pre-exposure HIV prophylaxis with lenacapavir in cisgender women

 A recent study found that lenacapavir was a very effective med to prevent HIV infection in cisgender women (see hiv pre-exp proph lenacapavir cisgender women NEJM2024 in dropbox, or DOI: 10.1056/NEJMoa2407001

 

Details:

-- 5338 HIV-negative women in South Africa and Uganda were recruited into a phase 3, double-blind, randomized controlled trial of 3 groups to assess pre-exposure prophylaxis against HIV (PrEP):

    -- subcutaneous lenacapavir 927mg every 26 weeks (with a window of up to 7 days) plus placebo tablets for F/TAF and F/TDF

    -- daily oral F/TAF (emtricitabine-tenofovir alafenamide) plus placebo injections

    -- daily oral F/TDF (emtricitabine-tenofovir disoproxil fumarate) plus placebo injections, serving as an active control

-- the background in these countries: at least 3.5 adolescent girls and young women per 100 person-years developed incident HIV infections if not using PrEP

-- the participants in the study were 16-25yo, were in sexual relationships with male partners, had unknown HIV status, and had no HIV testing in the prior 3 months (they did not want to bias the cross-sectional incidence cohort to women less likely than the general population to have HIV infection)

-- HIV testing was done on initial enrollment, and those who were positive were referred for HIV care

-- all particvipants received standard HIV counseling, male and female condoms and lubricant, and contraception if desired, along with evaluation for intimate partner violence or social harm from trial participation

-- women who were later than 28 weeks after the lenacapavir injection had HIV testing

-- medication adherence for the pills was defined as low (<2 tablets/week), medium (2-3 tablets/wk) or high (at least 4 tablets/wk)

-- 10% of each group had blood samples assessed for the presence of tenofovir

 

-- primary endpoint: incident HIV infection in participants

-- efficacy analysis used a modified intention-to-treat approach that excluded participants who had HIV infection at the time of study randomization; safety endpoints including adverse events and lab abnormalities

 

 

Results:

-- 55 women developed incident HIV infections, with incidence rate ratios:

    -- lenacapavir group (n=2134): 0 infections, 0 per 100-person-yrs (0.00-0.19)

    -- F/TAF (n=2136): 39 infections, 2.02 per 100 person-yrs (1.44-2.76)

    -- F/TDF (n=1068): 16 infections, 1.69 per 100 person-yrs (0.96-2.74)

-- as a reference: the background HIV incidence in the screened population for this study (n=8094): 2.41 per 100 person-yrs (1.82-3.19)

 

-- Comparing these 3 interventions:

    -- lenacapavir group vs other 2 regimens: incidence rate ratio 0.00 (0.00-0.04), p<0.001

    -- incidence rate for F/TAF did not differ significantly from background HIV incidence

    -- difference between F/TAF and F/TDF was not statistically significant, incidence rate ratio 1.20 (0.67-2.14)

 

-- Adherence to meds:

    -- lenacapavir: injecions were administered on time for 91.5% of participants

    -- F/TAF: decreasing from 34% having low adherence (<2 doses/week) at week 8, to 70% by week 26, to 84% by the week 52

        -- 34 of 37 participants had low or no detection of  TAF in their blood

        -- and, those who had medium or high adherence to F/TAF did have an 89% lower odds of getting an HIV infection, OR 0.11 (0.01-0.4)

    -- F/TDF: decreasing from 50% having low adherence (<2 doses/week) at week 8 to 89% by week 26, to 93% by the week 52

        --13 of 14 participants had low or no detection of  TDF in their blood

-- the incidence of C. trachomatis, N gonorrhoeae, and T vaginalis at asymptomatic screening every 26 weeks was high and similar in the 3 groups:

    -- lenacapavir: 48.7 per 100 person-years (930 events)

    -- F/TAF: 50.8 per 100 person-years (965 events)

    -- F/TDF: 48.4 per 100 person-years (452 events)

 

-- Safety concerns: none

-- Adverse events: lenacapavir had injection site reactions in 68.8% (including subcutaneous nodules in 63.8%, vs 16.6% having placebo injections); almost all injection-site reactions were grade 1 or 2 (4 women discontinued the shots because of injection-site reactions). The likelihood of injection-site reactions diminished dramatically with subsequent injections

    -- other adverse events:

        -- headache: lenacapavir in 13.3%, F/TAF in 16.5%, F/TDF in 14.5%

        -- urinary tract infection: respectively in 14.4%, 14.3%, 15.2%

        -- GU tract chlamydia infection: respectively in 14.0%, 14.8%, 12.1%

        -- all other adverse events: under 10% for each group (and no real difference between groups): nausea, vomiting, vaginal discharge, vulvovaginal candidiasis, gonococcal infection, diarrhea, dizziness

        -- 6 deaths in the F/TAF group, none considered to be related to the meds

        -- essentially all of the adverse events were Grade 1 or 2 out of 4

        -- changes in lab results during the study: many checked and all were sporadic and very rare (1-3 cases, all <0.2% of their groups)

-- 510 pregnancies: no significant difference between groups; only one congenital anomaly found, polydactyly in an infant exposed to lenacapavir, but in a family with strong family history of that condition

 

Commentary:

-- there has been a knowledge gap in the prior trials for HIV pre-exposure prophylaxis (PrEP) in cisgender women, though there is still a gap in studies for pregnant women: https://gmodestmedblogs.blogspot.com/2019/10/new-recs-to-prevent-hiv-transmission.html

    -- and, of course, cisgender women have lots of new HIV infections globally: 1.3 million new ones annually

-- Lenacapavir is a potent, new multi-stage HIV-1 capsid inhibitor (a protein shell that protects the HIV’s genetic material and enzymes needed for replication) with a long enough half-life that it can be administered twice a year

    -- HIV-1 capsid inhibitors are a new class of HIV meds, fundamentally different from the other meds used in HIV prophylaxis and treatment

    -- Lenacapavir is  much more effective against HIV-1 than HIV-2, being on the order of 11- to 14-fold less potent for the latter: https://pubmed.ncbi.nlm.nih.gov/38060982/

    -- though less effective in those with HIV-2, it still might work clinically in people (though with more aggressive monitoring of virologic and immunologic responses) and may still have use as PrEP in countries with more prevalent HIV-2 infections: https://www.croiconference.org/abstract/antiviral-activity-of-lenacapavir-against-hiv-2-isolates/

-- in a small study of 72 patients having multi-drug-resistant HIV-1 infection given lenacapavir in addition to their failing but optimized therapy, there was a very impressive decrease in their HIV viral load and improvement in their CD4 counts: https://pubmed.ncbi.nlm.nih.gov/35544387/

 

-- this current study found that the injected lenacapavir was uniformly protective: ie, 100%  as compared to the pill combinations, and the pills were not significantly different from each other or from the background HIV infection rate without meds

    -- though, the adherence to the pills was a tad on the paltry side; when blood samples were checked, there was significant protection by F/TAF in those with medium or high adherence rates (89% in those taking at least 2 pills/week. ??even better if taking meds daily)

    -- and as confirmation of the efficacy of lenacapavir, there was no difference between the three groups in terms of contracting other sexually-transmitted diseases (chlamydia, gonorrhea, trichomonas)

-- one question about the meds is that TAF has about 10-fold lower concentration in rectal tissue than TDF; conversely, TAF has 6 times higher concentrations in vaginal  than TDF: https://pmc.ncbi.nlm.nih.gov/articles/PMC8144741/

    -- this variability with TAF vs TDF poses a theoretical barrier to using these meds for full HIV prophylaxis. The actual clinical significance of this is unclear (a small study found promising results for TAF in rectal tissues: https://www.aidsmap.com/news/feb-2023/promising-new-prep-method-undergoes-first-safety-study-anal-sex )

 

-- as a comparison of other types of PrEP formulations:

    -- the dapivirine vaginal ring decreased the acquisition of HIV by 31%, but there were still 4.1 seroconversions per 100 person-years: https://pubmed.ncbi.nlm.nih.gov/27959766/

    -- injectable cabotegravir was better, but there were still some cases, 0.2 cases per 100 person-years vs 1.85 cases per 100 person-years in those on F/TDF in a sub-Saharan Africa study: https://pubmed.ncbi.nlm.nih.gov/35378077/

    -- another study of cabotegravir in high-risk cisgender men and transgender women, both having sex with men, found incident HIV in 0.41 per 100- person-years vs 1.22/100 person-years with F/TDF: https://pubmed.ncbi.nlm.nih.gov/34379922/

        -- though cabotegravir requires injection every 2 months

        -- the costs of  both of these meds are obscenely high (lenacapavir at $44819/yr vs cabotegravir at $22200/yr), though ½ the cost with cabotegravir, though would have some increase in costs of administration (6 vs 2 times/year) and perhaps there may need more HIV testing on cabotegravir since there are more breakthrough infections???? Further studies might clarify that.

        -- and, resistance to cabotegravir (a rare occurrence) could lead to resistance to the most powerful single agents we have (INSSTIs) to treat HIV

 

 

Limitations:

-- this study was done in 2 African countries and may not have generalizable results to other areas (different comorbidities, meds, diet/exercise, sexual practices, underlying infections....). And, would these results apply to countries with more HIV-2 infections??

-- this study was unable to assess the pharmacologic differences between the groups: F/TAF actually work quite well when there was high adherence to taking them: the main issue (the most important one) is having a med that is associated with a higher adherence.

-- there were relatively few HIV infections in this study (and none in those on lenacapavir); there likely would be some infections in a larger group. There could be adverse outcomes from acquired HIV infection while on lenacapavir that could not be assessed in this study. However, lenacapavir does have the benefit over cabotegravir in that it is a novel drug, not in the class of the integrase inhibitors such as cabotegravir, so is unlikely to have the consequences of resistance to integrase inhibitors or other meds

    -- that being said, cabotegravir does have a high barrier to resistance and is still a reasonable choice for PrEPand HIV treatment: https://www.sciencedirect.com/science/article/pii/S0166354222001966

-- it is great to have a large study in cisgender women. Though this is a hugely important group, there are no studies in other groups (though results of lenacapavir are very likely to be a generalizable  to all)

 

So,

-- this study provided impressive evidence that lenacapavir is a safe and powerful preventer of HIV transmission in cisgender women

    -- there is one key question not fully answered: if there were better adherence to the oral medications (eg daily, or even just 4x/week) would F/TAF or F/TDF have worked as well as the injection of lenacapavir??

        -- it is certainly true that taking medicine on a regular basis as prophylaxis often has suboptimal adherence.

        -- of course, some cisgender women will be totally adherent, as many are with oral contraceptives

        -- and, there might have been higher adherence if the oral meds were needed on-demand instead of daily, as found in the IPERGAY trial: https://gmodestmedblogs.blogspot.com/2019/10/new-recs-to-prevent-hiv-transmission.html

    -- though, notably, the ease of a very safe injection every 6 months provides such impressive protection with no almost no increase in adverse effects, other than relatively minor injection-site pain and nodules. And these decreased dramatically with subsequent injections

 

-- so, lenacapavir is a very promising PrEP medication: it works remarkably with documented benefit in cisgender women, it has no significant increase in adverse events vs the pills, it involves only 1 shot (but two 1.5ml injections) every 6 months, and (not surprisingly) it has much higher medication adherence than pills.

    -- the only significant adverse effect was in injection-site tenderness and nodules, but the incidence of that decreased dramatically on subsequent injections

    -- and it seems to have no adverse effect in the women who become pregnant on it or for their infants (though this observation was not a prespecified outcome of the study, there were many pregnancy events with no clear concerns

    -- given the lack of any transmission of HIV from its use, there was no evidence of any HIV drug resistance by using it (though, of course, a larger study may well find a few cases of HIV transmission…i doubt that if HIV resistance develops that it would have a large effect on current HIV therapy, since this is a new class of HIV meds)

-- and, perhaps most importantly, oral PrEP formulations have a pretty low uptake in women at risk for HIV infections, so an effective and safe injection every 6 months would likely be utilized by more women.

    -- injectable cabotegravir is also quite effective, though requires injections every 2 months

-- this study did not find any difference in the groups in the acquisition of other sexually-transmitted diseases, reinforcing the importance of still using barrier protection

 

 

geoff

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