral density in men who take the drug for pre- exposure prophylaxis in the iPrEx study. Bone development is most rapid during adolescence and usually continues in young adults up to the age of 25. Beyond this age bone is subject to a continual process of renewal and repair. There is concern among researchers that the use of PrEP among young people may impair normal bone development, leaving them vulnerable to early-onset osteoporosis in later life.
The iPrEx study randomised men who have sex with men and transgender women who have sex with men to receive tenofovir/emtricitabine (Truvada) pre-exposure prophylaxis or placebo.
A sub-study to evaluate changes in bone mineral density using dual X-ray absorptiometry (DXA) scans recruited 500 consecutive participants at seven study sites in five cities in North and South America, Thailand and South Africa. Participants were exposed to tenofovir for a median of 1.2 years during the randomised phase of the study, during which they underwent DXA scans of the spine and hip at baseline and every 24 weeks until they stopped PrEP at the end of the study. They were then followed for a median of 1.5 years, during which time they had a follow up DXA scan six months after stopping PrEP. A total of 289 participants received a further DXA screen on entry to the iPrEx OLE (open label) study, a median of 1.5 years after stopping PrEP.
The median age of participants was 25 years, 43% were smokers and 81% drank alcohol. Eleven per cent were trans identified.
The study compared changes in bone mineral density between the placebo group and study participants with blood levels of tenofovir diphosphate associated with 90% efficacy and use of 2-3 tablets per week (> 16fmol/m) at week 24 and those with lower drug concentrations indicating lower PrEP efficacy and lower drug exposure at week 24.
There was no significant difference in bone mineral density between the placebo group and those with sub-optimal levels of tenofovir diphosphate throughout the study and follow-up period. In contrast bone mineral density declined by 1% in the hip and 1.81% in the spine by the end-of-study visit in those with optimal tenofovir diphosphate levels, before recovering to the same level in the spine as the placebo group at the 6-month follow-up visit. Bone density in the hip took longer to recover: it had returned to baseline levels by the time participants entered the iPrEx open-label study, one and half years after stopping PrEP.
When recovery was analysed by age as well as by drug concentration, those under 25 displayed faster recovery in bone mineral density than those aged 25 and over, recovering to baseline levels in both spine and hip by six months after the time they had stopped PrEP.
PrEP News Coverage
Halting Truvada restores BMD Healio 25 February 2016 http://www.healio.com/infectious-disease/hiv-aids/news/online/%7B6a15f1be-ef00-4d20-ac3e- a93452ef99ad%7D/halting-truvada-restores-bmd
Although pre-exposure prophylaxis use has been shown to weaken bone mineral density, late-breaking data from a substudy of the iPrEx trial presented at CROI 2016 suggested that stopping the preventive treatment may lead to full hip and spine recovery.
“PrEP containing [tenofovir disoproxil fumarate (TDF)] has been associated with a 0.5% to 1.5% decrease in [bone mineral density (BMD)] depending on the amount of adherence and drug exposure,” Robert M. Grant, MD, MPH, of the Gladstone Institutes in San Francisco, said during a presentation. “Recovery of BMD after stopping PrEP has not been fully evaluated.”
To do so, Grant and colleagues conducted a substudy of the iPrEx trial and iPrEx open-label extension, which studied the efficacy of Truvada (emtricitabine [FTC]/TDF, Gilead Sciences) as PrEP for men who have sex with men and transgender women who have sex with men. The substudy examined BMD among participants consecutively enrolled in both trials using X-ray absorptiometry (DXA) every 24 weeks during PrEP use, 24 weeks after halting PrEP and at the initiation of the open-label extension. As a tenofovir-diphosphate (TFV-DP) concentration of 16 fmol/million cells was associated with 90% HIV protection, the BMD of participants who recorded this TFV-DP level at 24 weeks were compared with those who either did not achieve the protective concentration or were randomly assigned a placebo. iPrEx enrollees (n = 498) from five international cities were included in the substudy’s analysis (median age, 25 years). Of these, 11% identified as transsexual, 43% were smokers and 81% reported alcohol use. More than 70% received DXA scans 24 weeks after stopping PrEP, and 58% were scanned upon their initiation into the open-label extension.
After a decline in BMD during treatment, DXA after stopping PrEP revealed an average annual spinal recovery rate of 1.81% (P = .01) and an average annual hip recovery rate of 1.13% (P = .002) among participants with protective drug concentrations at 24 weeks. This group also demonstrated complete spinal recovery by 6 months, and complete hip and spine recovery at the initiation of the open-label extension (median, 73 weeks). This recovery persisted after adjusting for age and drug concentrations, although younger participants demonstrated swifter hip recovery than older participants.
“BMD appears to be a dynamic process, which does return to placebo levels after stopping PrEP,” Grant said. “The guidance regarding when to start and stop PrEP are important for maximizing PrEP benefits and minimizing its side effects, including its effect on BMD.” – by Dave Muoio PrEP News Coverage The Kidney Report - CROI 2016 NATAP Christina Wyatt 24 February 2016 http://www.natap.org/2016/CROI/croi_49.htm
Renal safety of tenofovir alafenamide (TAF)
The results of ongoing and completed trials of TAF continue to suggest a potential for improved renal safety, including the 48-week results of a randomized switch study comparing FTC/TAF versus FTC/TDF in adults previously suppressed on FTC/TDF (Oral abstract 29). Similar to prior studies comparing E/C/F/TAF to E/C/F/TDF, there were statistically significant improvements in CrCl and bone mineral density among participants randomized to FTC/TAF, along with a decline in urinary excretion of the low molecular weight proteins retinol binding protein (RBP) and beta2-microglobulin (B2M). Study drug was discontinued in one participant with pre-existing proteinuria in the FTC/TDF arm and no participants in the FTC/TAF arm.
In 72-week follow-up of an open label study of E/C/F/TAF in virologically suppressed adults with CrCl 30- 69 at enrollment, study drug was discontinued in 2% of participants because of decreased CrCl (Abstract 680). All five participants had baseline CrCl<50 ml/min and at least one traditional risk factor for chronic kidney disease (CKD). In participants who switched from a TDF-containing regimen, albuminuria and proteinuria declined significantly, while bone mineral density increased. More importantly, the prevalence of clinically relevant albuminuria and proteinuria also decreased significantly following the switch to E/C/F/TAF.
The top-line 48-week results of two randomized trials comparing E/C/F/TAF to E/C/F/TDF in participants with CrCl > 60 ml/min were previously published in Lancet and presented in support of regulatory applications. Two post hoc analyses used the data from this combined study cohort to provide additional information on the renal safety of TAF. The first analysis evaluated the safety of TAF in participants at increased risk of CKD as assessed by the D:A:D CKD risk score (Abstract 681). The stratified analysis suggests that the favorable effect of TAF on CrCl and urinary excretion of RBP and B2M is maintained in participants with risk factors for CKD. Fewer participants in the TAF arm experienced a decline in CrCl below 60ml/min, although the difference was of marginal statistical significance. There were also significantly greater declines in proteinuria and urinary RBP and B2M in participants randomized to TAF versus TDF.
A second analysis evaluated the renal safety of TAF at 96 weeks (Abstract 682). Consistent with published data and the other studies presented at CROI, this analysis demonstrated a favorable effect of TAF on CrCl and low molecular weight protein excretion. There was also a significant difference in study drug discontinuation for renal adverse events, with 6 events occurring in participants randomized to E/C/F/TDF and no events in those randomized to E/C/F/TAF (p=0.03).
Taken together with the switch study in participants with decreased CrCl, these data provide the first evidence that the improvement in renal biomarkers observed with TAF versus TDF may ultimately translate into an improvement in clinically relevant outcomes with cumulative use. Although urinary RBP and B2M are sometimes considered biomarkers of tubular injury, they are more accurately classified as biomarkers of proximal tubular dysfunction. The rapid decline in these biomarkers previously reported PrEP News Coverage in participants switching from TDF to TAF are more consistent with tubular dysfunction than true injury, raising the question of whether these improvements predict an improvement in more relevant clinical outcomes such as overt proximal tubular injury, proteinuria, or decline in GFR. Longer follow-up in real world populations will determine the true clinical significance of the observed improvements in surrogate markers with TAF.
Renal Safety of Tenofovir Disoproxil Fumarate (TDF) in HIV treatment
Several observational studies provided additional insight into kidney toxicity with TDF. A retrospective analysis in the UK-CHIC cohort evaluated the incidence and risk factors for TDF-associated proximal tubulopathy, as defined by at least 2 markers of proximal tubular dysfunction (n=52) or biopsy-proven acute tubular necrosis (n=17). The definition did not require decline in CrCl, which accompanied approximately half of the cases (Abstract 683). In adjusted analysis, factors independently associated with proximal tubulopathy included older age, white race, longer TDF exposure, lower CD4 nadir, and PI use.
Analysis of data from 18,596 HIV-positive adults in NA ACCORD demonstrated no significant decline in CKD-EPI GFR over the first 6 months of TDF versus other NRTIs in participants with baseline eGFR ≥ 90ml/min/1.73m2 (Abstract 684). In participants with lower baseline eGFR, there was a significantly greater decline in eGFR in those on TDF. Although there was some recovery in eGFR after the first 6 months in participants on TDF, additional studies are needed to determine the clinical relevance of the early decline.
In a cross-sectional study of 884 HIV-positive men in MACS, cumulative exposure to TDF was associated with small but statistically significant increases in urine biomarkers of kidney injury (IL-18 and KIM-1) and a proposed marker of renal fibrosis (Abstract 685). There was no significant association between TDF exposure and albuminuria. Future studies should consider whether these biomarkers can predict clinically relevant kidney injury in individuals exposed to TDF, or whether they can provide insights into the mechanism of injury. These biomarkers are not currently recommended for clinical use in the diagnosis of TDF toxicity.
A prospective cohort study of 310 HIV-positive adults with baseline CrCl >60ml/min and without comorbid diabetes or hypertension evaluated risk factors for TDF discontinuation (Abstract 426). In addition to demographic factors and comedications, the authors considered the predictive ability of proximal tubular dysfunction (as defined by elevations in urinary RBP), plasma and urine tenofovir concentrations, and genetic polymorphisms in transport proteins that have been linked to TDF toxicity or tenofovir concentrations in prior studies. TDF was discontinued in 32 participants over median followup of 21 months, including 24 discontinuations for suspected kidney injury. In adjusted analyses, TDF discontinuation for kidney injury was associated with older age, male sex, PI use, and ABCB1 TT genotype (encoding multidrug resistance protein 1, or MRP1). Lower urine: plasma tenofovir concentration was associated with higher levels of urinary RBP and urinary protein, but was not independently associated with TDF discontinuation in this small study. As with prior genetic studies, the role of MRP1 in promoting TDF toxicity is not clear, as this transporter is not thought to play a major role in tenofovir transport.
Renal safety of TDF-based PrEP
PrEP News Coverage Three abstracts presented in a themed discussion evaluated the renal safety of TDF-based PrEP. In a substudy of the iPrEx open-label extension study (iPrEx OLE, n=202), hair levels of tenofovir were shown to correlate with eGFR decline and with risk of MDRD eGFR<70 ml/min/1.73m2 in men (Abstract 866). Other factors associated with eGFR decline included baseline eGFR < 90 and age > 40 years.
In a substudy of the US Demo Project, dried blood spots were used to evaluate the correlation between tenofovir plasma concentrations and CrCl decline in 557 men (Abstract 867). There was a mean decline in CrCl of 6ml/min from baseline to week 12, with no further decline through 48 weeks. Tenofovir concentrations consistent with ≥ 2 doses/week were associated with greater decline in CrCl, with a dose response relationship noted for higher levels of dosing. In adjusted analysis, tenofovir concentrations indicative of ≥ 2 dose/ week and concurrent use of medications for diabetes or hypertension were associated with greater decline in CrCl. In contrast to the majority of studies, which have associated older age with GFR decline, age < 25 years was associated with greater CrCl decline in this relatively young population. Of note, there were no cases of CrCl<60 ml/min and no confirmed creatinine events through 48 weeks.
In a random substudy of Partners PrEP (n=1549), there was no statistically significant difference in the prevalence of proximal tubulopathy at 24 months between participants randomized to FTC/TDF versus placebo (Abstract 868). There was a higher prevalence of isolated hyperuricosuria and isolated non- albumin proteinuria in the active PrEP arm. In a nested case-control study, proximal tubopathy and individual markers of proximal tubular dysfunction did not predict clinically relevant decline in eGFR, defined as ≥ 25% decline from baseline.
These three studies suggest a low incidence of clinically relevant kidney injury among healthy HIV- negative adults taking PrEP for HIV prevention, although there is evidence of a dose-response relationship with mild decline in CrCl or eGFR. Individuals with lower baseline eGFR also appear to at greater risk for kidney function decline. Future studies should focus on identifying individuals at highest risk of kidney injury with longer exposure to TDF-based PrEP, to guide toxicity monitoring and/ or the use of alternative preventive measures.
Chronic kidney disease in HIV-positive adults
Several observational studies focused more broadly on CKD in HIV-positive adults. In a prospective cohort study, HIV-positive adults (n=191) and HIV-negative controls (n=100) underwent direct measurement of GFR by iohexol clearance (iGFR) at baseline and annually (Abstract 687). At baseline, measured GFR was lower in HIV-positive adults, although there was no significant difference in estimated GFR at baseline or in iGFR slope over time between HIV-positive and HIV-negative participants overall. Among HIV-positive participants, non-suppressed HIV-RNA, albuminuria, and higher hemoglobin A1c were associated with more rapid iGFR decline. The investigators also measured plasma levels of fibroblast growth factor 23 (FGF23), a regulator of phosphorus metabolism that has been associated with CKD and mortality (Abstract 651). Among HIV-positive participants, higher baseline FGF23 levels were associated with worsening of albuminuria and carotid intima media thickness, a noninvasive surrogate marker of atherosclerosis.
Three studies evaluated the association between markers of immunosuppression and risk of CKD. In the D:A:D cohort, several measures of immunosuppression based on CD4 cell count were associated with increased risk of CKD, as defined by a confirmed CrCl < 60 ml/min (Abstract 687). In adjusted analysis, the percentage of follow-up time with CD4 < 200 was independently associated with CKD. The impact of PrEP News Coverage immunosuppression was more pronounced in individuals who were otherwise at low risk of CKD as determined by the D:A:D risk score. In a cross-sectional substudy of the Aquitaine cohort (n=849), investigators evaluated the correlation between a recently published index of immune activation/ immune senescence and prevalent CKD, as assessed by ICD-9 diagnostic codes and registry linkage (Abstract 689).
In adjusted analysis, a higher index of immune activation/ immune senescence was independently associated with eGFR < 60ml/min/1.73m2. In a single-center cohort study from Denmark, baseline levels of plasma soluble CD163, a marker of monocyte/ macrophage activation, were associated with incident CKD over a median of 10.5 years of follow-up (Abstract 690). In adjusted analysis, the highest quartile of soluble CD163 levels was associated with a > 8-fold increase in the risk of CKD. Taken together, these studies support a role for systemic inflammation and immune dysregulation in promoting CKD in the setting of HIV infection.
A biomarker substudy of the WIHS cohort (n=902) was recently published in Nephrology Dialysis Transplantation (Abstract 691). A panel of 3 urine biomarkers modestly improved the prediction of CKD when added to a multivariable model including relevant clinical variables. Future studies are needed to develop simple cut-offs and standardize biomarker assays prior to adoption in clinical practice.
In a cohort of 540 HIV-positive adults with documented ESRD in NA ACCORD, there were 255 deaths over a median follow-up of 2.5 years (Abstract 688). In adjusted analysis, baseline factors associated with increased mortality included age > 60 years, hypercholesterolemia, AIDS-defining illness, lack of ART prescription (at time of ESRD diagnosis), use of TDF prior to ESRD diagnosis, and lower CD4. As in the HIV-negative ESRD population, older black patients had a survival advantage over older white patients, while this pattern was reversed in those younger than 60.
ViiV and Janssen take long-acting HIV regimen into phase III PMLive 25 February 2016 http://www.pmlive.com/pharma_news/viiv_and_janssen_take_long- acting_hiv_regimen_into_phase_iii_940884
Healthcare and Janssen are advancing the development of a two-drug injectable therapy - given just once every few weeks - that could free people living with HIV from daily doses of tablets.
The combination of ViiV's long-acting integrase inhibitor cabotegravir and Janssen's non-nucleoside reverse transcriptase inhibitor (RTI) Edurant (rilpivirine) was shown to suppress HIV levels as effectively as a three-drug oral regimen in data released last year.
Now ViiV - a joint venture between GlaxoSmithKline, Pfizer and Shionogi - has confirmed it intends to take the combination into phase III testing later this year.
PrEP News Coverage The announcement came as ViiV and Johnson & Johnson subsidiary Janssen reported the results of the LATTE-2 trial to clinicians at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.
After 32 weeks' treatment, viral suppression rates for cabotegravir/rilpivirine were 95% for a regimen given every eight weeks, 94% for a four-weekly injection and 91% in patients given the triple oral therapy, which consisted of cabotegravir plus two RTIs.
John Pottage, ViiV's chief scientific and medical officer, said: “There continues to be a need for new HIV medicines, including those that could offer more flexible dosing regimens for people living with HIV. "The LATTE-2 study results provide the first evidence that a long-acting two-drug injectable regimen may offer an alternative to daily, oral three-drug therapy for people who have achieved viral suppression." The cabotegravir and rilpivirine combination has been tipped as a future blockbuster for Janssen and ViiV and along with other new drugs such as integrase inhibitor Tivicay (dolutegravir) could help the companies claw back market share lost in recent years to Gilead Sciences.
Gilead currently dominates the HIV treatment sector thanks to drugs like Truvada (emtricitabine and tenofovir disoproxil fumarate) and Atripla (favirenz/emtricitabine/tenofovir disoproxil fumarate), but ViiV is fighting back.
This week, the joint venture company closed its $1.5bn acquisition of Bristol-Myers Squibb's HIV portfolio, bolstering its pipeline with a number of programs at different stages of discovery, preclinical and clinical development.
First data on cabotegravir as HIV preventative Meanwhile, ViiV has reported the first data from trials of cabotegravir as a preventative for HIV infections. In the phase IIa ECLAIR trial, cabotegravir was given to HIV-uninfected healthy adult males not at high risk of acquiring the virus, initially once a month and then once every 12 weeks. The results showed that injections were preferred to daily oral dosing by the trial subjects, and that the drug was well-tolerated. However, blood analyses showed that cabotegravir levels were not maintained at a sufficiently high level for pre-exposure prophylaxis (PrEP), so a bi-monthly dose will be tested in subsequent studies.
"There are more than 36m people worldwide living with HIV today and, despite considerable progress made in the fight against HIV, infections are still increasing in parts of the world", commented Pottage. "Preventative measures like PrEP could play an important role in reducing the number of new infections and help contribute to the goal of ending the global AIDS epidemic”, he added.
Injected Long-Acting Cabotegravir Protects Macaques From Injected SIV NATAP Mark Mascolini 25 February 2016 http://www.natap.org/2016/CROI/croi_34.htm PrEP News Coverage
Twenty-one of 24 macaques (87.5%) receiving various doses of long-acting injected cabotegravir remained free of SIV injected 2 weeks after cabotegravir [1]. The findings suggest that injectable cabotegravir should be evaluated as HIV PrEP in people who inject drugs.
Long-acting cabotegravir, formulated as a 200-mg/mL nanosuspension, is being tested for preexposure prophylaxis (PrEP) of sexually transmitted HIV [2] and as maintenance therapy in combination with rilpivirine [3]. Plasma concentrations of cabotegravir in macaques are comparable to those attained in humans [4], and cabotegravir prevents intrarectal and intravaginal simian HIV (SHIV) transmission in macaques [4].
The new study aimed to determine whether injected cabotegravir protects macaques from intravenous challenge with SIVmac251. Aaron Diamond AIDS Research Center investigators and colleagues tested three dosing patterns in three groups of 8 macaques each: (1) 50 mg/kg on week 0 and 4 with SIV challenge at week 2, (2) 50 mg/kg on week 0 with SIV challenge at week 2, and (3) 25 mg/kg on week 0 and 50 mg/kg on week 4 with SIV challenge at week 2. Cabotegravir concentrations should be optimal 2 weeks after injection. The SIVmac251 exposure was planned to simulate a per-act probability of infection comparable to blood transfusions.
Five macaques who did not receive cabotegravir all became infected 1 week after SIV challenge. Of the 8 macaques who received two doses of cabotegravir, 7 remained free of SIV through week 24 (P = 0.0047 versus untreated animals). At the time of SIV challenge, cabotegravir plasma concentrations in all 8 macaques, including the 1 who got infected, exceeded the target concentration of 4 times the protein binding-adjusted 90% inhibitory concentration (IC90).
Among the 8 macaques who received a single 50-mg/kg dose of cabotegravir, all 8 remained free of SIV infection for 20 weeks (P = 0.0008 versus untreated animals). Among the 8 macaques who received a 25 mg/kg dose at week 0 and 50 mg/kg at week 4, 6 of 8 remained free of SIV through week 24 (P = 0.021 versus untreated animals); the second 50-mg/kg dose at week 4 did not appear to affect the outcome.
Plasma cabotegravir averaged 2.58 ug/mL (range 1.00 to 5.56) in the 21 macaques who resisted infection and 1.17 ug/mL (range 0.67 to 1.93) in the 3 macaques who became infected (P = 0.0524). The researchers suggested that cabotegravir concentrations at the time of viral challenge may be more important than sustained concentrations after that challenge.
The investigators believe their results "support the evaluation of cabotegravir long-acting as PrEP in people who inject drugs."
PrEP News Coverage CROI 2016: Long-Acting Cabotegravir PrEP Injection Tolerable and Acceptable, but Dose Adjustment Needed HIV&Hepatitis 29 February 2016 http://www.hivandhepatitis.com/hiv-prevention/hiv-prep/5619-croi-2016-long-acting-cabotegravir- prep-injection-tolerable-and-acceptable-but-dose-adjustment-needed
Attendees at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston heard results from the first Phase 2 (safety, acceptability, and dose-finding) study of a long- lasting injectable formulation of the integrase inhibitor drug cabotegravir for use as pre-exposure prophylaxis (PrEP) in HIV-negative people. The previous day researchers also presented a study of the same injectable drug, plus another injectable, rilpivirine, used as treatment for people with HIV.
[Produced in collaboration with Aidsmap.com]
In the cabotegravir PrEP study, dubbed ÉCLAIR, a couple of surprises awaited the researchers. First, the rate of absorption of the drug into the body was faster than expected, meaning that an injection will probably have to be given every 8 weeks, instead of every 12 weeks as hoped. Second, the duration and severity of pain and other effects of the injections were greater than expected. However, few people dropped out of the study because of them, and three-quarters of participants said they would be happy to continue taking cabotegravir injections as PrEP should it become available.
The ÉCLAIR study lasted for 81 weeks altogether; presenter Martin Markowitz of the Aaron Diamond AIDS Research Center did not present final results, as the final follow-up phase of the study has just finished.
For the first 4 weeks, participants took a daily oral cabotegravir pill or a placebo pill (1 in 5 took the placebo). This oral phase was intended as a precaution to weed out any subjects who have unusual adverse reactions to cabotegravir -- since one of the drawbacks of an injectable formulation is that is cannot be suddenly stopped.
At weeks 5, 17, and 29, participants were given 3 doses of injectable cabotegravir or saline as placebo. These consisted of 800 milligrams of cabotegravir given as 2 injections of 2 milliliters each, one in each buttock. The injection phase was defined as lasting until week 41, or 12 weeks after the last injection. There was then a follow-up phase of 40 weeks until week 81; not all the data has yet been collected from this phase.
The study population consisted of men aged 18 to 64 defined as being at low risk of HIV infection (as this is largely a safety, not a prevention trial). Their average age was 30.5 years, 57% were white, 32% were African-American, and roughly 80% were gay and 20% heterosexual. A total of 126 men entered the trial, 105 allocated to cabotegravir and 21 to placebo.
During the first 4 weeks on the oral pill, 11 people withdrew from the study who were taking cabotegravir, and 1 who was taking placebo. During the injection period, a further 7 people, all on cabotegravir, withdrew, 4 of them due to intolerance of the injections.
PrEP News Coverage Markowitz attributed the fact that more people withdrew during the oral phase to caution on the part of the investigators in ensuring that no one who showed any possibility of side effects went forward to the injection phase. In particular, 3 participants in the oral phase saw an increase in levels of creatine phosphokinase, an enzyme that can indicate injury to muscle tissue; although these were almost certainly not drug-related, the men were withdrawn from receiving intramuscular injections as a precaution.
In the injection phase, the primary adverse event was injection site reactions: these were almost universal among the subjects receiving cabotegravir, with 93% reporting them, as did 57% receiving placebo. Injection site reactions largely consisted of pain in the muscle at the injection site. Pain was generally mild in placebo recipients, but in cabotegravir recipients 37% defined it as "moderate" and 10% as "severe," and lasting, on average, for 5.4 days. Other injection site reactions included itching, swelling, and heat at the injection site. The only non-local side effect was fever, experienced by 7% of men receiving cabotegravir.
Despite this, 62% of people on cabotegravir said they were satisfied with their study medication, and 74% said they would be happy to continue receiving it. In fact, more people said they preferred the 12- weekly injection to having to take a daily tablet.
Drug level measurements of cabotegravir showed that it was absorbed by the body faster than expected. This meant that the peak level of drug in the bloodstream, just after the injection, was higher than expected, and the trough level, just before the next injection, was lower than expected.
A model had forecast that the peak level in blood would be 3 micrograms per milliliter (mcg/mL) when in fact the average level was 5-6 mcg/mL, and that the average trough level would be 1 mcg/mL when in fact it was 0.3-0.6 mcg/mL. This is of concern since it is close to the IC90 -- the level of drug that cuts 90% of viral replication -- and drug levels should be well above this to ensure efficacy. The proportion of trial subjects whose trough drug levels fell below the IC90 was 24% after the first injection, 31% after the second, and 15% after the third.
Markowitz said that the reason for the faster absorption was unknown, but it would probably mean that cabotegravir PrEP would have to be given every 2 months rather than every 3.
There were 2 cases of HIV infection in the study. One person receiving placebo tested HIV-positive at week 23. The other had received cabotegravir, but tested positive at week 53, nearly 6 months after his last cabotegravir injection. At this point he still tested HIV antibody-negative but had a viral load of over 3 million copies/mL, so it must have been a very recent infection. He had no detectable cabotegravir in his bloodstream at this point.
Markowitz concluded that these results indicate that cabotegravir injections were safe and, despite injection site reactions, relatively well-tolerated. A parallel trial is happening in women, and when this has concluded the final decision will be made about taking injectable cabotegravir PrEP forward into a full-fledged effectiveness trial, where it would be compared with oral tenofovir/emtricitabine (Truvada).
PrEP News Coverage Injectable PrEP Given Every 8 Weeks Passes Safety Test HIVEqual 24 February 2016 David Heitz http://www.hivequal.org/hiv-equal-online/injectable-prep-given-every-8-weeks-passes-safety-test
Injectable, long-lasting PrEP in males not at high risk for contracting HIV has passed the safety test, according to ViiV Healthcare, maker of cabotegravir.
A phase IIa study investigating the use of the integrase strand transfer inhibitor as PrEP showed that the most frequent side effect was pain at the injection site.
The study randomized 127 HIV-negative participants to cabotegravir or placebo. Initially, study participants were given oral cabotegravir or placebo tablet, and then given injections of 800 mg of either the drug or placebo once every three months for three cycles.
The study, which only evaluated safety, showed that levels of the drug in the bloodstream were lower than anticipated nearing the end of each three-month cycle. Therefore, future studies will evaluate a 600 mg injection every two months, according to a news release issued by ViiV. The results were presented at the 23rd Conference on Retroviruses and Opportunistic Infections in Boston on Wednesday.
“We are encouraged by these first results from the ECLAIR study and look forward to understanding the potential efficacy and broader safety profile of cabotegravir in the PrEP setting as we move into phase III development later this year,” said Dr. John C. Pottage, chief scientific and medical officer for ViiV.
Meanwhile, in other findings presented at CROI, results from the large iPrEx and iPrEx OLE studies showed that bone mineral density loss by young adult males and transgender participants taking Truvada as PrEP is reversible. It is unknown whether such bone density loss is reversible in older participants who take PrEP. Bone density loss often comes with aging even in healthy Americans not taking medications.
“Data from the sub-study presented today illustrate that bone mineral density decreased a measurable but clinically insignificant amount over the course of a year in young adult males and transgender participants with an average age of 24 taking a protective amount of PrEP,” the National Institute of Allergies and Infectious Diseases, a division of the NIH, reported in a news release. “However, six months after stopping the regimen, bone mineral density levels in the spines of these individuals increased to levels consistent with study participants of the same age who took a placebo. Hip bone mineral densities also increased in the first six months after stopping PrEP and returned to normal levels by a median follow-up time of 73 weeks.”
PrEP News Coverage CROI 2016: Long-Acting Injectable Cabotegravir + Rilpivirine Works Well as HIV Maintenance Therapy HIV&Hepatitis 23 February 2016 http://www.hivandhepatitis.com/hiv-treatment/experimental-hiv-drugs/5600-croi-2016-long-acting- injectable-cabotegravir-rilpivirine-works-well-as-hiv-maintenance-therapy A combination of 2 long-acting injectable antiretrovirals, cabotegravir and rilpivirine, given once every 4 or 8 weeks, maintained viral suppression as well as standard oral antiretroviral therapy (ART) and appeared safe and well-tolerated, according to results from the LATTE 2 trial presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) taking place this week in Boston.
Long-acting medications could offer an attractive option for people with HIV facing a lifetime of antiretroviral treatment. These agents have the advantage of being more convenient and potentially improving adherence, but the drawback is that a long-lasting drug cannot be easily removed from the body, so it is especially important to establish safety in advance.
To this end, the LATTE (Long-Acting Antiretroviral Treatment Enabling) trial evaluated ViiV Healthcare's experimental integrase inhibitor cabotegravir (formerly GSK1265744) and Janssen's NNRTI rilpivirine (Edurant) as a simplified 2-drug oral maintenance regimen for people who had already achieved undetectable viral load using standard 3-drug ART.
At last year's CROI David Margolis from ViiV presented 96-week findings showing that 76% of participants who switched to oral cabotegravir plus rilpivirine dual therapy maintained viral suppression, compared to 63% of people who stayed on a 3-drug regimen containing efavirenz (Sustiva); these results were also published in the October 2015 edition of Lancet Infectious Diseases.
The oral combination was safe and well-tolerated, which laid the groundwork for testing the long-acting injectable formulations of cabotegravir and raltegravir in the phase LATTE 2 trial (NCT02120352). Margolis presented 32-week results from LATTE 2 at this year's conference.
This Phase 2b analysis included 309 previously untreated HIV-positive participants. More than 90% were men, about 80% were white, and the median age was 35 years. At baseline the median CD4 T-cell count was 489 cells/mm3 and nearly one-fifth had a high viral load >100,000 copies/ml.
Participants in this open-label study first started a 3-drug induction regimen consisting of 30 mg once- daily cabotegravir plus abacavir/lamivudine (the drugs in Epzicom or Kivexa).
Those who achieved viral suppression (<50 copies/mL) during the induction period were randomly assigned either to receive intramuscular injections of cabotegravir and rilpivirine every 4 weeks (Q4W) or every 8 weeks (Q8W), or to stay on the same oral regimen. Previous research showed that injectable cabotegravir remains at therapeutic levels with either monthly or quarterly dosing.
The injectable regimen consists of separate 2-3 ml injections of cabotegravir and rilpivirine in the buttocks. Margolis suggested injections in the thigh might be possible to allow self-administration. He said there is some flexibility in dosing, so people can get the shots within a week before or after their scheduled date. PrEP News Coverage
Results
Of the 309 initial participants, 286 achieved viral suppression during induction and were randomized to maintenance therapy. During the maintenance period, 94% of patients who received the injectables every 4 weeks and 95% of those treated every 8 weeks maintained HIV RNA <50 copies/mL at week 32, as did 91% of those who stayed on the oral regimen. A small number of participants -- 1 in cabotegravir Q4W arm, 5 in the Q8W arm, and 2 in the oral therapy arm -- experienced virological non-response.
2 of these (1 in the Q8W arm and 1 in the oral arm) had protocol-defined virological failure, but neither showed evidence of integrase inhibitor or NNRTI resistance.
Injectable cabotegravir and rilpivirine were generally safe and well-tolerated.
Serious adverse events occurred in 6% of people who switched to the long-acting injectables and 5% of those who stayed on the oral regimen, but these were not considered drug-related.
The most common drug-related side effect was injection site reactions, occurring in more than 90% of injection recipients; out of 4286 total injections, 2282 led to reactions such as pain and swelling.
These reactions were mostly mild or moderate, usually resolved within a week (median duration 3 days), and became less common over time, but they led 2 people to withdraw from the study.
The most common drug-related adverse events other than injection reactions were fever, fatigue, and flu-like illness, experienced by 19 participants taking the injectable drugs and 1 person on the oral regimen.
Laboratory abnormalities of grade 3 or higher were seen in 16% and 14%, respectively. Pharmacokinetic analysis showed that the long-acting injections maintained cabotegravir levels similar to those seen with oral therapy in the original LATTE study.
Cabotegravir concentrations started out low after in injection and then increased; Margolis said they are working on strategies to increase early levels.
Rilpivirine concentrations rose over time, but stayed well below the level that might present a risk for heart problems.
Study participants reported a high level of satisfaction with their treatment -- more than 90% receiving the long-acting injections reported that they were satisfied, compared with about 70% of those on the oral regimen.
Neither the Q4W or Q8W dosing regimen was clearly better. LATTE 2 follow-up will continue through week 96 and researchers plan to further evaluate the long-acting injectable regimen in larger Phase 3 trials.
PrEP News Coverage The long-acting formulations of cabotegravir and rilpivirine are also being studied for pre-exposure prophylaxis, or PrEP -- data that are also being presented this week at CROI.
The Possibility of PrEP that's Not Truvada HIVEqual David Heitz 23 February 2016 http://www.hivequal.org/hiv-equal-online/the-possibility-of-prep-that-s-not-truvada
Results from the HPTN 069/ACTG 5305 trial (aptly dubbed NEXT-PREP) are in, and they show that Maraviroc-based regimens are highly effective at preventing HIV.
A research abstract showed that among 406 men enrolled at 12 sites, five seroconversions occurred among those being given a version of Maraviroc as PrEP. Four of those were associated with low or undetectable drug levels. The results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.
Maraviroc is an already FDA-approved HIV entry inhibitor that concentrates in the genital tract/rectum and is taken once daily, making it a possible alternative to Truvada PrEP.
Related HIV Equal News: The Big PrEP Huddle: “Sexperts” Gather to Discuss HIV Prevention
The phase II trial examined the safety and tolerability of four regimens: Maraviroc alone, Maraviroc plus emtricitabine (FTC), Maraviroc plus tenofovir (TDF) and TDF plus FTC (Truvada as PrEP).
In a random test of 122 participants at random times, 93 percent had detectable study drug plasma levels. Among the five seroconversions, two subjects never had study drug present in their plasma at any visit. The three other seroconversions occurred in the branch given Maraviroc alone.
All of those who seroconverted had R5 virus (a common strain of HIV that attaches to the CCR5 co- receptor on a CD4 cell) and no genotypic resistance.
To participate in the study, participants had to be adult, HIV-negative men who reported a history of condomless anal intercourse with at least one HIV-infected or unknown-status man within 90 days. “Patients received randomized study regimens for 48 weeks with follow-up visits at weeks two, four, eight, and then every eight weeks,” according to the abstract. “At each study visit, interval history, physical exam, safety laboratories, blood plasma for drug levels, and HIV and adherence counseling and tested were conducted.”
PrEP You Don’t Swallow: The Future of Anal HIV Prevention
The 406 men had a median age of 30 but ranged in age from 18 to 70. More than 60 percent of the volunteers were white, 28 percent black, 22 percent Latino, and 10 percent other races. Of the initial PrEP News Coverage 406, 9 percent permanently discontinued the study regimen prior to 48 weeks and 9 percent were lost to follow-up.
The rates of grade two to four adverse events did not differ in pairwise comparisons among study arms.
“Given as HIV PrEP in MSM, MVC-based regimens were comparably safe and well-tolerated versus the control regimen of TDF+FTC,” the authors concluded.
Related HIV Equal News: Is PrEP Necessary When Your Partner is Undetectable?
Breaking HIV Prevention News for Women, too: Vaginal Ring Shows Success
Meanwhile, a vaginal ring that continuously releases antiretroviral medication has shown a modest level of protection against HIV in a large clinical trial in sub-Saharan African countries.
The National Institute of Allergies and Infectious Diseases announced Monday in a news release that the ring reduced the risk of HIV infection by 27 percent in the study population overall and by 61 percent among women ages 25 and older, who used the ring more consistently.
The results were announced at CROI and published simultaneously in the New England Journal of Medicine.
“Women need a discreet, long-acting form of HIV prevention that they control and want to use,” said Dr. Anthony Fauci, director of the NIAID, part of the National Institutes of Health (NIH). “Further research is needed to understand the age-related disparities in the observed level of protection.”
Related HIV Equal News: PrEP Works for Transgender Women, but only if they take it