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Clinical Pharmacology at CROI 2023
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Courtney V. Fletcher, Pharm.D.
Professor
UNMC Center for Drug Discovery
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 2023 (30th) Conference on Retroviruses and Opportunistic Infections (CROI) was an in-person and virtual CROI. 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) new drugs, pharmacokinetics 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
Several abstracts were presented on long-acting cabotegravir-rilpivirine (LA-CAB/RPV). The following is a summary of some of those abstracts and some commentary.
SOLAR - switch to LA-CAB/RPV or continue BIC/F/TAF (#191).
The SOLAR study randomized 670 individuals with HIV-RNA <50 cpm for >6 months on BIC/F/TAF to either continue on that regimen (n=223) or switch (n=447) to every two-months (Q2M) LA-CAB/RPV (with or without an oral lead-in). 47% of population at baseline reported an always/often psychosocial challenge with daily oral therapy. At month 12, the primary endpoint, LA-CAB/RPV was non-inferior to continuing oral BIC/F/TAF. By intention-to-treat exposed (ITT-E) analysis, 3 in the LA-CAB/RPV arm developed confirmed virologic failure (CVF) with resistance versus none (0) in the BIC/F/TAF arm. For the secondary analysis of HIV-RNA <50cpm, the proportions were 90% for LA-CAB/RPV and 93% for BIC/F/TAF. Rates of adverse reactions leading to withdrawal were: 16 (4%) in LA-CAB/RPV and 2 (<1%) for BIC/F/TAF.
CROI: SOLAR 12-MONTH RESULTS: RANDOMIZED SWITCH TRIAL OF CAB+RPV LA VS ORAL B/FTC/TAF - (03/27/23)
Low CAB and RPV concentrations seen in patients switching to LA-CAB/RPV (#195).
At two hospitals in Paris, concentrations of CAB and RPV were monitored 58 persons with HIV-RNA <50 cpm switching from oral therapy to LA-CAB/RPV. These investigators selected threshold concentrations for CAB and RPV of 1120 ng/mL and 32.1 ng/mL, which are the reported 1st quartile values, 4 weeks after the 1st injection, from data in 1039 persons receiving LA-CAB/RPV (Cutrell AG, et al. AIDS 2021; DOI:10.1097/QAD.0000000000002883 ). At months 1 and 3 after the start of LA-CAB/RPV they found the percent of persons with concentrations below these thresholds were 60% and 77% for CAB and 28% and 27% for RPV. There were notable differences in CAB concentrations at 1 and 3 months depending on whether oral lead-in dosing was used. At month 3, for example, the median trough in those who received oral lead-in was 1103 ng/mL, compared with 625 ng/mL in those who did not. Furthermore, interpatient variability, particularly in CAB concentrations was high. At month 3, for example, the interquartile range for CAB concentrations was 440 to 1087 ng/mL. CVF occurred in 1 participant, who had low CAB and RPV concentrations at month 1 (CAB 701 ng/mL and RPV 27.2 ng/mL) and no other risk factors for VF.
CROI: Low trough concentrations of cabotegravir and rilpivirine in patients infected with HIV switching to long-acting treatment - (02/23/23)
Thigh injections of LA-CAP/RPV (#519LB).
Presently, LA-CAB/RPV is injected into the gluteal muscle by a health care provider. Injection of LA-CAB/RPV into the thigh muscle (vastus lateralis) was evaluated in 118 participants of the ATLAS-2M study receiving Q4 week and Q8 week injections. No significant differences in CAB and RPV PK were seen in those who received Q4 week administration. In those who received injections Q8 week, there were some comparisons where thigh administration resulted in higher concentrations (for example, CAB maximum concentration after the first thigh injection was higher compared with gluteal), but this was not consistent across all comparisons. There were no PK parameter comparisons where thigh injections resulted in lower concentrations. No participant had an HIV-RNA >50 cpm during this 16-week substudy. Injection site reactions (ISRs), with pain the most common, did not appear different for thigh and gluteal administration.
CROI: Thigh Injections of Cabotegravir + Rilpivirine in Virally Suppressed Adults With HIV-1 - (02/23/23)
Commentary
The SOLAR study showed LA-CAB/RPV was non-inferior to BIC/F/TAF and most who were randomized to the LA-CAB/RPV arm preferred it. But it didn't show better rates of virologic suppression, and it didn't show better tolerance as rates of adverse reactions leading to study withdrawal were higher than once-daily oral therapy with BIC/F/TAF. Furthermore, rates of CVF with resistance were higher with Q2M LA-CAB/RPV. Related, a higher rate of CVF was seen in the 152-week results from ATLAS of Q2M vs QM LA-CAB/RPV. In that study, rates of CVF were 2.3% for Q2M and 0.4% for QM. (Overton ET, Clin Infect Dis 2022, https://doi.org/10.1093/cid/ciad020 ).
In my opinion, the SOLAR study then is as important for what it showed - as for what it didn't show. For PWH who want or need something other than daily oral therapy, LA-CAB/RPV is a good option to have available but given the higher rate of CVF with Q2M dosing, I'd pick monthly LA-CAP/RPV. Finally, SOLAR, as well as ATLAS and FLAIR, with near perfect adherence to LA-CAB/RPV, also showed just how really, really good our current, once daily oral regimens are.
Islatravir (ISL) clinical development has resumed (#192 and 497)
Clinical development of ISL was stopped in Dec 2021 due to a reduction in total lymphocyte counts seen in clinical studies for treatment and PrEP. Across a range of doses from 0.25 to 2.25 mg daily, 20 mg weekly, and 60 to 120 mg every month, a dose/exposure response relationship was observed. A greater reduction in lymphocyte counts was seen with higher doses, for example, 0.75 mg daily, 20 mg weekly, and 60 and 120 mg monthly, vs lower doses. The mechanism reported is accumulation of supratherapeutic concentrations of ISL-triphosphate (ISL-TP) in lymphocytes leading to apoptosis (stated as not related to mitochondrial toxicity).
Abstract 497 describes very nice PKPD modeling of dose and exposure (including ISL-TP concentrations) with response modeling, to select revised ISL doses with a safer lymphocyte profile. As a result of these analyses, a daily dose of 0.25 mg and a weekly dose of 2 mg have been selected for treatment studies, and clinical development of ISL/DOR at 0.25 mg/100 mg once daily, and ISL 2mg with lenacapavir 300 mg orally once weekly have resumed.
CROI: MODELING TO OPTIMIZE ISLATRAVIR QW DOSE IN HIV VIROLOGICALLY SUPRESSED PWH - (02/24/23)
CROI: Islatravir at CROI 203: treatment, prevention, LA implant - (02/28/23)
Lenacapavir (LEN)
LEN (formerly GS-6207) is a first in class, highly potent inhibitor of the HIV-1 capsid protein, with an elimination half-life of 30-40 days. HIV capsid is essential for virus replication at multiple stages of the life cycle. Safety and PK data in healthy volunteers were presented at CROI 2019, dose-response information at CROI 2020, drug-interaction and phase 2/3 data in heavily ART-experienced persons at CROI 2021, and week 54 data in 182 treatment-naïve persons at CROI 2022. LEN was approved by the FDA for treatment of HIV in heavily treatment-experienced adults in Dec 2022. The FDA-approved label can be found at this link:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215973s000lbl.pdf
At CROI 2023, multiple abstracts on the continued development of LEN were presented. A population PK analysis (abstract #504) showed that a ± 2-week window for every 6-month (26 weeks) maintenance therapy with subcutaneous (SC) dosing maintained adequate concentrations. The ± 2-week window is included in the FDA-approved label. The 52-week results of the phase 3 trial in persons with multidrug-resistant HIV (CAPELLA) were presented in abstract #523. Overall, 78% (56/72) persons had HIV-RNA <50 cpm at week 52. The 26-week results of this trial have been published and can be found here: https://www.nejm.org/doi/full/10.1056/NEJMoa2115542
Week 80 results of SC LEN with oral ARVs and oral LEN and ARVs were presented in abstract #522. Using the FDA shapshot analysis, the proportions of the 4 dosing regimens with HIV-RNA <50 cpm at week 80 were: SC LEN (every 6 months) plus oral TAF, 87%; SC LEN plus oral BIC, 75%; daily oral LEN plus oral FTC/TAF, 87%; and oral BIC/FTC/TAF, 92%. Abstract #992 described an investigation of SC LEN for PrEP of SHIV rectal transmission in macaques. Complete protection was observed in the animals with LEN concentrations above the target value. These data provide support for HIV prevention studies. Finally, abstract #193 described a phase 1 study of SC LEN combined with 2 long-acting broadly neutralizing antibodies (bNAbs) all given every 6 months. 124 PWH on ART with HIV-RNA <50 cpm were screened for susceptibility to each of the 2 bNAbs and 55 were susceptible to both. 21 were enrolled and 20 completed the study. 18 of 20 participants had HIV-RNA <50 cpm at week 26. These results show promise for a twice yearly (i.e., every 6 month) treatment regimen, but the need for susceptibility screening to both bNAbs and the number of PWH screened who were excluded on that basis (56%, 69/124) presents a rather daunting hurdle.
CROI: Long-Acting Lenacapavir in a Combination Regimen for Treatment Naïve PWH: Week 80 - (02/25/23)
CROI: Week 52 Subgroup Efficacy of Lenacapavir in Heavily Treatment-Experienced PWH - (02/24/23)
CROI: LENACAPAVIR WITH bNAbs GS-5423 AND GS-2872 DOSED EVERY 6 MONTHS IN PEOPLE WITH HIV - (02/23/23)
CROI: CROI 2023: Lenacapavir Treatment, Prevention - (03/01/23)
Anticholinergic medication use and side effect (i.e., burden) in PWH (#502).
Anticholinergic medications or drugs with anticholinergic side effects (hereafter, ACMs) are among the most commonly used prescription and over-the-counter medications. These include drugs such as: amitriptyline, codeine, diphenhydramine (Benadryl) citalopram (Celexa), loperamide and cetirizine (Zyrtec). Abstract #502 investigated ACM burden in 721 PWH. 23%, essentially 1 in 4, were taking an ACM. 28.6% experienced at least one side effect. The most common were: constipation (20.1%), serum electrolyte abnormalities (16.5%), dry mouth (14.6%), daily sleepiness (7.9%) and prolonged QTc (6.7%). Related, at CROI 2022, users of ACMs were more likely to report falls (17% vs 6% in non-ACM users, p<0.001) and frailty (32% vs 17%, p<0.001). Use of ≥2 ACMs was associated with an increased odds of falling after adjustment for confounders (Abstract 35). These drugs are overused and can be associated with serious adverse reactions. Clinicians should avoid and reduce use of ACMs as much as possible.
CROI: Screening approaches and clinical description of the anticholinergic burden in people with HIV - (03/02/23)
Common ARV combinations and depressive symptoms in women (#469).
The effects of ART regimens on somatic (sleep, appetite) and non-somatic (sadness) depressive symptoms were investigated in 1538 Women's Interagency Study (WIHS) participants. The most common ARVs were TDF (54%) and TAF (20%); INSTIs were used by 49%, NNRTIs by 33% and PIs by 31%. Women were divided into 3 groups based on depression scale scores: high, low and none. In the high depression group, TAF in combination with a cobicistat-boosted EVG, DRV or both (EVG and DRV) was associated with greater somatic symptoms, while no difference was observed with TDF in these combinations. This finding is surprising to me: there isn't an obvious mechanistic difference between TAF and TDF that would explain this; CSF concentrations of tenofovir are lower with TAF than TDF (although this doesn't necessarily mean brain tissue concentrations are). This finding clearly warrants further study.
CROI: EFFECT OF COMMON ANTIRETROVIRAL COMBINATIONS ON DEPRESSIVE SYMPTOMS IN WOMEN WITH HIV 2nd report - (03/02/23)
Another HIV Cure.
In a paper published in Nature Medicine coinciding with CROI 2023, the authors report an update of a man in Düsseldorf, Germany, who received a CCR5Δ32/Δ32 (i.e., HIV resistant) hematopoietic stem cell transplant and has now been monitored for more than 9 years and off ARV therapy for four years. There is no evidence of viral rebound and no immunological correlates of antigen exposure. Thus, strong evidence for another cure of HIV. The Nature Medicine paper can be found here: https://www.nature.com/articles/s41591-023-02213-x
II. Pre-Exposure Prophylaxis (PrEP)
Delayed LA-CAB dosing in HPTN 084 (#159).
This abstract described CAB concentrations in women who participated in HPTN 084 and received LA-CAB and had a delayed injection. The effect of the delayed injection on CAB concentrations was evaluated as a function of whether the concentration was ≥4 times or >8 times the protein-adjusted 90% inhibitory concentration (PA-IC90). Not surprisingly, a delay in injections decreases the concentrations of CAB in the body more than would be seen with on-time injections. For example, in the Q8 week phase of LA-CAB administration, 94% of CAB concentrations were ≥8x PA-IC90 and 100% were ≥4x PA-IC90 at the time of the next injection (i.e., 8 weeks later). When injections were delayed by 4-6 weeks, 6-8 weeks and 8-10 weeks, the proportion of CAB concentrations that were <4x PA-IC90 were 2%, 6% and 10%. CAB concentrations <4x PA-IC90 likely increase the risk of acquiring HIV infection, as seen in the one participant who acquired HIV and had a CAB concentration of 0.42 µg/mL, which is <4x PA-IC90. The authors concluded these data might allow up to a 6-week delay in LA-CAB dosing. These data have been suggested as a motivation to study quarterly dosing. Importantly, the authors of #159 emphasized that evidence would be needed to support this alternative regimen in women and should not be pursued in men because of different pharmacokinetic characteristics.
Regarding whether quarterly dosing should be pursued in women, I certainly understand the desire to give injections no more frequently than needed. But, when I look at these data, I don't see a convincing argument for a dosing interval less often than q8 weeks. Less frequent dosing will increase the proportion of women who have concentrations at trough <4x PA-IC90 and pose some increased risk of acquiring HIV. Furthermore, I think the only way such a regimen could be approved (or not), would be by doing a head-to-head study of the HPTN 084 regimen with the proposed alternative. HPTN enrolled more than 3000 women in 20 research sites in 7 countries over 3 years at a cost of I don't know how many hundreds of millions of dollars. Those dollars would buy a lot of q8week LA-CAB for women where the need is greatest now.
CROI: Cabotegravir Pharmacology in the Background of Delayed Injections in HPTN 084 - (02/22/23)
Pharmacy PrEP delivery in Kenya (#978).
Speaking of getting PrEP where it is needed, abstract 978 described pharmacy delivered PrEP or PEP in Kenya. The motivation is these pharmacies may reach populations at risk that are not reached by public health facilities. Important results of this pilot project are that (1) pharmacy providers are capable of initiating and managing clients on PrEP or PEP and (2) 70-100% of clients reported they liked getting their PrEP or PEP at the pharmacy. This work emphasizes the need to get PrEP and PEP services where the need is.
Adherence Symposium (#O2) - Monitoring Antiretrovirals and Adherence
I'd refer readers interested in adherence testing today and in the future, digital technologies and strategies for improving adherence to this symposium. The three lectures provided a great overview. I'd particularly call out Peter Anderson's lecture on the Landscape of Adherence Testing.
III. New Drugs, Pharmacokinetics, and Formulations
CROI has been a home during these last few years for drug development for COVID-19 and this year, for Mpox. In keeping with that, I'll start this section with 2 abstracts on COVID-19 - a new drug and guidance on drug-drug interaction (DDIs)
Ensitrelvir for mild-to-moderate COVID-19 (#166).
Ensitrelvir (S-217622) is an inhibitor of 3C-like protease (like nirmatrelvir, the active drug in Paxlovid) essential for the replication of SARS-CoV-2. Ensitrelvir has recently received regulatory approval in Japan for SARS-CoV-2 and clinical trials in non-hospitalized and hospitalized patients with COVID-19 are underway in the US and other countries. Different from nirmatrelvir/ritonavir (Paxlovid), ensitrelvir does not require co-administration with ritonavir and has a much longer elimination half-life of approximately 48 hours. Similar to nirmatrelvir/ritonavir, however, ensitrelvir is a substrate and an inhibitor of CYP3A, and is also an inhibitor of certain transporters including P-gp and BCRP. Thus, it has the potential to be both a victim and perpetrator of DDIs.
Abstract 166 described a phase 2/3 placebo-controlled trial of ensitrelvir in persons with mild-to-moderate COVID-19. Ensitrelvir was given for 5 days, as a 375 mg oral loading dose on day one followed by 125 mg orally for the next four days. The time to resolution was significantly shorter in ensitrelvir recipients, by a median of approximately 1 day, and the decrease in viral RNA titers was significantly greater by approximately -1.5 logs. There were no deaths or serious adverse reactions in either group and the rates of adverse events were similar between ensitrelvir and placebo. Ensitrelvir appears to be a very promising drug.
CROI: Ensitrelvir for mild-to-moderate COVID-19: Phase 3 part of Phase 2/3 study - (03/14/23)
DDI guidance for COVID (#515)
Abstract 515 describes a global collaboration among the University of Liverpool, the Ontario Science Table contributors, and the NIH COVID-19 Guidelines Panel to develop guidelines for DDI management for nirmatrelvir/ritonavir (NMV/r). The basis for NMV/r DDI management during clinical trials and as found, for example, in the FDA EUA is that for ritonavir use for treatment of HIV infection. The short, 5-day course of treatment for COVID-19, however, creates an opportunity for more permissive guidance but requires expert review and interpretation. An additional opportunity is to harmonize DDI guidance across three widely used sources for DDI management. The abstract describes the methods and results of this effort - and that indeed these DDI experts were able to harmonize recommendations and arrive at some more permissive co-administration recommendations. You can find these recommendations in the links below from Liverpool, Ontario, University of Waterloo/University of Toronto, and the NIH:
• https://covid19-druginteractions.org
• https://hivclinic.ca/downloads/paxlovid/paxlovid_guide_live.pdf
• https://www.antimicrobialstewardship.com/paxlovid-ddi-oncology
https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/ritonavir-boosted-nirmatrelvir--paxlovid-/?utm_source=site&utm_medium=home&utm_campaign=highlights
As I mentioned above, ensitrelvir is a substrate and an inhibitor of CYP3A, and is also an inhibitor of certain transporters including P-gp and BCRP. Thus, it has the potential to be both a victim and perpetrator of DDIs. This global collaboration has recently expanded their efforts to incorporate DDI information and guidance on ensitrelvir into their websites. The Liverpool COVID DDI checker now includes ensitrelvir, and they have prepared a very nice side-by-side comparison chart of DDIs for the major therapies - you can download this chart here:
www.covid19-druginteractions.org/prescribing_resources/summary-antiviral [covid19-druginteractions.org]
A few brief bullets:
EFV and Nicotine (#509).
The nicotine metabolite ratio (NMR) is a validated biomarker for nicotine metabolism. A higher NMR has been associated with higher daily cigarette use and greater difficulty with stopping smoking. Abstract #509 investigated the NMR in PWH on EFV-based ART switching to non-EFV-containing ART. The NMR was higher in those on EFV. This may be because of the known enzyme inductive effects of EFV. Smoking is much more common in PHW than in the general population. This abstract is intriguing because it suggests certain drugs, in this case EFV, may contribute to a greater difficulty with success in stopping smoking.
TAF-EVG rectal insert (#164).
Abstract #164 described the development of a fast-dissolving rectal insert containing TAF and elvitegravir (EVG) as a potential product for PrEP. 21 volunteers inserted one (n=21) or two (n=19) inserts and concentrations were measured in plasma, and rectal fluid, tissue and cells. High rectal fluid and tissue concentrations of EVG and TFV were seen, but systemic concentrations were low. In an ex-vivo model of HIV infectivity with rectal tissue explants, inhibition of HIV infection was seen for up to 72 hours. The product appeared to be safe. Collectively the results indicate potential for on-demand HIV prevention.
CROI: Good Rectal TAF/EVG Levels With Rectal Inserts in HIV-Negative Men and Women - (02/25/23)
Ultra-long acting islatravir implant (#165).
This abstract described the development of an islatravir (ISL) refillable, long-acting implant for HIV PrEP. A 20-month PK study was done in macaques (NHPs) and the efficacy for prevention of rectal and vaginal efficacy was evaluated. ISL was loaded into the implant after implantation and constant concentrations of ISL and ISL-TP were maintained over 20 months. 100% protection against infection from both rectal and vaginal challenge was observed. The implants were well tolerated. Though there is a long way to go before this technology might be shown to have clinically utility, it is nonetheless exciting and demonstrates the potential of new drug delivery technology.
CROI: Vaginal PrEP Efficacy of Biodegradable Islatravir Implants in Macaques Islatravir Implant Protects Macaques From Vaginal SHIV Infection - (02/24/23)
CROI: ULTRA LONG-ACTING REFILLABLE ISLATRAVIR IMPLANT FULLY PROTECTS NHP AGAINST SHIV - (02/23/23)
It was a delight to attend the meeting in person, along with 2946 others, and while there was a lot of catching-up to do, we were able to see and hear the outstanding science of CROI 2023. The efforts of the organizers to sustain the meeting and the quality expected during the COVID-19 pandemic have been extraordinary. I look forward to being in Denver in March 2024 for the 31st CROI 2024.
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
CAB, cabotegravir
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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