Gilead shot prevents all HIV cases in trial
bloomberg.com
bloomberg.com
It sounds simple but for a lot of people it’s not a trivial thing to take a pill every day or adhere to a strict appointment schedule to get an injection. I’d imagine that adoption & compliance goes way up if it’s that much easier.
Just to avoid the accidentally missing a dose or the chance interactions (lower efficacy) with dairy and many fiber supplements, this would be amazing.
Would be nice to never need to worry about that or think, hey I missed a dose is it actually true that it doesn’t matter or do I need to wait a full week. Half a week?
My only concern here though, if it’s in your system for 6 months what if you have an adverse reaction or just some unpleasant symptoms.
Why not just save money and not install those ECP brakes on your vinyl chloride freight train?
Why not just use one unshielded Raspberry Pi on that spacecraft instead of a 3-of-5 quorum from the output of 5 identical engineered-for-space systems?
Using/requiring condoms AND being on PrEP helps me live my best life with less fear-based inhibition and cognitive load.
In case of a pill perhaps negative side effects.
I have no clue how often a person in high HIV risk has sex or behaves.
It should be fine to ask that question
It is. I interpreted the parent post as a neutral question, and I intended my reply to involve playful analogizing. I'm sorry that it didn't reach you as such through the side-channel-impoverished medium of text.
1. in sex work, "not using a condom" is an "extra" that clients will pay quite a bit for
2. people who "party and play" tend to be in an altered state of consciousness that biases against use of condoms
To me, that is such a weird thing.
People literally paying money for something that can damage them for life and may even kill them.
Though the same can be said of addictive things (smoking comes to mind), is this some form of that maybe?
i'm confused. are we acting like we don't full-well know that using a condom sucks for everyone involved? it's like wondering why people didn't like using a face mask during covid: because it sucks. that, of course, is independent from whether it's prudent, but if something sucks, it's no surprise when people avoid it, right?
We all choose to take risks all the time and often pay for the privilege, sometimes explicitly seeking out the thrill of a risk.
I'm guessing what makes this specific scenario weird for you is more likely that this risk doesn't seem worthwhile to you relative to what you get from it (and I agree with that - I've never had an appetite for taking risks with STDs)
You could say the same about sky-diving.
As someone who took the condom off in a risky situation recently, there’s no comparison between the on and off feeling. It’s like licking a piece of candy vs crushing it with your teeth and sucking it all at once.
Preventative:
1. Gardasil 9 (vaccine against 9 strains of HPV, prevents genital warts and cancers caused by HPV)
2. Monkeypox vaccine
3. Meningitis ACYW vax
4. Meningitis B vax (35% effective against gonorrhea)
5. doxyPEP (two pills of doxycycline taken after sex, 90% effective against syphilis, 80% chlamydia, 50% gonorrhea)
6. PrEP (prevents HIV infections)
7. and the usual suite of vaccines against the rest like hepatitis A/B, mumps etc
Treatment of the bacterial ones (which transmit through oral too):
1. syphilis - butt shot of penicillin 2. chlamydia - 1 pill of an antibiotic 3. gonorrhea - a week of doxycycline pills or one butt shot of ceftriaxone
Remaining: HSV. Half of the population has it, so no big deal. Condoms dont prevent it either.
As for hepatitis: even though it requires blood contact and as such is not necessarily considered an STI, hepatitis c is curable these days thanks to DAAs taken over the course of 8-12 weeks. a/b have vaccines.
Preventatively using antibiotics is a horrible idea, for one it increases the risk of creating resisitant strains, and we are already running out of antibiotics (especially broadband ones). Moreover, antibiotics in general are known to mess with you gut biome whose importance we are just beginning to understand (we know it plays a role in many physical and mental illnesses for example). Then there are the side effects which for doxycyline include diarrhea, increased risk of bowel cancer, higher sensitivity to the sun (and associated risk of skin cancer).
Suppose you’re immunocompromised. Wouldn’t it be worth the diarrhea to avoid infections your body couldn’t fight off?
Suppose you’re in a situation where you’re having lots of opportunities for infection. Whether you can or can’t control that situation, the end result is the same: you know your body is going to be challenged by infectious disease frequently in a way that most people’s bodies aren’t. Isn’t it plausible that the infectious agent may have less opportunity to evolve if you didn’t contract it as frequently?
Different forms of therapy might be both individually and collectively optimal for people in different situations. What’s right for a person who isn’t at risk isn’t the same as what’s right for a person who is at risk.
The overuse of antibiotics is mostly in farm animals, which represent 73% of global antibiotics use, and 90% of American antibiotics use.
In the early days of AIDS (wasn't called HIV back then) the recommendation was to use a condom or dental dam (depending on the hardware of the recipient). That's how I learned what a dental dam was. Later it was suggested that plastic food wrap would work (the jokes just write themselves).
Sadly the ubiquity of paper toilet sheet covers in US bathrooms dates back to the 80s due to straight paranoia over AIDs + widespread and overt anti-gay prejudice, so every time I see one of those dispensers I grit my teeth.
Reminds me of the early days of COVID (not the anti-gay part, but the weird practices when nobody really had yet a good theory of what's going on).
The reason for the reversal in terms is treatment options. When HIV was first found, there were no treatments so AIDS was inevitable. Nowadays, medication can permanently prevent HIV from progressing to AIDS, so AIDS is much less common than HIV.
You might be thinking of “GRID” (gay related immuno deficiency), the original name of AIDS when it was believed it only affects gay people. Once the virus causing the illness was identified it was called HIV.
Personally I’d say that’s a pretty good tradeoff: fear, stigma, and death for a different problem that’s more an annoyance than a mortal threat right now.
lol what
https://www.cdc.gov/hiv/risk/condoms.html "condoms are highly effective in preventing HIV"
https://pubmed.ncbi.nlm.nih.gov/9141163/ 1997, "reexamination of HIV seroconversion studies suggests that condoms are 90 to 95% effective when used consistently"
https://www.cdc.gov/hiv/prevention/condoms.html "Most condoms are effective in preventing HIV and certain other STIs"
https://www.cdc.gov/hiv/risk/prep/index.html
>PrEP reduces the risk of getting HIV from sex by about 99%.
Last I checked 99 was greater than 95.
This is how you end up with super STD's
Worse still--large scale casual sex is a great way to introduce new, novel and un-contemplated STDs into the population. STDs are opportunistic that way, just ask Mr. triple-resistant Gonorrhea.
It's decidedly not the way I want it to be, but that's just how it works. For casual sex to be safe I think its more like "Hi, please spit into this tube so we can get busy" and red means HIV, Green means Monkeypox, comprehensively.
moreover, condoms can have numerous issues like tearing or stealthing
We all know exactly at a individual level what to do and not. We can keep asking "Why not just use a condom?" and see how far that gets us, or actually understand psychology and use patterns and work with what people actually do (good or bad).
Same can be said about (illicit) drugs, why not just not do drugs? Simple!
It is actually simple. Just not easy. Same with losing weight - consume fewer calories than you burn.
Edit: lmao touched a nerve? I will never understand why folks here get so prudish when we talk about sex... "Just wear a condom!" is remarkably insensitive, as though 100% of HIV transmission is your own fault, and not, say, someone else who has bad intentions.
This is like saying to someone killed in a motorcycle accident why didn’t you use a car. It’s a reductive, unempathetic and frankly unproductive take. Please think before asking this again.
there's a few good injection sites (upper arm, buttock, thigh or even pecs) and after I was shown once how it's done, I can do it myself. it's also essentially painless.
I'm Hypogonad and I'm on self administration of sub q injections twice a week and it's quite annoying. My urologist told me it's best to split it this way since more frequent injections avoids a "crash".
I would like to have less frequent injections if I could!
The most common - Testosterone Cypionate should be best used twice a week to avoid the "crashes" - if you care about keeping your levels relatively stable. Other forms of Testosterone have different half-lives and should be taken at differing schedules.
I never saw the point in subq shots for TRT. They are less effective, and are recommended solely for patient comfort and compliance. If you can manage a twice-weekly deep IM injection, I personally have had great results with that once I learned the locations. Nearly as painless as subq and better more consistent results.
Overall it doesn't matter a whole ton unless you are doing it for specific performance enhancing reasons. Being off "optimal schedule" a few days isn't going to make a meaningful difference for most.
I don't see why I change and my doctor essentially said the same.
Both graphs are 200mg per week. Green is dosed at once every 7 days, while the blue is broken into 7 smaller doses per week. (I haven't included axis and such, because it's really just the shape I'm trying to highlight)
As you can see, more frequent dosing results in steadier levels.
When administering your testosterone once per week, you will have to make one of a couple trade offs:
1) Dose high enough that you are above the level you want to be by the end of the week. This avoids the "crash" you mention, which will consist of both low-testosterone (low-libido, fatigue, etc) and low-estrogen[1] (joint pain, etc) side effects. Dosing higher means you shift the whole graph up, and you will be at supra-physiological levels of testosterone and estrogen, and the high estrogen side effects are no fun: nipple sensitivity, emotional fluctuations (think crying at the sight of puppy pictures), gynecomastia (development of breast tissue), horrible back acne, etc.
2) Dose on the lower side to avoid avoid high testosterone/estrogen side effects. This shifts the whole graph down, and now you're below where you want to be by the end of the week, and you now feel more like you did before you started TRT.
3) Somewhere between the above two options, and add an aromatase inhibitor (like anastrozole) to minimize high estrogen levels. You'll still have excessively high testosterone though... and you'd really be better off avoiding the high testosterone peaks instead of adding another drug to the mix.
I used to go into a clinic once a week for an intramuscular injection of testosterone cypionate. In order to not feel like shit the last two or three days of the week, I had to up my dose such that my back broke out in a constellation of acne, and probably negatively impacted my health in other more meaningful (but less obvious) ways.
Now I inject testosterone propionate every night. I managed to lower my dose so that I'm always hovering right around where I want to be, instead of bouncing all over the place.
That's another benefit of increased injection frequency: you can lower the total amount of testosterone injected per week while staying within therapeutic range.
1: Your body produces estrogen by aromatising testosterone. More testosterone and/or more aromatase -> higher estrogen. Less testosterone and/or aromatase -> lower estrogen.
Ideally they'd break down at a constant rate (they don't, but close enough) leading to steady levels despite levels of the prodrug steadily diminishing. This makes once a week dosing of testosterone cypionate (for example) viable for many, but not all, as you've discovered.
Dosing less but more often helps minimize the uncertainty/variability in breakdown/conversion, thus being more reliable at the cost of convenience.
For what it’s worth you might want to try a weekly dose if you haven’t. Most do better on it.
https://www.nhs.uk/contraception/choosing-contraception/how-...
One dynamic I was shocked to hear was the prevalence of marriages where one partner (always the husband in this context) is HIV positive and the other is secretly on prep. In this context infidelity may be a norm and traditional cultural and gender norms may look negatively or skeptically at anti-retrovirals.
While this isn’t the majority of the HIV experience in South Africa, it’s certainly a sizable group.
Further, adherence more generally is a massive problem. The cost of travel to a clinic in both rural and urban settings can be prohibitive for many and cause major adherence drop-off.
Drugs like this, if made affordable, will go a long way to immediately easing pressure on these groups - and that’s exciting.
Source: Was born in South Africa.
It seems much more likely that the husbands refuse to allow their wives to get prep out of spite. The implication of infidelity angle does not feel plausible.
Otherwise the men are setting themselves up for a lose:lose scenario regardless of what the wife does.
But that only makes sense if the husband thinks his wife doesn't believe he has HIV.
These are cultural contexts where the woman has no right to question any of this.
One of my main motivations in college and grad school was to work in drug discovery, specifically for HIV. At the time (~1995-2000) we were just starting to see positive results from protease inhibitors and reverse transcriptase inhibtors came somewhat later leading to the current "managment of HIV through HART" https://en.wikipedia.org/wiki/Management_of_HIV/AIDS
All of this came slowly - decades between significant new technologies/improvements in treatment. many sources of infection such as blood transfusions are now much less risky (people in the 70s and 80s were getting hep C and HIV from blood taken from HIV-positive donors). And the disease presents very differently in the US vs. other areas such as Sub-Saharan africa. But with extensive effort, prevention has gotten better and treatments have gotten much better. If there are truly usable preventatives for at-risk populations, and those medications are affordable, it will be a huge boon to the recipients.
Some interesting things to note:
- there was a lot of controversy about the source of infection and a lot of people used this to criticize gay people and injected drug users.
- one of the world's most famous virologists, https://en.wikipedia.org/wiki/Peter_Duesberg actively denied that HIV caused AIDS and instead thought it was transmitted by drug use. Note "Duesberg entered a long dispute with John Maddox, then-editor of the scientific journal Nature, demanding the right to rebut articles that HIV caused AIDS." which I think presages the current arguments about what scientists can say regarding the origins of COVID. The impact of his statements in South Africa was significant. From what I can tell he was completely off base and never made any truly convincing arguments for his position.
- Fauci, of COVID fame, played a big role in getting NIH and the various AIDS community organzations working together and making large improvements to HIV/AIDS treatment. Before that, Fauci was heavily criticized by various LBGTQ orgs (see https://www.nytimes.com/2022/12/31/opinion/anthony-fauci-hiv...) "Larry Kramer, one of the group’s founders, wrote an open letter to Dr. Fauci in The Village Voice calling him a murderer and comparing him to the Holocaust organizer Adolf Eichmann." Again, all this presages the later treatment of Fauci by various political groups during COVID. I often think back to Fauci during HIV/AIDS while reflecting on the current situation around COVID and I think we got lucky to find somebody like him, even if he said a few dumb things, and we'll be lucky if any public servants are willing to take up his role in the future.
- modern gene therapy often uses variants on HIV as the vector. That's right: it's so good at getting into cells and modifying the genome, that we use it as the preferred method. it took quite some time before the vectors were made safe enough (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152689/)
You get new evidence and you update your beliefs. This is literally how science works and progress is made. If you had to put every student of science on the spot for everything wrong they said/did, there wouldn't be as much progress.
I'm curious about his claim that retroviruses (retrovirii?) must be harmless to survive and multiply. What is the mainstream consensus on this?
To be clear: I know next to nothing about viruses (virii? I mean I don't even know how to call them) and I have no idea whether it really supports Peter Duesberg's claims about AIDS in general. I'm just wondering whether he's pointed out an interesting peculiarity of HIV that is not further investigated by others for fear of being accused of denialism.
Scientists can get very like that.
>> (...) the current arguments about what scientists can say regarding the origins of COVID.
It reminded me most about John Ioannidi's polemic against the way COVID was dealt with, rather than its origin. Ioannidis is a leading epidemiologist so he had to be taken seriously, although of course his opinion was rejected by most everyone else.
The mainstream consensus is the he was wildly wrong about HIV specifically, that HIV causes AIDS, and that his influence in South Africa to not deploy anti-viral medications killed hundreds of thousands of people before the policy was reversed.
Part of his hypothesis was that viruses in general, not just retroviruses, were not connected to cancers, the consensus view is that this is completely wrong. We have a very large body of evidence on many virus caused cancers now.
Even at the time he was arguing this, it was clear that the retrovirus HTLV was disease causing in humans https://en.wikipedia.org/wiki/Primate_T-lymphotropic_virus
So, the two known human retroviruses both cause disease and retroviruses cause diseases in animals. Duesberg held on to and promoted this concept long after it should have been clear to him that there was zero empirical support for his idea.
See https://www.nytimes.com/2024/05/20/world/europe/britain-cont... for some recent discussion of the scope and scale of HIV contamination.
Yet apparently to this day he draws over 200k/yr in salary from Berkeley. I believe they are not entirely funded by tuition/endowments which means California tax payers support him at least in part.
Moreover, why would a disease even 'care' about the host? As long as it can jump hosts quickly, it can afford to kill many of them. If achieving fast transmission is tough on the host, so be it. Other diseases may select for the opposite approach, of course.
I don't know enough (my retrovirus knowledge is out of date), but if you look at authoritative knowledge (IE, textbooks), you will see many non-harmless retroviruses:
- oncoretroviruses: as a side effect of how they integrate, they often cause cancer in patients. There is lots of time between infection and death for the virus to be transmitted.
- lentiviruses (this is also known as a "slow virus"). There is often lots of time between infection and death for the virus to be transmitted.
It's possible that scientists are avoiding directly attempting to argue with Deusberg's observations, but in general, the consensus seems to be that he brought nothing useful to the debate except irrational claims that were inconsistent with the evidence. We don't live in an ultrarational world where every fringe theory can be investigated.
As for Ioannidis... not sure what to say. I think his big mistake was going to the white house and trying to make Trump an ally and not shut down everything because he predicted the virus wouldn't spread and wouldn't be fatal at the rates that were later observed. Diseases like COVID are multidimensional problems with partial information and a high level of politics, corp, and media involvement. I think fauci and others have finally admitted that they may have made some mistakes in the specific details of the shutdowns, in particular, it took people a while to realize that the impact on children (who by and large are not at risk from COVID) was enormous.
If your goal is to affect public health policy, you have to be a truly 4D thinker, and even that's not enough dimensions.
You reminded me hat Ioannidis made very specific predictions that turned out to be false (about the number of deaths we could expect). And that, while measures were adopted that he claimed were useless. I agree Fauci saved lives - and last time I saw him in the news he was being attacked by Republican trolls, I don't have any other word for those people.
As you probably know, it can stay dormant for 10 years or more, but then gets into active stage, causes AIDS, and relatively quickly kills the host.
Sadly, there will be plenty of people desperately wanting that job. It is definitely a prime example of the saying those that want the job would not be good at the job and those that would be good at the job do not want it. Especially in today's environments where it will become a bully pulpit to push whatever agenda of whoever is in charge
We need somebody who takes on the pivotal role that Fauci played in the HIV and COVID epidemics, not just a career-motivated seat warmer.
Hopefully, the next administration doesn't come up with Schedule F once again and make all health-related government jobs political.
[edit] it’s prep, it’s been in use for several years already, but this injection last longer
Treatment of HIV+ people also reduces their infectiousness, and good treatment reduces the risk of passing the infection on nearly to zero. Providing sufficient HIV antivirals and medical care to everyone in the population, both HIV+ and at risk for HIV, in theory, could be enough to halt the pandemic. Some wealthy countries with sensible policies have seen remarkable gains. The UK is reasonably effective at getting drugs to both the HIV+ and to at-risk populations, and the number of new HIV infections there, has been reduced by approximately half in the last decade.
I don't see anything to indicate it's an implant - the prescribing information [1] says it's a subQ injection, and the trial information [2] seems consistent with that.
[1]: https://www.gilead.com/-/media/files/pdfs/medicines/hiv/sunl...
[2]: https://classic.clinicaltrials.gov/ct2/show/NCT04994509
Even if we can consider HIV “cured” in the developed world (where PrEP is available to anyone who wants it) there’s no way we eradicate HIV from impoverished countries with limited healthcare access until we either have 1) a vaccine, or 2) a shot (or something) that prevents HIV for a really freaking long time.
Not sure if 6 months will quite cut it, but it’s great to see progress in the right direction. More advancement is needed.
That’s not to say it’s not a great improvement, I happily await the day we can nearly eliminate some of these infectious diseases that plague humanity.
@dang
If there is one place socialised medicine makes so much sense that almost any argument against it is invalid, it's around contagious diseases. The prevention and treatment, inasmuch as it reduces transmission, which is true of virtually all HIV treatments, should be as effortless as possible. That starts with making it free.
Unfortunately it takes many years or evens decades for developing countries to afford these treatments.
https://en.m.wikipedia.org/wiki/President%27s_Emergency_Plan...
Unfortunately it's become a target of the right wing culture warriors and certain groups are trying to gut it, after huge strides have been made in reducing global transmission of HIV.
I know someone from a EU country that had to do medical tourism to Brazil to afford hepatitis and HIV treatment as the drugs are so expensive that the doctors at public hospitals (in that country at least) will not prescribed them and instead manage the illness in other ways for the first few years. This is bad because the disease progresses faster.
In the same way we eradicated COVID? /s
First of all, COVID is still around just less common.
Second, this HIV implant is a twice yearly implant. Not a one-time preventative cure.
Third, User Rlad in these comments calls into question its efficacy suggesting it merely stops replication but not infection. Once a cell is infected with HIV, a cell is permanently infected. This posit’s the concern that once a person stops receiving the implants, the dormant virus will then begin replicating —- fully infecting the individual. That makes this drug sound a lot like Luciferium from the video game Rimworld.
Fourth, the inactive ingredients need to be studied. If they contain heavy metals such as mercuries and aluminums, that a reason for pause and study. Autopsies of brains affected by Alzheimer’s usually find high levels of heavy metals in the brain. Heavy metal poisoning causes all sorts of cognitive issues.
Fifth and last, too large of an immune response is associated with the creation of new allergies. All allergies are a product of an immune response to something that the body shouldn’t have an immune response to. While HIV protection trumps new allergies, it’s worth examining side effects especially if some are mostly permanent. I also don’t know if this drug causes any kind of immune response. It’s all a starting point for someone who wants to study it more to study so you can come to your own conclusions after studying.
This also means that it actually does not stop infection. Cells still get infected, but this drug prevents more virus from being produced.
My question is, since there are infected cells in these individuals, if they stop taking the drug aren’t they likely to become immediately highly infected, because the drug only interferes with viral replication while it is present in the body? Once infected, a cell is permanently infected.
I think this should be the case, unless infected cells are somehow killed off through some other mechanism: maybe they get lysed through an accumulation of partially formed capsids?
Seems important to know anyway
https://www.mayoclinic.org/drugs-supplements/lenacapavir-sub...
Higher mutation rate and other shifts vs broadly neutralizing antibodies? Anyways, it would be nice to fully "solve" COVID-19 as it's still wreaking havoc somewhat silently (?)
I also wonder when or if we'll see therapeutic vaccines against either of these and more sooner than later?
Each time I only briefly start staring into the abyss that is "wetware" I'm gladly returning to our comparatively trivial (self-inflicted) complexity in the world of software / computing.
Vaccines are notoriously slow to develop, perfect, and test for safety and efficacy. The original Covid mRNA vaccines were developed at breakneck speeds as far as vaccines go. Unfortunately, much of the funding has since dried up.
In fact, it's HIV that's much harder to develop a vaccine for. HIV vaccine research has been going on for 40 years and hasn't really had any candidates that went beyond "plausible" until recently.
[1] https://www.nature.com/articles/s41423-023-01116-8
[2] https://mrdc.health.mil/index.cfm/media/news_releases/2021/p...
https://static.dw.com/image/59546575_7.png
https://healthnewshub.org/wp-content/uploads/2021/10/CDCcase...
https://arc-anglerfish-washpost-prod-washpost.s3.amazonaws.c...
https://static01.nyt.com/images/2021/10/28/us/virus-breakthr...
https://static01.nyt.com/images/2022/01/10/briefing/11-MORNI...
Evolution has driven the virus away from the neutralizing antibodies. This is called immune escape. Recent variants have very little antigenic overlap with the original strain. The original antibodies are not very effective, so people can actually get sick once again.
The FDA now updates the vaccine formulation every year. This means that every year, there is a time window during which the vaccine formulation and the circulating variant are the same. If you get an updated shot as soon as it becomes available, you're immune for all practical purposes until a new variant emerges.
And you’re far from immune with the newest formulations. From the CDC: “People who received the updated COVID-19 vaccine were 54% less likely to get COVID-19 during the four-month period from mid-September 2023 to January 2024.”
https://www.cdc.gov/ncird/whats-new/covid-19-vaccine-effecti...
Even with the original strain/vaccine, effectiveness waned after 6 months.
Regrettably, this is one's on the FDA, as XBB.1.5 was already on the way out when the FDA chose it. Part of the problem was their desire to include Novavax in the lineup. It has a much longer update turnaround time than Moderna and Pfizer, and Novavax had already committed to XBB.1.5 by the time the 2023 VRBPAC meeting took place.
As for the original vaccine, the waning measurements were in terms of antibody titers, not in terms of actual effectiveness against the target variant. Delta emerged in the spring of 2021, and it had significant immune escape from WT (Wuhan.) By the time the population was immunized against WT, Delta had already driven WT out.
There have not been many reported cases of non-immunocompromised people getting infected with the exact same variant they had been vaccinated against or previously infected with, particularly with WT. There has been too much evolution in the timeline to even dig out the signal.
The original WT mRNA effectiveness measurements were 92-95% IIRC. For all we know, the missing 5-8% might be attributable to immune deficits, early infections, and/or incomplete B-cell maturation. I haven't noticed any research that measured the likelihood of single-variant breakthrough infection, but if you find some I'd like to look at it.
As for other diseases, they are not in the pandemic phase, so their vaccines can be optimized accordingly.
I would dispute that "easily evolve" notion, though. There have been billions of Covid cases since 2019, including countless immunocompromised patients who are basically walking virus incubators. Yet there have only been a handful of major saltations. It's actually quite likely that Covid will eventually be defeated completely.
That drug is still in use and also highly effective, the new improvement is to provide the same approach with a longer acting injected drug. One reason there has been great interest in this, despite the already effective oral PREP, is that there are thought to be socio-behavior advantages for cases like women in Africa as in this study. For example: the woman does not have to keep a supply of daily pills that a partner can find. Also possibly improved adherence with no missed doses.
The drug itself is not thought to be more biologically effective than the oral drugs, which are basically already at close to 100% effective assuming the patient actually takes them as scheduled.
Since people don't spontaneously recover from HIV infection, and the PrEP drugs have relatively few side-effects, the tradeoff is more favorable.
https://www.pnas.org/doi/10.1073/pnas.2319566121
In case you're wondering, this paper is 100% legit, see e.g. the bio for the big-shot author: https://en.wikipedia.org/wiki/Akiko_Iwasaki
No clue if this easy trick would induce immune escape if a large number of people started using it. I guess it's a good time to get in on the ground floor.
1. "Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19." 2. "Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. " 3. "In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)." 4. "In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants."
The mechanism appears to be that Neosporin triggers an ISG[1] (immune) response? Not a biologist etc, but the results showing that it prevents transmission is only in rodent models, and then showing that a similar biomarker shows up in (some of) the participants and the rodent models. They authors say:
> "These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections."
[1]
https://classic.clinicaltrials.gov/ct2/show/NCT05449392
Here's Eric Topol's chat with Iwasaki discussing the finding. Topol's blog may well be the best source for Covid research out there:
https://erictopol.substack.com/p/akiko-iwasaki-the-immunolog...
Obviously it’s not stimulating the immune system but it works as an antiviral barrier. I’ve been using it since I read that study and I’ve avoid 2 of my daughter’s colds since (and still got 3). That might not sound impressive but I have a terrible immune system and haven’t avoided a cold from someone I’ve had close exposure to in as long as I can remember.
That said, I might need to add some Neosporin to my mixture when she comes home with her nose running.
For 150ml of (distilled) water: 1.35g of salt 1.8g of iota carrageenan A drop of polysorbate 20
Heat up the water to close to boiling, add those things, shake it up, and there you go.
Note: That was supposed to be in line with the product that was tested, but I've found adding more water makes it come out of the nose spray bottle thing better. It's still pretty thick, just not a complete gel. Perhaps there's another type of spray bottle that would be better.
Essentially, yes, neomycin in the nose, if timed perfectly, can activate the innate immune system, but en mass this practice would cause the spread of antibiotic resistance.
Link: https://podcasts.apple.com/us/podcast/this-week-in-virology/...
Besides, we're already spiraling down the resistance chasm with antibacterial soaps, stuffing cattle with antibiotics, overprescribing, and so on.
" PURPOSE 1, a Phase 3, double-blind, randomized study, is evaluating the safety and efficacy of twice-yearly, subcutaneous lenacapavir for pre-exposure prophylaxis (PrEP) and once-daily oral Descovy® (emtricitabine 200mg and tenofovir alafenamide 25mg; F/TAF) in more than 5,300 cisgender women and adolescent girls aged 16-25 across 25 sites in South Africa and three sites in Uganda. The drugs are being tested in parallel, with one group receiving twice-yearly lenacapavir and one group taking once-daily oral Descovy. Additionally, a third group was assigned once-daily oral Truvada. Study participants were randomized in a 2:2:1 ratio to lenacapavir, Descovy and Truvada, respectively. Because effective PrEP options already exist, there is broad consensus in the PrEP field that a placebo group would be unethical; thus, the trial used bHIV as the primary comparator and Truvada as a secondary comparator.
There were 0 incident cases of HIV infection among 2,134 women in the lenacapavir group (incidence 0.00 per 100 person-years). There were 16 incident cases among 1,068 women in the Truvada group (incidence 1.69 per 100 person-years). The results demonstrated superiority of twice-yearly lenacapavir over bHIV (primary endpoint, incidence 2.41 per 100 person-years) and superiority of twice-yearly lenacapavir over once-daily Truvada (secondary endpoint), with p<0.0001 for both endpoints. In the trial, lenacapavir was generally well-tolerated and no significant or new safety concerns were identified.
[...]
Gilead expects results in late 2024/early 2025 from the program’s other pivotal trial, PURPOSE 2, which is assessing twice-yearly lenacapavir for PrEP among cisgender men who have sex with men, transgender men, transgender women and gender non-binary individuals who have sex with partners assigned male at birth in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States. "
Another aspect is that a lot of intellectualism is really activism with "intellectuals" trying to impede other people's lives for the sake of some arrogant moral purpose.
I'm not sure that most people are really all that comfortable. They're a lot more distracted though certainly.
I think there are a lot of different reasons people today have a problem with science and technology. Some are scared of it. Some just don't trust it, which can be entirely fair depending on the degree/situation. Some see that the regulations, oversight, and accountability we expect and depend on to keep us safe aren't working like they used to or like we thought they would.
Mostly I think people see not only what we've gained, but also what we've lost and could/should have again. Reliable and repairable products that weren't designed to exploit and work against the interests of the person who paid for them for just one example. We've had many trade offs, where they've improved things in some areas while making them worse in others. It hasn't always worked out in our favor. It's also frustrating when you see that amazing things are now possible, but we can't have them because of politics, or greed, or fear of change.
Personally, I hope people never stop wanting and expecting better from science and technology. Especially in those cases where what previous generations had was better than what we're expected to accept today or where we've created problems previous generations never had to put up with.
We often forget that many people have been genuinely negatively affected by technology or science or know someone who has. Let's not forget that many technological and medical advances have come at a real human cost. People have been poisoned by harmful chemicals either during their occupation or because an entire community has been exposed. Entire communities have been devastated by the opioid epidemic which the medical community is directly responsible for. Not to mention the countless people who have lost their jobs or will lose them soon to automation.
There are people with genuine concerns about the way science and technology are heading and pretending anyone skeptical of modern science is simply uneducated or stupid is extremely counter-productive.
Between corporations being able to buy whatever research they think will get them a favorable headline, peer reviewed journals accepting any paper if you pay them to publish it (this one being a personal favorite https://www.sciencealert.com/a-neuroscientist-just-tricked-4...), the reproducibility crisis more generally, the total lack of any meaningful consequences when companies are caught outright knowingly poisoning people or selling dangerous drugs, it's really getting harder to explain to people at the fringes like antivaxxers why they should have more faith in the data we have and on the systems put in place to protect them.
If the people aren't held accountable for causing harm and scientists don't do a much better job self-policing I think the situation is only going to get much worse. Even if things do change it will likely take generations to undo the damage already done.
I think people in wealthy countries like the USA are very physically comfortable, but also quite unhappy- possibly much more unhappy day to day than they were historically when there was a lot more disease and discomfort- and a lot of that is directly a result of excess comfort combined with a life without any real difficulty, challenge, or sense of meaningful purpose. We feel like we want comfort, but it's mostly harmful to us. Humans just aren't built to be "house pets." People need a sense of purpose, of overcoming difficult challenge, and an ability to directly see positive results from their efforts. The challenges need to be both mental, and physical.
What we have now is lots of empty entertainment, stupor inducing comfort, and lots of sedentary careers that feel pointless, where nobody even notices the difference if you work hard or not. More and more people are burned out at work, and socially isolated.
I don't think the answer is to go "backwards" and lose all of our progress in treating disease, making labor easier, etc. but in a cultural and personal change where we find some new meaning and challenges, to grow even more. Personally, I've found this through being a scientist where I can work on hard problems, as well as doing physically demanding and uncomfortable hobbies like weight training, fasting, and cold water swimming.
I've noticed that the more intentional physical discomfort I experience, e.g. from cold, the more content I feel, and the less I crave comfort, or other addictive things like social media and overeating.
OK, I’ll bite -examples?
More recently some people are unenthusiastic about promoting trans stuff and affirmative action.
Despite the far-right being on the rise as well as everywhere in Europe, they still have a harder time here, which I think is mostly due to these two education policies.
Federally, the AfD is around 15-18% [1], which is still way too high in my opinion, but they're far from any chance to gain relevant influence on politics. Statewide is a different beast, sadly in Eastern Germany (the equivalent of the "flyover states" in the US) they're almost at the 33% required to block major legislation [2]. I'm honestly not sure how to combat that any more, outside of a (well deserved, given e.g Höcke directly using banned NS slogans) ban on the party.
Perhaps by getting rid of these haughty, and one simply has to say: typisch-Wessi notions of the new Länder as being "flyover territory". Which is part of what drives people to vote for AfD in the first place. As if the former West Germany doesn't have its own stereotypically maligned areas as well.
Trip to a holocaust museum is nice and all, but it probably fails at making people understand the problem. They'll kind of nod that yeah, Nazis were bad but then happily go and blame others for their bad decisions and vote for populists with easy solutions.
Somehow half of Germany thinks Russia is OK, because they "saved Europe", hammer and sickle symbols are still not treated the same as swastikas and, of course, the main outcome of the kind of education you mention is that Germany is basically freeloading wrt defense and very unwilling to do the only reasonable thing, i.e. help prevent another genocide as it unfolds in Europe.
Hopefully something has changed in the last 2 years, but the preceding decade, spending over 100 million euros daily on Russian natural gas is hard to undo. And that's with pre-war historical minimum prices. Since you all didn't get the memo that you need to stop buying Russian stuff until NS2 got blown up, the flow of money for natural gas from Germany to Russia in 2022 and 2023 is likely several times the pre-war annual number.
And then you have people saying shit like "we have spent enough on Ukraine" or "Ukrainian refugees are coming because of our social safety net", not even from AfD politicians (I think some CDU idiot, lol). Yeah sure, but you gave 100x the money to Russia, who of course spent it on weapons because they don't give two fucks about their own people.
Being sorry about things from the last century, while failing completely to judge the situation in the present doesn't really help. Not to mention Poland still didn't get the war reparations for WW2 last I checked. They probably don't want to shake the boat too much and just hope Germany will at least stop being useless.
Would you have called intellectual abolitionists people trying to impede other people's lives for some arrogant moral purpose?
Like, I get it, nobody likes a woke-scold, but it is still weird to complain about the idea that an intellectual who comes to a moral understanding might want to act on that new understanding/change the world/convince others.
I'm sure we can at least make some judgements about whether a set of morals is better or worse than another, but all the obvious cases are already solved and people strongly disagree on the ambiguous ones where they really have no idea.
One big moral concept is individual freedom vs long term survival of the system of social order they belong to. You can't have individual freedom without a society to protect it but you can't sustain that society without restricting people's freedoms (eg. military conscription). It's popular today in the west to value the individual over the future of their society, but a lot of history and the rest of the world is the opposite. People from these two camps seem to be blind to the weaknesses of these underlying assumptions, so they end up with moral ideas that seem totally immoral to each other.
> "all the obvious cases are already solved"
This seems highly optimistic.
I can't imagine having to watch a loved one slowly die knowing that you are surrounded by doctors who could save them if you only had the tens to hundreds of thousands of dollars they demand or if you'd been living in basically any other developed nation on Earth.
I’m certain that the US is in no way unique in that. Countries with universal public healthcare care systems do cost-benefit analysis all the time and access to the newest effective treatment options outside of the richest/most developed countries (or even in them) is far from guaranteed. e.g good luck buying latest cancer drugs from the US on an East European salary after your local healthcare system bureaucrats have rejected them because they are too expensive and/or are taking a year or two to decide of they are worth buying.
> or if you'd been living in basically any other developed nation on Earth.
That’s just beyond absurd, unless you think that only Switzerland and a handful of other rich countries are “developed”. Yes getting some minimum/acceptable level of care when you’re not rich might generally be easier. Getting access to latest or even experimental drugs (most of which are developed in the US)? Not so much..
It doesn't always work like this. Some drugs are just too expensive to manufacture and the minimum profitable price is too high for the benefit in public health care. But often the bargaining and purchasing power of a public health care system can achieve lower prices for drugs and other tools.
I’m not sure that’s strictly true at least when it comes to the most expensive/newly developed drugs:
https://www.investigate-europe.eu/posts/deadly-prices-medici...
Doesn’t seem that massively different from the relationship between insurance companies and drug companies in the US.
> In countries with public health care, setting the price that high will typically result in near-zero sales
Interestingly enough it seems like the poorer Central/East European countries end up paying more than the richer ones.
Healthcare and medicine needs overhauling but it's maddening watching these downstream foreign benefactors damn the golden goose they'd be fucked without.
For the world's richest people you couldn't do better than to be a patient in America. For most Americans though, the US healthcare system is failing them. America does worse compared to other nations in some very basic measures like having a lower average life expectancy, a higher infant morality rate, more obesity and congestive heart failure and more hospital/pharmacy screw ups. A child or teenager in the US is less likely to live to adulthood compared to those in other developed countries. It's not any better when it comes to mental health either. The US is one of the worst nations when it comes to mental health outcomes and suicide and drug related deaths are higher in the US. Over thirty percent of the US population has been forced to put off getting the care they need due to the cost and preventative care is usually the first thing that people cut back on leading to bigger problems that could have been avoided entirely.
Even if you don’t do that there is a higher variance in life expectancy between different US states than inside the EU. e.g. California is about on par with the Netherlands, Germany, Britain while Mississippi and West Virginia are slightly below Bulgaria (of course mainly because of drugs..). IMHO that kinds of makes generalized comparisons semi-meaningless.
People in Portugal, where healthcare is "free", i.e. the government pays for it, frequently wait for years before being able to see a specialist due to long waitlists. The obvious outcome is that only poor people use the system and if you can you use private healthcare.
People in Czechia with single payer healthcare system with e.g. average wage of 2000 USD pay from 100 euros a month for health insurance (unemployed) to e.g. 500 euros (with 4000 USD salary) or more if you make more. You get the same shitty service (something like 20 years behid the US), you just pay a lot more if you make anything resembling a US salary.
There's no such thing as free healthcare. Can you make a single payer healthcare system that works better? Sure, it's just hard and even if everything is ideal you get maybe 50% discount. The main way to make healthcare cheaper is to drop coverage for diseases that are expensive to treat.
- The obesity and congestive heart failure issues is a function of poor dietary choices most Americans make (choosing fast/process food over cooking/making healthy foods), and not a function of healthcare access
Medicaid has a ton of other problems starting with eligibility, but even if you are eligible and you successfully jump through all the hoops to keep it (which are sometimes totally insane: https://youtube.com/watch?v=bVIsnOfNfCo), you still may not be able to get the services you need. Many doctors won't accept it and you can die just waiting for an appointment. Studies have shown there was effectively one psychiatrist for every 8,834 Medicaid beneficiaries and just one cardiologist for every 4,543 Medicaid beneficiaries. These doctors can't possibly see, let alone adequately treat and manage the care of, everyone who needs them.
The closest we get to free healthcare in the US is care in the emergency room which is only required to "stabilize" you. They'll try their best to keep you alive if you're actively dying, but then they push you out the door and send you a massive bill. They won't give you chemo or radiation to keep your cancer from spreading
Even if we assume that's the case - as in, normal margins would be insufficient to finance the research - that does not account for the medical treatments themselves.
> the whole world laughs at us
Most of the world doesn't care.
The US cost of healthcare is about 17% of GDP. In other first world nations it's about 11%. This isn't service delivery or value, it's underlying cost. Per capita healthcare costs over twice of what it does in the UK. Similar for Australia. Both those are socialised and have very active R&D communities.
The average life expectancy in the US is about 78. In other first world nations it's almost unilaterally closer to 84.
The US is ranked 69th globally in terms.of health system performance. The US is also ranked worse than the OECD38 average for death by preventable causes.
The biggest difference between those places I mention and the above is that the US views healthcare as a capitalist endeavour and tries to claim that competition will lower prices. Quite the opposite has occurred, and the system has become perverted. Intellectual property laws applied in this fashion ensure that you cannot have competition for health care since drugs are limited to a single supplier. You also don't get a choice in hospital care or doctors in most cases when you really look at how medical competition works.
In other places, the costs are socialised through taxation. Drugs are purchased through nationalised efforts where suppliers must either come to the table and negotiate prices properly or lose access to entire markets. It's funny how they can still be quite profitable even under this scenario, and yet the prices still be so significantly less by orders of magnitude than US pricing per patient/dose.
American exceptionalism ceases to be felt when you go spend time in other first world nations for any meaningful length of time. You realise it's reassurance of self rather than truth on basically all but defence technology spending.
It doesn’t help that (at least when it comes to healthcare) US is a dozen of different countries in a trench coat.
Life expectancy in richer states like California or New York is very close to that in Germany, the Netherlands, Britain etc. (and if adjusted for the massive disparity in drug related deaths they’d probably be closer to Italy, France or even Switzerland) while the poorest states are about on par with Eastern European countries where it’s barely above 75 years or so. So any average figure is semi meaningless.
How much of the money that flows into the US healthcare system really goes towards medical R&D, and how much is effectively wasted due to the inefficient bureaucracy and out-of-control litigation?
Literally tens of billions are wasted annually on advertising. The cost is pushed to the sick and hurting while doctors are bribed to overprescribe whatever drug people are being trained to "ask their doctor about". I'd worry about that way before I gave a thought to "out-of-control litigation". Especially considering how companies like Purdue Pharma and Philips Respironics can knowingly kill people with their drugs and medical devices, try to hide the fact they were doing it, yet face no meaningful consequences and not one person is put behind bars. If anything, I'd say America should be demanding more justice from the legal system not less.
If the government funded research that resulted in a more eco-friendly car I wouldn't expect to see one delivered to my driveway or that the car with the fancy new tech (which might be a lot more involved in terms of costs) should be priced the same as the old tech.
Healthcare should just be made accessible and affordable to everyone. It looks like the best way to do that is with publicly funded health systems.
>I wouldn't expect to see one delivered to my driveway or that the car with the fancy new tech (which might be a lot more involved in terms of costs) should be priced the same as the old tech.
we often pay a new user tax, or monopoly tax like the epipen thing. that should not be possible.
Don't blame the world for your Pharma executives needing a third private jet for their mistresses.
Wouldn’t that discourage these companies from spending money to develop new drugs on their own in the future?
Also in the 1970s the Cambodians were searching out their intellectuals and executing them and the Chinese did a slightly less extreme version in the cultural revolution whereas now you get none of that and China is becoming a science superpower.
Admittedly some in the US seem to be pushing antivax and climate denial but it's not like the past events. Also it seems a bit local. I'm a Brit for example and see almost no climate denial here. A bit of antivax maybe.
It makes the most stupid and uneducated person think that they are equal to the top minds of present day in many aspects.
You can hold both opinions that an mRNA vaccine is an incredible new technology that has enormous potential, while a new technology that had never been tested on humans shouldn't be forced on people for whom the benefit was marginal at best (kids, healthy population under 50, people who already had covid).
And you can hold both opinions that health authorities clearly misbehaved or acted in a moronic way (lying about masks, origin of the virus, forcing vaccines on people who had already been infected, telling you you can't go outside, except if it's to protest for BLM, etc) while acknowledging that coming up with a vaccine against a new virus in only weeks is a technological wonder.
It's absurd to be systematically anti-intellectual, but also some healthy skepticism is well warranted.
only thing thats changed this time is anti-intellectualism is given a microphone.
It appears the company name is an allusion to the balm of Gilead (https://en.m.wikipedia.org/wiki/Balm_of_Gilead)
But maybe this company can incorporate all that in their market to targeted ad the nation’s schizophrenics, the ones that will draw a connection where there is none
It's a retrovirus, so it makes two copies of itself and replaces cellular DNA. Two RNA welded together make up DNA, so it more or less gives you the equivalent of a genetic disorder.
"Here's a shot, go have sex with people with HIV"? I hope the young women conducting the trials were compensated sufficiently for the risk taken, especially those who contracted HIV during the period.
Normally, some percentage of the population will get HIV in any given year. So what you do is give a bunch of people the shot and track them long term. You count how many got HIV after N years, compared to what would be expected in a normal population.
Nobody is exposed to HIV as part of the study, that exposure would come through the participants living their ordinary lives.
But paying people to be studied tends to be effective.
In that case, someone at high risk for HIV infection could be prevented from getting treatment because of the study protocol. The ethical solution, which the authors of the study chose, was to provide the highest standard of care as the placebo - in this case it was Truvada.
Since the treatment was actually even more effective than the existing standard of care, it was a home run success. Their conclusion is even stronger than it would be if they used a non pharmaceutical placebo, so in retrospect their decision was clearly correct.
In this case the study cites that as being unethical due to the high prevalence of HIV in the target population. So the actual trial gave some people the shot, and some other people the known-working daily pills as a control.
Poking around, it's my understanding that double blind procedure only covers treatment allocation--that is, who gets the placebo or not--and does not exclude general experiment communication to patients. I imagine trial communication is something generic along the lines of "We're running a novel drug trial, help us gather more data for $50/shot."
As a South African, I appreciate that we're also the most unequal country in the world (by Gini coef). So, some of what was going on in my mind as I read the Bloomberg piece, was:
* did they choose people at random, because the high HIV rate is obviously skewed towards vulnerable groups (think a young woman who's financially dependent on her boyfriend, who has multiple partners)
* just because the HIV rate is prevalent, doesn't mean that young sexually active people would have multiple partners, so how do they account for situations where we were sexually active, but with 1 or safe partners
* condoms are freely available in clinics and often public toilets, and we've generally gone past the fear of asking for them. So how does safe sex affect their study
[0] https://www.wits.ac.za/news/latest-news/opinion/2024/2024-04....
They chose around 5000 people; they randomized them to either try the new shot, or one of two existing PREP drugs.
Of the 2000 people in the lenacapavir group, 0 got HIV, while dozens got HIV in the existing PREP groups.
When you have that many people and shuffle them, the groups end up pretty similar. You'd have to be really unlucky to get all the promiscuous people in the PREP groups.
PREP is already pretty effective; to have such a crushing result over PREP is a breakthrough.
It is in their interest to ... fudge the truth a little.
Now pfizer did this a different time by removing 2/3rds of the treatment group, and only counting "infections" if they occurred after all doses/boosters were administered. If you compare actual results to what pfizer published and claimed, you see that it was 7 infections in the placebo group and over 100 in the test group. they claimed <7 in the treatment group (i don't think it was 0, but it was like 2), and 7 in the placebo, saying "see, reduced infections by 80%!" Well, yeah, if you don't count infections and remove 2/3rds of the people who would have counted as infections possibly.
which means, and you don't even have to squint very hard, that the vaccine was actually increasing the chances of infection.
A lot of us are completely burned out and therefore wary on multinationals, regardless of their vertical. Pharma has a lot to answer for. Nestle has a lot to answer for. Chevron (et al) have a lot to answer for.
> The trial involved about 5,300 women and female adolescents ages 16 to 25 in South Africa and Uganda, some of whom who received Gilead lenacapavir, and others who received older once-daily drugs from Gilead, including Truvada or Descovy.
Not to mention a superficial understanding of how drug trials are conducted would exclude that method.
As I skim TFA, they say nobody who got the shot ended up getting HIV, which would be statistical anomaly for the population they tested.
They're not comparing the new treatment to nothing. They're comparing it to existing treatments.
> The shot was also superior to once-daily Truvada, another Gilead drug that is used for HIV prevention.
That's good news. As I understand it the existing treatments were already very good. And these injections are only once per year.
It's like giving police officers new buller-proof vests, and then none of them getting in the firing line. You can't say that your vests are more efficient than other vests if they technically didn't get tested.
So, my thinking was how they ensure that all test groups are sexually exposed to other people with HIV, for the trial to be effective.
Think about it like studies on which cars perform better in crashes. They don't need to have people drive more wrecklessly to determine if the car is safer. They just need to look at the expected risk compared to the outcomes of the people who drive that car. They are already doing the risky thing.
They don't. Some people will organically have sex with people with HIV, and some will not. Your study just needs to recruit enough participants that it is likely some will. Your study absolutely does not tell people to deliberately have sex with HIV+ partners.
1: https://www.youtube.com/watch?v=-IffpoUQpDc&pp=ygUUdGhlIHZpY...
This was in South Africa. You might as conclude on life in America based on observations in Caracas.
This is explicitly referred to as a risk factor in the study, although they say "gender-based violence"