Time Stamps

• 02:25 HIV PReP Daily Truvada and Descovy
• 07:48 On-Demand Prep
• 13:25 Purpose Trials
• 20:56 Discussion of Effectiveness to Efficacy

Show Notes

Background

• Globally, roughly 1.3 million people acquire Human immunodeficiency virus (HIV) every year and 630 000 people died from AIDS-related illnesses worldwide in 2023
  • More than 30,000 new HIV cases in the US annually
• We have come a long way since the AIDS epidemic of the 1980s, with the advent of ART.
• With ART, HIV is now a manageable chronic disease
  • However, because the virus  integrates into our genome, it never goes away
  • Since there is no cure, prevention is crucial to ending the HIV epidemic
• Pre-exposure prophylaxis, or PrEP, is an important way to prevent HIV infection in those at risk and can reduce HIV transmission risk through sex by >99% and through injection drug use by >74% .
• These medications prevent HIV from replicating in the body once someone is exposed, and thus prevent it from establishing a long term infection
• However only a third of those who have indications for PrEP are prescribed it, and uptake has been most limited in those at highest risk (at-risk African Americans, Hispanic, adolescents and transgender people)

Guidelines 

• The United States Preventative Services Task Force recommends PrEP for all those who are at increased risk of HIV infection. This includes anyone who
  • has a sexual partner with HIV (if viral load detectable or unknown)
  • has not consistently used a condom during sex in the last 6 months and has multiple sexual partners
  • has been diagnosed with a sexually transmitted infection (STI)in the past 6 months.
  • Injects drugs and has an injection partner with HIV, shares needles, syringes, or other equipment to inject drugs.
  • has used multiple courses of post exposure prophylaxis or who reports continued risk behavior 

See HIV.gov for more details: https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-medication-to-reduce-risk/pre-exposure-prophylaxis

PrEP trials

DAILY PREP

iPrEx, NEJM, 2020

• In 2010, the RCT, iPrEx, compared the effectiveness of once daily oral PrEP in the form of tenofovir disoproxil and emtricitabine (TDF-FTC), or Truvada, to placebo in reducing the risk of HIV acquisition.
• TDF and FTC are both nucleoside reverse transcriptase inhibitors (NRTIs), which act as decoys that  get incorporated into the growing DNA chain and block it from growing further. 
• The trial population consisted of nearly 2,500 men who have sex with men (MSM)  
•  A 44% reduction (95% confidence interval, 15 – 63;  P=0.005) in HIV infections was seen in the Truvada arm
  • Investigators were actually disappointed at this result because they were expecting the drug to be more efficacious (which it would have been, if adherence had been better)
• A reduction in transmission of >96% was seen in individuals who had blood drug concentrations consistent with taking >4 doses per week
• Other trials found that daily oral Truvada reduced risk of acquiring HIV in people who inject drugs, heterosexual men and women, and HIV discordant heterosexual couples. 
• Thus Truvada may be used in people of any gender who are at risk of acquiring HIV through sex or injection drug use
• Notably, RCTs in cisgender women have shown reduced efficacy in this population, largely due to poor adherence. 
  • However, a recent pooled analysis of post marketing data shows that oral PrEP has high efficacy when taken every day, or almost every day, in this population

DISCOVER, Lancet, 2019

• In 2019 the DISCOVER trial showed that  tenofovir alafenamide-emtricitabine (TAF-FTC), Descovy, was non inferior to TDF-FTC (Truvada) for use as PrEP in transgender men who have sex with men and cisgender MSM 
• Thus TAF-FTC (known as Descovy) is approved in transgender women and cisgender MSM 
• Has not been well studied for PrEP in women or others who have vaginal or neovaginal sex, or in those who inject drugs.
• TAF is thought to have less bone and renal toxicity compared with TDF; but increased hyperlipidemia and weight gain
  • TAF is a pro-drug and is converted to the active agent in CD4 cells, therefore there is less plasma exposure to tenofovir, which is what causes renal and bone toxicity.

ON DEMAND PREP

ANRS-IPERGAY, NEJM, 2015

• On demand Truvada (taken before and after sex) was compared to placebo in MSM and transgender women who have anal sex
• Dosing is 2-1-1 (2 pills 2-24 hours before sex, 1 pill 24 hours after the first dose, and 1 pill 24 hours after the second dose)
• There was a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002) compared to placebo
• Reasonable for cisgender MSM who are taking TDF-FTC and can reliably predict when they will have condomless sex or certain transgender men, having anal intercourse
• NB cannot use on-demand PrEP for those with concurrent hepatitis B, as TDF treats hepatitis B and stopping the drug can lead to a hepatitis flare

PREVENIR, Lancet, 2022

• A prospective observational cohort study in France comparing daily Truvada with on-demand Truvada in MSM and transgender women
• Participants were tested for HIV every 3 months
• The median age was 36 years, 99% were MSM. About 1500 opted for daily PrEP and 1500  opted for on-demand PrEP. At a median follow-up of 22·1 months and there were three HIV infections in the daily PrEP group and three in the on-demand PrEP group.
• Thus there was no difference in effectiveness in daily versus on-demand PrEP

LONG ACTING INJECTABLE PREP

HPTN 083, NEJM, 2021

• In 2021, HPTN 083 showed that receiving long-acting intramuscular injectable, cabotegravir (an integrase strand transfer inhibitor), every eight weeks was superior to Truvada (TDF-FTC) at preventing HIV acquisition among cisgender men who have sex with men and transgender women who have sex with men (hazard ratio, 0.34; 95% confidence interval, 0.18 – 0.62).  
• This is likely due to improved adherence with the long-acting medication, comparing to oral PrEP, which needs to be taken every day
• Long-acting cabotegravir was later shown to be superior to Truvada ( TDF-FTC) in cisgender women- hazard ratio 0·12 (95% CI 0·05–0·31) (HPTN 084, Lancet, 2022)
• During these trials an altered presentation of HIV infection in patients who were on long acting cabotegravir, called “long-acting early viral inhibition,” was observed in 17/41 (41.5%) patients with new HIV infection across both of these trials.. Features of this include low HIV RNA levels and delayed diagnosis due to negative HIV 4th generation (antibody/antigen) screening test. This presents a caveat that 

LONG ACTING VAGINAL RING PREP

MTN-020-ASPIRE, NEJM 2016

• In 2016 the Ring and ASPIRE studies showed that a silicone vaginal ring releasing dapivirine, a non-nucleoside reverse transcriptase inhibitor, and replaced monthly, reduced HIV infection in cisgender women ages 18 and older. 
• The dapivirine ring reduced the incidence of HIV infection by 27% (95% confidence interval [CI], 1 to 46; P=0.046) compared to placebo
• This has been approved in several African countries but is not approved used in the United States

NEW LONG ACTING PREP DRUG IN PURPOSE 1 and PURPOSE 2 – LENACAPAVIR

Lenacapavir

• Lenacapavir (Sunlenca) is a novel, first-in-class, multistage HIV-1 capsid inhibitor with high potency and a long half-life, which has so far been approved for treatment of multi-drug resistant HIV in heavily treatment experienced individuals
• Lenacapavir binds to protein subunits in the HIV capsid, which is within the HIV lipid membrane and surrounds HIV RNA.
• This prevents capsid disassembly, transport of HIV RNA into the host cell nucleus, and, the other end of the HIV life cycle, capsid reassembly.
• It can effectively inhibit HIV at concentrations as low as 50 picomolar, while most antiretrovirals work at nanomolar concentrations. 
• It also has a half life of 38 days
• No homologues in body (unlike NRTI targets) so less toxicity
• The downside is that it has a low barrier to resistance: HIV requires only one point mutation to become resistant.  By contrast, integrase strand transfer inhibitors (like cabotegravir)  have a high barrier to resistance.  This is less of an issue if used for PrEP since acquiring HIV while on PrEP would be rare.

PURPOSE 1 trial 

• PURPOSE 1 was a double-blind, active-controlled RCT involving cisgender women in South Africa and Uganda, which compared subcutaneous lenacapavir every 26 weeks, to daily TDF/FTC (Truvada) and TAF/FTC (Descovy)
• Since TAF/FTC (Descovy)  had not been extensively studied in cisgender women, the trial also aimed to assess its the efficacy of the agent in this population
• Trial was performed in South Africa and Uganda where background incidence of HIV in cisgender women not on PrEP is high- 3.5 per 100 person-years
  • Remember, incidence (rate of new infections) is not the same as prevalence (proportion of total infections)
• South Africa updated its PrEP guidelines in 2021, recommendingendorsing PrEP use for persons at greatest risk for HIV infection, including adolescent girls and young women as well as MSM, among others.
• Participants were randomized 2:1:1 to lenacapvir, TAF/FTC and TDF/FTC groups
• Since oral Truvada is known to be so effective in reducing HIV infection when taken consistently, a placebo group was considered unethical. 
  • Background HIV incidence was instead estimated from patients screened at the start of the trial who were newly HIV positive at the outset. 
  • An antibody based assay allowing estimation of the time since HIV infection was then used to infer the HIV incidence in a population not on any PrEP
• Primary endpoint was incident HIV infection in the lenacapavir group, and in the TAF/FTC group, compared to the background HIV incidence
• Safety endpoints- adverse events, clinical/lab abnormalities
• In 5338 initially HIV negative participants there were 0 infections among 2134 participants in the lenacapavir group, 39 infections among 2136 participants in the TAF/FTC group, and 16 infections among 1068 participants in the TDF/FTC group. 
• HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and compared to HIV incidence with TDF/FTC (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). 
• HIV incidence with TAF/FTC did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21), and there was no significant difference in HIV incidence between TAF/FTC and TDF/FTC (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14).
  • Interpreted as no real impact on daily oral PrEP in reducing new HIV infections in this population
• Injection-site reactions were the most common adverse event and they were more common in the lenacapavir group (70%) than in the Truvada and Descovy group combined (35 %)
• Adherence to oral PrEP was low and decreased over time
  • This was , quantified by measuring levels of tenofovoir diphosphate, the active agent in oral PrEP, in red cells in a random 10% sample of participants

PURPOSE 2 trial

• PURPOSE 2 was a double-blind, active-controlled RCT which assessed the efficacy of  subcutaneous lenacapavir every 26 weeks, compared to daily oral TDF/FTC  (Truvada) in cisgender men, transgender women, transgender men, and gender-nonbinary people.
• Patients were randomized 2:1 to subcutaneous lenacapavir every 26 weeks and daily oral TDF/FTC
• The primary outcome was incident HIV infection in the lenacapavir arm compared to the background HIV incidence
• Adherence to lenacapavir and to oral Truvada was measured by measuring concentrations of these in a random 10% sample of participants
• The median age was 29 years, with a third of participants younger than 25. 98 % were assigned male at birth, and 22 % identified as gender diverse. Two thirds identified as non-White, which broke down to 38 % who identified as Black, 13% as Asian and 63% as Hispanic or Latine
• There were HIV infections in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77)
• The incidence of HIV infection in the lenacapavir group was significantly lower than the the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P=0.002).
• Adherence to oral PrEP was good in this population

Discussion/takeaways

• The results of PURPOSE 1 and PURPOSE 2 are striking and could be revolutionary in the effort to end the HIV epidemic.
•  In PURPOSE 1, amongst cisgender women in Subsaharan Africa, there were no HIV infections in the lenacapavir group – a substantial reduction compared to the background HIV incidence and compared to oral Truvada, currently the most common form of PrEP.
• By contrast Descovy (TAF/FTC), which had not been extensively studied in women, appeared to be no different to TDF/FTC  in reducing HIV infections in women.
• Interestingly TAF/FTC did not reduce HIV infections compared to the background HIV incidence – tests to measure drug concentrations in a sample of participants showed that this could largely be explained by non-adherence
• PURPOSE 2, in MSM and gender diverse people, showed a similar striking result – a substantial reduction in HIV infection compared to both background HIV incidence and to the Truvada arm.
• However adherence to oral Truvada was higher in this population compared to PURPOSE 1, which aligns with prior data regarding poor adherence to oral PrEP in cigender women
• As a long acting medication which requires only two injections per year, lenacapavir is an option for patients who find adherence to a daily medication difficult, or who experience stigma associated with taking a daily medication
• There is a caveat: efficacy (the ability of an intervention to work under ideal conditions like in an RCT) is different to effectiveness (the ability of an intervention to improve the health of patients in a real world setting).
• Effectiveness is often much lower than efficacy due to hurdles in  implementation of an intervention after it is approved
• The long-acting injectable PrEP medication, cabotegravir, is a case in point: despite the excitement following approval in 2021, it still only accounts for 1-3% of PrEP prescriptions in the US, due to poor insurance coverage and logistical challenges related to setting up clinics to administer the medication
• In order to end the HIV epidemic globally, there needs to be an effort to make lenacapavir affordable in low and middle income countries, which bear the greatest burden of HIV.
• Thus ending the HIV epidemic requires efforts on the part of individual clinicians, but also momentum from public health agencies and, more broadly, political will.

Transcript

Dr. Greg Katz: Welcome to the Beyond Journal Club, a collaboration between Core IM and the NEJM Group.

Dr. Clem Lee: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling the story of how we got to where we are, and what it means for how we take care of patients.

Dr. Greg Katz: I am Dr. Greg Katz, a cardiologist at NYU.

Dr. Clem Lee: I’m Dr. Clem Lee, a former fellow and current editor for NEJM Group.

Dr. Abarna Pearl: And I’m Dr. Abarna Pearl, an editorial fellow at the New England Journal of Medicine and a hospitalist at BIDMC, with training in infectious diseases. Today, we’re going to discuss the PURPOSE 1 and 2 trials, which investigated the use of a long acting injectable drug, lenacapavir, to prevent HIV. 

Dr. Greg Katz: Abarna, I still remember the writer’s pitch day. When you pitched this trial you just lit up about it. 

Dr. Abarna Pearl: Yes! The Purpose 1 and 2 trials were such a clear pick for me because they represent a huge advance in HIV pre-exposure prophylaxis, aka PrEP

Dr. Greg Katz: it’s amazing how far we have come in HIV care. We thought this disease was going to plague humanity forever. Like when I started med school, PrEP did not exist. The nature of what science has done to transform something that automatically killed you, or which you could only avoid via modifying exposure, to essentially a chronic disease that you can take pills to protect you from getting, is incredible

Dr. Clem Lee: And now the trick is how to get the medications to people in the most accessible way and that is where the PURPOSE trials come in

Dr. Greg Katz: And this matters. Most people think of HIV as more of a  global health disease, but actually over 30,000 people in the US are diagnosed with HIV yearly. To put that into perspective — that’s more HIV than acute leukemias in the US annually.  

Dr. Clem Lee: OK during today’s episode we’ll start with the basics of what PrEP is.

Dr. Greg Katz: Then we’ll look at prior PrEP trials and what they have taught us about efficacy — or how good a medication is in an ideal setting — and compare it to effectiveness, which is how good a medication actually is when used in real life

Dr. Clem Lee: We’ll also talk a bit about how each PrEP drug works

Dr. Abarna Pearl: And finally we’ll discuss the PURPOSE trials and see how they have the potential to bridge the gap between efficacy and effectiveness and revolutionize HIV prevention

HIV PReP Daily Truvada and Descovy 

Dr. Clem Lee: Abarna, you’re the ID doc here – can you give us a quick refresher on HIV and the theory behind PrEP? 

Dr. Abarna Pearl: Yes. The reason why HIV is so hard to cure is that it’s an RNA virus that integrates into the human genome, and so it never completely goes away, even with antiretrovirals. 

Dr. Greg Katz: so for those of us who aren’t as experienced with PrEP, can you walk us through the mechanism of how prep prevents HIV infection? 

Dr. Abarna Pearl: So, the idea of PrEP is that it nips HIV in the bud once you’re exposed and stops it from replicating in the body

Dr. Clem Lee: I’m going to be honest, every time I think about those HIV drug categories, names, and abbreviations, my head spins

Dr. Abarna Pearl: Yes it’s very confusing, and many first year infectious disease fellows obsess over these acronyms so you don’t have to. One of my goals with this podcast is to help people feel more comfortable with these meds …you know, only a third of patients who should take PrEP actually take it and  we should do anything we can to close that gap.

Dr. Greg Katz: The scope of HIV therapy is massive, and so we’re going to focus our discussion solely on the drugs used for PrEP. The names here get confusing because there’s an acronym, a generic name, and a brand name. We’re going to introduce each drug with it’s generic name, mention the acronym – because that’s what you’ll often see written in notes – and then refer to it mostly with the brand name because that’s how patients are going to refer to their meds. 

Dr. Abarna Pearl: First up we have, Tenofovir desoproxil fumarate (TDF) and emtricitabine (FTC)- these are both nucleoside reverse transcriptase inhibitors.

Dr. Greg Katz: TDF and FTC are sold together in a pill known as Truvada

Dr. Abarna Pearl: An important feature of HIV, which is a RNA virus, is that it gets transcribed into DNA. And so drugs like Truvada act as decoys that  get incorporated into the growing DNA chain and block it from growing further. 

Dr. Clem Lee: In the first ever PrEP trial, which was the Iprex trial in 2010, researchers randomized 2500 adult men who have sex with men (MSM) and transgender women to Truvada orplacebo  and followed them for a median of 1 year.

Dr. Abarna Pearl:  36 new HIV infections were seen in the group receiving Truvada for PrEP  compared to  64 in the placebo group. In other words there was almost a 50%  reduction in HIV infection with PrEP  — that’s pretty huge

Dr. Greg Katz: So yes, Truvada did reduce the number of new HIV infections in the study group compared to the control group, but the result was actually a bit disappointing compared to  what the trial investigators had hoped. And this was largely due to adherence challenges.

Dr. Clem Lee: We know that because they looked at levels of Truvada in the blood. In patients with a detectable level,  the reduction in HIV risk was much higher at 92%.

Dr. Greg Katz: This gets to a theme that we’re going to keep hitting on when it comes to the data on PrEP – it’s really protective against HIV infection, but only when it’s actually taken. What good is a drug that people don’t consistently take?

Dr. Abarna Pearl: Another theme that we’ll see across the PrEP trials – you can’t just extrapolate results from a trial in one group of patients (like men who have sex with men) and think that it applies to everyone – like cisgender women.  

Dr. Greg Katz: But reassuringly, In  the trials that followed IPREX, daily oral PrEP with Truvada was found to be efficacious in other populations too including those who inject drugs, heterosexual men and women, and heterosexual couples where one person has HIV and the other does not.

Dr. Clem Lee: So it sounds like it was beneficial in different populations, but was it  equally beneficial  across all the populations that were studied? 

Dr. Abarna Pearl: So unfortunately, many studies have found that PrEP is often not taken as prescribed by cisgender women…and of course oral PrEP is less effective when doses are not taken consistently.

Dr. Greg Katz: Of course its hard to remember to take pills. Anecdotally after talking to hiv colleagues, i heard that there is stigma surrounding prep, particularly in africa. Apparently Truvada is called “the little blue pill” and suggests that you are either 1) unfaithful/promiscuous. 2) work in the sex trade or 3) already have HIV. That stigma adds another layer to the adherence challenges.

Dr. Abarna Pearl: I find patients also have a hard time taking pills for a disease that they don’t have. And then on top of that, people behave differently inside and outside trials. In fact, studies done outside trial conditions suggest that PrEP may have better uptake in women. So again, efficacy and effectiveness are not the same. 

Dr. Clem Lee: That brings us to our 2nd option for HIV PrEP: tenofovir alafenamide and emtricitabine (or  TAF-FTC), more commonly known to patients as Descovy. 

Dr. Greg Katz: The use  of Descovy for PREP was established for men who have sex with men in the DISCOVER trial, published in the Lancet, where it was shown to be noninferior to daily Truvada.

Dr. Abarna Pearl: Yep so in 2019 Descovy was approved for PrEP in MSM and transgender women, but has not been approved or extensively studied in those who have receptive vaginal sex, pregnant persons, or people who inject drugs. 

Dr. Greg Katz: Hey, wait Why does the tenofovir in truvada get called TDF but the tenofovir in descovy get called TAF? 

Dr. Abarna Pearl: They are similar and are both prodrugs of tenofovir diphosphate, which is the active agent. Truvada is converted to the active agent in the gut and plasma BUT Descovy is converted to the active agent in CD4 cells. So with Descovy there is thought to be less plasma and organ exposure to tenofovir, and hence a bit less renal and bone toxicity. 

Dr. Clem Lee: But as with all of medicine, there’s no free lunch — , Descovy, is linked to hyperlipidemia and weight gain 

Dr. Abarna Pearl: Yes but Truvada is generally still preferred by ID doctors for the typically young, healthy patients on PrEP, especially as it is generic and more affordable now. 

Dr. Greg Katz: So to recap, both Truvada and Descovy are effective in PrEP in MSM and transgender women, and there’s data for Truvada in cisgender women and other patient populations. But both of these daily pills have adherence challenges.

On-Demand Prep

Dr. Abarna Pearl: So since we knew that taking oral meds every day could be hard, the next question was does on-demand PrEP work?

Dr. Greg Katz: For people not willing to take a preventative medication every day, the thought was that on demand PrEP might be more attractive, as it only needs to be taken before and after sex. 

Dr. Abarna Pearl: To be more precise, you would take 2 pills at least 2 hours before sex, 1 pill 24 hours after the first dose, and 1 pill 24 hours after the second dose

Dr. Clem Lee: Ok quick rundown on the big trial looking at on-demand PReP: The IPERGAY trial in 2015 looked at on demand Truvada compared to placebo in MSM and transgender women. In the median 9 months of follow-up, there was a 86% relative reduction in new HIV in the study arm.

Dr. Abarna Pearl: Following this, the PREVENIR study, a prospective, observational cohort study, showed that both daily and on demand PrEP were effective at preventing HIV infections, and that there was no difference in effectiveness between the two methods.

Dr. Greg Katz: I can see how on demand PrEP might make the pill easier to swallow so to say, but in some ways remembering to take a pill whenever you think you might have sex may be harder than taking a pill every day.

Dr. Abarna Pearl: So the next step in improving adherence to PreP was asking whether we can make longer acting therapies that stay in the system for weeks, avoiding the need to remember a daily medication or an on-demand pill

Dr. Clem Lee: So cue intro music for  long acting injectable, cabotegravir (Cabenuva). (maybe death cab for cutie? get it?)  in 2021 cabotegravir,  given IM every 2 months, was superior to daily Truvada at preventing HIV infections in MSM and transgender women who have sex with men

Dr. Abarna Pearl: And guess which population they later found it worked in?  In cisgender women in sub-Saharan Africa, where long-acting injectable cabotegravir was more efficacious than daily truvada 

Dr. Clem Lee: And cabotegravir is an integrase strand transfer inhibitor, Abarna can you remind me what that is?

Dr. Abarna Pearl: Yes – just as a comparison, the prior class of meds (truvada and descovy) prevented HIV DNA from being made. Integrase strand transfer inhibitors like cabotegravir prevent the DNA from being integrated into the host CD4 cell genome. 

Dr. Greg Katz: The strategy of a long acting inhibitor of DNA integration with cabotegravir seems pretty impressive. Compared to Truvada, it reduced HIV infections by almost 2/3 in MSM and transgender women and about 7/8th in cisgender women

Dr. Abarna Pearl: But of course there is a caveat to this one too.

Dr. Clem Lee: Yeah an issue that is being recognized more  is that these long-acting injectables could cause delayed detection of acute HIV infections, though this has so far been rare

Dr. Abarna Pearl: The reason why is when someone gets infected with HIV while they are on long-acting prep, the HIV RNA and antibody response is dampened so the usual HIV screening test is not as good  at picking it up.   

Dr. Greg Katz: Nothing is perfect and understanding the pitfalls is part of using these novel treatments effectively in practice.

Dr. Clem Lee: Even though long-acting injectable seems like an opportunity for better adherence, they are still not used very often and only account for about 2 % of prep prescriptions in the US! There are a bunch of reasons why – it costs a lot, we need to have specialized staff, we need to remind ppl to come back, insurance issues 

Dr. Abarna Pearl: I also wanted to mention a 4th HIV PrEP option: a silicone vaginal ring that releases the drug, dapivirine into the vaginal mucosa over a month.  

Dr. Clem Lee: Dapivirine isn’t used in the United States but has been approved in several countries in Africa. I’m so glad they have this in the PrEP arsenal, since in sub-Saharan Africa, women and girls made up 63% of all new HIV infections in 2021

Dr. Greg Katz: So let’s recap up what we’ve discussed so far. 

Dr. Clem Lee: PrEP can practically eliminate the risk of HIV transmission by sexual intercourse and is also pretty good at preventing HIV from needle exposure. Of course that is when PrEP is used consistently. right now the most common medications used for PrEP are Truvada and Descovy, which are both tablets and can be difficult to remember to take

Dr. Abarna Pearl: That led to more research on taking PrEP meds on demand. To me, it seems more difficult to take an on-demand med for an unpredictable activity, like sex or using drugs, than to remember to take a pill everyday.   

Dr. Clem Lee: That then led to the development of  long-acting medications like cabotegovir, which was a win for  cisgender women  who do not appear to adhere to oral PrEP as well, at least in trials.

Dr. Greg Katz: I want to emphasize the importance in understanding efficacy versus effectiveness. The efficacy of a drug is how it performs in ideal conditions like a randomized trial, where patients may behave differently because they are being monitored. The effectiveness, on the other hand, refers to how well a drug performs in real-world settings and is often, but not always, lower than efficacy.

Dr. Abarna Pearl: Yeah actually in some cases we find that people are more adherent to medications after a trial and FDA approval, since they know the drug works and it’s no longer “experimental.”

Dr. Clem Lee: Yes this distinction is crucial and is one reason why HIV researchers continued to work on drugs for PrEP  even though we already had evidence they were efficacious . Their real-world effectiveness was way lower due to adherence.

Dr. Greg Katz: This brings us to the PURPOSE trials, which studied a long acting injectable agent called lenacapavir, for PrEP 

Purpose Trials

Dr. Clem Lee: First things first, how exactly does lenacapavir work? I’m guessing it’s going to have yet another different mechanism of action than the drugs we discussed so far?

Dr. Abarna Pearl: Yes you guessed correctly! Lenacapavir (Sunlenca) is a novel, HIV-1 capsid inhibitor with high potency and a long half-life. 

Dr. Clem Lee: Why do we think  a capsid inhibitor can be effective? 

Dr. Abarna Pearl: So lenacapavir binds the viral capsid around the HIV RNA, it prevents HIV’s genetic material from being released into the cell, and stops it from getting to into host genome. And then on the end of the life cycle, lenacapavir prevents new viral particles from being assembled. 

Dr. Greg Katz: that’s why lenacapavir is called a “ multistage” capsid inhibitor. And the really long half life when given subcutaneously allows the drug to be dosed infrequently – like once every 6 months. 

Dr. Clem Lee: It sounds like a miracle drug-  are there any downsides to its use?

Dr. Abarna Pearl: One of the known downsides is that HIV can easily mutate to escape lenacapavir’s activity- only one point mutation is required. But hopefully, that won’t be much of an issue when using lenacapavir for PrEP on a population level. 

Dr. Greg Katz: Yeah so let’s find it with what happens when we study lenacapavir in these PURPOSE trials.

Dr. Abarna Pearl: Sure. PURPOSE 1 was a double-blind RCT involving cisgender women in South Africa and Uganda. It compared subcutaneous lenacapavir every 26 weeks, to daily oral Descovy and daily oral Truvada.

Dr. Clem Lee: Participants were randomized in a 2:2:1 ratio to lenacapavir, Descovy, and Truvada. Women in the lenacapavir group received placebo tablets that looked like oral PrEP medication and those in the oral PrEP groups received placebo injections that looked like  lenacapavir. 

Dr. Greg Katz: Real quick to point out, Descovy had not been studied in cisgender women before, so this was another important feature of the trial.

Dr. Abarna Pearl: Patients also received HIV prevention and  drug adherence counseling and testing for STIs at each study visit.

Dr. Greg Katz: The investigators compared the incidence of HIV for each type of PrEP with the background HIV incidence among screened persons not enrolled in the trial. 

Dr. Abarna Pearl: I just want to really emphasize the fact that this study was in cisgender women in South Africa and Uganda.  In this part of the world all young women are recommended to be PrEP, which is different from US where heterosexual women generally  aren’t really considered at-risk.

Dr. Clem Lee: can you tell me more about the background HIV incidence? Authors suggested this was a novel feature of the trial.

Dr. Abarna Pearl: Essentially since we know oral PrEP is highly effective, it would have been unethical to test lenacapavir against placebo. But oral PrEP is known to be so effective that you would need to enroll a lot of people to show that lenacapavir is better. So instead, they took the people who showed up to screen for the trial but did not make it to the trial because they already had HIV.. And then they took those people and calculated the incidence of recent HIV infections as “Background HIV incidence.”

Dr. Greg Katz: It’s actually a pretty clever way of figuring out how good this drug really is — so with that, let’s get to the results.

Dr. Abarna Pearl: In the lenacapavir group, there were 0 infections among ~2000 or so participants, in the Descovy group, 39 infections among ~2000 participants and in the Truvada group, 16 infections among ~1000 or so participants. 

Dr. Greg Katz: This is absolutely amazing. Oh wow, I heard the results were impressive, but not 0 infections- impressive!

Dr. Clem Lee: To be more specific, the HIV incidence of 0 infections with lenacapavir was significantly lower than background HIV incidence and  HIV incidence with Truvada. 

Dr. Abarna Pearl: As you may guess, the most common adverse reaction was injection site reactions, which occurred in about 70% of patients in the lenacapavir group.

Dr. Clem Lee: And there was also no significant difference in HIV incidence between Descovy  and Truvada and between Descovy and the background incidence.  This was a novel result for Descovy, which had not been studied in cisgender women before.

Dr. Greg Katz: Am I correct in interpreting this as  basically that the oral agents were no better at preventing HIV infection than taking nothing at all, in this population

Dr. Abarna Pearl: Yes but that’s not because the oral PrEP doesn’t work- it was because of low adherence, which the investigators quantified by measuring levels of oral PrEP in red cells in a random 10% sample of participants in these groups. Adherence to Descovy and Truvada was low and decreased over time. And most women with new HIV infection had low or no detectable oral PrEP medication in their red cells. 

Dr. Greg Katz: This just reinforces that medications don’t work if they aren’t taken and highlights the difficulty that many people have taking a daily preventative medication – remember efficacy under perfect conditions isn’t the same as being effective…in this trial participants struggled to take a pill, even in trial conditions.

Dr. Clem Lee: It looks like this trial had a part 2? Should we talk about PURPOSE 2?

Dr. Abarna Pearl: PURPOSE 2 looked at lenacapavir in completely different population —  cisgender men who were gay or bisexual, transgender women, transgender men, and gender nonbinary persons. Most trial sites were in the United States, but there were also sites in Thailand, South Africa, and Central/South America

Dr. Clem Lee: Like we mentioned before, the pt population really matters when we are looking at PrEP studies. The median age was 29 years, with a third of participants younger than 25. 98% were assigned male at birth, and 22 % were gender diverse. Most patients  – ⅔ – were non-white. 

Dr. Greg Katz: Participants were randomized in a 2:1 ratio to lenacapavir or Truvada. Similar to the trial in cisgender women, patients in the lenacapavir group received placebo tablets and those in the Truvada  group received placebo injections.

Dr. Clem Lee: Lenacapavir concentrations and Truvada  concentrations were also randomly assessed in 10% of participants 

Dr. Greg Katz: Let’s talk about the results.

Dr. Clem Lee: There were 2 HIV infections in the lenacapavir group, compared to 9 in the Truvada group.

Dr. Greg Katz: It’s worth noting that those 2 patients developed resistance to lenacapavir while on the drug. specifically was from an N47D capsid mutation. But remember, there were only 2 infections, so it’s likely that the benefits on a population level outweigh the risks of inducing lenacapavir-resistant HIV. 

Dr. Abarna Pearl: So how did this drug do in this population? The lenacapavir group had 96% fewer infections than the background HIV incidence and 89% fewer infections compared to Truvada.

Dr. Clem Lee: And actually Truvada did OK compared to the background HIV incidence in this PURPOSE 2 study compared to PURPOSE 1 when it was basically useless? Do we know why that is?

Dr. Abarna Pearl: Yeah right in PURPOSE 2, there was higher adherence to truvada compared to PURPOSE 1. This may be from the different populations studied. PURPOSE 1 was in cisgender women in subSaharan Africa whereas  PURPOSE 2 was in mostly MSM and transgender women in US.   

Dr. Greg Katz: Taking a daily oral pill and possibly the stigma associated with that could reduce the adherence in women.

Dr. Clem Lee: Alright Greg do you want to help summarize the PURPOSE trials and what we learn from them?

Dr. Greg Katz: Sure. So in two very different populations, long-acting injectable lenacapavir reduced HIV incidence compared to both  Truvada and background incidence, and notably, the PURPOSE 1 showed that adherence to oral PrEP was particularly poor in women and as a consequence did not appear to prevent HIV at all because people were not taking it.

Discussion of Effectiveness to Efficacy 

Dr. Clem Lee: So where does this study leave us?

Dr. Abarna Pearl: I’m just left thinking about the striking result –  In PURPOSE 1, in cisgender women, there were no infections in the lenacapavir arm, compared to 39 in the Descovy and 16 in the Truvada arm.

Dr. Clem Lee: This drug could be revolutionary in the world of HIV prevention – adherence rates were high, it only requires two injections per year,  and the main adverse effect was injection site reactions – in general, it was well tolerated.

Dr. Abarna Pearl: It is exciting that this medication seems to be acceptable, particularly in populations like cisgender women in Sub-saharan Africa. as we talked about there was so many other studies, cisgender women unfortunately poor  adherence to oral PrEP.

Dr. Greg Katz: Can we just step back for a second? I have been blown away as I have been diving into this episode. This is basically game changing: we already have the tools that can turn HIV from a death sentence into a chronic disease. This is – of all of the trials we have talked about on this podcast – honestly the one that makes me the most idealistic and the most inspired because I think it is so freaking cool that science has figured HIV out.

Dr. Abarna Pearl: Yeah, I mean, I agree with Greg and I have to say, I think it’s remarkable, Greg, that you’ve come full circle. I remember when I first brought up this trial, you seemed to be the most cynical of the group about the impact it would have on medicine.

Dr. Greg Katz: I didn’t know about the data then. I mean, I’ve been thinking about this nonstop. I’ve been talking about this to lots of people in my life, and the advances in HIV are so remarkable, and I think we should be celebrating it.

Dr. Abarna Pearl: I think it really says something when you get a cardiologist excited about Infectious diseases.

Dr. Greg Katz: I take that as a compliment and an insult. So thank you, and I’m offended.

Dr. Clem Lee: Haha not to break up this heartwarming moment but I think we have a few more hurdles before HIV is completely eradicated right? How do we know lenacapavir won’t fall into the “new and expensive” category of drugs, like cabotegravir, and suffer from poor uptake? Are we worried about lenacapavir induced resistance? what about the difficulty in diagnosing new HIV infections when someone is on such a long acting drug?

Dr. Greg Katz: Yes and every single thing one of those questions is important and also all these inequities about who’s getting it and who has access  – don’t get me wrong, those are gigantic problems and they’re serious problems. But it is okay to say, we have climbed over the first HIV mountain and now we need to climb over the second HIV mountain. 

Dr. Clem Lee: You might have lost me a bit there Greg – im not a big mountain climber. To be explicit — the first mountain …?

Dr. Greg Katz: Yes I mean, it is astounding how incredible these advances are, and we have so many brilliant researchers to thank for this. Everyone is standing on the shoulders of giants, and we should absolutely be screaming this from the rooftops that we can stop the HIV epidemic if we can figure out the implementation science.

Dr. Clem Lee: Ah yes, so the implementation science is the second mountain. Let’s get into that then. Now that we know lenacapavir works, what should we be thinking about to get it to the people who need it most?

Dr. Abarna Pearl: Its not just implementation science – it involves a lot of advocacy and policy, it doesn’t fall just on the shoulders of individual clinicians and people in their local environments – on a macro level there are bigger issues like insurance coverage and globally it’s the low income countries that bear the highest burden of HIV and are often forgotten when it comes to expensive drugs like lenacapavir. And that’s where it will make the most impact. 

Dr. Clem Lee: And of course there needs to be political will and momentum to really end the HIV epidemic — People in power must continue to see HIV as an important problem to overcome

Dr. Greg Katz: The policy/advocacy realm is certainly important. Another point is the clinician-on-the-ground perspective — that the PrEP solution for each person should be individualized based on their own circumstances and demographics. And so understanding how likely is somebody to be adherent to a daily pill versus how squeamish is somebody about a twice yearly injection. Lenacapavir is incredible, but many patients may be fine taking the cheap and cheerful, generic oral TDF (Truvada).

Dr. Clem Lee: Abarna, in a world where lenacapavir is available and affordable to everyone, who do you think will be the most accepting of it 

Dr. Abarna Pearl: I would say the people where adherence is a challenge, who might not remember to take something daily but can remember to come into the office twice a year. And in certain groups where taking a pill for HIV is stigmatized, maybe such as in subsaharan africa. Injections may be more effective in these groups

Dr. Greg Katz: Yeah this reminds me of the editorial by Dr. Lindsey Baden, deputy editor at the New England Journal of Medicine and former CDC director Rochelle Walensky. It all goes back to effectiveness, not efficacy. How do we choose what is right for which person? And some of that will probably be based on what somebody’s sex is and who they have sex with and what their risk factors are. But some of it is honestly going to be – how likely are they to come to appointments? And if somebody is not going to come to a twice yearly appointments, maybe they’re better off not getting lenacapavir

Dr. Clem Lee: Yes I can see the same issues with efficacy  not translating into effectiveness with oral PrEP also plaguing this long-acting medication. But can I also be idealistic for a second?

Dr. Greg Katz: Sure Clem. This is a new leaf for both of us. Our listeners are used to us being cynical.

Dr. Clem Lee: I imagine when this first rolls out, it will be in the hands of ID docs. But I am envisioning a world where it doesn’t have to be. Primary care docs are used to setting up annual or semi-annual injections or infusions, such as for IV iron, Depo progesterone, or IV bisphosphonates. So I’m hoping that the more we talk about it and stress its importance PCPs will take up the mantle for lenacapavir as well.

Dr. Greg Katz: It starts with people knowing how good these medications are and understanding that we have this suite of tools. And like all new drugs, lenacapavir will be really freaking expensive and almost nobody is going to be able to afford it at first. But the nature of this stuff is that prices come down as time goes on…and hopefully sooner in low and middle income countries. And so maybe today, April 2025, almost no patients have this accessible to them, but pretty soon, lots of people are going to have this accessible to them.

Dr. Abarna Pearl: I think that’s a bright note to end on. I think we can all agree that the more diverse options we have to serve the diverse people that are at risk for HIV – instead of a one-size-fits-all mentality — the better off we are. So now we will task you, the listeners, with spreading awareness about PrEP, to bolster its use and to ensure everyone everywhere can access the lifesaving medications that science has made available.

Dr. Clem Lee: And that’s a wrap! 

Dr.Greg Katz: That is all for today, thank you so much for listening. If you have ever gotten any value from the podcast, please please please share this with at least one other colleague who might also get something out of the episode

Dr. Clem Lee: Thanks to our reviewer, Dr. Lindsey Baden for this podcast. Thank you to Dr. Jimin Hwang for the accompanying graphics. 

Dr. Greg Katz: Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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Tags: Beyond Journal Club, clinical trials, HIV, HIV advances, PrEP trials