icon-    folder.gif   Conference Reports for NATAP  
  Conference on Retroviruses
and Opportunistic Infections (CROI)
Boston, Massachusetts
March 4-7, 2018
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Clinical Pharmacology at CROI 2018
  Courtney V. Fletcher, Pharm.D.
Dean and Professor
College of Pharmacy
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 2018 (25th) Conference on Retroviruses and Opportunistic Infections (CROI) was held in Boston, MA, from March 4-7, 2018. In this report I will highlight abstracts focused on pharmacologic issues that are of broad interest or might benefit from some expert clarification. Abstracts will be discussed in the categories of: (i) the therapy of HIV infection, (ii) co-infection, (iii) PrEP, (iv) drug-drug interactions and (v) new drugs. You can find more information on these abstracts on the CROI website and many are covered in depth elsewhere on the NATAP http://natap.org website.
I. The Pharmacotherapy of HIV Infection
A switch to BIC/FTC/TAF from DTG/ABC/3TC was non-inferior to continued DTG/ABC/3TC in maintaining HIV-RNA suppression (abstract 22).
These results have already received plenty of coverage, and you can find detailed information on the NATAP website, so I'll give just the bottom line conclusions and provide a few comments.
In this study, 563 adults virologically suppressed on DTG/ABC/3TC who had estimated GFR rates ≥ 50 mls/min were randomized to continue DTG/ABC/3TC or to switch to BIC/FTC/TAF. The primary endpoint was the proportion with HIV-RNA ≥ 50 copies/mL at week 48. At week 48, the results were 1.1% of BIC/FTC/TAF recipients compared with 0.4% of DTG/ABC/3TC had plasma HIV-RNA ≥ 50 copies/mL. This 0.7% difference was within the margin of noninferiority, showing that both regimens maintained similar high rates of virologic suppression. Furthermore, both regimens were safe and well tolerated and no treatment emergent resistance was seen in either arm.
In a related study, a switch to BIC/FTC/TAF was evaluated in an all women international trial (abstract 500). Virologically suppressed women on EVG/cobi combined with either FTC/TAF or FTC/TDF, or ATV/RTV plus FTC/TDF were randomized to stay on their existing regimen or switch to BIC/FTC/TAF. The primary endpoint was the proportion with HIV-RNA ≥ 50 copies/mL at week 48. 470 women were enrolled. At week 48, 1.7% of women who remained on their existing regimen and 1.7% of those who switched to BIC/FTC/TAF had HIV-RNA ≥ 50 copies/mL. Similar to the switch study above, both approaches to maintenance were safe and well tolerated and no treatment emergent resistance was seen.
Finally, the PK, safety and efficacy of a BIC/FTC/TAF regimen in adolescents was evaluated in 24 virologically suppressed adolescents (12 to < 18 years) in abstract 844. The primary endpoint was the plasma PK evaluations and safety and tolerability of the switch to BIC/FTC/TAF at week 24. At week 24, 100% of the adolescents maintained virologic suppression. The PK data showed that the plasma concentrations of BIC, FTC and TAF were very comparable between these adolescents and those in adults. Though I wouldn't expect a surprise, it would have been informative to see intracellular triphosphate concentrations for FTC and TAF in these adolescents. The BIC/FTC/TAF regimen was well tolerated with only mild to moderate adverse events; no adverse event led to drug discontinuation.
Some perspectives on BIC/FTC/TAF. The combination tablet was approved by the FDA on February 7, 2018, and indicated for ARV-naïve adults or to replace current therapy in persons who are virologically suppressed for at least 3 months. It is not recommended for persons with creatinine clearance < 30 mls/min. It can be taken with or without food. From the published literature, the phase 3 trials of BIC vs. DTG based regimens in ARV-naïve persons, showed both achieved high rates of virologic suppression and BIC demonstrated noninferiority (see Lancet, November 4, 2017). Both regimens were safe and well tolerated. Nausea occurred significantly less often with BIC/FTC/TAF (10%) than with DTG/ABC/3TC (23%), a difference not seen when DTG was combined with FTC/TAF implicating the ABC/3TC backbone. At CROI 2018, we saw convincing data on switch studies in adults and in adolescents. How will clinicians and patients choose between BIC and DTG? Here are a few considerations.
Flexibility. DTG gets the nod because it can be obtained separate from a coformulated tablet allowing it to be combined with anything. It also allows for dose adjustment to 50 mg twice daily for certain patients and to manage some drug-drug interactions (see section IV below). Furthermore, at least right now, the flexibility is playing to DTG's favor in developing countries with coformulations being made by generic manufacturers (again, see section IV below).
Drug-drug interactions. Neither BIC nor DTG require a pharmacokinetic booster, thus minimizing the potential for DDIs. That said, each drug does have some potential for clinically important interactions. For example, rifampin is contraindicated to be given with BIC but it may be able to be given with an increased dose of DTG (see drug interaction section).
Tablet size. Clear win for BIC/FTC/TAF. The picture below is from abstract 844 and shows the differences of Biktarvy, Genvoya and Triumeq. In terms of tablet length, Biktarvy is 15mm, Genvoya is 19mm and Triumeq is 22mm. This is one of many telling illustrations of how far HIV therapeutics have come.


BIC/TAF/FTC will be interesting and advantageous for several reasons. It will provide an INSTI FDC that will allow clinicians to avoid issues associated with ABC and pharmacokinetic boosting (e.g., EVG/cobi). It will also, I suspect open avenues for third party payers to look at competitive bidding for a preferred FDC INSTI, like what we have seen in the HCV marketplace. The marketing campaign is likely to be fierce.
Bictegravir at CROI (03/13/18)
II. Co-Infection
The biggest news at CROI 2018 involving treatment of co-infections was ACTG 5279, which showed one month of INH+rifapentine was as good as 9 months of INH in HIV-infected persons to prevent TB (abstract 37LB). This trial enrolled 3000 HIV-infected persons, and randomized them to receive the standard regimen of 9 months of daily isoniazid (INH) or one month of daily INH+rifapentine (RPT). Treatment follow-up was for 3 years after the last participant enrolled. This study demonstrated that one month of INH+RPT was noninferior to the standard 9-month regimen, was associated with fewer adverse events and had better rates of treatment completion.
Rifapentine (RPT) has the potential to substantially decrease the concentrations of certain anti-HIV drugs in the body to levels that are no longer effective. This is one reason the shorter course INH+RPT regimens have not been recommended for persons infected with HIV and taking anti-HIV therapy. ACTG 5279 allowed persons to enter the study taking either an EFV or NVP-containing regimen. This was because at the beginning of the study, a drug-drug interaction substudy was conducted in 87 persons that showed RPT did not cause a clinically meaningful reduction in EFV concentrations and did not adversely affect virologic suppression (see: https://www.ncbi.nlm.nih.gov/pubmed/26082504 ). ACTG 5279 is an exceptionally important study. Globally, TB is the leading cause of death for persons living with HIV, and this short course regimen of INH+RPT offers a new tool to prevent TB. This study will change guidelines, and if implemented should reduce morbidity and mortality.
WEBCAST: http://www.croiwebcasts.org/console/player/37077?mediaType=slideVideo&&crd_fl=1&ssmsrq=1522764666922&ctms=5000&csmsrq=948
a. Dapivirine ring: improved adherence and reduced rates of HIV seroconversion. In 2016, two randomized, double blind, placebo controlled trials (Aspire and Ring) of a monthly dapivirine vaginal ring conducted in healthy, sexually active women in sub-Saharan Africa were reported in the NEJM. The findings from both studies were very similar showing the dapivirine ring reduced HIV seroconversions by approximately 30%. See: Baeten, http://www.nejm.org/doi/full/10.1056/NEJMoa1506110 and Nel, http://www.nejm.org/doi/full/10.1056/NEJMoa1602046
At CROI 2018, preliminary results from open label follow-ups of both studies (Hope for Aspire participants and Dream for Ring participants) were reported (abstracts 143LB and 144LB). And again, the results of both studies were comparable showing an approximate 50% reduction in the incidence of HIV seroconversions. Adherence looked to be improved in both of these open label follow-up studies from that in the placebo controlled trials, and likely explains the improved efficacy. Development of the dapivirine ring continues to move forward; an unsettling and likely to be unanswered question is how good is it vs. oral TDF/FTC?
CROI: High uptake and reduced HIV-1 incidence in an open-label trial of the dapivirine ring (03/08/18)
CROI: HIV Incidence and Adherence in DREAM -An Open-Label Trial of Dapivirine Vaginal Ring (03/12/18)
b. Early termination of a TDF-containing vaginal ring (abstract 1059LB). This abstract described a placebo-controlled study of a tenofovir disoproxil fumarate (TDF) vaginal ring. 17 women were enrolled; 12 were randomized to the TDF-vaginal ring and 5 to placebo. 8 (67%) of 12 TDF-ring recipients stopped ring use early, on average day 32 of use, for vaginal and cervical ulceration vs. none of the placebo recipients. The investigators concluded these findings preclude further development of the TDF-vaginal ring.
c. Oral Truvada is highly effective for PrEP - what will it take to get it to those in the United States who need it (abstract 86)? One of the most sobering presentations at CROI 2018 was that from the CDC on the number of persons in the US who have an indication to take PrEP and the fraction who are doing so. In 2015, the CDC estimated 1.1 million persons in the US had an indication to take PrEP. The majority were MSM (71%) and most of those with any indication for PrEP were black (44%). A minimal estimate of PrEP use in the US was less than 10%; PrEP coverage for Black and Hispanic Americans was less than that for White Americans. This is a travesty and a tragedy; we are in desperate need of leadership and activism.
CROI: By Race/ethnicity, Blacks Have Highest Number Needing PrEP in the United States, 2015 (03/28/18)
CROI: The PrEP Care Continuum and HIV Racial Disparities among Men Who Have Sex with Men (03/28/18)

IV. Drug-Drug Interactions
I have picked just a few of the drug-drug interaction studies presented at CROI 2018 that highlight the importance of this field to the pharmacotherapy of HIV infection by identifying drug combinations to be avoided and strategies to manage others.
a. EFV and ATV/r profoundly alter, in different directions, the levels of vaginal ring contraceptives (Abstract 141). Kim Scarsi and colleagues have previously shown EFV can significantly reduce levonorgestrel concentrations in women using the levonorgestrel implant, and that this reduction was associated with contraceptive failure and unintended pregnancies (see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772838/ ).
At CROI 2018, Dr. Scarsi presented the results of ACTG 5316, which evaluated whether EFV and ATV/r based ART would alter the plasma contraceptive concentrations released from a vaginal ring. 74 HIV-infected women were evaluated, 25 controls and 25 taking EFV and 24 taking ATV/r. The vaginal ring product used was NuvaRing, which contains an estrogen and a progestin. Of these 2 components, the progestin component is primarily responsible for suppressing ovulation (preventing pregnancy). Compared with control, concentrations of etonogestrel (the progestin) in the presence of EFV were decreased approximately 80%; in the presence of ATV/r, etonogestrel concentrations were increased approximately 80%. These data indicate that EFV is likely to impair the effectiveness of the vaginal ring contraceptive and that women receiving EFV should use an alternative method of contraception.
WEBCAST: http://www.croiwebcasts.org/console/player/37313?mediaType=slideVideo&&crd_fl=1&ssmsrq=1522766287513&ctms=5000&csmsrq=696
b. Once Daily TAF and Rifampin - this combination may be OK (abstract 28LB). Rifamycins (rifampin, rifabutin and rifapentine) are presently not recommended to be given with TAF because of a concern that co-administration will decrease TAF concentrations. A study presented at the 16th European AIDS Conference (see: http://www.natap.org/2017/EACS/EACS_65.htm ) evaluated TAF 25 mg twice-daily in combination with 600 mg rifampin (RIF) in healthy volunteers. The mean ratio of tenofovir plasma concentrations with to without RIF was 0.799. The mean ratio of intracellular TFV-diphosphate concentrations was 0.763. These data indicate that twice-daily TAF given with RIF achieve plasma concentrations about 20% lower and intracellular concentrations about 25% lower than the usual once daily TAF dose without RIF. Importantly, the intracellular concentrations (which are responsible for anti-HIV activity) achieved by TAF even when given with RIF were still about 2-fold higher than those seen with usual dose TDF. These data would suggest that TAF 25 mg twice daily with RIF could be clinically acceptable. This study did not evaluate plasma and intracellular concentrations with the usual 25 mg once daily dose of TAF when given with RIF.
At CROI 2018, Cerrone and colleagues filled in that important gap: the effect of RIF on plasma and intracellular tenofovir concentrations with given with TAF 25 mg once daily (abstract 28LB). 17 healthy volunteers received TAF 25 mg once daily alone, then TAF with 600 mg of RIF, and finally TDF (no concomitant RIF). Plasma concentration of tenofovir were reduced approximately 55% when TAF was given with RIF, confirming the expected interaction between TAF and RIF. Intracellular tenofovir concentrations were reduced approximately 40% in the presence of RIF. However, when the tenofovir intracellular concentrations seen with TAF plus RIF were compared with those achieved by TDF, the concentrations were about 80% higher with TAF plus RIF.
When TDF is given with RIF, there is no clinically important change in the plasma PK parameters of tenofovir (see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC547290/ ). This would imply that there is also no change in the intracellular tenofovir concentrations, though they were not measured. There are no recommendations against concomitant administration of TDF with RIF. The data from Cerrone and colleagues provide a strong pharmacologic basis to support co-administration of TAF at the usual dose of 25 mg once daily with RIF. This should be confirmed, because it is generally a good idea and also because these studies were done in healthy volunteers and not those who would benefit from this combination, HIV-infected persons co-infected with TB.
WEBCAST: http://www.croiwebcasts.org/console/player/37065?mediaType=slideVideo&&crd_fl=1&ssmsrq=1522768494958&ctms=5000&csmsrq=739
c. Twice daily bictegravir (BIC) isn't enough when given with rifampin (abstract 34). This study conducted in healthy volunteers evaluated whether 50 mg of BIC twice daily would be sufficient to overcome the enzyme inducing effects of rifampin (RIF). It wasn't. The ratios of BIC concentrations when given twice daily with RIF compared with once daily and no RIF were: AUC, 0.395; Cmax, 0.53, and Ctrough, 0.197. The 80% reduction in trough concentrations could not be expected to achieve the high level of virologic response seen in the clinical trials of BIC.
CROI: Pharmacokinetics of Bictegravir Administered Twice Daily In Combination With Rifampin - (03/06/18)
d. On a brighter note, preliminary data on twice daily DTG given with RIF look promising. Dooley and colleagues reported interim results of a twice-daily DTG based ART regimen vs. an EFV based regimen in ARV-naïve persons receiving RIF containing TB therapy (abstract 33). At week 24, the proportions of participants with plasma HIV RNA < 50 copies/mL were DTG, 81% and EFV, 89%. The investigators stated the lower DTG response rate was driven by non-treatment related failures. Twice daily DTG was well tolerated. We will need to see the complete results of this study before concluding twice daily DTG is safe and effective when given with RIF, but so far the result are promising. These data do provide additional support for the ability to use standard dose EFV (600 mg once daily) based ART with a RIF-containing TB regimen, a point that seems to be overlooked.
There is likely to be a practicality issue for the dosing of DTG and TAF with RIF-containing TB therapy. A generic formulation of DTG/FTC/TAF (50mg/200mg/25mg) has recently received tentative FDA approval for the PEPFAR program (see: http://newsroom.mylan.com/2018-02-20-Mylan-Receives-Tentative-Approval-for-Combination-HIV-Treatment-DTG-FTC-TAF-Under-FDAs-PEPFAR-Program ). Assume that twice daily DTG when given with RIF is safe and effective, and once daily TAF (vs. twice daily) with RIF is as well. How will this be accomplished with such a generic fixed dose table formulation? Would you give just an extra dose of DTG? Or, would you give two tablets of the DTG/FTC/TAF generic formulation. Or, would you use a once daily EFV based regimen? Something to think about.
e. It is unlikely that rifampin (RIF) can be given with long-acting cabotegravir and rilpivirine. Physiologically based pharmacokinetic modeling (PBPK) has become a very useful tool to predict, for example, drug disposition, drug-drug interactions, and clinical efficacy. Rajoli and colleagues (abstract 458) predicted the effect of RIF if given with long-acting cabotegravir (CAB-LA) and rilpivirine (RPV-LA). This PBPK study predicted that CAB concentrations would be reduced approximately 40% and RPV concentrations by about 80% with RIF co-administration. This magnitude of reductions would result in subtherapeutic levels. The logistics and ethics of conducting this study in healthy volunteers let alone in HIV-infected persons with TB are almost, if not completely, insurmountable - and these modeling results don't provide any reason, in my opinion, to do so.
V. New Drugs
I've written before about the development of MK-8591 (EFdA). This is a very potent NRTI with a long plasma and intracellular half-life. The development of this drug continues and at CROI 2018 two abstracts were presented.
a. Abstract 26 described a dose finding study of MK-8591 in healthy volunteers. Doses of 0.25 mg, 0.75 mg and 5 mg daily were evaluated with measures of plasma and intracellular concentrations, and rectal and vaginal tissue concentrations. The authors concluded the lowest dose of 0.25 mg once daily provided concentrations that would be associated with anti-HIV activity. That appears true. But, in the single dose study in HIV-infected persons presented at IAS in 2017, doses of 10 and 30 mg achieved a greater drop in HIV-RNA at 7 days than did a dose of 0.5 mg. At steady state, a dose of 0.25 mg once daily would about maintain the intracellular concentration seen at 7 days after a single dose of 10 mg. I don't think the present data are strong enough to pick 0.25 mg once daily as the optimal dose for MK-8591. Fortunately, the phase II study will evaluate daily MK-8591 doses of 0.25 mg, 0.75 mg and 2.25 mg combined with doravirine and 3TC (see https://clinicaltrials.gov/ct2/show/NCT03272347?term=NCT03272347&rank=1 ). This study should provide the PK and PD basis for that selection.
b. Abstract 89LB described the evaluation of progressively lower oral doses of MK-8591 for their ability to prevent SHIV infection in macaques. These investigators had demonstrated that 3.9 mg/kg once weekly prevented SHIV infection (intrarectal challenge) in 8 of 8 macaques. These macaques were then given de-escalating doses of 1.3 mg/kg, 0.43 mg/kg, and finally 0.1 mg/kg. All animals remained uninfected at the 1.3 and 0.43 mg/kg doses; 2 of the 8 became infected at the 0.1 mg/kg dose. The mean estimated MK-8591 intracellular triphosphate concentration at the 0.1 mg/kg dose was 24 fmol/10^6 cells; the mean triphosphate concentration at 0.43 mg/kg was 102 fmol/10^6 cells. This will be informative for the design of PrEP studies using MK-8591: 24 fmol/10^6 cells wasn't enough for 100% protection; 102 fmol/10^6 cells was, in a short-term challenge study in macaques. I'll repeat my caveat above that while these are very informative data for human PrEP studies, I don't think they are strong enough to select, for example, 102 fmol/10^6 cells as a threshold concentration for complete protection.
CROI: Low-Dose Oral MK-8591 Protects Monkeys From Rectal SHIV Infection - (03/06/18)
All in all, CROI 2018 was an outstanding meeting, and progress on several fronts was reported. CROI 2019 will be in Seattle, WA on March 4-7, 2019.
%CV, percent coefficient of variation
ABC, abacavir
ACTG, adult AIDS clinical trials group
APV, amprenavir
ARV, antiretroviral drug
ART, antiretroviral drug therapy
AUC, area under the concentration-time curve
ATV, atazanavir
BIC, bictegravir
BID, twice daily
C12, drug concentration at 12 hours post dose
Cmax, maximum drug concentration
Cmin, minimum drug concentration
CVC, cenicriviroc
CNS, central nervous system
c or COBI, cobicistat
CSF, cerebrospinal fluid
CVF, Cervicovaginal fluid
Ctrough, concentration immediately before the next dose
CYP, cytochrome P450 drug metabolizing enzymes
DBS, dried blood spot
DCV, daclatasvir
DHHS, Department of Health and Human Services
DSMB, data safety monitoring board
DTG, dolutegravir
DRV, darunavir
ddI, didanosine
DOR, doravirine
EFV, efavirenz
EVG, elvitegravir
FDV, faldaprevir
FTC, emtricitabine
ETR, etravirine
fAPV, fosamprenavir
GMR, geometric means ratio
HAND, HIV-associated neurocognitive disorders
HDAc, histone deacetylase
IC50, concentration of drug required to inhibit viral replication in vitro by 50%
IC90, concentration of drug required to inhibit viral replication in vitro by 90%
IDV, indinavir
IM, intramuscular
IQ, inhibitory quotient
IVR, intra-vaginal ring
3TC, lamivudine
LDV, ledipasvir
LPV, lopinavir
MVC, maraviroc
MPA, medroxyprogesterone acetate
NVP, nevirapine
NRTI, nucleoside reverse transcriptase inhibitor
NNRTI, non-nucleoside reverse transcriptase inhibitor
PACTG, pediatric AIDS clinical trials group
PBMCs, peripheral blood mononuclear cells
PD, pharmacodynamic
PEG-IFN, pegylated Interferon
PG, pharmacogenetics/pharmacogenomics
PK, pharmacokinetic
PI, inhibitor of HIV protease
PrEP, pre-exposure prophylaxis
QD, once daily
r or RTV, ritonavir
RAL, raltegravir
RBT, rifabutin
RBV, ribavirin
RPT, rifapentine
RIF, rifampin
RPV, rilpivirine
SQV, saquinavir
SC, subcutaneous
SOF, sofosbuvir
TAF, tenofovir alafenamide
TDF, tenofovir disoproxil fumarate
TFV, tenofovir
TDM, therapeutic drug monitoring
TPV, tipranavir
TB, tuberculosis
ZDV, zidovudine