Mixed forecast on the future of antiretroviral therapy: an interview with Charles W. Flexner, MD.
Article Type: Interview
Subject: Medical teaching personnel (Interviews)
Medical colleges (Faculty)
Medical colleges (Interviews)
Author: Mascolini, Mark
Pub Date: 09/22/2009
Publication: Name: Research Initiative/Treatment Action! Publisher: The Center for AIDS: Hope & Remembrance Project Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 The Center for AIDS: Hope & Remembrance Project ISSN: 1520-8745
Issue: Date: Fall, 2009 Source Volume: 14 Source Issue: 2
Persons: Named Person: Flexner, Charles W.
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220766483
Full Text: Professor of Medicine and Pharmacology, and International Health

Johns Hopkins University School of Medicine and

Bloomberg School of Public Health

Baltimore, Maryland


Nucleoside-sparing first-line regimens

Mascolini: There's a fair amount of ongoing work testing nucleoside reverse transcriptase inhibitor (NRTI)-sparing first-line regimens, either protease inhibitors (PIs) with raltegravir or PIs with maraviroc (Tables 1-4). So far, are these combinations looking OK pharmacokinetically?

Flexner: Yes. One of the attractive things about combining the integrase inhibitor raltegravir with other antiretrovirals is its low potential for drug-drug interactions. That, combined with its very good safety profile and activity results to date, makes it one of the more attractive antiretrovirals for this kind of application.

Having said that, I think combination regimens are becoming more convenient in general as a consequence of coformulation, so the entire concept of an NRTI-sparing regimen doesn't have nearly the urgency it did maybe 5 years ago, when we were more worried about convenience and toxicity.

I think you can draw a distinction between the attractiveness of such a regimen for treatment-naive versus treatment-experienced patients. Certainly most treatment-naive patients can tolerate a coformulated drug like Atripla (efavirenz/tenofovir/ emtricitabine). We don't worry very much about the toxicities of lamivudine and emtricitabine any more except in patients who are chronically coinfected with hepatitis B virus. And the only patients in whom we have a concern about tenofovir toxicity are patients with underlying kidney disease or people at risk of developing renal insufficiency.

Mascolini: Given those facts, do you think there's enough enthusiasm to push these no-NRTI combinations through trials into clinical practice for previously untreated people?

Flexner: If we could develop a two-drug, coformulated, once-a-day combination that lacked a nucleoside analog and show in a large, prospective, randomized clinical trial that it is as good as the current gold standard--which right now is Atripla--I think clinicians would be very attracted to that. But a lot would depend on pricing and other issues. I do think it is possible to put together two very potent antiretrovirals with good safety profiles and produce a regimen that at least in a treatment-naive population would be seen as more attractive than Atripla.

NRTI-sparing options for experienced patients

Mascolini: The ACTG OPTIONS trial (1) and other trials are exploring NRTI-sparing salvage therapy. What are the potential pluses and minuses of this approach?

Flexner: The biggest minus of a nucleoside-sparing regimen in a heavily treatment-experienced patient population is that we don't yet have much experience with head-to-head comparisons of an NRTI-sparing regimen and an NRTI-containing regimen. Also, we are comfortable with the value and activity of NRTI-containing regimens even in patients who are highly treatment experienced. So for example I think we've come to believe--whether it's true or not (2-4)--that using lamivudine or emtricitabine in a regimen to maintain the M184V mutation is probably of some virologic benefit. But I could make the case that the virologic benefit of maintaining that M184V so far has been quantitatively modest. I could certainly see that in a head-to-head comparison it might not make that much difference.

The real issue is whether we're capable of doing comparative effectiveness research that will provide enough evidence to change the practice of medicine. In other words, will a trial like the OPTIONS trial provide definitive evidence that an NRTI-sparing regimen is better than or equivalent to the current practice, which in most cases is to include NRTIs in the regimen? And the answer to that question will await the outcome of the study.

Maintaining early response with PI monotherapy

Mascolini: We've seen lots of work on maintenance therapy with lopinavir/ritonavir alone, (5) and recently with darunavir/ritonavir. (6,7) Are the potential benefits of this approach worth the potential risks?

Flexner: This is one of the most interesting under-the-radar topics in antiretroviral therapy. I don't think it's gotten the publicity it warrants. Boosted-PI monotherapy is becoming de facto a very popular strategy in Europe for treatment-naive patients. Why this is appealing to the European docs and not to the US docs, I don't know. Part of it may be drug pricing and who's paying for drugs and the benefit to the government payer of using one drug versus three. But part of it may also be that most of the simplification research has been done in Europe, and they feel this is their idea and they ought to be using it.

In a patient who is fully suppressed, I think there's a strong virologic rationale to use a simplification strategy that involves a potent boosted protease inhibitor with a high genetic barrier to resistance, because I do believe it is possible in such a patient to suppress their virus replication indefinitely without concern about resistance, if they take that drug every day as prescribed.

The problem in getting a lot of people to buy into this approach is that, because of coformulation, multiple drug regimens are just as convenient as--or more convenient than--a "simplified" boosted PI regimen. The boosted PI involves at a minimum multiple tablets (in the case of lopinavir/ritonavir) or even multiple prescriptions (in the case of darunavir/ritonavir). So then you have to ask, if a patient is doing well on a coformulated drug like Atripla, where's the simplification? It's not fewer pills. The only real value is that it's fewer pharmacologically active agents and it avoids the potential long-term toxicities of tenofovir, if that's a concern.

Boosting antiretrovirals without ritonavir

Mascolini: What are the potential advantages of a booster other than ritonavir, and do you see such an agent becoming a clinical reality?

Flexner: The answer to the second question is yes. Gilead is pushing ahead full steam with GS9350. (8) They already have it in a trial to boost the integrase inhibitor elvitegravir in combination with tenofovir/emtricitabine (9) and in another trial comparing it with ritonavir to boost atazanavir. (10) Unless there's some unexpected toxicity with GS9350, I think there is a high likelihood that it will eventually get approval.

The attraction of a non-ritonavir booster is the possibility of less frequent long-term toxicity, particularly the lipid effects of ritonavir, but also short-term effects: There are some patients who get nausea even with low doses of ritonavir, and there are other rare short-term side effects related to ritonavir. Some people are very supportive of alternatives to ritonavir because they think the pricing might be better. I'm not so sure about that. And there certainly may be advantages with respect to convenience of formulation. For example, the only approved ritonavir formulation (without lopinavir) is the capsule, although it is expected that the tablet will be approved soon. One of the big disadvantages of ritonavir boosting for resource-poor countries is the need to refrigerate the capsule. Presumably that problem will be addressed when the tablet is released.

I already mentioned that a lot of people are excited about moving away from ritonavir because of concerns about long-term toxicity. But there are so few clinical data on any of the non-ritonavir PK enhancers that I believe there are still many questions about the long-term safety of those drugs. Those questions need to be addressed before we all go rushing off to say that ritonavir is a thing of the past.

Mascolini: Are side effects inescapable when you inhibit a P450 enzyme over a period of years?

Flexner: I don't think that's true. I think the gastrointestinal and lipid side effects from ritonavir are not related to inhibition of cytochrome P450 3A4. There are a number of 3A4 inhibitors on the market, some of them used for chronic diseases, although none of them is nearly as potent as ritonavir. But as far as I can tell, there are no class-specific side effects from inhibiting cytochrome P450 3A4, other than the production of drug interactions.

The evidence I'm aware of suggests that cytochrome P450 3A4 is not responsible for any critical endogenous host-mediated metabolic reactions. In other words it's not responsible for maturing hormones, or for breaking down cytokines, or doing something else to an endogenous host substrate. That suggests to me we can probably inhibit the heck of 3A4 for a long time and not have to worry about what that's doing to the host.

Nanoparticle delivery of antiretrovirals

Mascolini: Is the work on nanoparticle delivery of antiretrovirals far enough along to get a sense of whether it will work?

Flexner: All we can say is that there's one nanoparticle antiretroviral tested in human subjects, and that's Tibotec's long-acting rilpivirine (Table 5). (11) It hasn't gone in to very many human subjects, and Tibotec has had some formulation issues with that product.

I think nanoparticle delivery is a very important concept, particularly as related to the strategy called "test and treat," that is, trying to develop simple ways to go into areas where there is a high incidence of new HIV infections and treating people in high-risk groups to try to block further spread of the virus. (12) I think you're more likely to succeed in doing that if you have very long-acting drugs.

Although this is a very important topic, right now it is strictly a research topic. I don't think we have a product that is anywhere close to a phase 3 study. This is a topic that's going to require a whole lot more activity, and hopefully we'll see something come out of this in the near future.

Prospects for pharmacogenetic-guided therapy

Mascolini: Is pharmacogenetic-guided antiretroviral therapy likely to expand beyond screening for abacavir hypersensitivity? (13)

Flexner: I don't know. I have not seen very many examples of genetic determinants of outcomes for antiretrovirals that ate strong enough to suggest to me a high likelihood that it will change the way we prescribe those drugs.

If you want to look at parallels, the closest we have outside the HIV arena for a commonly used drug to treat a chronic condition is the anticoagulant warfarin. And pharmacogenetically guided dosing of warfarin has really not taken off in the clinical practice community for a variety of reasons. (14) I think prescribing physicians need very, very strong evidence about a new diagnostic test, like a genetic polymorphism, before they incorporate it into their practice.

Eradication and its daunting risk/benefit equation

Mascolini: I surveyed 28 clinical investigators for the review article in this issue of RITA! Almost every one of them ranked viral eradication as a top research priority, but almost no one thought eradication would be viable in the next decade. What do you think?

Flexner: Right now it's possible to eradicate HIV from an individual. Unfortunately, I don't think it's possible to do that without a high risk of killing the patient! I believe this is something we're unlikely to see in the next 30 years, except in extraordinary circumstances, for example, people undergoing bone marrow transplantation for non-Hodgkin lymphoma. But I do not believe it's going to be easy to come up with a strategy that will eradicate HIV from an infected individual without enormous potential toxicity and even the risk of fatality.

Given how well tolerated and effective current antiretroviral combinations are, it's going to take some proof to convince patients to go along with this if they think they can take a coformulated drug like Atripla once a day for the rest of their life and have a normal life expectancy. Why on earth would you subject yourself to total lymphoid irradiation and toxic chemotherapy and other things we might have to do, if we can suppress your virus probably indefinitely?

Mascolini: Relative to HIV vaccine research, how much priority should be given to eradication research?

Flexner: We should keep our eyes open for clever new ideas, and I definitely agree that we should be supporting small studies of clever strategies that have a reasonable likelihood of success. I don't think we should be devoting a big chunk of our research budgets to the eradication effort, particularly as compared to vaccine research, because I believe an effective HIV vaccine is much more likely to control the epidemic than strategies to eradicate the virus from single individuals who, by the way, might go out and get infected again.


(1.) ACTG 5241: The Optimized Treatment that includes of Omits NRTIs (OPTIONS) Trial. To compare treatment success (defined as the probability of not experiencing virologic failure or discontinuation of NRTI strategy by week 48) between subjects taking a new regimen of more than two active agents (defined by a cPSS > 2.0) that includes versus excluded NRTIs. http://www.clinicaltrials.gov/ct2/show/NCT00537394.

(2.) Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-l-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20:795-803.

(3.) Fox Z, Dragsted UB, Gerstoft J, et al. A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial. Antivir Ther. 2006;11:761-770.

(4.) Turner D, Brenner BG, Routy JP, Petrella M, Wainberg MA. Rationale for maintenance of the M184V resistance mutation in human immunodeficiency virus type 1 reverse transcriptase in treatment experienced patients. New Microbiol. 2004;27(2 Suppl 1):31-39.

(5.) Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 2009;23:279-291.

(6.) Arribas J, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB106-LB.

(7.) Katlama C, Valentin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136 C. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WELBB 102.

(8.) Mathias A, Lee M, Callebaut C, et al. GS-9350: a pharmaco-enhancer without anti-HIV activity. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 40. http://www.retroconference.org/2009/Abstracts/34852.htm.

(9.) Study of the safety and efficacy of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 (QUAD) versus Atripla in HIV infected, antiretroviral treatment-naive adults. NCT00869557. ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT00869557.

(10.) Safety and efficacy of GS-9350-boosted atazanavir compared to ritonavir-boosted atazanavir in combination with emtricitabine/tenofovir disoproxil fumarate in HIV-1 infected, antiretroviral treatment-naive adults. NCT00892437. ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT00892437.

(11.) Van t'Klooster G, Verloes R, Baert L, et al. Long-acting TMC278, a parenteral-depot formulation delivering therapeutic NNRTI concentrations in preclinical and clinical settings. Fifteenth Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 134. http://www.retroconference.org/2008/Abstracts/31749.htm.

(12.) Dieffenbach CW, Fauci AS. Universal voluntary testing and treatment for prevention of HIV transmission. JAMA. 2009;301:2380-2382.

(13.) Phillips E, Mallal S. Successful translation of pharmacogenetics into the clinic: the abacavir example. Mol Diagn Ther. 2009; 13:1-9.

(14.) Rosove MH, Grody WW. Should we be applying warfarin pharmacogenetics to clinical practice? No, not now. Ann Intern Med. 2009; 151:270-273.
Table 1. Trials of NRTI/sparing regimens in early therapy:

Antiretrovirals       Sponsor           Recruiting?
(Clinicaltrials.gov   (Sites)

Raltegravir +         National              Yes
atazanavir [+ or -]   Centre in HIV
ritonavir             Epidemiology
(NCT00874523)         and Clinical

Raltegravir +         Community           Not yet
atazanavir [+ or -]   Research
tenofovir +           Initiative of
emtricitabine         New England
(NCT00931801)         (Boston)

Raltegravir +         Peter J. Ruane        Yes
atazanavir            (Los Angeles)

Raltegravir +         Bristol-Myers         No
atazanavir [+ or -]   Squibb, Merck
ritonavir [+ or -]    (United States)
tenofovir +

Raltegravir +         Yale                  Yes
atazanavir, other     University,
antiretrovirals       Bristol-Myers
(NCT00814879)         Squibb

Antiretrovirals       Trial name and design

Raltegravir +         Raltegravir and
atazanavir [+ or -]   Atazanavir Dosing
ritonavir             Strategy Study (SPARTA)
                      Arm A: ATV 300 mg + RAL
                      400 mg twice daily for 4
                      weeks then ATV 300 mg +
                      RTV 100 mg + RAL 800 mg
                      once daily for 4 weeks

                      Arm B: ATV 300 mg + RTV
                      100 mg + RAL 800 mg once
                      daily for 4 weeks then
                      ATV 300 mg + RAL 400 mg
                      twice daily for 4 weeks

Raltegravir +         A Pilot Study of the
atazanavir [+ or -]   Novel Antiretroviral
tenofovir +           Combination of Atazanavir
emtricitabine         and Raltegravir in HIV-1
(NCT00931801)         Infected Subjects With
                      Virologic Suppression on
                      a Standard Regimen of
                      Boosted Atazanavil.
                      Tenofovir and
                      Emtricitabine (BATAR)

                      Arm 1 : ATV/RTV 300/100
                      mg once daily + RAL 400
                      mg twice daily

                      Arre 2: ATV 300 mg twice
                      daily + RAL 400 mg twice

                      Comparator arm: Continued
                      baseline regimen of ATV/
                      RTV 300/100 mg once daily
                      + TDF/FTC 300/200 mg once

Raltegravir +         Raltegravir and
atazanavir            Atazanavir Replacing
(NCT00751153)         Current Suppressive
                      Treatment Because of Side
                      Effects in Current

                      RAL 400 twice daily + ATV
                      400 mg daily

Raltegravir +         Phase IIB Pilot of ATV +
atazanavir [+ or -]   RAL (SPARTAN)
ritonavir [+ or -]
tenofovir +           Arm A1: ATV 300 mg twice
emtricitabine         daily + RAL 400 mg twice
(NCT00768989)         daily

                      Arm A2: ATV 300 mg once
                      daily + RTV 100 mg once
                      daily + TDF/FTC 300/200
                      mg once daily

Raltegravir +         Pilot Study of a
atazanavir, other     Raltegravir Based NRTI-
antiretrovirals       Sparing Regimen
                      Experimental: RAL 400 mg
                      twice daily + ATV 300 mg
                      twice daily

                      Comparator: Standard

For a summary of completed work on nucleoside-sparing first-line or
early maintenance regimens mens, see page 8, of this issue of RITA!

Table 2. Trials of NRTI-sparing regimens in early
therapy: raltegravir/darunavir

(Clinicaltrials.gov   Sponsor
identifier)           (Sites)           Recruiting?

Raltegravir +         Dallas VA             Yes
darunavir +           Medical Center
ritonavir [+ or -]    (Texas)
tenofovir +

Raltegravir +         ACTG                  No
darunavir +           (United States)

identifier)           Trial name and design

Raltegravir +         Raltegravir And Darunavir
darunavir +           Antiretroviral in
ritonavir [+ or -]    Antiretroviral-Naive
tenofovir +           Patients (RADAR)
emtricitabine         Experimental: RAL 400 mg
(NCT00677300)         twice daily + DRV 800 mg
                      once daily + RTV 100 mg
                      once daily

                      Comparator: DRV 800 mg
                      once daily + RTV 100 mg
                      once daily + TDF/FTC
                      300/200 mg once daily

Raltegravir +         Safety and Effectiveness
darunavir +           of Raltegravir and
ritonavir             Darunavir/Ritonavir in
(NCT00830804)         Treatment-Naive
                      HIV-Infected Adults
                      Single arm: RAL 400 mg
                      twice daily + DRV/RTV
                      800/100 mg once daily

Table 3. Trials of NRTI/sparing regimens in early therapy:

(Clinicaltrials.gov   Sponsor
identifier)           (Sites)           Recruiting?

Raltegravir +         Saint Michael's       Yes
lopinavir +           Medical Center
ritonavir             (New Jersey)

Raltegravir +         University            Yes
lopinavir +           of Miami
ritonavir [+ or -]    (Florida)
tenofovir +

Raltegravir +         Emory                 Yes
lopinavir +           University
ritonavir; other      (Georgia)

Raltegravir +         California            Yes
lopinavir +           Collaborative
ritonavir;            Treatment
efavirenz +           Group
tenofovir +           (California)

Raltegravir +         Abbott                No
lopinavir +           (United States)
ritonavir [+ or -]
tenofovir +

identifier)           Trial name and design

Raltegravir +         Safety Study of
lopinavir +           Lopinavir-Ritonavir With
ritonavir             Raltegravir in HIV-
(NCT00752037)         Infected Patients

                      Single arm: RAL 400 mg
                      twice daily + LPV/RTV
                      400/100 mg twice daily

Raltegravir +         Raltegravir + Lopinavir-
lopinavir +           Ritonavir or
ritonavir [+ or -]    Emtricitabine-Tenofovir
tenofovir +           for HIV Treatment-Naive
emtricitabine         Subjects
                      Experimental: RAL 400 mg
                      twice daily + LPV/RTV
                      400mg/100 mg twice daily

                      Comparator: RAL 400 mg
                      twice daily plus TDF/FTC
                      300/200 mg once daily

Raltegravir +         Kalera-Isentress
lopinavir +           Treatment Evaluation
ritonavir; other      (KITE)
(NCT00700115)         Experimental: RAL
                      400 mg twice daily +
                      LPV/RTV 400/100 mg twice

                      Comparator: Continued
                      standard antiretroviral

Raltegravir +         Raltegravir + Lopinavir-
lopinavir +           Ritonavir Versus
ritonavir;            Efavirenz + Tenofovir +
efavirenz +           Emtricitabine in
tenofovir +           Treatment-Naive Patients
(NCT00752856)         Experimental: RAL 400 mg
                      twice daily + LPV/RTV
                      400/100 mg twice daily

                      Comparator: EFV + TDF +
                      FTC (as Atripla)

Raltegravir +         Study Comparing
lopinavir +           Lopinavir/Ritonavir +
ritonavir [+ or -]    Emtricitabine/
tenofovir +           TenofovirDisoproxil
emtricitabine         Fumarate With a
                      Regimen Consisting of
                      Lopinavir/Ritonavir +
                      Raltegravir (PROGRESS)

                      Experimental: RAL 400 mg
                      twice daily + LPV/RTV
                      400/100 mg twice daily

                      Comparator: LPV/RTV
                      400/100 mg twice daily +
                      TDF/FTC 300/200 mg once

Table 4. Trials of NRTI/sparing regimens in early therapy:
maraviroc/protease inhibitors

(Clinicaltrials.gov   Sponsor
identifier)           (Sites)           Recruiting?

Maraviroc +           Northwestern        Not yet
darunavir +           University
ritonavir             (Chicago)

Maraviroc +           Pfizer                Yes
darunavir +           (United States)
ritonavir OR
atazanavir OR
lopinavir [+ or -]
tenofovir +

Maraviroc +           Barry M.            Not yet
lopinavir +           Rodwick
ritonavir             (Florida)

identifier)           Trial name and design

Maraviroc +           Maraviroc Plus Darunavir/
darunavir +           Ritonavir for Treatment-
ritonavir             Naive Patients Infected
(NCT00993148)         With R5-Tropic HIV-1

                      Single arm: MVC 150 mg
                      once daily + DRV/RV 800/
                      100 mg once daily

Maraviroc +           A Pilot Study Of A Novel
darunavir +           Treatment Regimen,
ritonavir OR          Maraviroc + Ritonavir
atazanavir OR         Boosted Atazanavir, In
lopinavir [+ or -]    Treatment Naive HIV-
tenofovir +           Infected Patients
(NCT00827112)         Arm A: MVC 150 mg once
                      daily + ATV/RTV (300/100
                      mg) once daily OR MVC +
                      DRV/RTV 800/100 mg once
                      daily OR MVC + LPV/RTV
                      400/100 mg twice daily

                      Arm B: TDF/FTC 300/200
                      once daily + ATV/RTV
                      300/100 mg once daily OR
                      TDF/ FTC + DRV/RTV
                      800/100 mg once daily OR
                      TDF/FTC + LPV/RTV 400/100
                      mg twice daily

Maraviroc +           Pilot Assessment of
lopinavir +           Lopinavir/Ritonavir
ritonavir             and Maraviroc (PALM)
                      Single arm: MVC 150 mg
                      twice daily + LPV/RTV
                      400/100 mg twice daily

Table 5. Rilpivirine nanosuspension in 36 HIV-negative volunteers (11)

* Average rilpivirine nanosuspension particle size 200 nM
* Six panels of 8 healthy adults received 200, 400, or 600 mg of
  rilpivirine (n = 6) or placebo (n = 2)
* Rilpivirine administered at doses of 200, 400, or 600 mg by
  intramuscular or subcutaneous injection
* Pharmacokinetic profiles similar after intramuscular and
  subcutaneous administration
* Intramuscular injection better tolerated
* No serious adverse events or premature discontinuations
* Plasma concentration reached maximum around 3 days
* Plasma concentration fell to 60% of maximum by day 14
* Plasma concentration fell to below 10 ng/mL by 12 to 26 weeks
  (half-life about 5 weeks)
* Maximum concentration normalized to a 100-mg dose, 20.9 ng/mL
* Atea under the curve for week 0 to 12 normalized to a 100-mg dose,
  14,500 ng * h/mL
* Pharmacokinetics dose-proportional
* Intersubject variability low
* Once monthly 600 mg of rilpivirine nanosuspension predicted to
  achieve troughs similar to 25 mg of oral rilpivirine once daily
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