bictegravir as good as dolutegravir in HIV

A recent article reinforced the efficacy and safety of the combination pill bictegravir, emtricitabine, and tenofovir alafenamide (BIC/TAF/FTC), finding it to be equal to the combination ofdolutegravir, emtricitabine, and tenofovir alafenamide (DTG/TAF/FTC). This current study provides 96 week results, after the prior 48 week results that led to BIC/TAF/FTC approval (see hiv doluteg vs bicteg lancethiv2019 in dropbox, or doi.org/10.1016/S2352-3018(19)30080-3)

Details:

-- randomized, double-blind, noninferiority study done in 26 outpatient centers in 10 countries, beginning in 2015-16

-- treatment naïve adults over 18 yo with HIV-1 infection, eGFR >30, and virus sensitive to FTC and tenofovir

-- 657 patients were enrolled, 645 completed the 96 weeks

-- 96 week secondary outcome: proportion of participants with plasma HIV viral load <50 copies/ml comparing these 2 medications, with prespecified noninferiority margin of -12%

Results:

-- at week 96, HIV viral load <50:

    -- DTG/TAF/FTC: 86%

    -- BIC/TAF/FTC: 84%

-- in prespecified per-protocol analysis at week 96 (ie, those actually taking meds regularly during the full study), HIV viral load <50:

    -- DTG/TAF/FTC: 98%

    -- BIC/TAF/FTC: 100%

-- propotion of patients with HIV viral load <20 copies/ml:

    -- DTG/TAF/FTC: 80%

    -- BIC/TAF/FTC: 78%

-- all of above numbers on achieved viral loads were not significantly influenced by age, sex, baseline HIV viral load, baseline CD4,region, and study drug adherence: ie, there was no difference in the efficacy of these drugs by pretreatment CD4 (< vs >200), or viral loads (> vs < 100K)

-- all of the above comparisons showed non-inferiority of BIC/TAF/FTC to DTG/TAF/FTC

-- CD4 increases at week 96:

    -- DTG/TAF/FTC: increase of 281, to 733

    -- BIC/TAF/FTC: increase of 237,  to 693

    --CD4 increases were more significant with DTG/TAF/FTC, p=0.008

--no viral resistance developed in either group

--2% of patients had hepatitis B co-infection: those who took meds throughout the 96 weeks, 4 of 4 with BIC/TAF/FTC and 4 of 6 with DTG/TAF/FTC, had HBV viral load <29 IU (the 2 not achieving undetectable HBV viral loads had initial virus >170 million IU, with decreases to 55 and 70 IU on treatment)

-- adverse events at week 96:

    -- DTG/TAF/FTC: 89%, 10% had "any serious event", 2% discontinued medications from an adverse effect

        -- most common: diarrhea 16%

        -- study drug-related adverse effects: 28%

        --adverse events leading to discontinuation of study drugs: 2 events felt to be study drug-related (1 depression and 1 lipoatrophy)

    -- BIC/TAF/FTC: 88%, 17% with "any serious adverse event", 2% discontinued medications from an adverse effect

        -- most common: diarrhea in 18%

        -- study drug-related adverse effects: 20%

        --adverse events leading to discontinuation of study drugs: 4 events felt to be study drug-related in 4 different patients (chest pain; abdominal distension; sleep disorder, dyspepsia, tension headache, depressed mood and insomnia,all occurring within first 48 weeks; and  depression occurring between 48-96 weeks)

-- 3 individuals died in each group, none were considered to be related to treatment

-- 9 women had 11 confirmed pregnancies on meds: study drugs were discontinued when the pregnancy was confirmed

    -- in the bictegravir group, 1 woman had elective aborition, 3 had spontaneous abortion, and 3 had uncomplicated term pregnancies

    --in the dolutegravir group, 1 woman had an elective abortion and 3 had uncomplicated term pregnancies (a lingering concern is the Botswana study where 4 women had infants with neural tube defects, more than would have been expected in women taking other antiretrovirals)

Commentary:

 --the newest HIV treatment guidelines promote integrase strand transfer inhibitors (INSTIs) along with 2 NRTIs as the standard of care for new HIV patients and can be started right away, with bictegravir/TAF/FTC as one of the recommended first line therapies, see https://gmodestmedblogs.blogspot.com/2018/07/new-hiv-treatment-guidelines.html . Also, the US Health and Human Services report earlier last year that strongly supported bictegravir/TAF/FTC, leading to its approval see http://gmodestmedblogs.blogspot.com/2018/04/hiv-guidelines-new-combo-pill-gets-top.html , which also has pricing information at that time and more analysis of BIC/TAF/FTC 

--Bictegravir is part of a potent, once-a-day pill coformulated with TAF/FTC, which has in-vitro high barrier to resistance and even has activity against HIV resistant to elvitegravir and raltegravir (and sensitivity to some HIV variants that have decreased sensitivity to dolutegravir).  It is also very well-tolerated and does not seem to be associated with increased cardiovascular risk, as with abacavir (which is a potential concern with the combination pill of dolutegravir, abacavir and lamivudine, which also has more neuropsych adverse effects than BIC/TAF/FTC). 

    --one drawback of this combination is that bictegravir is not available as a single agent, so patients with eGFR<30 cannot take it (the FTC component is too potent for those with lower eGFR's) and would need to be on dolutegravir with reduced dose of FTC or 3TC

--the above study is great news to me. BIC/TAF/FTC is the only med i have been prescribing over the past year or so for new HIV patients, given the initial studies suggesting its potency, barrier to resistance, and being one pill a day independent of food. i have also been using this for my patients doing well on older meds but either have some concerns about bone or kidney (for TDF-based regimens). I am also switching several other patients who are on boosted regimens with ritonavir or cobicistat, where i am concerned that as HIV has become a chronic disease, these patients may well end up accumulating various medical comorbidities, which raise issues about increased drug-drug interactions. And, as per a prior blog, even giving inhaled or injected steroids can be a problem with ritonavir or cobicistat (see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html)

    --the really reassuring thing about this 96-week study is that i have had a few patients develop viral load blips on bictegravir, and i was concerned that the issue might have been with bictegravir.  does not really seem to be an issue...

--overall, there was a significanlty lower incidence of drug-related adverse events in the bictegravir broup, with the largest differences being in GI and CNS/sleep sypmtoms

-- there was a slight increase in creatinine in both groups, from a baseline of about 0.90 to 1.00 at week 96; this increase was felt to be more from inhibition of tubular secretion of creatinine via cation trransporter 2 by both agents (though happens more with dolutegravir) and not from nephrotoxicity. for dolutegravir, this increase is the same for combination with TAF/FTC as with abacavir/ lamivudine (ie, it is not tenofovir nephrotoxicity)

--this study was limited by the fact that most people were young, not so many women, no useful data on pregnancy, few had advanced HIV, mostly involved people from middle- and high-income countries

so, this article reaffirms that we now have really potent HIV therapies that have nearly uniformly full viral suppression (<50 copies/ml), can be started right away, are largely without adverse effects, can be taken with or without food, and do not have significant drug-drug interactions (though not give with rifampin and some other meds: best guide for drug/drug interactions: https://www.hiv-druginteractions.org/).  It has reached a point where HIV care is some of the easiest clinical care that i do.... 

geoff

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