New Medications Advance HIV Treatment and Prevention

Since effective regimens first became available in the mid 1990s, antiretroviral therapy (ART) has become progressively easier to use, safer, and better tolerated, making treatment success possible for almost all patients who are committed to care.

The most recent iteration of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (Guidelines) lists 5 recommended and 7 alternate regimens for initiation of therapy.¹

The typical patient initiating ART today could achieve treatment success with almost any of these regimens, although subtle differences could make certain regimens preferable for certain patients. Recently approved drugs have expanded options for treatment and agents in the development pipeline may further advance both HIV treatment and prevention.

Dolutegravir.  Dolutegravir, an integrase strand transfer inhibitor (INSTI), is an important recent addition to the antiretroviral armamentarium. It shares with the other members of this therapeutic class a favorable safety and tolerability profile, potency, and rapid suppression of replication of the human immunodeficiency virus (HIV).² 

It also has the advantages of once-daily dosing without use of a pharmacokinetic enhancer, preserved activity against certain INSTI-resistant HIV variants, and a high genetic barrier to resistance.² Randomized trials in treatment-naive patients compared dolutegravir to other widely used third agents and have shown that it is noninferior to raltegravir and superior to efavirenz and darunavir/ritonavir.³ Superiority resulted from fewer discontinuations for adverse events with dolutegravir.³ It also is effective in treatment-experienced patients, including those for whom treatment with other INSTIs failed.⁴ Dolutegravir is possibly the closest thing to an ideal antiretroviral as has yet been developed. It is available as a stand-alone drug (Tivicay, ViiV Healthcare) and co-formulated with the nucleoside analogues abacavir and lamivudine (Triumeq, ViiV Healthcare). Both dolutegravir plus tenofovir disoproxil fumarate (TDF/FTC, Truvada, Gilead Sciences) and Triumeq are regimens recommended by the Guidelines for initiation of ART.¹ Dolutegravir is an inhibitor of renal tubular secretion of creatinine and causes modest increases in serum creatinine. This results in a lower estimated glomerular filtration rate (eGFR) without affecting actual GFR. The co-formulation provides a single-tablet, once-daily regimen, although concerns about the potency and cardiovascular safety of abacavir linger. Also, testing for the presence of HLA-B*5701 is required prior to any abacavir use due to a high risk of hypersensitivity reactions in individuals with this haplotype.

A New Booster for Two Protease Inhibitors. 

Contemporary practice includes concurrent use of a pharmacokinetic enhancer (“booster”) in protease inhibitor-based ART. The current Guidelines include darunavir plus ritonavir as a preferred regimen and atazanavir plus ritonavir as an alternate regimen for initial ART, both given with TDF/FTC.¹ However, use of low-dose ritonavir as the booster has caused protease inhibitor-based regimens to typically have a higher pill burden and greater cost than other regimens. In early 2015, both darunavir and atazanavir were approved in separate co-formulations with cobicistat, an alternate booster (Prezcobix, Janssen Pharmaceuticals; Evotaz, Bristol-Myers Squibb). 

A randomized, double-blind trial demonstrated atazanavir plus cobicistat was non-inferior to atazanavir plus ritonavir, both combined with TDF/FTC.⁵ The approval of darunavir/cobicistat was based on pharmacologic similarity⁶ and a single arm, open-label trial.⁷ Cobicistat, like dolutegravir, is an inhibitor of creatinine secretion, causing modest increases in serum creatinine and lower eGFR without affecting actual GFR. When these new co-formulations are used with TDF, eGFR should exceed 69 mL/min/m² prior to initiation. Both are listed in the Guidelines as alternate regimens when combined with TDF/FTC.¹ Darunavir/cobicistat may also be given with abacavir/lamivudine.¹ 

These two new co-formulations provide a modest reduction in pill burden and may reduce patient co-pays. They are welcome treatment options, assuming they are not more expensive than the individually formulated protease inhibitors plus ritonavir. Clinical data supporting use of atazanavir/cobicistat are presently strongly than those for darunavir/cobicistat.

Tenofovir alafenamide. TDF, a prodrug of tenofovir, is generally safe, effective, and well tolerated. When combined with FTC, it is the only nucleoside backbone that may be combined with any of the Guidelines-recommended or alternate third agents.¹ Still, in some patients it causes declines in GFR and proximal renal tubule dysfunction, and it may exacerbate the decline in bone mineral density associated with ART initiation. Tenofovir alafenamide (TAF), an investigational alternate prodrug of tenofovir, is in late stage clinical development. It achieves high concentrations of tenofovir diphosphate—the active form of tenofovir—in lymphocytes, with lower plasma concentrations. The results of recently published trials demonstrate that TAF has similar efficacy with less renal and bone adverse effects than TDF.⁸ TAF is being developed in co-formulation with FTC and in 3 single-tablet regimens adding either rilpivirine, elvitegravir or darunavir, with the last two also including cobicistat. TAF represents an advance in ART in that it reduces the risk of the most worrisome adverse effects seen with TDF. The darunavir-containing co-formulation would be the first protease inhibitor-based, single-tablet regimen, which represents an important advance in HIV treatment. However, as TDF is well tolerated by most patients, if TAF is substantially more expensive it may be reserved for patients who have preexisting renal or bone disease or who have experienced prior adverse effects while taking TDF.

Long-Acting Parenteral ART. Improvements in ART make it possible for most patients to achieve long-term control of HIV with daily oral medication. Yet certain patients are unable to maintain a high level of adherence or experience “pill fatigue” after periods of good adherence. TDF/FTC is effective as pre-exposure prophylaxis  (PrEP) in high-risk, HIV-negative individuals, but is also highly dependent on adherence to daily oral dosing.⁹  

A long-acting injectable antiretroviral regimen would be a welcome treatment option in both situations. Rilpivirine (Janssen Pharmaceuticals), an approved oral nonnucleoside reverse transcriptase inhibitor (NNRTI) and cabotegravir (ViiV Healthcare), an investigational INSTI, are being developed in nanosuspension formulation for intramuscular injection. Pharmacokinetics in healthy subjects suggests therapeutic levels of both drugs can be achieved with dosing every 12 weeks.¹⁰ 

The combination was effective for prevention of HIV  infection in an animal model.¹¹ The path to development of injectable drugs for use in PrEP in high-risk but otherwise healthy individuals will need to progress in steps. An early clinical trial has shown the combination of daily oral cabotegravir plus rilpivirine is safe and as effective as a standard regimen for maintenance of viral suppression after 24 weeks of induction therapy with a 3-drug regimen.¹² The oral regimen may have clinical usefulness as a nucleoside-sparing option for patients intolerant of or resistant to nucleoside-containing ART.

More importantly, this trial supports the conduct of future trials to establish that the injectable formulations are effective as maintenance therapy and can induce and maintain viral suppression in patients for whom standard oral ART failed due to poor adherence. For PrEP, either long-acting cabotegravir alone or the combination of the two drugs may be effective. 

Since cabotegravir is still in early-stage clinical development, considerable safety data from use in HIV-infected patients and HIV-uninfected subjects will be needed to support large-scale PrEP trials in HIV-uninfected individuals. 

A Novel Attachment Inhibitor. The antiretroviral armamentarium is currently stocked with many potent and tolerable agents with varying mechanisms of action. Still, there are some patients who have experienced treatment failure with many approved drugs for whom alternate therapies would be desirable. Fostemsavir (BMS 663068, Bristol-Myers Squibb) is the prodrug of an HIV-attachment inhibitor with a novel mechanism of action. It binds to HIV envelope protein gp120 to prevent the conformational changes needed to expose the CD4 binding site. The mechanism is different from chemokine (C-C motif) receptor 5 (CCR5) inhibitors. This investigational drug has intrinsic activity against most but not all naturally occurring HIV strains. 

Clinically important virologic activity was seen in treatment-experienced patients receiving 7 days of monotherapy followed by combination therapy with other active agents, and no serious safety signals were observed.¹³ To be eligible for this trial, participants had to have a baseline HIV isolate with a 50% inhibitory concentration <100nM in a phenotypic assay using the active form of fostemsavir. Six percent of those screened were ineligible based on this criterion. This novel attachment inhibitor has promising activity and safety that would be useful in treatment-experienced patients with multiclass antiretroviral resistance. Phase 3 clinical trials are ongoing. An important unanswered question is whether clinical use of this drug should be preceded by a specialized phenotypic assay to document susceptibility, a requirement that has blunted the uptake of CCR5 inhibitors. 

A New NNRTI. The NNRTI class of antiretrovirals has been widely and successfully used in clinical practice, yet no currently approved NNRTI has ideal features. Efavirenz has frequent although usually transient neuropsychiatric adverse effects. Rilpivirine is somewhat less potent. Etravirine is active in many efavirenz-experienced patients but its role in initial therapy has not been adequately defined. All NNRTIs have a low genetic barrier to resistance. As a consequence, the Guidelines no longer include NNRTIs among the recommended regimens.¹ Doravirine (MK-1439, Merck) is an investigational NNRTI that appears to have many favorable features. It is dosed once daily and in vitro develops resistance by a unique pathway that does not overlap those of current NNRTIs.¹⁴ A phase 2b clinical trial in treatment-naive individuals has shown efficacy comparable to efavirenz when combined with TDF/FTC, with less neuropsychiatric adverse effects.¹⁵ Doravirine appears to have desirable characteristics that could improve upon those of currently licensed NNRTIs. Phase 3 trials are underway.

David H. Shepp, MD is an Associate Professor of Medicine, Hofstra-North Shore LIJ School of Medicine; Division of Infectious Diseases, North Shore University Hospital, Manhasset, New York.

References

1.     National Institutes of Health. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Updated April 8, 2015.  Accessed September 14, 2015.

2.     Osterholzer DA, Goldman M. Dolutegravir: a next generation integrase inhibitor for treatment of HIV. Clin Infect Dis. 2014;59:265-271. DOI: 10.1093/cid/ciu221.

3.     Patel DA, Snedecor SJ, Tang WY, et al. 48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. PLoS One. 2014;9:e105653. doi: 10.1371/journal.pone.0105653.

4.     Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014;210:354362. doi: 10.1093/infdis/jiu051.

5.     Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1–infected patients: week 48 results. J Infect Dis. 2013;208:32-39.

6.     Kakuda TN, Opsomer M, Timmers M, et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol. 2014;54:949-957. doi: 10.1002/jcph.290.  

7.     Tashima K, Crofoot G, Tomaka FL, et al. Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther. 2014;11:39. doi:10.1186/1742-6405-11-39.

8.     Sax PE, Wohl D, Yin MT, et al; GS-US-292-0104/0111 Study Team. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385:2606-2615. doi: 10.1016/S0140-6736(15)60616-X.

9.     Grant RM, Anderson PL, McMahan V, et al; iPrEx Study Team. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14: 820-829. doi: 10.1016/S1473-3099(14)70847-3.

10. Spreen W, Williams P, Margolis D, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Syndr. 2014;67:487-492. doi: 10.1097/QAI.0000000000000365.

11. Andrews CD, Spreen WR, Mohri H, et al. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science. 2014;343:1151-1154. doi: 10.1126/science.1248707.

12. Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir and rilpivirine as 2-drug oral maintenance therapy: LATTE W96 results. Presentation at: CROI 2015; Seattle, WA; February 23-26, 2015:Abstract 554LB.

13. Thompson M, Lalezari J, Kaplan R, et al. Attachment inhibitor prodrug BMS-663068 in ARV-experienced subjects: Week 48 analysis. Presentation at: CROI 2015; Seattle, WA; February 23-26, 2015: Abstract 545.

14. Feng M, Wang D, Grobler A, Hazuda DJ, Miller MD, Lai MT. In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother. 2015;59:590-598. doi:  10.1128/AAC.04201-14.

15. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. Presentation at: CROI 2014; Boston, MA; March 3-6, 2014:Abstract 92LB.