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Clinical Pharmacology at CROI 2022
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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 2022 (29th) Conference on Retroviruses and Opportunistic Infections (CROI) was the 3rd Virtual CROI because of the COVID-19 pandemic. 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) pharmacokinetics, pharmacodynamics and pharmacogenomics, and (iv) 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
NADIA - at week 96, DTG and DRV/r remain non-inferior, but tenofovir is now superior to zidovudine (#137).
The NADIA trial was designed to address 2 questions: first, whether DTG was non-inferior to DRV/r in second line therapy and second, whether TDF/FTC was non-inferior to ZDV/3TC. At CROI 2021, week 48 results showed equivalent proportions of participants achieved the primary outcome of plasma HIV-RNA <400 at week 48: 90.2% of DTG and 91.7% of DRV/r. For the second question, the week 48 results showed that TDF was non-inferior to ZDV: 92.3% of TDF recipients and 89.6% of ZDV recipients achieved plasma HIV-RNA < 400 copies/mL at week 48. These results were published in the NEJM
( https://www.nejm.org/doi/pdf/10.1056/NEJMoa2101609?articleTools=true ).
At CROI 2022, the investigators presented updated results to the end of the trial at week 96. At week 96, the proportions undetectable with DTG and DRV remained essentially unchanged: 89.8% for DTG and 86.9% for DRV. However, the findings for TDF compared with ZDV, were now different showing superiority for TDF: 91.8% in the TDF group and 84.8% in the ZDV group had HIV-RNA <400 copies/mL. Viral rebound to ≥1000 copies/ml occurred in 5.6% in TDF recipients compared with 14.3% in the ZDV group. Furthermore, 5 of the 6 cases of DTG resistance occurred in the ZDV group, suggesting some protective effect of TDF. I wrote last year that despite the non-inferiority finding of TDF vs. ZDV at week 48, I thought it was preferable to maintain use TDF over switching to ZDV. These 96 week results provide clear evidence to do so and illustrate the value of long-term follow-up.
Lenacapavir (LEN) given subcutaneously (SC) or orally maintains high rates of virologic suppression at 1 year (#138).
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 who received single doses SC were presented at CROI 2019, dose-response information at CROI 2020, and drug-interaction and phase 2/3 data in heavily ART-experienced persons at CROI 2021.
At CROI 2022, abstract #138 described week 54 data in 182 treatment-naïve persons randomized to 1 of 4 regimens. The regimens were: SC LEN with daily TAF, SC LEN with daily bictegravir (BIC), oral LEN with daily TAF/FTC, or oral BIC, TAF, FTC. Those who received SC LEN first received 28d of SC LEN with daily oral TAF/FTC. At week 54, proportions with plasma viral load <50 copies/mL were: 90%, 85%, 85%, and 92% across the 4 treatment groups, respectively. LEN was well tolerated: only 3 participants discontinued SC LEN for injection site reactions; the most common non injection related side effect were headache and nausea. These data add to accumulating evidence that LEN given SC (every 6 months) or orally is potent, well-tolerated and produces substantial declines in viral load in treatment-naïve and experienced persons (see abstract #491 for week 52 results in treatment-experienced persons). Continued evaluation is warranted for treatment of HIV.
Anticholinergic medications are associated with falls and frailty (#35)
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). Common side effects of anticholinergics are: dry mouth, blurred vision, dizziness, cognitive disturbance (confusion) urinary retention and constipation. Abstract 35 reported on the use of ACMs and falls and frailty in 669 HIV-infected persons >50 years. ACM use was reported by 193 (28%) with 64 (9%) on ≥2 ACM. The most commonly used ACMs were codeine (12%), citalopram (12%), loperamide (9%), amitriptyline (7%) and diazepam (6%). Those participants using ACMs use 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.
Because of the seriousness of side effects associated with ACMs, The Beers Criteria (J Am Geriatr 2019; 67:674-94), which are highly regarded guidelines of medications inappropriate in older adults, recommend that ACMs should be avoided. This investigation in HIV-infected persons shows how common the use of ACMs is and potentially serious complications associated with their use. Clinicians should avoid and reduce use of ACMs as much as possible.
Point-of-Care testing for urine tenofovir to guide drug resistance testing (#s 451 and 515).
A central question in persons on ART with detectable virus is whether the viremia is a result of drug resistance or low adherence. Drug resistance testing is costly (including the laboratory infrastructure), isn't rapid and requires expert interpretation. Measuring drug concentrations could be used to inform whether (a) the expected concentrations of drug are present, which would provide a basis for resistance testing or (b) no or low drug concentrations are present, which would indicate a need for adherence counseling and avoid unnecessary resistance testing. For recent discussions on this topic, I have cited 3 recent published papers below.
Abstract 451 presented information on use of a point-of-care (POC) test for the presence of tenofovir (TFV) in urine. These investigators used a case-controlled study where cases all had viral loads ≥200 copies/mL and controls all had viral loads <50 copies/mL. TFV was positive in 30.7% (70/228) of case samples and in 100% (53/53) of control samples. These results show a negative urine test for TFV has high specificity for viremia. In those cases with confirmed failure and sequencing data (n=44), NRTI resistance was detected in 50% (10/20) with at least 1 TFV positive sample versus 8.3% (2/24) of cases with continuously TFV-negative samples. This finding shows that participants with viremia and a positive urine TFV test (such as might arise from intermittent adherence) had a higher risk of resistance to the NRTI backbone, which may confer an increased risk of selection of integrase resistance.
This work demonstrated the potential utility of a POC urine test for TFV, where in persons with viremia, a negative urine test would identify persons with low adherence, who don't need drug resistance testing but might benefit from adherence counseling, and a positive test would indicate an increased risk for drug resistance and thus a need for drug resistance testing. This study used the OraSure POC test for urine TFV, which is a POC test available for research use (see: https://www.orasure.com/products-infectious/Objective-Adherence-Testing.html ). A POC urine test is also available for research use from UrSure (see: https://www.ursureinc.com/how-it-works ). See also abstract 515 at this meeting for the use of a TFV POC urine test to detect drug resistance.
Measurement of drug concentrations has been shown to discriminate the efficacy of PrEP, predict risk of future viremia in those on treatment, and inform on emergence of resistance and the need for drug resistance testing. Testing approaches are expanding to commercial easy-to-use POC tests. I believe the value in patient management is clear. What is necessary going forward, in my opinion, is broader implementation of drug concentration measurement and additional demonstrations of the need and value; the availability of analytical technology is not going to be a rate-limiting step.
For additional reading, see: (1) Kristofich M, Anderson PL, Castillo-Mancilla JR. Ther Adv Infectious Dis 2021; 8:1-4; (2) Hermans L et al, J Acquir Immune Defic Syndr 2021;87:1072-1078; and (3) Hermans L et al, JIAS 2020;23e25501.
II. Pre-Exposure Prophylaxis (PrEP)
An update on the efficacy and safety of CAB-LA vs. TDF/FTC in HPTN 083 (#96).
CAB-LA, given IM every 8 wks, has been shown superior to oral, daily TDF/FTC for prevention of HIV infection (Landovitz R, NEJM Aug 12, 2021). At CROI 2022, the HPTN 083 investigators presented efficacy and safety data on one year of additional follow-up. 46 additional incident HIV infections were identified: 13 in CAB-LA recipients and 33 in TDF/FTC; 4 occurred during the blinded phase (2 CAB, 2 TDF/FTC), 42 after unblinding (11 CAB, 31 TDF/FTC). The 2 new blinded CAB arm infections were both in the setting of on-time injections; the 11 newly-identified unblinded CAB arm infections included 1 with on-time injections, 3 with delayed injections, and 7 that occurred ≥6 months after the last CAB exposure (2 of these 7 never received a CAB injection). No new safety concerns were identified. The hazard ratio favoring CAB-LA remained unchanged from the first-reported blinded analysis through this additional year of follow-up.
A pressing question is why does CAB-LA fail for PrEP in some persons with perfect adherence? This question also extends to CAB-LA and RPV-LA for maintenance treatment of HIV-infection. I've written before about some potential reasons. Possible intrinsic factors include: biologic sex, age, weight and body composition, co-infections and inflammation, and pharmacogenomic. Possible extrinsic factors include: lead-in regimen, maintenance dosing regimen and pharmacokinetics, administration technique, pharmacodynamics, concomitant medications, rectal inflammation related to sexually transmitted infections and adherence. From the ATLAS and FLAIR treatment trials, some information has emerged showing that BMI ≥ 30kg/m2 , in addition to at least one other factor, is associated with an increased risk of confirmed virologic failure (see: https://pubmed.ncbi.nlm.nih.gov/33730748/ ). I believe it is quite important to carefully investigate possible reasons. If, for example, body size (weight, BMI) is important or the dosing interval (every 8 weeks for PrEP or every 4 or 8 weeks for treatment) those are "fixable" problems. Though the numbers of persons who fail LA PrEP or therapy are small, I believe we have an obligation to see if we can make failure an even less frequent occurrence.
On demand and daily PrEP had equivalent rectal mucosal efficacy in an ex vivo explant model (#441).
At CROI 2021, the results of the Prevenir study - an ongoing open-label evaluation of daily or on demand PrEP with TDF/FTC were reported. On demand dosing is a double dose of 2 TDF/FTC tablets taken 2-24 hours before sex, a third tablet 24 hours after the first two, and a fourth tablet 48 hours after the first two tablets (2+1+1). No difference in the number of participants who acquired HIV infection was found between these 2 approaches to PrEP (CROI 2021, Abstract 148).
At CROI 2022, the Prevenir team reported results of an investigation of the mucosal efficacy of TDF/FTC using an ex vivo rectal tissue infection model. The rectal biopsies were obtained from Prevenir study participants taking on demand (n=13) and daily (n=12) TDF/FTC. There was no difference in efficacy between the 2 dosing regimens, as judged by levels of p24 antigen. These data are consistent with the results available to date from the Prevenir study and indicate this model may be useful to evaluate other dosing strategies or PrEP agents.
Serum hormone concentrations are not affected by TDF/FTC PrEP and no changes in effect of hormone therapy were perceived in those taking PrEP(#84).
In this study, transgender men (TGM) and women (TGW) participating in a PrEP study had DBS samples obtained for TFV-DP concentrations and sex hormones were measured. There was no difference in TFV-DP levels between those not on sex hormones and those receiving them. Among the TGW on stable estrogen, there was no difference in serum estradiol concentrations after the start of TDF/FTC PrEP. Similarly, among TGM on stable testosterone, there was no difference in testosterone levels after the start of PrEP. There were also no changes in participant satisfaction with the desired effects of hormone therapy or gender transition. These findings are reassuring that TFV-DP concentrations are not affected by hormone therapy, and that conversely, hormone therapy is not affected by TDF/FTC PrEP.
Pharmacy-based PrEP initiation in Kenya (#928).
A pilot study of PrEP initiation and maintenance at 5 private retail pharmacies in western and central Kenya is described in Abstract 928. 575 clients accessing services associated with HIV risk at these retail pharmacies were screened and 287 (49%) were initiated on PrEP. PrEP continuation rates were 54% at 1 month, 35% at 4 months and 21% at 7 months. None who continued in care acquired HIV infection. These continuation rates were reported to similar to or to exceed those in public clinics. This is a novel model of PrEP delivery in Kenya and in sub-Saharan Africa that shows promise to improve convenient access and thereby reduce barriers to PrEP.
III. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics
Dose adjustment needed for levonorgestrel (LNG) when used for emergency contraception by women also taking rifampin (#77).
LNG is metabolized by CYP3A4 and rifampin is a well-known, potent inducer of CYP3A4. Thus, there is a potential for rifampin to significantly lower LNG concentrations and reduce the effectiveness of LNG when used for emergency contraception. Abstract 77 investigated the PK of a double-dose of LNG (3mg) in women taking RIF and compared those values to women on DTG-based ART but not receiving rifampin who received the usual dose (1.5mg). The maximum concentration (Cmax) of LNG is considered the PK parameter linked with effectiveness of emergency contraception. Median Cmax with the usual LNG dose was 18.7 ng/mL and with the double dose was 28 ng/mL. These data support use of double-dose LNG in women also taking concomitant rifampin.
Avoid concomitant use of darunavir/cobicistat (DRV/c) with rifapentine/isoniazid (#431).
Rifapentine/isoniazid is a recommended therapy for latent tuberculosis (LTBI) in persons with HIV infection (PWH). Abstract 431 investigated the PK of DRV/c (800/150 once daily) with once weekly rifapentine/isoniazid in healthy volunteers. The AUC and C24 (trough) of DRV were significantly decreased, up to 71% and 96%, respectively, with rifapentine/isoniazid, with some C24 concentrations less than the protein-binding adjusted 50% effective concentration (PA-EC50) of 0.055 µg/mL. DRV/c should not be used with rifapentine/isoniazid.
Twice daily DTG could be OK with daily rifapentine/isoniazid but proceed cautiously (#78).
Abstract 78 presented an interim analysis of PK data on the combined use of DTG with rifapentine/isoniazid from 25 of 36 planned participants who had an indication for LTBI treatment. These participants were on DTG-containing ART (50mg QD) with HIV RNA <50. All received 28-days of daily rifapentine/isoniazid (600mg/300mg) with DTG increased to 50mg BID during concomitant therapy. At baseline of DTG 50mg once daily, the median trough concentration was 1745 ng/mL and was 2146 ng/mL on day 28 (at 50mg twice daily with rifapentine/isoniazid). The investigators chose a threshold DTG concentration of 158 ng/mL. At Day 28, all troughs remained above 158 ng/mL. However, a small number of participants had trough concentrations that approach this threshold value.
These data appear to suggest that doubling the DTG dose to 50mg twice daily allows concomitant therapy with rifapentine/isoniazid. However, there are some uncertain aspects. First, and there were several questions from the audience on this point, is the basis for selecting 158 ng/mL as the threshold concentration. This is the 5th percentile of trough concentrations at the DTG dose of 10mg from the SPRING-1 dose ranging study in treatment-naïve persons. Why the 5th percentile of a dose that isn't clinically used or FDA approved? And, why values in treatment-naïve persons when the intended population is HIV-infected persons needing LTBI treatment who may be treatment-experienced? In a DTG vs. RAL study in treatment-experienced persons who were INSTI-naïve, an FDA efficacy analysis found that those with DTG troughs in the lowest quartile (median 260 ng/mL) had the lowest virologic response rates (HIV-RNA <50 copies/mL at week 24.
(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf )
It is worth noting that at baseline on 50mg once daily, all of these study participants had DTG trough concentrations >600 ng/mL. Why is it a good idea to allow their troughs to drop as low as 158 ng/mL? I think the 158 ng/mL threshold is too low. With a higher threshold such as above 260 ng/mL from the FDA analysis, a small number of participants could have trough concentrations below this value placing them as some risk for loss of virologic control. If clinicians are going to use this regimen the DTG dose should be increased to 50mg twice daily and I'd suggest close, careful monitoring of plasma HIV-RNA.
Is Machine Learning - Artificial Intelligence the future for predicting clinically relevant drug interaction (#430).
One of the real challenges in the drug-drug interaction (DDI) field is predicting the clinical relevance of a DDI (or DDIs among several concomitant medications). Abstract 430 may be a glimpse into the future. Investigators developed a deep learning algorithm that has the ability to learn from actual data (physicochemical properties and Liverpool DDI database) and extract patterns to make future predictions. In this investigation, the deep learning algorithm had an overall accuracy of 85% in predicting DDIs among first-line ARVs and 687 comedications. Pretty good - and I for one would be happy to take all the help I can get in predicting clinical significance of DDIs!
IV. New Drugs and Formulations
A few brief bullets:
Abstract 80 described an approach to combine DTG or CAB and etonogestrel (ENG) or medroxyprogesterone acetate (MPA) into a single formulation for prevention of HIV infection and unplanned pregnancies. PK and safety studies in mice supported feasibility. Further development of such multipurpose prevention technology will be exciting to watch.
LONG-ACTING INJECTABLE FOR PREVENTION OF HIV AND UNPLANNED PREGNANCY
Abstract 82 described the safety and PK of a tenofovir (TFV)-containing vaginal ring intended to provide 90 days of HIV prevention. 40 women, not HIV infected, were enrolled into a Phase 1 study. Results showed that TFV-diphosphate concentrations were above the target of 1000 fmol/mg in cervical tissue for 56 days, but then dropped to 456 fmol/mg by day 91. The ring was well tolerated. While this version did not achieve the target of 90 days of effective concentrations, the potential remains.
Abstract 446 described a newer approach to long-acting (LA) drug delivery of subcutaneous injection of a formulation that then forms an implant, which releases drug and could be removed to stop drug delivery. This technique was applied to doravirine (DOR). The injection of 2 LA-DOR formulations in mice showed drug release for 5 months and high penetration to relevant tissues (e.g., vagina, cervix, rectum). When LA-DOR was given as PrEP, 1 of 8 mice that received DOR became infected compared with 4 of 5 controls. This is a promising approach to LA drug delivery with the advantage that the implant can be removed. Another quite interesting approach to watch for further development.
Islatravir (ISL) is a very potent NRTI with a long plasma (≈ 60 hrs) and longer intracellular half-life (≈ 190 hrs). ISL has been under development, in both oral and implant formulations, for treatment and prevention, and several abstracts were presented at CROI 2022 (see: 83, 85, 444, 445). However, all clinical development of ISL is presently on hold because of decreases in total lymphocyte and CD4+ T-cell counts in some participants. The mechanism of this effect isn't clear. It does seem to have some resemblance to the decrease in total lymphocyte and CD4+ T-cell counts seen with longer-term didanosine (ddI) therapy. The mechanism of this ddI adverse effect is suggested to be a reduction in endogenous nucleotide concentrations in PBMCs.
This unfortunate development with ISL reminds us that drug discovery and development is a risky endeavor, with, on average, only 1 in 8 compounds that reach clinical trials ultimately receiving FDA approval. The development of antiretroviral agents has been so extraordinarily successful we sometimes forget that.
The science of CROI 2022 was outstanding, as usual. The efforts of the organizers to sustain not just the meeting but the quality expected during the COVID-19 pandemic were extraordinary. I look forward to being at CROI 2023 - in person.
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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