Clinical Pharmacology at CROI 2020
Courtney V. Fletcher, Pharm.D. |
UNMC Center for Drug Discovery
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 2020 (27th) Conference on Retroviruses and Opportunistic Infections (CROI) was to be held in Boston, from March 8-11, 2020, but instead became the 1st 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
DTG had superior virologic efficacy compared with EFV and TAF/FTC had fewer adverse pregnancy outcomes in pregnant women who started therapy at 14-28 weeks gestation (IMPAACT 2010 #130LB).
Last year, I led off my 2019 review of the pharmacotherapy of HIV infection with two studies in pregnant women. I'm continuing that this year with the IMPAACT 2010 study in pregnant women that I thought was the most important clinical trial presented at CROI 2020. In this study, ART-naïve, pregnant women between 14-28 weeks gestation were randomized to one of 3 treatment arms: DTG+TAF/FTC; DTG+TDF/FTC; and EFV+TDF/FTC. Just over 200 women were enrolled in each arm. The primary virologic endpoint was proportion with HIV-RNA <200 copies/mL at delivery. This study found the combined DTG arms had superior virologic efficacy vs EFV: 97.5% of DTG recipients vs. 91% of EFV had HIV-RNA <200 copies/mL. The DTG arms also had a shorter time to viral suppression. For the endpoint of any adverse pregnancy outcome, the rates for the 3 arms were: TAF/FTC+DTG, 24.1%; TDF/FTC+DTG, 32.9%; and TDF/FTC+EFV, 32.7%. The TAF/FTC+DTG arm had fewer adverse pregnancy outcomes and fewer neonatal deaths.
This study strongly supports current guidelines that recommend DTG as a preferred agent for ARV-naïve pregnant women because of superior virologic efficacy compared with an EFV-based ART regimen. Equally important, this study provided new data on ART safety that indicated TAF/FTC is safer than TDF/FTC in pregnant women.
CAB+RPV every two-months in non-inferior to once-monthly intramuscular injection (ATLAS-2M #34).
Much has already been written about this study (see the natap.org website) so I'll only highlight the bottom line. ATLAS-2M enrolled 1045 participants who were randomized to every two-months (Q8W) or once-monthly (Q4W) CAB+RPV IM injections. 391 of the participants receiving Q4W as part of the ATLAS study transitioned to ATLAS-2M. At 48 weeks, 94.3% of Q8W and 93.5% of Q4W participants had HIV-RNA <50 copies/mL, meeting the definition of non-inferiority. Virologic non-response rates (HIV-RNA ≥50 copies/mL at week 48) were 1.7% (n=9) vs. 1% (n=5) for Q8W and Q4W, respectively. Adverse reactions, including injection site reactions (ISR) were similar between the arms, though interestingly, the Q8W ISR rate was 30% vs. 20% for Q4W. So, less frequent injections didn't achieve a lower frequency of ISRs.
My interpretations. ATLAS and FLAIR demonstrated that Q4W CAB+RPV was non-inferior to oral ART for maintenance of HIV-RNA suppression. ATLAS-2M showed that Q8W CAB+RPV was non-inferior to Q4W also in persons who have achieved suppression of plasma HIV RNA to <50 copies/mL. CAB+RPV has received regulatory approval in Canada, for virologically stable and suppressed persons, given once-monthly. Long-acting CAB+RPV represents an advance in HIV pharmacotherapy and the biggest implication right now, in my opinion, is a contribution to patient choice and convenience. That Q4W CAB+RPV, even with perfect adherence (as in the ATLAS and FLAIR studies) isn't better than oral ART is important to acknowledge, and in some ways is a limitation given that other therapeutic advances have more often been shown superior to existing therapies; for example, DTG was superior to EFV and to DRV/r (NEJM 2013, DOI: 10.1056/NEJMoa1215541 and Lancet 2014, DOI: 10.1016/S0140-6736(14)60084-2 ).
There is a lot we need to learn about use of long-acting CAB+RPV, for example, management of the prolonged pharmacokinetic tail after treatment discontinuation, how Q4W or Q8W injections will be administered in clinical settings, and management of non-adherence. Additionally, is the current dosing regimen optimal? Long-acting CAB and RPV accumulates to steady-state slowly: CAB reaches steady-state at approximately 44 weeks while RPV is at 80% of steady-state by week 48. For both drugs, between weeks 8-12 after the start of IM dosing, average plasma concentrations are 2-fold lower, approximately 1400 ng/mL for CAB and 40 ng/mL for RPV, than at week 48. Furthermore, interpatient PK variability with injectable CAB and RPV is higher than oral. In ATLAS and FLAIR combined, six participants receiving LA-CAB+RPV had virologic failure; none missed any injections. All six had CAB and RPV plasma concentrations lower than the average and some were less than the 5th percentile, approximately 380 ng/mL for CAB and 17 ng/mL for RPV, values only 2-fold above the protein-binding adjusted IC90 , versus the intended >4-fold above; indicating an increased risk of virologic failure associated with low CAB and RPV concentrations. In the ATLAS trial, it is notable that virologic failure was detected between weeks 8-20 in the three participants. As adherence was perfect (i.e., no missed injections) we have to acknowledge that the "patient did not fail therapy" but rather, "the therapy failed the patient". These findings point to the need for optimization of the dosing regimen particularly as this strategy moves outside of clinical trials and to scenarios of less than perfect adherence, as well as investigations of individual characteristics, such as gender and high body-mass-index that may be associated with an increased risk, early after initiation of LA CAB+RPV, for virologic failure.
Every-2-Month Maintenance CAB + RPV Noninferior to Monthly Dosing for 48 Weeks - (03/09/20)
LONG-ACTING CABOTEGRAVIR + RILPIVIRINE FOR HIV TREATMENT: FLAIR WEEK 96 RESULTS - (03/11/20)
II. Pre-Exposure Prophylaxis (PrEP)
Strict adherence to TDF/FTC PrEP is necessary for pregnant women, because tenofovir-diphosphate (TFV-DP) are lower during pregnancy (#980).
PK data on TDF/FTC for PrEP in pregnant women are extremely limited. In this study, the PK of TDF/FTC PrEP in pregnant and postpartum adolescent girls and young women (16-24 years) were investigated by measuring tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS). Daily TDF/FTC was administered under direct observation in 20 pregnant (median 18 weeks gestation) and 20 postpartum (median 7 weeks after delivery) adolescent girls and young women. The median TFV-DP concentration was 965 fmol/punch in pregnancy and was 1406 fmol/punch postpartum. For comparison, the median value in men is 1540 fmol/punch. In the iPrEx study, a threshold of 700 fmol/punch, corresponding to ≥ 4 doses per week of TDF/FTC was associated with 86-100% levels of protection from HIV acquisition. In these pregnant adolescent girls and young women, the 25th percentile of TFV-DP concentrations was 650 fmol/punch. Thus, to achieve the same threshold level of protection as in men, daily TDF/FTC is necessary in pregnant adolescent girls and young women.
CROI: TFV-DP in DBS for pregnant/postpartum adolescent and young women on PrEP in Africa - (05/18/20)
Disparities in access to PrEP (#1009).
We are all familiar with the quote "drugs don't work in persons who don't take them". Drugs also don't work in persons who can't get them!
This abstract looked at prior authorization (PA) policies for TDF/FTC PrEP at qualified health plans in the US. PA requires the clinician to obtain approval to use a drug BEFORE it can be prescribed and reimbursed/covered. PA places a burden on the clinician and clinic and creates some delay in the patient receiving the medication. This study found that 37% of qualified health plans in the South region of the US required PA compared with 13% in the Midwest, 6% in the West, and 2% in the Northeast. Plans in the South were 16-times more likely to require PA for TDF/FTC for PrEP than were plans in the Northeast. Within the South, plans in Texas, Florida, Georgia, Mississippi and Arkansas had the highest rates of PA. Requiring PA for PrEP with TDF/FTC in my opinion creates a barrier to access a safe and highly effective drug to prevent acquisition of HIV, and there is no safety or economic justification for it. We have a responsibility to use our voices to stop this practice.
CROI: Study Suggests PrEP Access Issue: Disparity in Prior Authorizations Across US Regions - (05/20/20)
Safety and tolerability of BIC/FTC/TAF for post-exposure prophylaxis (#996)
I thought this was a very informative abstract on the comparative safety and tolerability of ARV regimens for post-exposure prophylaxis (PEP). Investigators at a Boston community health center compared the clinical experience of 48 persons enrolled in a clinical trial of BIC/FTC/TAF for PEP with historical PEP regimens back to 2000. The historical regimens were: AZT/3TC/PI (n=119); TDF/FTC/RAL (n=100); and EVG/c/FTC/TDF (n=100). The most striking finding to me was the differences in rates of completion of the PEP regimen as prescribed: 38%, AZT/3TC/PI; 57%, TDF/FTC/RAL; 71%, EVG/c/FTC/TDF; and 85%, BIC/FTC/TAF. No HIV seroconversions have been detected with the BIC/FTC/TAF regimen. The high rate of completion of the regimen, corresponding with the safety and tolerance, provide support for use of BIC/FTC/TAF for PEP.
FTC/TAF + BIC Postexposure Prophylaxis Protects Macaques Against Rectal SHIV Infection - (03/11/20)
III. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics
CSF penetration of the broadly neutralizing antibody (bNAb) VRC01 and bictegravir (#s 453, 454).
VRC01 concentrations were measured in the CSF of 3 participants in a trial of analytic treatment interruption during acute HIV infection. In these 3 individuals, CSF and plasma samples were obtained 2, 4, and 16 days after the last VRC01 dose. Plasma concentrations were 203 to 528 µg/mL. CSF concentrations were 0.38 to 0.73 µg/mL for an approximate ratio of 1000-fold lower concentrations. It is notable that there was some CSF penetration of VRC01. Whether these concentrations have any anti-HIV activity in the CSF is uncertain, as reported 50% inhibitory concentrations for VRC01 are 1-5 µg/mL.
Abstract 454 described CSF concentrations of BIC/FTC/TAF in 20 PLWH (8 females) with CNS impairment. BIC total plasma concentrations were (median) 2630 ng/mL and unbound plasma was 9.2 ng/mL. Median BIC CSF concentrations were 11.3 ng/mL, consistent with the unbound level in plasma. 95% (19/20) of the measured BIC CSF concentrations were above the CSF IC50 for BIC of 3.5 ng/mL with a median CSF/IC50 ratio of 3.4, which would suggest anti-HIV activity. Median FTC CSF concentrations were 86 ng/mL. Median tenofovir CSF concentrations were 1.5 ng/mL and remember this is with TAF administration.
Some interpretations. First, the BIC CSF concentrations are consistent with those recently reported by Tiraboschi (J Infect Dis 2020, DOI: 10.1093/infdis/jiz624) in 15 PLWH who had median BIC CSF concentrations of 6.9 ng/mL. These investigators also measured unbound concentrations in CSF (vs. in the 454 abstract they measured unbound BIC in plasma). The median unbound BIC level in CSF was 2.5 ng/mL. We are used to thinking that because the CSF has low binding protein concentrations compared with plasma that most drug present in the CSF is unbound. We are finding this isn't uniformly true, and this is seen in the BIC work from Tiraboschi where only 35% of total BIC in the CSF was unbound BIC. This can change our interpretation of anti-HIV activity. Using a CSF IC50 for BIC of 3.5 ng/mL, the CSF/IC50 ratio from Tiriboschi based on total CSF levels is 2 (6.9/3.5), and using unbound CSF the ratio is 0.71 (2.5/3.5). Does this give a clinically important different interpretation of BIC activity in the CSF? We don't know, and this highlights a gap in our pharmacologic knowledge of what should be the target for CSF concentrations of ARVs, a level equal to the IC50 , the IC90 , 4x the IC90 , etc. As approximately 50% of PLWH on ART are estimated to have some form of HIV-associated neurocognitive disorders (HAND) and recent data suggest that even in the setting of long-term viral suppression, there is evidence for ongoing progression of HAND, addressing these gaps in our CSF/CNS pharmacologic knowledge is critical.
Abstract 454 also provided important information on the CSF concentrations of tenofovir (TFV) achieved with TAF. The median TFV CSF concentration was 1.5 ng/mL. CSF concentrations of TFV from TDF administration have averaged around 6 ng/mL, or about 4x higher than with TAF. Remember plasma concentrations of TFV with TAF compared with TDF are quite lower; Cmax, for example is 100-fold lower (30 ng/mL vs. 300 ng/mL). Given the comments above about CSF activity, we need to add to the list answering the question of whether the lower CSF concentrations of TFV with TAF are clinically important.
CROI: INFILTRATION OF VRC01 INTO THE CEREBROSPINAL FLUID IN HUMANS IN THE RV397 STUDY - (05/20/20)
CROI: Bictegravir/FTC/TAF CSF Diffusion in HIV-Infected Patients with CNS Impairment - (05/18/20)
CAB and RPV concentrations persist after treatment discontinuation including in pregnant women (#s 466 and 775).
33 persons who discontinued Q4W and 5 who stopped Q8W had PK assessments 1, 3, 6, 9 and 12 months after stopping. At 3 months after discontinuation, more than 90% of subjects had CAB and RPV concentrations above their respective protein-binding adjusted IC90 . This is consistent with the long elimination half-lives of these drugs, estimated in this study at a median of 47 days for CAB and 207 days for RPV. At 6 months, 38% and 75% had CAB and RPV concentrations, respectively, above their protein-binding adjusted IC90 . 12 months after discontinuation, none had CAB but 50% had RPV concentrations above the protein-binding adjusted IC90. Data were presented in abstract 775 on 3 women who discontinued long-acting CAB + RPV after becoming pregnant. Concentrations of CAB were followed quarterly throughout pregnancy and postpartum for 52 weeks. CAB concentrations were detectable throughout pregnancy and remained detectable postpartum in 2 of 3 women for 2-23 weeks. The decline of CAB in these 3 women followed the same general pattern as seen in men and non-pregnant women. As discussed above, the prolonged presence of residual concentrations will require management strategies after treatment discontinuation and informed approached are yet to be developed. The Canadian approved package insert recommends that it is essential a fully suppressive antiretroviral regimen is started no later than 1 month after the final injection doses of CAB + RPV.
CABOTEGRAVIR PHARMACOKINETIC TAIL IN PREGNANCY AND NEONATAL OUTCOMES (03/17/20)
CABOTEGRAVIR AND RILPIVIRINE PK FOLLOWING LONG-ACTING HIV TREATMENT DISCONTINUATION (03/16/20)
TFV-DP concentrations (in dried blood spots) predict virologic failure and resistance (#520).
TDV-DP concentrations measured in DBS have been shown highly informative of adherence to PrEP and adherence and concentration thresholds have been established. Similarly, TFV-DP in DBS have been shown strongly associated with virologic suppression in PLWH receiving TDF-containing ART (Castillo-Mancilla, Clinical Infect Dis 2018, DOI: 10.1093/cid/ciy708 ). In this study, TFV-DP concentrations were investigated for associations with virologic failure and drug resistance in 2 clinical sites in South Africa. 1000 ART-naïve participants were enrolled. Cases were persons who developed virologic failure (HIV-RNA >1000 copies/mL); controls had a viral load <1000 copies/mL. Geometric mean TFV-DP concentrations (fmol/punch) were: controls, 707; failure but unable to genotype, 402; failure with resistance, 259; and failure without resistance, 56. This study shows the expected, but not often identified, relationship among drug concentrations-response-and resistance. Resistance didn't develop in persons with high levels (consistent with high adherence) and also didn't develop in persons who don't or rarely take the drug (very low adherence = no pressure on the virus to develop resistance); in contract, those with intermediate TFV-DP levels (and adherence) are at risk for virologic failure and development of resistance. DBS measurement of TFV-DP has shown utility for monitoring PrEP adherence; this study shows potential for monitoring adherence to treatment that could extend to a benefit of avoiding emergence of resistance.
High efavirenz concentrations may protect against weight increase (#s 81 and 82).
The ADVANCE trial (NEJM 2019, DOI: 10.1056/NEJMoa1902824 ) compared DTG plus either TAF/FTC or TDF/FTC with EFV/TDF/FTC in 1053 ART-naïve persons in low- and middle-income countries. The percent of participants with HIV-RNA <50 copies/mL at week 48 was: TAF/FTC/DTG, 84%; TDF/FTC/DTG, 85%; and TDF/FTC/EFV, 79%. The DTG regimens were non-inferior to the standard of care regimen, TDF/FTC/EFV. There was greater weight gain with the DTG-containing regimens.
Abstract 81 investigated the risks of metabolic syndrome, diabetes and cardiovascular disease in participants from this trial. Treatment-emergent metabolic syndrome (definition includes presence of clinical obesity) rates were: DTG/FTC/TAF, 8%; DTG/FTC/TDF, 6%; and EFV/FTC/TDF, 3%.
Abstract 82, investigated CYP2B6 genotype and weight gain in participants from the ADVANCE trial randomized to EFV/FTC/TDF. The percent weight gain differed by 2B6 genotype with extensive metabolizers having the greatest weight increase and slow metabolizers the least; the greatest weight increase was seen in female extensive metabolizers. Weight gain in the extensive metabolizers (EFV/FTC/TDF recipients) was no different from that in the DTG/FTC/TDF arm, whereas weight gain was lower in the intermediate and slow metabolizers. These data strongly suggest an association between CYP2B6 and weight gain, where slow metabolizers, who would have the highest EFV concentrations, have less weight gain. Thus, the weight gain differences between the DTG and EFV regimens in the ADVANCE trial, appears attributable to the regimen AND individual pharmacogenomics.
Predicted Rise in Diabetes Risk With TAF/FTC+DTG Versus TDF/FTC+DTG - (03/12/20)
CYP2B6 GENOTYPE AND WEIGHT-GAIN DIFFERENCES BETWEEN DOLUTEGRAVIR AND EFAVIRENZ - (05/06/20)
Suboptimal management of statin dosing with ART is common (#447).
Statin therapy to manage dyslipidemia is common among PLWH taking ART and can be challenging because some ARVs cause increased lipids and some interact with many of the statins. Abstract 447 from the Swiss HIV Cohort Study examined the use of 4 statins, rosuvastatin, atorvastatin, pravastatin and pitavastatin in PLWH who were taking ART. Laboratory assessments included total cholesterol, LDL and plasma concentrations of the statins. Evaluations included whether lipids were controlled or not, and whether the statin dose was correctly adjusted for any drug-interaction or not. In 259 PLWH on one of these 4 statins, the rates of statin underdosing and lipid not controlled were: rosuvastatin, 30%; atorvastatin, 23%; pravastatin, 17%; and pitavastatin, 24%. Overall, the investigators found that 41% of these statin prescriptions were associated with a suboptimal response. Obviously, we need to do better. Managing complex interactions among concomitant medications in PLWH can be challenging, and this is a particular area where involving a clinical pharmacist can be particularly helpful.
CROI: REAL-LIFE MANAGEMENT OF DRUG-DRUG INTERACTIONS BETWEEN ANTIRETROVIRALS AND STATINS - (05/20/20)
IV. New Drugs and Formulations
Safety and pharmacokinetics of GS-9722 in persons not infected with HIV and PLWH (#39).
GS-9722 (now elipovimab, EVM) is a derivative of the broadly-neutralizing antibody (bNAb) PGT121. Remember PGT121 is the bNAb that was combined with a toll-like receptor (TLR) agonist (GS-9620) in SHIV-infected monkeys and demonstrated a delay in virus rebound after ART was discontinued (Nature 2018, doi.org/10.1038/s41586-018-0600-6 ).
In the present study, GS-9722, was given intravenously, in various single and multiple doses to HIV-negative and HIV-infected participants. GS-9722 was safe, had a long half-life of around 26 days, and PK wasn't different between HIV-negative and HIV-infected participants. In the multiple-dose study, a dose of 500 mg achieved concentrations 14-days post dose that were 2x above the target minimum of 50 µg/mL. These data provide support for ongoing studies of EVM as part of combination strategies for HIV cure.
SAFETY & PHARMACOKINETICS OF GS-9722 IN HIV-NEGATIVE PARTICIPANTS AND PEOPLE WITH HIV - (03/09/20)
Dose-response relationship of the long-acting capsid inhibitor, lenacapavir (GS-6207) (#s 469 and 470).
Lenacapavir (formerly GS-6207) is a first in class, highly potent inhibitor of the HIV-1 capsid protein. 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 subcutaneously (SC) were presented at CROI 2019. The elimination half-life ranged from 30-40 days, which should allow use in long-acting regimens.
At CROI 2020, two abstracts were presented: #469, a dose-ranging study with lenacapavir given subcutaneously (SC) in PLWH, and #470, a PK and food effect study of oral lenacapavir in healthy volunteers. For the SC dose ranging study, single doses from 20 to 750 mg were administered as monotherapy for 10 days; BIC/FTC/TAF was started on day 10. Mean day 10 plasma concentrations were 2.6 ng/mL with 20mg, 4.4 ng/mL with 50mg, 13ng/ml with 150mg, and 79ng/mL with 750mg. At day 10, the decrease in HIV-RNA was dose proportional: the mean drop in HIV-RNA with 20 mg was -1.4 log10 and was -2.3 with 750 mg. The single dose oral study gave doses of 50, 300, 900 and 1800mg. Maximum concentrations (approximately 4 hours post dose) were 8.2 ng/mL at 50mg to 53.8ng/mL at 1800mg. The elimination half-life was 11-13 days. Co-administration of lenacapavir with a hi- or low-fat meal did not affect the PK.
These studies indicate that lenacapavir when administered SC had a potent anti-HIV effect at 10 days after a single dose, that concentrations were dose-proportional, and that lenacapavir had a long elimination half-life of 30 days or longer. When given orally, while bioavailability was not 100% and concentrations were not dose-proportional, the drug was still well absorbed and reached concentrations in the SC dosing study associated with a potent anti-HIV effect. There were no short-term safety concerns. Collectively, these data support studies of both SC and oral dosing. Two trials in treatment-naïve (NCT04143594) and heavily treatment-experienced PLWH (NCT04150068) are underway investigating both oral and SC administration.
ABSENCE OF GS-6207 PHENOTYPIC RESISTANCE IN HIV Gag CLEAVAGE SITE AND OTHER MUTANTS (03/16/20)
DOSE-RESPONSE RELATIONSHIP OF SUBCUTANEOUS LONG-ACTING HIV CAPSID INHIBITOR GS-6207 (03/16/20)
PK, Food Effect, and Safety of Oral GS-6207, a Novel HIV-1 Capsid Inhibitor (03/16/20)
Some quick comments on other investigational drugs.
• An oral dose of islatravir (formerly, MK-8591) of 0.75 mg once daily was selected for combination with doravirine, 100 mg once daily for HIV treatment studies (#462). Metabolic outcomes with islatravir in phase 2 study were described in #686.
Modeling-Supported Islatravir Dose Selection for Phase 3 - (03/12/20)
• Fostemsavir, an oral prodrug of temsavir, is an investigational attachment inhibitor. Abstract #463 described investigations of concentration-response relationships. Overall, the data supported a dose of 600 mg twice daily, and that no dose adjustments appear necessary for meals, body weight and strong inhibitors and likely moderate CYP inducers. Coadministration with strong inducers (e.g., rifampin) is contraindicated as significant reductions in plasma concentrations were seen (P-05, 14th Pharmacology Workshop, Amsterdam, April 2013). The results of a phase 3 trial in adults with multi-drug resistant HIV -infection have just been published (Kozal M, et al. NEJM, March 26, 2020).
FOSTEMSAVIR EXPOSURE-RESPONSE RELATIONSHIPS IN TREATMENT EXPERIENCED HIV PATIENTS (03/16/20)
• Two oral prodrugs of tenofovir developed by Merck (correct, Merck, not Gilead) were described in #468. Both of these prodrugs had quite variable reduction in HIV-RNA and neither matched the short-term anti-HIV effect seen with TAF. These authors concluded that these results raise questions about the feasibility of tenofovir prodrugs in extended-interval dosing regimens. I disagree with that conclusion. Just because these 2 prodrugs couldn't match the activity of TAF, I don't believe that in anyway means someone could not develop other prodrugs that match or exceed the potency and duration of the anti-HIV effect of TAF.
MK-8504 and MK-8583 (Tenofovir Prodrugs) Single-Dose PK and Antiviral Activity in HIV Infection (04/13/20)
• And speaking of formulation science, abstract #1000 illustrated some of the promise of this area of work. These investigators described development of a multipurpose (for HIV prevention and hormonal contraception) biodegradable implant of TAF, etonogestrel and levonorgestrel that achieved sustained drug delivery over 7 months. I think this is an exciting area - watch this space
CROI: Biodegradable Implant for Sustained Delivery of Antiretroviral (ARV) - (05/18/20)
The science of CROI 2020 was outstanding, as usual. Given the short amount of time the organizers had to respond to the emerging COVID-19 pandemic, their effort was extraordinary and virtual format worked. Note, the 23rd IAS AIDS 2020 Conference, scheduled for July 6-10, 2020, has also announced they are going virtual as well. CROI 2021 is scheduled to be in Chicago, IL on March 7-10, 2021. Hopefully, science will prevail, and we will be there in person.
%CV, percent coefficient of variation
ACTG, adult AIDS clinical trials group
ARV, antiretroviral drug
ART, antiretroviral drug therapy
AUC, area under the concentration-time curve
BID, twice daily
C12, drug concentration at 12 hours post dose
Cmax, maximum drug concentration
Cmin, minimum drug concentration
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
DHHS, Department of Health and Human Services
DSMB, data safety monitoring board
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%
IQ, inhibitory quotient
IVR, intra-vaginal ring
MPA, medroxyprogesterone acetate
NRTI, nucleoside reverse transcriptase inhibitor
NNRTI, non-nucleoside reverse transcriptase inhibitor
PACTG, pediatric AIDS clinical trials group
PBMCs, peripheral blood mononuclear cells
PEG-IFN, pegylated Interferon
PI, inhibitor of HIV protease
PrEP, pre-exposure prophylaxis
QD, once daily
r or RTV, ritonavir
TAF, tenofovir alafenamide
TDF, tenofovir disoproxil fumarate
TDM, therapeutic drug monitoring