[HN Gopher] Prevention of HIV
___________________________________________________________________
Prevention of HIV
Author : etiam
Score : 181 points
Date : 2024-08-07 19:11 UTC (3 hours ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| sillysaurusx wrote:
| In terms of protecting oneself, what are the actual steps? (E.g.
| if you're HIV- but are participating in activities either
| directly with someone who is HIV+ or whose partner is HIV+.)
|
| Do you schedule a doctor appointment and ask for something
| specific? And is there anything else to do, such as something
| over-the-counter?
|
| There's a dizzying array of terms to learn in this space. PrEP is
| apparently different from PEP, which I think is also unrelated to
| what this article is talking about. It'd be nice if someone put
| together a 2024 guide for what the latest preventative /
| protection mechanisms are.
| toomuchtodo wrote:
| Assuming you do not currently have a viral load of HIV, you can
| meet with your provider, indicate that you are at risk, and
| request a prescription for PrEP [1] (Planned Parenthood can
| assist with sourcing if you don't have a PCP or other stable
| medical providers). Longer term, it is likely there will be a
| shift to a twice yearly injectable (Gilead's Lenacapavir) [2].
| State of the art is an undetectable viral load due to antiviral
| treatment means you cannot transmit to others [3] [4] [5].
|
| Not medical advice, educational purposes only. Seek a medical
| professional's guidance for your personal circumstances.
|
| [1] https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-
| medi...
|
| [2] https://news.ycombinator.com/item?id=40742163
|
| [3] https://www.hiv.gov/hiv-basics/staying-in-hiv-care/hiv-
| treat...
|
| [4] https://www.niaid.nih.gov/diseases-conditions/treatment-
| prev...
|
| [5] https://www.hiv.gov/blog/science-validates-undetectable-
| untr...
| ClarityJones wrote:
| From [5] https://www.hiv.gov/blog/science-validates-
| undetectable-untr...:
|
| > Even when viral load is undetectable, ... may have
| detectable HIV genetic material in ... semen, but there is no
| scientific evidence that such material is associated with HIV
| transmission.
|
| What? Isn't that the primary transmission vector?
| toomuchtodo wrote:
| From that same link you cite:
|
| > Findings from the breakthrough NIH-funded HPTN 052
| clinical trial, a decade-long study involving more than
| 1,600 heterosexual couples, offered clear-cut evidence that
| ART that consistently suppresses HIV also prevents sexual
| transmission of the virus. In 2011, the HPTN 052
| investigators reported that starting ART when the immune
| system is relatively healthy, as opposed to delaying
| therapy until the immune system has been weakened by the
| virus, dramatically reduces the risk of sexually
| transmitting HIV. The protective effect of starting ART
| early was sustained over four additional years of follow-
| up. Importantly, when viral loads were measured, no HIV
| transmissions were observed when ART consistently, durably
| suppressed the virus in the partner living with HIV.
|
| Wild speculation is that the genetic material you mention
| is inactivated and therefore unable to transmit the virus,
| but is still detectable. I am just an internet rando
| surfing the knowledge graph, but the science appears sound.
|
| https://www.nih.gov/news-events/news-releases/hiv-control-
| th...
|
| https://web.archive.org/web/20150106032855/http://www.niaid
| ....
|
| https://www.clinicaltrials.gov/study/NCT00074581
| Vecr wrote:
| I don't buy U=U, I've not seen a proper impossibility proof
| re. provirus mutation. There's probably infections drowned
| out against the background rate.
| 4fterd4rk wrote:
| This has been extensively studied and you are wrong.
|
| https://www.thelancet.com/journals/lancet/article/PIIS014
| 0-6...
| Vecr wrote:
| I don't think I am, in the provirus state you can think
| of it as essentially a DNA virus in an inert state, and
| if the DNA fragments the right way it would turn into
| something similar to a bare DNA vaccine. That design of
| vaccine essentially does not work, but they have an
| effect that is not literally zero. I think there's enough
| holes in the layers of "Swiss cheese" that normally
| prevent this chain of events that U does not literally
| equal U.
|
| Edit: right, I'm also assuming the possibility of
| provirus mutation before this chain of events, and I
| don't think anyone can deny at least the mutation of HIV
| before it becomes a provirus.
| theideaofcoffee wrote:
| Are you a virologist, epidemiologist or other specialist
| with peer-reviewed research pointing in the direction
| opposite to the conclusions in the paper above? If so,
| you should publish your findings because that would be a
| huge refutation of current knowledge and would possibly
| help the epidemiology of transmission in the greater
| public.
|
| Until then, I'll take the word of public health
| practitioners who've been steeped in the field for their
| entire careers. Their work has been significant enough to
| be published in Lancet which is a pretty good signal to
| this layman (though with a bachelor's of science in an
| unrelated scientific field, so no stranger to reading
| primary literature).
| Vecr wrote:
| I probably could write something, but HIV is an
| epidemiologist's game at this point, and I honestly think
| the epidemiologists want to say HIV can't transmit in
| ways that the Hepatitis B virus, a DNA virus, has clearly
| been demonstrated to transmit. If you press a virologist
| in private I'm not sure they'll stick to "can't",
| especially after the COVID-19 virus mutation rate fiasco,
| and, though not a virus, the prion situation.
|
| I think "can't" deserves at least something physically
| (as in physics) unlikely, not something that's been
| demonstrated in a DNA virus previously (and like I said,
| HIV in provirus form is not unlike a DNA virus).
| chimeracoder wrote:
| > Longer term, it is likely there will be a shift to a twice
| yearly injectable (Gilead's Lenacapavir)
|
| That's debatable. Injectable PrEP has been around for years
| already (Lencapavir is not the first, just the most recent).
| Lencapavir has also not yet been tested on all at-risk
| groups, so unlike other forms of PrEP, it's not a universal
| solution because it cannot be prescribed to all candidates.
|
| Given the price, which is quite high _even with_ the programs
| Gilead has said that it will issue to reduce the cost, it
| remains to be seen how widely-used Lencapavir becomes outside
| of specific markets.
| borski wrote:
| I'm confused. The parent comment said "longer term," and
| you went on to discuss how it is not going to be used in
| the short term, due to the need for more testing and cost.
|
| Cost comes down over time, and more testing occurs over
| time, somewhat by definition.
|
| So... what specifically is debatable about the longer term?
| chimeracoder wrote:
| > Cost comes down over time, and more testing occurs over
| time, somewhat by definition.
|
| Truvada has been around for over twenty years, and
| generic for 4-5 years. It still costs $2000/month list
| price.
|
| More testing doesn't just magically happen either. Gilead
| has chosen for years not to pursue testing, let alone
| approval, for Descovy in various groups excluded from the
| original clinical trials. They've decided it's not
| profitable enough for them. The same could very easily
| happen with lencapavir, and in fact there's good reason
| to suspect it will.
| borski wrote:
| Why is it so expensive? And is it covered by insurance?
| If so, then I'm not sure the list price matters all that
| much from a 'to most people' perspective, even if there
| is a moral argument to be had here (in which we'd
| probably agree).
|
| I'm not entirely sure what the argument is, though - is
| it just the cynical argument of "well, these companies
| don't care about solving problems, just profit, so
| they're never going to do anything with it"? If so, then
| at least I understand your argument, even if I don't
| necessarily agree.
|
| But I tend to be an optimist.
| nerdjon wrote:
| The problem I think really comes down to there being a
| generic Truvada.
|
| Insurance for a bit seemed fine with covering Descovy but
| it seems that is less of a case now since it's so much
| more. I would expect the same with a shot like this.
|
| However I would hope that the added benefit of not needing
| to worry about adhering to taking it every day could
| outweigh that financial cost for insurance.
|
| I recently switched insurance companies and my new one
| covers Truvada completely, not even a copay. It's honestly
| kinda wild I pay more for my Adderall than I do prep.
| Obviously I don't know for sure but I have wondered if it
| is related to it being preventative and the potential
| alternative cost makes it smarter to remove any barriers.
| chimeracoder wrote:
| > The problem I think really comes down to there being a
| generic Truvada.
|
| Truvada has been generic for about six years now.
|
| > I recently switched insurance companies and my new one
| covers Truvada completely, not even a copay. It's
| honestly kinda wild I pay more for my Adderall than I do
| prep.
|
| That's because under the ACA, insurance companies are
| legally required to cover PrEP at no out-of-pocket cost,
| without any cost-sharing, copays, or deductibles applied.
| This also applies to associated labwork and outpatient
| office visits.
|
| Unfortunately, many insurance companies ignore this
| requirement, and it's very difficult as an individual to
| get them to comply.
| argonaut wrote:
| Almost all health insurance companies in the USA are
| required to fully cover PrEP, including Descovy. This
| doesn't stop health insurance companies from trying to
| deny you, of course. You would have to appeal the denial
| all the way up to your state's department for health
| insurance, but you would definitely win.
|
| EDIT: I was mistaken, this only applies in California.
| nerdjon wrote:
| That... is good to know. I knew they were required but
| figured generic Truvada was the requirement.
|
| Well kinda irrelevant. My previous insurance loved to
| deny things, it's why my company changed.
|
| I worked with my doctor, tried multiple times to get them
| to cover Descovy (I struggled with the larger pills, I
| finally just forced myself to get used to it) and was
| never successful. Just gave up.
| chimeracoder wrote:
| See my sibling comment. GP is half-correct. They are not
| required to cover Descovy specifically. Covering Truvada
| is sufficient to comply with the law (assuming they are
| also covering all associated labwork and outpatient
| visits, and not requiring you to pay anything out-of-
| pocket for any of those).
| chimeracoder wrote:
| > Almost all health insurance companies in the USA are
| required to fully cover PrEP, including Descovy. They
| aren't even allowed to require that you try (generic)
| Truvada first before trying Descovy.
|
| They are required to cover PrEP, but that doesn't mean
| that they are required to cover Descovy specifically. If
| they cover Truvada and all associated labwork or
| outpatient visits without any out-of-pocket costs for
| you, that's sufficient to comply with the law.
|
| > This doesn't stop health insurance companies from
| trying to deny you, of course. You have to appeal the
| denial all the way up to your state's department for
| health insurance, which you will definitely win.
|
| Having helped many people who've been in this exact
| situation, it's unfortunately not a given that you will
| win (you have to play your cards _exactly_ right), and
| most people who need it can 't afford to pay over
| $2000/month for the several months it takes for this to
| happen[0].
|
| The most likely scenario is that the insurance company
| wins, because you give up.
|
| [0] The insurance company has something like 30 days to
| respond for the first appeal, then an additional 45 for
| the second and third rounds, and that's assuming
| everything happens on schedule and you respond to
| everything immediately.
| argonaut wrote:
| You are right, my comment is only valid in California.
| nerdjon wrote:
| What I have noticed is that in most situations saying "PrEP" is
| enough. For my doctor that meant discussing Truvada, Descovy,
| and what is just kinda dubbed "Injectable Prep". This aligns
| with most apps also just saying "on prep" with no
| distinguishing between what prep.
|
| I would imagine that if/when this comes to market it would
| likely similarly fall under "Prep" for the general community
| and then you discuss the specifics with your doctor.
|
| Edit: There is also Doxypep (I just say Doxy), which while
| related to STD's is not related to HIV.
| 4fterd4rk wrote:
| PrEP - An HIV negative person taking Truvada or Descovy once a
| day to prevent HIV infection.
|
| PEP - An HIV negative person taking a course of antiretrovirals
| within 72 hours after exposure to HIV to prevent HIV infection.
|
| This article is referring to injectable PrEP. This is already
| available via an injection every two months and is typically
| used in populations that can't be expected to take a pill every
| day (drug addicts, etc.). The article is referring to a new
| form of injectable PrEP that extends this to once every six
| months.
| chimeracoder wrote:
| > This is already available via an injection every two months
| and is typically used in populations that can't be expected
| to take a pill every day (drug addicts, etc.).
|
| That is a pretty bold parenthetical statement. Not only is it
| _not_ true that "drug addicts" can't be expected to take a
| pill every day, but neither cabotegravir nor lenacapavir are
| tested or approved for HIV acquired through non-sexual means,
| which makes them a poor choice for PrEP for "drug addicts"
| compared to oral forms, which _are_ effective against all
| forms of HIV transmission.
|
| Source: former counselor and educator for HIV and substance
| use
| fragmede wrote:
| > Not only is it not true that "drug addicts" can't be
| expected to take a pill every day,
|
| The general population can't be expected to take a pill
| every day, what would make anyone believe people with SUD
| are able to?
|
| Source: person who's expected to take a pill every day, and
| knows other people who are supposed to taste a pill every
| day.
| chimeracoder wrote:
| > The general population can't be expected to take a pill
| every day, what would make anyone believe people with SUD
| are able to?
|
| The general population _does_ take PrEP regularly enough
| to be protected. You seem think that people with
| substance use disorders are excluded from that, and that
| belief is grounded in stereotype and bias, not science.
|
| Source: clinical data and professional experience
| masspro wrote:
| PEP means "post-exposure prophylaxis"; PrEP means "pre-exposure
| prophylaxis". You take PrEP regularly (if you know you're at
| risk due to sexual habits etc whatever), but only take PEP in
| response to a specific possible-exposure event (and not already
| on PrEP). You want pre-exposure instead of post-exposure
| because post-exposure is very hard on your body and makes you
| feel sick.
| pfdietz wrote:
| It's a wonderful (if rare) event when a medical trial is stopped
| for efficacy.
| hodder wrote:
| Please forgive my lack of understanding. This appears to be a
| great achievement. Is there any risk that a Lenacapavir resistant
| strain would rise up in many years as a result of treating a
| large portion of the global at risk population (estimated to be
| 60m people receiving the injection to materially lower global HIV
| rates)?
|
| Sort of like how antibiotic resistant bacteria rates seems to
| evolve out of the use of antibiotics? Or is that not a thing and
| Im just clueless?
| 4fterd4rk wrote:
| From another source:
|
| "The medication works in two ways: First, it interrupts viral
| replication by preventing HIV from reaching the nucleus of an
| infected cell, which then blocks reproduction.
|
| The second mechanism is for cases in which integration of the
| HIV genome has already occurred. In this instance, lenacapavir
| interferes with production of viral progeny, "making them
| defective so that they are not able to infect other cells."
| Therefore, it works in both early and late stages of the HIV
| life cycle to disrupt replication."
|
| Since the drug works in two ways, it would be difficult for the
| virus to adapt. Similarly to how the current commonly
| prescribed PrEP regimen (Descovy or Truvada) is two different
| drugs in one pill and has not lead to any significant rise in
| resistance.
| gibolt wrote:
| Difficult doesn't mean impossible. Trillions and trillions of
| chances for mutations to happen may lead to resistance over
| some period of time.
|
| Hopefully not, but evolution is a powerful beast.
| Vecr wrote:
| Yes that is correct, it's pretty easy to create escape
| variants in the lab. I don't think people should be doing
| it with virus like HIV and SARS, but they do.
| ljsprague wrote:
| What about with coronaviruses?
| fwip wrote:
| SARS was caused by a coronavirus.
| nkozyra wrote:
| Fair argument for doing it with highly mutative viruses
| like coronavirus and influenza, because it gives you a
| chance to prepare.
| chimeracoder wrote:
| > Please forgive my lack of understanding. This appears to be a
| great achievement. Is there any risk that a Lenacapavir
| resistant strain would rise up in many years as a result of
| treating a large portion of the global at risk population
| (estimated to be 60m people receiving the injection to
| materially lower global HIV rates)?
|
| Not really. This same principle has been used for over a
| decade. The only difference here is that the previous version
| of injectables needed to be administered every two months,
| whereas this can be done every six months.
| argonaut wrote:
| HIV drug resistance is a real issue, not sure why other
| comments are dismissing the risk of resistance. The risk of
| resistance is why HIV positive individuals take a cocktail of
| drugs, and why PrEP (Truvada or Descovy) requires regular HIV
| testing (because if you end up positive you need to upgraded to
| a cocktail of drugs).
| ProfessorLayton wrote:
| PrEP is incredibly effective, and even better than condoms at
| preventing HIV. There's various reasons it requires regular
| testing:
|
| - While very effective, it requires people to actually take
| it consistently, which is why the injectable form is better
| for some than the pill.
|
| - PrEP is not without side effects for a small portion of its
| users. In some cases it can cause bone density loss, or
| kidney damage. These tests are intended to catch any issues
| before they cause any permanent damage.
|
| - Since people are coming in to get tested for the
| aforementioned issues, they also run a full STI panel. This
| is great and it means those on PrEP (And those managing HIV)
| are tested more frequently than the general population, and
| are less likely to transmit an STI than those who don't come
| in for regular testing.
| gwbas1c wrote:
| (Joke) I'm still waiting for bacteria to evolve a resistance to
| boiling!
|
| (Seriousness) Different infectious agents can / can not evolve
| around their vaccines. We don't get yearly polio shots, we do
| get yearly covid/flu shots.
|
| (Speculation) It's probably too early to tell if there's a way
| for HIV to evolve around this, but it might have something to
| do with how effective we are at killing HIV in our population
| to begin with.
| shrimp_emoji wrote:
| Are you an elcor?
| Vecr wrote:
| Polio can and does mutate almost instantly around the
| vaccines, but since some of the vaccines are live polio
| anyway people don't really care. "Mutation" is not really a
| word that matters, what matters is if a variant is causing
| problems.
| foobiekr wrote:
| On rare occasions the live vaccine actually reverts. Polio
| is an amazing story because the live vaccination campaign
| may have had collateral impact on the families of the
| vaccinated as they shed particles.
| foobiekr wrote:
| I know it was a joke but lots of bacteria can survive simple
| boiling as endospores.
| thisrod wrote:
| I wonder how much this will cost? A drug you take 2 times a year
| could be much cheaper than one you take 365 times a year, and
| that's a big deal.
|
| The existing daily pill is really expensive. Australia knew that
| PrEP would practically eliminate HIV transmission. Even so, the
| decision to pay for it took years and was fiercely contested.
| That was before COVID, and people are more willing to pay for
| public health today. But cheap PReP would make a big difference
| in the poor countries where HIV prevention really matters.
| argonaut wrote:
| The shot will likely be exorbitant in the USA. Gilead charged
| almost $2k/month for Truvada (list price, of course) and
| Descovy is the same. Generic Truvada is like $30/month now, so
| the price was never about the cost to manufacture. Obviously
| Gilead is developing these new drugs/shots for when Descovy's
| patent expires.
|
| They rely on the government mandating that health insurance
| companies cover the shots. This drives up the price.
| ortusdux wrote:
| The price is rarely ever about the manufacturing cost.
|
| "A new study in 2020 estimated that the median cost of
| getting a new drug into the market was $985 million, and the
| average cost was $1.3 billion, which was much lower compared
| to previous studies, which have placed the average cost of
| drug development as $2.8 billion.[4]"
|
| https://en.wikipedia.org/wiki/Cost_of_drug_development
| chimeracoder wrote:
| > "A new study in 2020 estimated that the median cost of
| getting a new drug into the market was $985 million, and
| the average cost was $1.3 billion, which was much lower
| compared to previous studies, which have placed the average
| cost of drug development as $2.8 billion.[4]"
|
| PrEP repurposed Truvada, an existing blockbuster drug that
| had already reaped immense profit for Gilead for use in HIV
| treatment by the time the trials for PrEP began. The trials
| for PrEP were funded by the government, not Gilead. Gilead,
| however, got to retain all profits earned from PrEP.
| HideousKojima wrote:
| Did Gilead fund the R&D? There's a lot more to developing
| a new drug than just trials (though I think Gilead should
| have foot the bill for the trials too).
| roughly wrote:
| I don't know if it's the case here, but very, very, very
| often in biotech you've got the primary foundational
| research happening at university labs funded by grants,
| and it's the productionization of the research (and then
| clinical trials, etc) that are what the biotech companies
| are doing. I'm not sure where that shifts the "who
| deserves what" conversation, but without university
| research labs, there's no pharma industry.
| pfdietz wrote:
| It should be pointed out that looking at the average cost
| of developing a drug is misleading, since one has to
| include the cost of all the drugs that failed to make it to
| market. One also has to include the money spent by small
| companies that failed and were not bought out, not just the
| money the big companies spend buying the successful ones.
| Analemma_ wrote:
| I'm no fan of pharma industry but there's an unfounded and
| troubling assumption embedded in this comment: that any drug
| price over cost-to-manufacture can only be extortion. How do
| people recoup R&D costs (which are the vast majority of costs
| in getting a new drug onto the market)?
| asveikau wrote:
| Doesn't the government also fund a lot of pharma R&D?
|
| Here's a 2019 article that came up in a Google search:
| Taxpayers funded this HIV research. The government patented
| it. Now a company profits
| https://www.latimes.com/business/la-fi-gilead-sciences-
| truva...
| tptacek wrote:
| Taxpayers fund all sorts of stuff that is ultimately
| commercialized!
| chimeracoder wrote:
| Gilead's R&D costs for Truvada as PrEP were literally
| almost zero. They paid none of the costs for actually
| conducting the trials.
|
| Their only contribution was that they donated the actual
| pills used in the trials - in other words, the unit price
| of 30 pills per person for the duration of the trial.
|
| PrEP has been pure, risk-free profit for Gilead.
| yieldcrv wrote:
| Although this is a discussion about costs
|
| I just want to point out that the government has assumed
| the role of telling everyone how to take risks for its
| economy, and literally all you have to do is do that,
| successfully, and it will privilege your rewards by
| reducing risk on profits or reducing taxes
|
| This is not controversial when you look at the state's
| role in these outcomes
| jayshua wrote:
| Gilead claims that is false and that they spent 1.1
| billion on developing Truvada.
| https://www.gilead.com/news-and-press/company-
| statements/gil...
| WalterSear wrote:
| > the vast majority of costs in getting a new drug onto the
| market
|
| Debatable.
|
| > according to these firms' annual reports, 16 percent of
| revenues was taken as profit, and * 31 percent went for
| marketing and administration. That's nearly three times as
| much as their R&D spending.
|
| https://www.bu.edu/sph/files/2015/05/Pharmaceutical-
| Marketin...
| reducesuffering wrote:
| Like the other commenters allude to, how would you like
| software mandated to cost just 10% margin over COGS? Do you
| think selling cloud services for 10% more than the cost of
| server parts is going to be a business when there's thousands
| of software engineers in R&D needed?
| LeifCarrotson wrote:
| I would love that, as long as the cost includes that R&D
| and those engineers, the actual bits might be immaterial
| but the engineer salaries are part of the cost of the
| goods.
|
| The problem is that we're being told that the cost of
| insulin is $270 per vial, or that Daraprim used to estimate
| its cost per dose at 90% of $13.50 and then Shkreli decided
| to raise it to $750.
| bobthepanda wrote:
| There is a two-month shot now (Apretude) and I was quoted $4K
| a shot when I asked about it.
|
| Health insurances in the US mostly only cover Truvada. Some
| cover Descovy but not many.
| w10-1 wrote:
| This is an historic achievement with huge benefits, particularly
| for Africa.
|
| AFAIK, Gilead hasn't detailed any commitment to making it
| available to all who need it. There's been talk of $4K -$42K
| yearly price. Gilead just this month is promising regulatory
| submissions for approvals soon. The drugs sounds quite
| complicated and hence difficult to manufacture, perhaps making it
| an enduring franchise.
|
| The original post is raising a most interesting question: in a
| world where preventing infection is possible, what's the standard
| or incentive for a vaccine? It's rare to get 100% prevention from
| a vaccine. The incentive would seem to depend only on cost, and
| any vaccine developer would know that Gilead can likely lower
| cost at will, making it impossible to recoup vaccine development
| costs.
| ReptileMan wrote:
| >The incentive would seem to depend only on cost, and any
| vaccine developer would know that Gilead can likely lower cost
| at will, making it impossible to recoup vaccine development
| costs.
|
| This is a good argument that some drugs should be developed by
| state grants or bounties and the patent is in the state.
| Something similar delivered covid vaccines in record time - in
| the form of massive pre purchase agreements.
| KoolKat23 wrote:
| It will be virtually non-existent in Africa if it is priced
| like that.
| DoreenMichele wrote:
| A lot of health care problems are undermined by the profit
| motive angle.
|
| I don't know how to solve that because there's no such thing as
| a free lunch and the people developing solutions deserve to be
| paid.
|
| But Africa is extremely poor and the rest of the world suffers
| the consequences when we can't be arsed to make their problems
| solvable at a price point they can afford.
| inasio wrote:
| One other very cool thing here is that this new treatment
| represents a whole new family of drugs (very sophisticated at
| that, per Derek Lowe's assessment). I thought back in the late
| 2010s with integrase inhibitors (e.g. dolutegravir), there was a
| real chance they could achieve the 90-95% reduction targets in
| new cases, and hopefully this new drug makes that even more
| feasible.
|
| There's always the risk of losing previously effective drugs due
| to resistance, so the value of redundancy cannot be overstated
| w10-1 wrote:
| Here's a summary including the mechanism of action from a UW
| professor in 2022:
| https://www.youtube.com/watch?v=9IbzMbfEMIY
| hilbert42 wrote:
| Not my field so please bear with me. Before watching the
| video the notion of interfering with the capsid as a
| mechanism for stopping the virus made sense.
|
| However, what I still don't have a handle on is how does
| lenacapavir act so long that it only needs to be administered
| every six months?
|
| From the explanation lenacapavir works on the capsid
| directly, it's not acting on the immune system by training
| the body's defences as with a traditional vaccine. Surely
| this molecule can't just hang around for six months without
| being gobbled up by the liver or such.
|
| What am I missing here?
| jaggederest wrote:
| It's got so many fluorines running around that intuitively
| as an amateur chemist I would expect it to have an
| extraordinarily long half life in the human body,
| especially so if it's administered as a depot injection in
| something with a large molecular weight. It takes your body
| a long time to chew through the inactive components in a
| depot injection.
| hilbert42 wrote:
| Yeah, I also noted the fluorines (and Lowe's comment),
| and I know they're used to prolong action such as with,
| say, fluoxetine with its three fluorines but six months
| seems extremely long. I'd have thought it'd have been
| flushed out long before that. Presumably, it must bind to
| lipids, fats etc.
| nothrowaways wrote:
| > The medication interrupts viral replication by preventing HIV
| from reaching the nucleus of an infected cell.
|
| How does it actually do it?
| mrtesthah wrote:
| by preventing viral capsid assembly, as noted in the article.
|
| Once bound to the P24 capsid protein, the drug also interferes
| with other stages of the virus' lifecycle[1]:
|
| > _Lenacapavir is a multistage, selective inhibitor of HIV-1
| capsid function that directly binds to the interface between
| capsid protein (p24) subunits in hexamers. Surface plasmon
| resonance sensorgrams showed dose-dependent and saturable
| binding of lenacapavir to cross-linked wild-type capsid hexamer
| with an equilibrium binding constant (KD) of 1.4 nM.
| Lenacapavir inhibits HIV-1 replication by interfering with
| multiple essential steps of the viral lifecycle, including
| capsid-mediated nuclear uptake of HIV-1 proviral DNA (by
| blocking nuclear import proteins binding to capsid), virus
| assembly and release (by interfering with Gag /Gag-Pol
| functioning, reducing production of capsid protein subunits),
| and capsid core formation (by disrupting the rate of capsid
| subunit association, leading to malformed capsids)._
|
| 1.
| https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e56...
| tjohns wrote:
| From Wikipedia:
|
| "Lenacapavir works by binding directly to the interface between
| HIV-1 viral capsid protein (p24) subunits in capsid hexamers,
| interfering with essential steps of viral replication,
| including capsid-mediated nuclear uptake of HIV-1 proviral DNA,
| virus assembly and release, production of capsid protein
| subunits, and capsid core formation[1]... It functions by
| binding to the hydrophobic pocket formed by two neighboring
| protein subunits in the capsid shell. This bond stabilizes the
| capsid structure and inhibits the functional disassembly of the
| capsid in infected cells.[2]"
|
| In other words, it prevents the virus' protein shell (capsid)
| from being built properly, which in turn prevents the virus
| from properly opening ("uncoating") once it enters a host cell.
|
| [1]: https://en.wikipedia.org/wiki/Lenacapavir
|
| [2]: https://en.wikipedia.org/wiki/HIV_capsid_inhibition
| nothrowaways wrote:
| > Among 5338 participants who were initially HIV-negative, 55
| incident HIV infections were observed...
|
| Wait what?
| matthewmacleod wrote:
| All 55 of those infections were observed in trial participants
| randomised to the tenofovir/emtracitabine groups. There were no
| infections in the lenacapavir group.
| kemitche wrote:
| The site also indicated that "Adherence to F/TAF and F/TDF
| was low" which means those that got infected most likely
| weren't taking their pills on a daily basis, unfortunately.
| cypherpunks01 wrote:
| Yes, it can be confusing if you only read part of a sentence.
| Recommend continue reading if you're interested in the findings
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