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Clinical Pharmacology at CROI 2017
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Courtney V. Fletcher, Pharm.D.
Dean and Professor
College of Pharmacy
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 2017 (24th) Conference on Retroviruses and Opportunistic Infections (CROI) was held in Seattle, WA, from February 13-16, 2017. CROI is the premier HIV-focused scientific meeting. 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) PrEP, (iii) co-morbidities, (iv) drug-drug interactions and (v) new drugs and formulations. 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. The big 3 clinical trials: DTG+RPV maintains virologic suppression after a switch from conventional ART (44LB); Doravirine (DOR) is non-inferior to DRV/RTV (45LB); and Bictegravir (BIC) has virologic activity not significantly different from DTG (41).
These clinical trials presented at CROI 2017 have already received plenty of coverage, and you can find detailed information for each on the NATAP website. I'll give just the bottom line conclusions and provide a few comments.
The SWORD Study (abstract 44LB) showed a switch from current ART in persons with HIV-RNA < 50cpm for 12 months to the once daily combination with food of DTG+RPV (N=513) was non-inferior to remaining on current ART (N=511): 95% of participants in both regimens maintained HIV-RNA < 50cpm. There was an improvement in bone turnover markers for those switched to DTG+RPV.
Abstract 45LB gave the 48 weeks results of the phase III trial of doravirine (DOR) 100 mg once daily or DRV/RTV, both in combination with dual NRTIs in ARV-naïve persons. In 769 persons, DOR was non-inferior to DRV/RTV: proportions with HIV-RNA < 50cpm at week 48 were 84% for DOR and 80% for DRV/RTV. Rates of adverse events were similar between both arms, including, importantly, the rates of neuropsychiatric events (11% DOR recipients and 13% DRV/RTV recipients).
Bictegravir (BIC) was compared with DTG both given with TAF/FTC in a phase II trial in ARV-naïve persons (Abstract 41). At weeks 24 and 48, there was no difference in the proportions with HIV-RNA <50cpm: week 48 results were 97% for BIC vs. 91% for DTG. Both regimens were equally well tolerated. The results of this paper have now been published in Lancet HIV: https://www.ncbi.nlm.nih.gov/pubmed/28219610
A few words about the clinical pharmacologic profile of BIC (Abstract #40). BIC has a long half-life of 18 hours, which allows for once daily dosing. It is hepatically metabolized by the cytochrome P450 (CYP) system and by glucuronidation. As such, it will be susceptible to some drug-drug interactions. Co-administration of BIC with DRV/COBI increased the AUC of BIC by approximately 70% (primarily a CYP inhibition effect). Co-administration with ATV/COBI, however, increased the AUC of BIC by 310% or nearly 4-fold, because of a combined inhibition of CYP and glucuronidation. Rifampin decreased the AUC of BIC by 75%. BIC had no effect on the PK of oral contraceptives.
These three clinical trials show treatment options for HIV-infected persons that are potent, safe and convenient continue to expand – and that is good news. A regulatory filing for DTG+RPV is planned. This will presumably be in a fixed dose combination (FDC) tablet given that bioequivalence studies of a FDC have been completed (see https://clinicaltrials.gov NCT02741557 and NCT02373930). The 12 month results of the 2 drug maintenance regimen are encouraging evidence for this approach. But, I would be slow to declare victory. 12 months of evidence is short when viewed from the need for life-time therapy for the HIV-infected person.
What impressed me the most with the DOR vs. DRV/RTV study was that it went up against a potent PI and was virologically non-inferior. There was no difference in neuropsychiatric adverse effects supporting DOR is superior to EFV in this regard and additionally, DOR recipients had statistically significant lower levels of fasting low density lipoprotein cholesterol (LDL-C), versus DRV/RTV group. Doravirine is also being evaluated in several ongoing studies as a fixed dose single tablet regimen with 3TC and TDF.
Finally, BIC (with TAF and FTC) phase III trials are fully enrolled (see NCT02607930 and NCT02607956); we may see 48 week results the end of this year. A FDC of BIC+TAF+FTC is being used in the phase III trials and the BIC dose has been reduced from the 75 mg used in the phase II studies to 50 mg, because of improved bioavailability in the FDC. The entry (presumably) of the FDC of BIC/TAF/FTC will be interesting 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 will be fierce.
CROI: SWORD 1 & 2: Switch to DTG + RPV Maintains Virologic Suppression Through 48 Weeks, a Phase III Study
CROI: Randomized Trial of Bictegravir or Dolutegravir with FTC/TAF for Initial HIV Therapy
CROI: Doravirine in Non-Inferior To Darunavir+Ritonavir in Phase 3 Treatment-Naive Trial at Week 48
CROI: Bictegravir Dissociation Half-life from HIV-1 G140S/Q148H Integrase-DNA Complexes
b. From the D:A:D study: cumulative use of DRVRTV, but not ATV/RTV, was independently associated with a small, but increased cardiovascular disease risk (Abstract 128LB).
The Data Collection of Adverse Events of Anti-HIV Drugs (D:A:D) study is an international collaboration that has provided important data on ARV safety. For example, and relevant to this abstract, is the association of first generation protease inhibitors and an increased risk of myocardial infarction (MI), see: http://www.nejm.org/doi/pdf/10.1056/NEJMoa062744
In Abstract 128LB, the D:A:D investigators reported on 35,711 patients who have been prospectively followed from the original cohort of 49,709 participants. After adjustment for other potential causes such as smoking status, kidney and liver function, 5-year cumulative exposure to DRV/RTV was independently associated with a 53% increased risk of cardiovascular disease (CVD; a composite endpoint of MI, stroke, sudden cardiac death, etc.). No increased risk was seen with ATV/RTV. The investigators stated the relationship for DTV/RTV was not explained by dyslipidemia, as suggested for first generation PIs.
These results are a signal and should not be dismissed; but, D:A:D is an observational study. What we need now is a mechanistic understanding.
CROI: Cessation of cigarette smoking and the impact on cancer incidence in the D:A:D Study
CROI: Association between Cardiovascular Disease & Contemporarily Used Protease Inhibitors - D:A:D
II. Pre-Exposure Prophylaxis (PrEP)
There is no question that PrEP with TDF/FTC works – when taken; it is highly effective and very safe. Two particular challenges then are how to increase access and improve adherence. A Themed Discussion (TD5) called PrEP Without Borders: New Delivery Options addressed these challenges, and I think the abstracts presented deserve some mention.
With regard to access, Abstract 961 presented an evaluation of the feasibility of a pharmacist run (through a collaborative practice agreement between a pharmacist and physician) PrEP clinic in a community pharmacy setting in Seattle, WA. The investigators found a higher than expected response from MSM persons seeking PrEP indicating the clinic was meeting a need. The patient retention rate was also very high at 75%. Finally, the clinic PrEP services were found to be financially sustainable.
Pharmacists in Virginia evaluated a pharmacist run HIV testing clinic through community pharmacies (Abstract 962). They found the setting met a need for persons who would not obtain testing at other sites such as local health departments.
The knowledge pharmacists in Nebraska and Iowa have regarding PrEP was evaluated in Abstract 963. Of 140 respondents, slightly more than half were familiar with the CDC guidelines for PrEP. 54% indicated they were likely or very likely to provide PrEP services with additional training.
78% of patients who filled a PrEP prescription at a municipal STD clinic in Seattle, WA opted in to a text messaging service to improve adherence and retention (Abstract 964). Those who opted in were significantly more likely to remain clinic patients than those who did not (76% vs. 53%).
The effect of a brief behavioral intervention on PrEP adherence was evaluated in a community clinic in New York City (Abstract 965). After 3 months, those who received the behavioral intervention had higher self-reported adherence and higher measured tenofovir concentrations in dried blood spots.
Collectively, these abstracts identify some remaining challenges and point the way to improving access and adherence to PrEP. Of the challenges, pharmacist knowledge of PrEP guidelines must be improved, particularly because the pharmacist is the most accessible health care professional. A pharmacist run PrEP clinic located in a community setting was shown to improve access to PrEP services (think of this similar to pharmacist provided flu shots). Text messaging improved patient retention and brief behavioral interventions improved retention and importantly, adherence as measured by tenofovir concentrations.
III. Co-Morbidities
There is plenty that can be written about co-morbidities from CROI 2017. In terms of where we need to focus attention and can make an impact, these two abstracts on smoking and myocardial infarction (MI) made a big impact on me.
HIV-infected adults have a 1.5 to 2-fold increased risk of MI compared with uninfected adults. Investigators with NA-ACCORD evaluated 29,515 adults; the median follow-up was 3.5 years; there were 347 MIs (Abstract 130). "Adjusting for demographics, eliminating smoking, hypertension, and hypercholesterolemia would avert 38%, 41% and 43% of MIs, respectively; eliminating all three would avert 86% of MIs."
The D:A:D initiative evaluated the benefits of smoking cessation on cancer risk (Abstract 131). 39,701 persons contributed 315,327 person years of follow-up; median follow-up was 9 years. At baseline, 46% were smokers, 20% ex-smokers, 31% never smoked and 4% unknown. Here are the bottom line findings: (1) smoking increased the risk of all cancers; and (2) smoking-related cancers, except lung cancer, declined after individuals stopped smoking. The incidence of lung cancer remained elevated for at least 5 years after smoking cessation.
The data are pretty clear, we can significantly reduce HIV-related morbidity and mortality if we eliminate smoking. Smoking cessation programs must become a major focus and effort.
IV. Drug-Drug Interactions
I have picked just two drug-drug interaction studies to highlight: to illustrate the unexpected and remind us that drug-drug interactions may occur with non-oral drug administration.
a. Drug interaction study of DTG with weekly isoniazid (INH) and rifapentine (RPT) was terminated early because of serious toxicities (Abstract 409a).
This healthy volunteer study was designed to evaluate the effects of weekly INH/RPT on the PK of DTG. The study enrolled 4 individuals; 3 completed the study and 1 withdrew before completing the study. 2 of the 3 who completed the study developed moderate to life-threatening (grade 2-4) adverse reactions including nausea, vomiting, fever, hypotension and elevated hepatic transaminases. Based on these adverse reactions, the study was terminated. DTG concentrations were reduced in the presence of INH/RPT: the AUC was reduced by 46% and trough concentrations by 74%. The mechanism of this effect is likely rifapentine-associated enzyme induction. RPT concentrations were consistent with historical data. INH concentrations, however, were significantly increased: concentrations were 67-92% higher than reference values in the 2 subjects who developed hepatic transaminase elevations. The mechanism of the increase in INH concentrations is not clear.
The increase in INH concentrations and hepatotoxicity were unexpected. Though the DTG and INH/RPT interaction had not been previously evaluated, a PK study in healthy volunteers had evaluated DTG PK with rifampin or rifabutin (but neither with INH). In that study, safety was acceptable, although one person did develop fever and hypotension, but no increase in liver transaminases (see: https://www.ncbi.nlm.nih.gov/pubmed/23075918 ). And, based on those results, the IAS-USA treatment guidelines had recommended DTG as an acceptable ARV choice with rifamycin-based anti-TB therapy (see: http://jamanetwork.com/journals/jama/fullarticle/2533073 ). Based on the safety and PK results of the DTG with INH/RPT study, co-administration of this combination should be avoided. I believe it would also be prudent, if possible, to avoid co-administration of DTG with either rifampin/INH or rifabutin/INH. Treatment choices for the HIV and TB-infected person are limited. It is important to identify the mechanism of this interaction promptly.
b. EFV may impair etonogestrel contraceptive implant efficacy (Abstract 938).
Kim Scarsi and colleagues have previously shown that 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/). IMPAACT study 1026s (Abstract 938) evaluated the effect of 3 ARV regimens on etonogestrel (ENG) PK in women using ENG implants for contraception. Median ENG concentrations with ATV/r and LPV/r were 604 and 469 pg/mL, respectively, and no participant had ENG concentrations < 90 pg/mL (ENG concentrations > 90 pg/mL are believed to reliably suppress ovulation). In contrast, when given with EFV, the median ENG concentrations were 42 pg/mL (about one-tenth) and 6 of 9 (67%) women had levels < 90 pg/mL. No significant effects were seen on ARV concentrations. One pregnancy occurred in a women taking EFV at 16 months after insertion of the ENG implant; the concentrations of ENG 6-7 weeks after the insert was implanted (and with the woman taking EFV) were 88.7 pg/mL. These data suggest the EFV based ART may impair the efficacy of the ENG implant and that women should use an alternative or additional contraceptive method.
V. New Drugs and Formulations
One of the exciting and promising aspects for the future of anti-HIV therapeutics at CROI 2017 was the clear evidence that the field of drug discovery and drug development is alive. Here are some of the new drugs presented and then a few words about the development of new formulations.
New NRTIs: GS-9131 and EFdA (MK-8591). NRTIs have a well-established record of safety and efficacy for treatment and prevention of HIV-infection. There are needs for new NRTIs such as for patients with NRTI resistance, and new opportunities for long-acting and/or parenteral formulations to complement or pair with other long-acting parenteral agents (e.g. cabotegravir).
a. GS-9131 has activity against HIV-1 with resistance patterns that other NRTIs are not active against (Abstract 436). GS-9131 is the prodrug of GS-9148 that has potent, broad activity against HIV-1 and HIV-2. The drug looks to have good selectivity (the balance between therapeutic vs. toxic effects). This isn't the first we have heard of GS-9131 and GS-9148. Papers in 2008 and 2009 described the design, activity and nephrotoxic potential (see: http://aac.asm.org/content/52/2/648.full.pdf+html and http://aac.asm.org/content/52/2/648.full) and preclinical PK data were presented at CROI 2008). The 2009 paper stated that GS-9131 was being evaluated in the clinic. The abstract authors stated an IND for development of GS-9161 was filed in December 2016 by Gilead.
b. EFdA (MK-8591) achieved lymph node concentrations in rats greater than those in blood, and has activity against HIV-2 including against multi-NRTI-resistant strains (Abstracts 435 and 440). I've written previously about EFdA (see 2016 CROI report). This is a very potent NRTI, with a long plasma and intracellular half-life, which may allow weekly oral dosing, and even more prolonged, perhaps every 6-month parenteral dosing. At this meeting two abstracts extended our knowledge. Abstract 435 reported that concentrations of EFdA assessed by quantitative whole body autoradiography (QWBA) were higher in the lymph node of rats than in the blood. This characteristic is important given the role of lymphoid tissues in HIV replication and persistence. What the QWBA is not able to tell us, however, is how much of the EFdA measured was EFdA-triphosphate, which is the pharmacologic-active moiety – this will be an important gap to fill in. EFdA-triphosphate concentrations were determined in rectal and vaginal tissue of macaques, and were found to be approximately equivalent after 7 days of oral dosing. This may indicate EFdA has different vaginal tissue penetration than TDF, as lower concentrations of TFV-diphosphate are seen in vaginal tissues. Clearly, lots more work to be done with MK-8591, but I think this remains a promising NRTI to keep your eyes on.
c. GS-CA1 is a potent HIV capsid inhibitor, with PK characteristics suggestive of potential for extended release formulation (Abstract 38). HIV capsid has an essential role in the life cycle of HIV, and inhibition of capsid function may impair viral particle assembly and maturation. GS-CA1 is very potent, in fact in vitro studies indicate it is more potent than currently approved NNRTIs, PIs, and INSTIs. Mechanistic studies indicate GS-CA1 inhibits late stage virion maturation that would result in a non-infectious virus, and also inhibits capsid core disassembly, an early life-cycle event. In rats, a single subcutaneous injection of GS-CA1 maintained plasma concentrations 9-fold higher than the protein-binding EC95 for more than 10 weeks. This might allow monthly dosing in humans. Obviously, time and lots of studies (and money) will tell us whether the promise of GS-CA1 can be translated into human therapeutics.
CROI: MK-8591 Concentrations at Sites of HIV Transmission and Replication
CROI: Antiviral Activity of EFdA [MK-8591] Against NRTI-Sensitive and -Resistant Strains of HIV-2
CROI: GS-9131 is a Novel NRTI with Activity Against NRTI-Resistant HIV-1
New Formulations.
There were several presentations at CROI 2017 the showed progression of new formulation development.
d. Oral nanoparticles allow dose reduction of EFV and LPV (Abstract 39). Andrew Owen and colleagues from Liverpool developed oral nanoformulations of EFV and LPV, and demonstrated in healthy volunteers that a 300 mg dose (one half of usual) of the EFV-nano would achieve bioequivalence with the oral 600 mg dose, and that a 200 mg dose (one half of usual) of LPV-nano, given with 100mg of RTV, would be bioequivalent with 400/100 LPV/RTV. What is most important about this work is that it is the first demonstration, to my knowledge, that an oral nanoformulation of an ARV, at a 50% dose reduction, can achieve bioequivalence with the conventional formulation. All other nanoformulation work with ARVs has been with parenteral formulations. Thus, this is an important step forward. Additionally, these 50% dose reductions would translate into a projected saving of $243 million.
e. A modified nanoformulation of cabotegravir (CAB) shows improved PKPD in mice (Abstract 439). Howard Gendelman and colleagues from Nebraska developed a modified nanoformulation of CAB that they called NMCAB, and compared the PKPD of this formulation with the current long acting parenteral version (CAB-LAP). In mice, they found that NMCAB had a longer elimination half-life and improved penetration into lymph node and spleen. When evaluated in HIV-infected humanized mice, there was evidence that NMCAB compared with CAB-LAP had improved anti-HIV effects in plasma and in tissues, such as the spleen, lung, lymph node and gut. I think an important take home message from this work is that all nanoformulations are not created equal – that plasma and tissue PK and therefore PD will be influenced by the characteristics of the nanoformulation itself.
CROI: A LONG-ACTING NANOFORMULATED CABOTEGRAVIR PRODRUG FOR IMPROVED ANTIRETROVIRAL THERAPY
CROI: HUMAN CONFIRMATION OF ORAL DOSE REDUCTION POTENTIAL OF NANOPARTICLE ANTIRETROVIRAL FORMULATIONS
f. Are long-acting antiretrovirals a paradigm shift? For those of you who are interested in the current status and future prospects for long acting antiretrovirals, I would urge you to take 30 minutes and listen to Dr. Charles Flexner's presentation on the topic as part of the Modern Art symposium on the final day of the conference. This was among the very best presentations at CROI 2017, and clearly and thoughtfully discusses myths and truths about this field and where it is heading. http://www.croiwebcasts.org/p/2017croi/croi33659
CROI: Long Acting HIV ART - is this the future? Nanoformulations - Implants
All in all, CROI 2017 was an outstanding meeting, and progress on several fronts was reported. CROI 2018 will be in Boston, MA, March 5-8, 2018.
Abbreviations
%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
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