HIV guidelines: new combo pill gets top billing

​A new US Health and Human Services report recommended a new single-pill alternative as initial therapy in adults with HIV, a combination of bictegravir/emtricitabine/tenofovir alafenamide (BIC/TAF/FTC), giving it an A1 recommendation ​ (see https://aidsinfo.nih.gov/news/2044/adult-arv-panel-classifies-bic-taf-ftc-as-recommended-initial-regimen-for-hiv ).

Details:

--2 large drug company-sponsored RCTs confirmed non-inferiority of BIC/TAF/FTC:

    -- one confirmed non-inferiority of the single drug combination BIC/TAF/FTC as compared to dolutegravir (DTG) plus TAF/FTC (see https://www.ncbi.nlm.nih.gov/pubmed/28867499 ), finding at week 48, 89% on BIC/TAF/FTC had HIV RNA <50 copies/ml, vs 93% on DTG/TAF/FTC

        --similar adverse events in both groups: 2% in BIC/TAF/FTC discontinued therapy vs <1% on  DTG/TAF/FTC (no individual adverse event happened in more than 1 person), though overall drug-related adverse events were less common on BIC/TAF/FTC than DTG/TAF/FTC (18% vs 26%, with none significantly more common in one group than the other)

    --another study compared BIC/TAF/FTC with DTG plus abacavir/lamivudine (ABC/3TC) (see http://www.ncbi.nlm.nih.gov/pubmed/28867497 ), finding at week 48, 92.4% vs 93.0% had HIV RNA <50 copies/ml

        --some increase in nausea in patients on DTG/ABC/3TC (23% vs 10%), No difference in overall grade 3 or 4 adverse events, but <1% in each group having drug-related serious adverse events, and 4 (1%) with an adverse event leading to drug discontinuation in the DTG/ABC/3TC group (no individual adverse event happened in more than 1 person) and only 1 (<1%) discontinued meds in the BIC/TAF/FTC group, which was for pregnancy (with subsequent normal infant). no difference in the small changes in bone mineral density in the 2 groups. ​

--no treatment-emergent resistance in either study

--BIC/TAF/FTC is not approved for those <18yo or if creatinine clearance <30ml/min

Commentary:

--BIC is a new integrase strand transfer inhibitor (INSTI) which, similar to DTG, has a high barrier to resistance, and a low potential for drug-drug interactions: BIC is a CYP 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A1 substrate, which means that its metabolism may be affected by inhibitors or inducers of these enzymes. Eg: not use BIC with dofetilide, rifamycins (rifampin etc), some anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), meds with polyvalent cations (eg Mg, Al, Ca, or Fe, such as calcium/iron supplements, antacids/laxatives with these metals, sulcrafate, buffered meds), and St John's Wort

 --but no drug interactions with ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, velpatasvir, voxilaprevir

--and, BIC is not itself a CYP3A4 inducer or inhibitor (unlike elvitegravir/cobicistat), so should not affect the metabolism of CYP3A4 substrates.

--BIC does decrease the tubular secretion of creatinine but does not affect the GFR (ie, will mildly increase the apparent creatinine level and calculated GFR, but does not really affect the true GFR), and this is similar to DTG and cobicistat

--no treatment-emergent mutations found yet with BIC; also, it has not been studied in people with prior INSTI-associated drug resistance mutations (ie, do not use BIV in these people til more data available)

--so, now the million-dollar question: how much does this cost???  my survey of a local CVS for the non-insurance cost to the patient:

    --BIC/TAF/FTC=$4000/month

    --DTG and TAF/FTC= $2000/month each, so (no doubt coincidentally) the cost of the new drug is the same as these 2 pills...

    --though, for those with access to 340B pharmacies, the new combo drug is not on the list yet, and the DTG ($837) and TAF/FTC ($435) are considerably cheaper than in the private pharmacies [might be nice to give everyone access to 340B pharmacies.....but alas George Bush the younger ("W") in proposing Medicare D decided to use only commercial for-profit pharmacies]

so, this elevates the new HIV regimen to one of the 5 initial preferred choices, including the single pill combos of DTG/ABC/3TC and elvitegravir/cobicistat/TAF/FTC, as well as the combos of DTG plus TAF or TDF/FTC and raltegravir plus TAF or TDF/FTC

--but, as per Paul Sax (see https://blogs.jwatch.org/hiv-id-observations/index.php/latest-dhhs-guidelines-initial-hiv-therapy-now-include-5-choices-really-2-best/2018/04/08/​ , (also, as a disclosure, lead author in the first of the above two BIC studies), there are some real concerns about a few of these choices:

    --raltegravir is BID and does have much lower barrier to resistance than DTG or BIC (as does elvitegravir, though that at least is once-a-day dosing) [i am personally surprised that raltegravir still makes it in the top recommended group]

    ​--also elvitegravir requires the addition of cobicistat to boost its levels, not necessary with DTG or BIC [again, i suspect this will be relegated to a lower position soon]

    ​--there is increasing concern about ABC and cardiovascular disease [though the combo of DTG/ABC/3TC​ is perhaps the best alternative in patients with tenofovir intolerance]