HIV PrEP: cabotegravir shines

 A recent study found that cabotegravir (CAB) was better than TDF-FTC (tenofovir disoproxil fumarate/emtricitabine, or truvada, which is available as a generic) for preexposure prophylaxis (PrEP) against HIV (see hiv pre-exp proph cabotegravir nejm2021 in dropbox, or DOI: 10.1056/NEJMoa2101016) 

 

Details: 

-- randomized, double-blind, noninferiority trial compared long-acting injectable CAB 600 mg given intramuscularly every eight weeks with daily oral TDF/FTC for the prevention of HIV infection in at-risk MSM and transgender women who have sex with men 

-- multicenter trial in the United States (37%), Latin America (Argentina 7%/Brazil 17%/Peru 18%), Asia (Thailand 12%/Vietnam 4%), and Africa (3%) 

-- 4566 participants were randomized, including 570 (13%) transgender women 

-- median age 26; in the US component, 845 (50%) were Black (ie, it was a racially diverse population) 

-- all had negative HIV viral load within 14 days before the trial; study excluded those with a creatinine clearance of < 60, illicit IV drug use within 90 days before enrollment, coagulopathy, buttock implants or fillers, seizure disorder, positive test for hepatitis B or hepatitis C, or QTc interval >500 msec  

-- those randomized to CAB (an Integrase Strand Transfer Inhibitor, INSTI), had daily oral 30 mg tablets for five weeks to verify the safety of the tablets, then were transitioned to the injectable CAB every 2 months 

-- trial visits were at 2, 4, 6, and 10 weeks, and then 2 weeks after each injection; all visits included an HIV rapid test 

-- blood drug levels were assessed in a random sample of those on TDF/FTC, and CAB levels in those who developed an HIV infection 

-- participant retention was 87% in one year 

-- follow-up 153 weeks 

-- primary endpoint: incident HIV infections 

-- trial was stopped early at the first preplanned interim endpoint analysis, after review of the results at that time and finding a significant difference between the meds

 

Results: 

-- adherence to medications: 97% by pill counts in the trial groups; 92% had their injections with a delay of less than two weeks [pill counts are not necessarily so accurate, i suspect more inaccurate in the setting of a study]

    -- CAB: see below; they used a cutpoint of 0.166 mcg/mL from the in vitro protein-adjusted 90% CAB inhibitory concentration

    -- TDF/FTC: 74% had concentrations >40ng/mL, the anticipated concentration from taking TDF/FTC daily in the previous week 

-- incident HIV infections occurred in 52 participants:  

    -- CAB: 13 people, incidence 0.41 per 100 person-years 

    -- TDF/FTC: 39 people, incidence of 1.22 per 100 person-years 

         -- 66% decrease with CAB, HR 0.34 (0.18-0.62), p<0.001 

        -- this effect was consistent across pre-specified subgroups: age <30 vs >30, transgender women vs MSM, Black vs non-Black, geographical region

-- review of reasons for breakthrough/incident infections (see hiv pre-exp proph cabotegravir jid2021 in dropbox, or DOI: 10.1093/infdis/jiab152, a separate article on the same study):

    -- CAB:

        -- 4 had baseline HIV positivity (prior to starting the study)

        -- 5 had no recent exposure to cabotegravir (either never got CAB injections or had last injection > 6 months before their first HIV-positive visit; and 3 occurred before the injections started, at least one of whom developing incident HIV infection had poor oral med adherence prior to starting injections)

        -- 4 developed HIV infection in the setting of on-time CAB injections

            -- INSTI resistance mutations were found in only 2 of these 4 cases, where "resistance was clearly acquired, since there was no resistance at the first HIV-positive visit" (see article for the specific mutations)

    -- TDF/FTC resistance in 39 patients with subsequent HIV infection

        -- only 2 had blood drug concentrations consistent with good PrEP adherence

        -- 4 incident HIV infections and 2 baseline infections had nucleoside or nucleotide reverse-transcriptase inhibitor mutations (K65R, M184V, M184I)

 

-- adverse events:

-- no significant safety concerns were identified: no significant difference for either grade 2 or 3 adverse events, with serious adverse events in 241 people (5.3%)

    -- most common was decreased creatinine clearance in 77%, no difference between groups

    -- injection site reactions : 81% CAB, 31% in TDF/FTC (they did have placebo injections), reactions being mild-to-moderate and decreasing in frequency over time, at a median of 1 day after injection

        -- only 2% discontinued injections because of injection-related adverse event

    -- CAB was associated with more weight gain (1.2 kg/yr) vs TDF-FTC (0.4kg/yr), mostly found in the first 40 weeks of treatment

-- other sexually transmitted infections, STIs (no significant difference between groups):

    -- new rectal or urethral GC: 13.5/100 person-yrs

    -- new rectal or urethral chlamydia: 21.4/100 person-yrs

    -- new syphilis (centrally adjudicated): 16.7/100 person-yrs

-- here is graph of incident HIV infections over time 

 

 

 

Commentary: 

-- the number of new HIV infections in the world is >5000 per day, despite the availability of preexposure prophylaxis. TDF/FTC can be used daily or as needed (see http://gmodestmedblogs.blogspot.com/2015/12/on-demand-hiv-pre-exposure-prophylaxis.html and   http://gmodestmedblogs.blogspot.com/2020/01/on-demand-prep-works-if-fewer-meds-and.html

-- CAB is a long-acting integrase strand-transfer inhibitor (INSTI), in the same family as dolutegravir and bictegravir, with potent anti-HIV activity in nonhuman primates and is safe in humans 

-- interesting that the weight gain was much more with cabotegravir. this has been found with INSTIs in general but has been at least as much with TDF in other studies (in the current study, there was actually weight loss in some with tenofovir. ??why): a study assessed weight gain wtih different meds, referenced in http://gmodestmedblogs.blogspot.com/2020/10/hiv-treatmentprevention-guidelines-2020.html 

    -- however, these researchers did not find such a high level of weight gain in HIV-uninfected people in their prior study after 41 weeks, with both groups having a 1 kg weight gain

-- not so surprisingly, there was a high risk of other STIs (including syphilis, with even higher rate than gonorrhea!!), so it is clearly  important to continue screening for these in this high-risk population

-- there was considerable concern that the delay in finding incident HIV infections might have led to the increase in INSTI resistance:

    -- 2 people on CAB were found to have newly-acquired INSTI resistance

            -- 1 had HIV that was sensitive to all meds at 1st visit when patient was viremic, but then developed 2 INSTI mutations by 6 weeks later that likely would likely have been associated with phenotypic resistance though there was phenotypic assay failure

            -- 1 was sensitive to all INSTIs when first viremic at week17 (BUT no change to aggressive treatment for the incident infection!!!), assay 112 days (week 33!!) had INSTI resistance mutation (R263K) but INSTI phenotype assay failure, another 5 days later found phenotypic resistance to all INSTIs

    --this all supports the importance of identifying HIV infections as early as possible, perhaps with the earlier detection from HIV viral load testing over the antibody test (assuming test turnover time is sufficiently fast)

-- BUT, the perspective should be reinforced that TDF/FTC does work extremely well when patients take sufficient quantity to maintain good blood levels (and only 2 patients with breakthrough HIV infections did have adequate blood levels in the above study: though ?? if those levels were reflected those for the duration of the study or just at the specific time the blood was sampled??). the likely interpretation of the this study is that the CAB worked better because it was a reliable injection and the TDF/FTC did less well because of less good adherence with a regular oral med (in the IPERGAY study, there was excellent HIV protection even though the median number of TDF/FTC pills was 15/month (see http://gmodestmedblogs.blogspot.com/2015/12/on-demand-hiv-pre-exposure-prophylaxis.html ), and followup study: http://gmodestmedblogs.blogspot.com/2020/01/on-demand-prep-works-if-fewer-meds-and.html 

-- this also raises the issue that the 5-week lead-in phase with oral CAB should be drastically shortened, since so many infections happened when people had to take daily oral pills for such a prolonged time...

 

Limitations: 

-- all of these studies were only with MSM and at-risk transgender women who have sex with men. Though it is likely that this therapy would work for high-risk women, this group has not been formally tested: so, it is unclear that this medication definitively works for women. 

    -- A small study found that female genital tract concentrations of CAB are 16-28% of median plasma concentrations and rectal tissue has <8% of plasma concentrations (see https://www.dovepress.com/getfile.php?fileID=32967 and DOI: 10.1097/QAI.0000000000000301))

    -- similarly, there have been studies with using TAF (tenofovir alafenamide)/FTC finding protection in MSM, was also not tested in women. BUT it turns out that vaginal levels of TAF are much lower than for TDF

        -- so I would be hesitant to use either CAB or TAF preparations in women until studies show their efficacy. continue TDF/FTC for now...

        -- that being said, other INSTIs (dolutegravir, raltegravir) are recommended therapies for post-exposure prophylaxis against HIV in men and women, so likely that CAB is okay in women (though these studies also should assess/discriminate between rectal and vaginal sources of HIV infection)

-- studies are pending about CAB in adolescents

-- this trial was stopped early because of clear superiority of the CAB. However, this does create a bias towards efficacy: efficacy is clear when a study is stopped early because of efficacy, whereas adverse events may take longer to manifest themselves 

-- the researchers comment that the case of INSTI resistance could be related to any of: low CAB plasma concentrations between injections, low CAB concentrations in rectal tissue, and/or rectal inflammation from concurrent STI

-- 2 of the patients with incident HIV infections who seemed to have developed resistance had delay of 6 weeks and 4 months (without initiating full HIV therapy) til resistance was documented, suggesting that there should probably be aggressive attempts to move them to a full HIV regimen as early as possible. seems like it should be a regimen with a boosted protease inhibitor or NNRTI, sparing the INSTI til full mutation pattern elucidated: see https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/what-start-initial-combination-regimens-antiretroviral-naive 

    -- it is not clear what the appropriate HIV testing rate should be in those on CAB, since HIV infection does seem to occur in those on the med (though still rarely), but that treatment early for the HIV may well decrease INSTI resistance. i suspect this should be individualized, though unclear what the discriminative factors are (eg, is it number or type of sexually transmitted infections that might increase rectal infection? or types of infections? or number of partners or sexual relations, or types of sexual relations, or ???) 

-- their INSTI resistance data was incomplete: 8 of 14 people did not have successful INSTI phenotypes done)

-- and, a significant hurdle for us in prescribing CAB is that the FDA has not approved it yet..... (though i assume will be soon??)
 

so, a few comments of this study:

-- cabotegravir seems great, largely because of improved adherence to treatment (TDF/FTC is also great, but taking daily or near-daily pills can be a burden for some in the longterm...)

-- this study also suggests an imperative to identify and treat those with incident HIV infections right away, before serious mutations occur that could lead to losing the most potent class of HIV meds (INSTIs)

    --and the earliest pickup of new HIV infections is by HIV viral loads vs antibody testing, assuming rapid turnaround times. and getting having a high enough viral load would allow for more rapid testing for resistance patterns.  seems like viral load testings should be done routinely

-- and, we do need studies on CAB protection in women, who comprise a substantial group getting new HIV infections: https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics

geoff

 

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