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Clinical Pharmacology at CROI 2019
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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 2019 (26th) Conference on Retroviruses and Opportunistic Infections (CROI) was held in Seattle, WA, from March 4-7, 2019. 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
RAL and DTG-based ART are both virologically superior to EFV-based ART in pregnant women (abstracts 39LB and 40LB).
I'm leading off my review of the pharmacotherapy of HIV infection with two studies in pregnant women. We don't see many large, controlled, clinical trials in HIV-infected pregnant women and to have two presented at the same meeting was a welcome change. The DHHS guidelines currently recommend both DTG and RAL as preferred agents for ARV-naïve pregnant women, but these recommendations are based largely on small PK and safety evaluations and not controlled comparative studies. These two independent studies found concordant results, that an integrase inhibitor (either RAL or DTG) based ART regimen was superior to an EFV-based ART regimen in terms of the rate of viral load decline and proportion of women who had undetectable viral loads at delivery.
In the RAL vs. EFV study, ARV-naïve pregnant women were randomized to RAL or EFV-based ART at 20 to <37 weeks gestation through delivery. 408 women were enrolled: 206 in RAL arm and 202 in EFV. The viral load decline was greater at weeks 2, 4 and 6 in RAL recipients. In the primary efficacy subgroup (no genotypic resistance to study ART) a greater proportion of those receiving RAL had viral loads <200 copies/mL at delivery (RAL, 94%; EFV, 84%); this difference was most pronounced in women enrolled 28 to <37 weeks (RAL, 94%; EFV, 72%). One RAL infant compared with four EFV infants were HIV-infected. Both regimens were well tolerated.
For the comparison of DTG vs. EFV, 268 women were randomized from 28 weeks gestation. Similar to the findings in the RAL vs. EFV study, the decline in viral load was faster in the DTG recipients, and a greater proportion of women had viral loads <50 copies/mL at delivery: 74% for DTG vs. 43% for EFV. Both regimens were equally well tolerated. Three infants were found to have HIV infection at birth, all in the DTG arms; all were considered likely to be in utero transmissions.
These two trials provide important safety and efficacy data that support use of DTG and RAL as preferred agents for ARV-naïve pregnant women. DTG is not recommended for women in their first trimester of pregnancy (up to 14 weeks gestation) because of the concern for neural tube defects (see below).
Integrase inhibitors and neural tube defects (NTD). No evidence presented at CROI 2019 for an increased risk, but the jury is still out.
Four abstracts (743, 744, 745 and 747) investigated the incidence of NTD in women. The largest of the datasets was from the Antiretroviral Pregnancy Registry (747) that reported a total of 20,064 pregnancies and 20,413 fetal outcomes with 19,005 live births. There were 1,193 live births with an integrase inhibitor exposure, of which 604 had periconceptional exposure: 174 DTG, 186 EVG, and 244 RAL. No NTD were observed among any of the integrase inhibitor exposed infants.
NTDs are rare; the estimated prevalence is 0.19% (19/10,000 birth outcomes). Timing is also critical as neural tube closure occurs by day 28 post conception. It has been estimated that 2000 exposures are required to rule out a three-fold increase in a rare event like NTD. The original report of a potential increased risk from the Botswana TSEPAMO study was based on 426 DTG exposures, and as above, the largest of the datasets at CROI 2019 reported on 174 DTG exposures. Thus, while the data from CROI 2019 does not show an increase risk, it also does not refute the increased risk signal from the original report. If there are no new defects found in the Botswana TSEPAMO study, data on 1400 exposures would be needed to refute the finding; if there is one new defect, then 2000 exposures would be required (Mofenson L, CROI 2019 webcast:
http://www.croiwebcasts.org/p/2019croi/59 ). It appears that data on 1400 exposures from the Botswana TSEPAMO study will be available around mid 2019. Thus, quite simply, and unfortunately for pregnant women and their care-givers, more data and time are needed.
Recommendations for further reading:
Neural tube defects with dolutegravir (this is original report of the Botswana TSEPAMO study from the NEJM)https://www.nejm.org/doi/full/10.1056/NEJMc1807653
Editorial: Protecting mothers and babies
https://www.nejm.org/doi/full/10.1056/NEJMp1809688?query=recirc_curatedRelated_article
Weight gain with Integrase Inhibitors (INSTIs) - is this a drug-associated toxicity?
There were several reports of INSTI-associated weight gain at CROI 2019: see abstracts 669 through 672. ACTG studies A5001 and A5322 followed participants from 1997-2017 and reported data on 972 adults who switched for INSTI. Yearly weight gain increased following switch to INSTI and the increases were particularly significant for women, blacks and persons age ≥60 (abstract 669). Abstract 670 was from the NA-ACCORD group and reported data on 21,886 ARV-naïve adults starting INSTI, PI or NNRTI therapy after 1/1/2007. At 2 years, weight gain was: INSTIs, 4.4kg; NNRTIs, 3.3kg; and PIs, 4.3kg. Among the INSTIs at 2 years, weight gain by INSTI was DTG, 5.6kg; RAL, 5.4kg; and EVG, 3.4kg. These authors concluded that those starting DTG and RAL were at a higher risk of weight gain than those starting NNRTIs. 3,468 treatment experienced persons were evaluated in abstract 671 and the annualized weight gain was ≥3%. Persons with a ≥3% weight gain were more commonly treated with INSTIs vs. PIs. Finally, weight gain in women was evaluated in 1118 participants in the Womens Interagency HIV Study (WIHS). Women who switched to or added INSTIs experienced a 2.1kg greater weight gain than did those who stayed on non-INSTI therapy (abstract 672).
At the European HIV meeting in Glasgow last year, an analysis from a randomized study of an immediate switch to DTG therapy or deferring the DTG switch for 48 weeks and remaining on PI-based ART was reported:
http://hivglasgow.org/wp-content/uploads/2018/11/P102.pdf. Those study participants who switch to DTG has a 0.82kg median weight increase by week 48 compared with a 0.25kg increase in those who remained on their PI regimen (p=0.008). For those who initially deferred the switch to DTG for the first 48 weeks, after they switched to DTG their median weight increase was 0.98kg over the next 48 weeks.
The randomized comparison from Glasgow and the reports from CROI 2019 collectively paint a pretty compelling picture of an association between INSTI therapy with weight gain. There are a number of potential complications associated with weight gain, cardiovascular being the most concerning. Is this a drug toxicity and if so, what is the mechanism; or, is this a component of the rising prevalence of obesity
(https://www.cdc.gov/obesity/data/adult.html )? This association deserves some attention as do approaches to minimize the weight gain.
HIV CURE: The London patient looks to be #2, and is a Dusseldorf patient #3?
The report (abstract 29) of what looks to be a second person cured of HIV infection has been widely reported (see the NATAP website, and this piece by Jon Cohen is also good and so, I'll not repeat the facts. The paper on the London patient has now been published in Nature:https://www.sciencemag.org/news/2019/03/has-second-person-hiv-been-cured
https://www.nature.com/articles/s41586-019-1027-4
Timothy Brown said it best (as taken from Jon Cohen's article): "It's great that I finally have someone added to my family. It's been too long. I think it's a movement in the right direction and proves that cure of HIV is possible but I think lots more work needs to be done to help everyone who is living with the virus,".
Abstract 394 described the case of a 49-year-old male with HIV infection who had hematopoietic stem cell transplantation (HSCT) in 2013 and remained on ART until November 2018, with undetectable plasma HIV RNA (and several other virologic evaluations negative for virus detection). ART was stopped in November 2018, and so far, this individual (the Dusseldorf patient) has remained undetectable. While promising, as the authors cautioned "longer surveillance is essential".
II. Pre-Exposure Prophylaxis (PrEP)
FTC/TAF (F/TAF) is non-inferior to F/TDF for PrEP: the DISCOVER trial (abstract 104;
http://www.croiwebcasts.org/p/2019croi/104)
This trial randomized 5387 MSM and transgender women at high risk of HIV infection to receive either F/TAF or F/TDF for PrEP. In this study, there were 22 HIV infections in 8756 person years of follow-up; 7 infections were in the F/TAF recipients and 15 in the F/TDF recipients. Overall, the HIV infection incidence was 0.16/100 PY for F/TAF and 0.34/100 PY for F/TDF, indicating that F/TAF was non-inferior to F/TDF. Of the 7 HIV infections in the F/TAF recipients, one person had suspected baseline infection and 5 had low levels of tenofovir-diphosphate (TFV-DP by dried blood spot measurement, which is an excellent marker of adherence) indicating poor adherence; the remaining individual had a medium level of TFV-DP. Among the F/TDF recipients 4 had suspected baseline infection; 10 had low levels of TFV-DP; one had a high level of TFV-DP. Thus, in both arms, the majority of infections occurred in persons with low drug levels. As has been seen in comparative trials of TAF vs TDF for HIV treatment, biomarkers of bone and renal safety favored TAF.
F/TAF works for PrEP in MSM and transgender women. That wasn't certain going into this trial as studies in non-human primates, women and HIV-infected persons found that the concentrations of TFV-DP (the active drug) were lower in rectal tissues with TAF than with TDF (see: Massud I, et al. J Infect Dis 2016;214:1058-62. Cottrell M, et al. J Antimicrob Chemother 2017;72:1731-40. and Fletcher CV, abstract 130 this conference [ http://www.croiconference.org/sessions/lymphoid-tissue-pharmacokinetics-tenofovir-alafenamide-vs-disoproxil-fumarate ]). I think this means that PrEP efficacy for TAF and TDF is likely dependent on systemic concentrations as well as local tissue concentrations. The clearest implication of the Discover trial to me, is that F/TAF would be preferred in persons with preexisting renal or bone disease.
Using electronic health records (EHR) to identify candidates for PrEP (abstract 105).
In the US, there is a considerable gap between the number of persons who could benefit from PrEP and those who are actually taking it (see: https://www.hiv.gov/blog/hiv-prevention-pill-not-reaching-most-americans-who-could-benefit-especially-people-color ). This abstract presented the development of a model to identify candidates for PrEP within a large health care system. Their final predictive model included factors such as Black race, urine positivity for methadone, and use of medications for erectile dysfunction. This seems like an attractive approach to identify persons at risk but not receiving PrEP in order to improve uptake and reduce HIV transmission. This and other strategies, are necessary and hopefully will receive some needed attention as a result of the new governmental initiative discussed by Dr. Fauci of the NIH in the opening session to end the HIV epidemic.
CROI: USING EHR DATA TO IDENTIFY POTENTIAL PREP CANDIDATES IN A LARGE HEALTH CARE SYSTEM
III. Co-Morbidities
Opioid deaths among persons with HIV-infection (abstract 147).
The opioid epidemic is a national health emergency and affects all segments of our society. Abstract 147 presented data compiled by the CDC on the toll it takes on the HIV-infected population in 2011-2015. They found the rate of all deaths among HIV-infected persons in 2015 was 12.7% less than in 2011 - good news! But, the opioid overdose death rate was 42.7% GREATER in 2015 than in 2011. The death rate was highest among persons who inject drugs, whites, females and those in the US Northeast. The opioid epidemic needs every bit as much governmental attention as does the newly announced effort to end the HIV epidemic. One step we can take is to make sure we are doing everything we can to make naloxone for opioid overdose reversal widely available. Remember, naloxone is available in three formulations: an injectable, a prefilled autoinjector syringe, and the nasal spray. If you want help about accessing or using these products - talk to a pharmacist.
PK and Safety of DTG with weekly rifapentine and isoniazid (abstract #80).
The development of concomitant treatment regimens for HIV and TB coinfection is an important priority. Abstract 80 described a study in HIV-infected persons on ART to evaluate the PK, safety and virologic response of a DTG-containing regimen with a TB preventative regimen of once weekly rifapentine and isoniazid (RPT/INH). Once weekly RPT/INH for 12 weeks is now recommended by WHO as an alternative to 6 months of INH for TB prevention. A previous drug interaction study of DTG with once weekly RPT/INH in healthy volunteers found unexpected and serious toxicities in 2 of 4 participants (Clin Infect Dis 2018;67:193-201.). It was imperative to conduct this study very carefully, which these investigators did. Of 61 participants, there was only 1 early discontinuation and that occurred prior to the coadministration of RPT/INH. After the first dose of RPT/INH, there were only three grade 1 or 2 adverse events. HIV viral loads throughout the study were <40 copies/mL. Thus, tolerance of this combination in HIV-infected persons was clearly acceptable and different from that in healthy volunteers, and viral suppression was maintained. All sounds good, right? Well, I'm not sure. Trough concentrations of DTG were decreased, as expected. On average, the decrease was 50-60% between 2-7 days after the RPT/INH dose, with median values ≥300 ng/mL. Based on safety, sustained suppression of viral load, and trough level data, the authors concluded DTG can be administered without dose adjustment with weekly RPT/INH.
I have concerns. First, and as noted by the authors, trough concentrations of 300ng/mL are approximately equivalent to a DTG dose of 10 mg once daily, which was a dose investigated in the phase 2 studies. A 10 mg dose is not as potent as a 50 mg dose. The viral load decrease in a 10-day monotherapy study was 2 logs for 10 mg and was 2.5 logs for 50 mg (AIDS 2011, 25:1737-1745). The authors note that in the phase 2 study of DTG at doses of 10 mg, 25 mg and 50 mg that at 48 weeks, the proportion of subjects with HIV RNA <50 copies/mL were essentially the same: 10mg, 91%; 50mg, 90% (Lancet Infect Dis 2012; 12: 111-18). They use this finding as the basis to conclude that 300ng/mL troughs are adequate. However, at 96 weeks, the picture was different. In those treatment-naïve persons, 11% of 10mg recipients experienced rebound compared with 4% of the 50mg per day recipients. To quote directly from the paper: "However, after week 84, there were more nonresponders among participants receiving DTG 10 or 25 mg." The proportion of subjects with HIV RNA <50 copies/mL was 79% with 10mg and was 88% with 50mg (AIDS 2013, 27:1771-1778). Thus, with time, a difference in rates of viral suppression emerged between the 10mg and 50mg doses - or average DTG troughs of 300ng/mL (with 10mg) and 1200ng/mL (with 50mg) (Lancet Infect Dis 2012; 12: 111-18).
Here is the gamble: the RPT/INH preventative regimen is only given for 12 weeks. So, will 12 weeks of reduced DTG trough concentrations, presuming patients have viral load suppression when the RPT/INH is started, be a short enough course of therapy that viral load suppression can be maintained in the face of lower DTG troughs; OR, as was seen at 96 weeks in ARV-naïve persons, will the less potent viral suppression difference with the 10 mg (equivalent dose) emerge?
I appreciate the need for preventative and treatment regimens for TB that can be given concomitantly with ART. I also appreciate the great care with which these investigators conducted this study. But, my evaluation of the data in the context of what we know about DTG PKPD leads me to believe we cannot confidently conclude that no adjustment of the DTG dose is necessary when given with weekly RPT/INH. In 2017, fewer than 1 million HIV-infected persons received preventative TB therapy; the WHO estimates 30 million eligible people between 2018-2022 (https://www.who.int/tb/publications/global_report/en/ ). The need for TB preventative regimens is huge, but so is the magnitude of risk if we get it wrong. I think further confirmation that this approach is efficacious is warranted.
IV. Drug-Drug Interactions
To follow from my comment above about drug-drug interaction management strategies, abstract 51 is an example of a PK management strategy that should have worked, but unexpectedly, didn't.
Double-dose levonorgestrel implant does not fully overcome the interaction with efavirenz (51).
Kimberly Scarsi has previously shown that efavirenz caused 57% lower levonorgestrel concentrations in women receiving the subdermal levonorgestrel implant, and that this interaction appeared to be clinically significant with three women experiencing unintended pregnancies (failure of contraception). It was hypothesized that doubling the dose of the levonorgestrel implant from 150mg to 300mg would be sufficient to overcome this interaction. In women receiving EFV and the double dose implant, though the magnitude of the interaction was less, levonorgestrel concentrations were 34% lower. Fewer women did have levonorgestrel concentrations ≤303 pg/mL in the double vs standard-dose group (46% vs 90%, respectively; p=0.002); 303 pg/mL is the concentration below which pregnancy was seen in the earlier standard dose study.
Dose adjustment is a common approach to manage drug-drug interactions, and by all accounts this should have worked. Why it didn't really needs to be understood, as does the question of whether the double-dose of the implant raised concentrations enough to ensure contraception effectiveness.
The David Back Plenary.
Dr. Back's plenary was a master class on the challenges of polypharmacy. I'd encourage you all to take 30 minutes and view this webcast.
http://www.croiwebcasts.org/console/player/41280?mediaType=audio&&crd_fl=0&ssmsrq=1552859329631&ctms=5000&csmsrq=5086
V. New Drugs and Formulations
I am going to end this report with a few comments on long acting cabotegravir (LA-CAB) and rilpivirine (LA-RPV) and the ATLAS (abstract 139) and FLAIR (abstract 140) studies as they are perfect examples of the progress and promise of new drug formulations. Much has already been written about these studies (see the natap.org website) so I'll only highlight the bottom lines.
ATLAS enrolled 616 HIV-infected persons on oral ART who had an HIV RNA <50 copies/mL for 6 months. They were randomized to monthly injections of LA CAB+RPV or to continued oral ART. For the primary endpoint of proportion with HIV RNA ≥50 copies/mL at week 48, the results were 1.6% of LA compared with 1% of oral ART. For the secondary endpoint of proportion with HIV RNA <50 copies/mL at week 48, the proportions were LA, 93% and oral ART, 95%. Serious adverse events were rare at 4% and 5%, respectively for LA and oral ART.
FLAIR enrolled ARV-naïve individuals; 566 were randomized to monthly LA CAB+RPV or oral ART (with DTG/ABC/3TC). For the primary and secondary week 48 endpoint (same criteria as ATLAS) the proportions were: primary, 2.1% for LA and 2.5% for oral; secondary, 93.6% for LA and 93.3% for oral. Again, serious adverse events were rare at 6% and 4%, respectively for LA and oral.
These are landmark studies in the continuum of progress in HIV pharmacotherapy. Both studies demonstrated that persons who have achieved suppression of plasma HIV RNA to <50 copies/mL on oral ART can sustain that suppression with monthly IM injections of two drugs. The biggest implication right now, is in how these new formulations add to patient choice and convenience. Injections, even monthly, however, won't be for everyone. Here as well there is important information from these two studies - look at how good oral ART was at 90%+ rates of HIV RNA <50 copies/mL; numerically, oral ART in ATLAS was a little better than LA (the statisticians won't like me saying that). There are some hurdles to overcome in roll out such as how to manage missed injections, and the need to make sure the convenience of where injections are delivered matches the convenience of the injections themselves. Finally (for now), I think the next issue to tackle is what about patients who are not doing well on oral therapy because of adherence issues (this was not the population persons enrolled in ATLAS and FLAIR). That is an important, unmet need.
All in all, CROI 2019 was an outstanding meeting, and progress on several fronts was reported. CROI 2020 will be in Boston, MA, March 8-11, 2020.
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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