Over two years ago, four new antiretrovirals were approved: Two of these introduced new classes of therapy, and two others provided new hope for already resistant viruses. These were added to the 20 existing antiretrovirals and have provided even more potent combinations that confer less resistance and long-term toxicities. In spite of these potent, cleaner regimens, resistance and intolerance are inevitable in some cases. Thus, there is a need for both new classes of antiretrovirals and enhancement of existing classes. There are over 50 new compounds in many different phases of development. This article will focus on medications currently in Phase II and III development.

Integrase Inhibitors

Integrase Inhibitors block the activity of the integrase enzyme, which is responsible for viral insertion into the DNA of the CD4+ cell. One such Integrase Inhibitor is Elvitegravir, Gilead's competitor to Isentress (raltegravir, Merck). However, elvitegravir may be dosed once daily when combined with a pharmacokinetic (PK) enhancer (i.e. ritonavir or cobicistat). Elvitegravir is one component of Gilead's "Quad," a 4-in-1 coformulation of elvitegravir, GS-9350 (cobicistat) and emtricitabine/tenofovir (Truvada). Phase II studies saw the Quad regimen meet the primary endpoint of non-inferiority in head-to-head trials versus Atripla (efavirenz/emtricitabine/tenofovir). Phase III trials are underway as of April 2010, with the "Quad" regimen going head-to-head against Reyataz (efavirenz and ritonavir-boosted atazanavir) in treatment-naive individuals.1

Another Integrase Inhibitor currently in Phase II trials is S/GSK1349572 (Viiv, Shlongi), which showed a significantviral load reduction over a ten day phase IIa dosing trial even in the absence of a PK enhancer. Resistance data showed this compound maintains activity despite integrase cross-resistance, which does not hold true for elvitegravir. Phase IIb trials are underway, with Phase III trials to commence in late 2010.2

Pharmacokinetic Enhancer

Ritonavir (Norvir) is the only "booster" approved by the Food and Drug Administration used to increase levels of antiretrovirals, most particularly protease inhibitors. While boosting is indicated in treatment-experienced patients, ritonavir carries side effects which make it intolerable in patients, such as gastrointestinal intolerance and lipid elevations. Cobicistat (GS-9350) is a "pharmacoenhancer" that possesses no antiretroviral activity. It increases drug levels through inhibition of Cytochrome P4503A -- the same mechanism as ritonavir. Phase II trials comparing cobicistat and ritonavir saw similar gains in CD4+ cell counts and decreases in viral load in their respective arms. Side effects were comparable, albeit less frequent, in the cobicistat arm. Phase III trials will commence later this year, comparing cobicistat versus ritonavir with various combinations. One point of concern in the cobicistat arm was a decrease in estimated glomerular filtration rate (GFR), through a false elevation in serum creatinine. Fortunately, this does not occur via the same pathway as most other nephrotoxic drugs. Further investigation is warranted to better understand the mechanism by which this occurs.1

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Currently, the NNRTI preferred by the Department of Health and Human Services is efavirenz. NNRTIs work to prevent DNA synthesis of the retrovirus through structural alteration of the Reverse Transcriptase enzyme. When resistance is an issue, most NNRTIs are rendered inactive with the exception of etravirine ilpivirine (TMC 278, Tibotec), a second generation NNRTI which demonstrates antiretroviral activity in the presence of the K103N mutation -- the signature efavirenz mutation. Rilpivirine demonstrated virologic efficacy comparable to efavirenz at week 48 (76.9% v. 80%) and sustained efficacy at week 96. The most commonly reported moderate to severe adverse events possibly related to study medication (e.g., nausea, dizziness, abnormal dreams, rash, somnolence and vertigo) occurred less frequently with rilpivirine than with efavirenz. Overall, rilpivirine demonstrates efficacy similar to efavirenz with a lesser incidence of neurological and psychiatric effects. Current Phase III trials are underway to replicate bioequivalence in the coformulation of riplivirine and emtricitabine/tenofovir. If approved, rilpivirine will be utilized as part of a first-line regimen -- unlike its Tibotec counterpart, etravirine, which is not indicated as such.3

Other NNRTIs in Phase II development include GSK2248761 (Viiv) and RDEA806 (Ardea). Both possess antiretroviral activity despite efavirenz resistance.

CCR5 Antagonists

Presently, maraviroc is the only FDA-approved CCR5 antagonist available. Maraviroc blocks the CCR5 coreceptor which HIV uses to bind and enter a human macrophage. It recently received indication for treatment in naive individuals and serves as an additional option in the presence of certain viral strains when other classes are not an option.4 Vicriviroc (Merck/Schering-Plough) is another CCR5 Inhibitor currently in Phase II/III trials. However, it has experienced obstacles. The first Phase II trials failed to establish an adequate dose. As of May 2008, two phase III trials (VICTOR-E3 and VICTOR E4) in treatment-experienced patients were initiated. Late stage clinical trials did not meet primary efficacy endpoints and Merck decided not to seek approval for the drug in treatment-experienced patients. However, trials in treatment-naive individuals will resume.5-8 Like maraviroc, multiple drug interactions with other antiretrovirals exist and side effects, such as increased risk of respiratory infection, may occur.4,5

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs are considered the backbone of antiretroviral therapy. Unlike their NNRTI counterparts, NRTIs structurally resemble compounds used in viral DNA chain elongation, essentrially tricking the virus into incorporating these analogues and terminating the growing chain. First-line combination(s) usually consist of lamivudine (Epivir) or emtricitabine (Emtriva) and another nucleoside, such as tenofovir or abacavir (Ziagen). While the regimens are highly potent, resistance to lamivudine and emtricitabine occurs quite frequently. Among the other nucleosides, multi-drug resistance or long-term morphological changes warrant the need for newer agents.

Amdoxovir (DAPD, RFS Pharmaceuticals) is currently in Phase II trials. Although it demonstrates activity against the main lamivudine/emtricitabine mutation, M184V, amdoxovir must be taken twice daily. In addition, visual problems may occur, but resolve upon discontinuation.9

Elvucitabine (ACH-126, Achillon) is virologically equivalent to lamivudine (3TC) when combined with efavirenz and tenofovir as a first-line regimen taken for 96 weeks. However, because of the small size of this phase II trial, and the high dropout rate, elvucitabine lagged 3TC from a statistical standpoint. Further research is needed to see where elvucitabine fits in treatment. Like lamivudine and tenofovir, elvucitabine also possess anti-Hepatitis B activity.18

Maturation Inhibitors

Maturation inhibitors, in later stages of viral replication, interfere with protease processing of a newly translated HIV polyprotein precursor called gag. This molecule contains a number of HIV proteins in a single polypeptide, which is then cleaved by an enzyme, called protease, to produce functional structural proteins. However, unlike the protease inhibitors, bevirimat binds to the gag protein, not protease. Two agents currently in Phase II trials include Bevirimat (PA457, MPC-4326, Myriad) and Vivecon (MPC-9055). While these agents offer a new opportunity, the potential for cross-resistance amongst previous protease inhibitor use is possible. Thus, baseline resistance testing may be warranted.

Monoclonal Antibodies

Similar to CCR5 antagonists, these compounds use monoclonal -- that is, all identical -- antibodies, rather than a drug molecule, to block the CCR5 co-receptor. PRO140 (Progenics) is currently in Phase II trials and has shown promise in terms of potency and duration of action. It is administered via subcutaneous injection, yet only requires dosing every other week, which may provide an option for patients where adherence may be an issue. PRO140 is generally well-tolerated, with injection site reactions (e.g., swelling, irritation, and pain) being the major side effects.10,11 In addition, Phase II studies of ibilazumab (TNX-355, Genetech) are scheduled to end by late 2010.12-17 Both compounds were granted fast-track status by the FDA, and may provide "salvage" in patients with a highly resistant virus, much like enfuvirtide (Fuzeon) did in 2003.

Michael Modzelewski is an AAHIVM certified pharmacist and has practiced in the New York City community for over 5 years, with a emphasis on specialized HIV care.


  1. Gilead Sciences. (2010, April 12) Gilead initiates phase III clinical program evaluating single-tablet, once-daily "quad" regimen for HIV. [Press Release].

  2. ViiV Healthcare. (2010, February 24). ViiV Healthcare highlights S/GSK1349572, Selzentry and Epzicom for HIV/AIDS at 17th CROI.

  1. Gilead Sciences. (2010, April 27). Gilead finalizes selection of bioequivalent formulation for thefixed-dose regimen of Truvada(R) and Tibotec pharmaceuticals' TMC278. [Press Release].

  2. Pfizer Inc. (2009, July 21). 96-week Merit Es analysis shows efficacy of Pfizer's HIV/AIDS treatment Celsentri/Selzentry (Maraviroc) in treatment-naive HIV patients. [Press Release].

  3. Highleyman L. (2008, May 11). CCR5 antagonist Vicriviroc shows continued benefits and good tolerability at 48 Weeks: Victor-E1 trial.

  4. Schering-Plough Corporation. (2008, April 15). Schering-Plough initiates phase II study with Vicriviroc in treatment-naive HIV-infected patients. [Press Release].

  5. Loftus P. (2010, January 20). Merck won't seek FDA approval for HIV drug. The Wall Street Journal.

  6. Pierson R. (2010, January 20). Merck HIV drug from Schering merger fails trials. Reuters.

  7. Kivel NM, Mathew J, Murphy RL, Ochoa C, Pascual ML, Schinazi RF, Zala C. (2010). Antiviral activity and tolerability of Amdoxovir with Zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals. Antiviral Therapy, 15(2): 185-192.

  1. Progenics Pharmaceuticals, Inc. (2006, February 22). Progenics pharmaceuticals' HIV drug, PRO 140, receives FDA fast-track designation. [Press Release].

  2. Horn T. (2007, September 21). Single-dose PRO 140 has lasting effects.

  3. TaiMed Biologics, Inc. (2009, September 9). Ibalizumab (TMB-355).

  4. DeJesus E, Godofsky E, Jacobson JM, Kuritzkes DR, Larson A, Lewis ST, Weinheimer SP (2009). Safety, pharmacokinetics, and antiretroviral activity of multiple doses of Ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrobial Agents & Chemotherapy, 53(2): 450-457.

  5. AIDSmeds. (2006, August 25). Ibalizumab (TNX-355).

  6. Tanox, Inc. (2006, May 2). Tanox reports 48-week results from TNX-355 phase 2 clinical trial.

  7. TaiMed Biologics, Inc. (2008, October 30). Dose-response study of Ibalizumab + OBR in patients with HIV-1.

  8. ChinaBio Today. (2007, September 18). Genentech partners with Taiwan company on AIDS drug seeking alpha.

  9. Bellos N, DeJesus E, Jefferson T, Kumarasamy N, Morales-Ramirez J, Olek E, Wade B. (Presented 2010, February 16-19). Abstract: Elvucitabine vs. Lamivudine with Tenofovir and Efavirenz in ART-naive HIV-1-infected patients: 96-week final results. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA.

  1. Microbicide Trials Network. (2010, May 23). Researchers report results of first microbicide trial in pregnant women. Study indicates small amount of drug passes to fetus. [Press Release].

  2. Armanasco N, Fletcher P, Herrera C, Nel A, Nuttall J, Romano J, Shattock RJ (Presented 2010, May 23). Abstract: Anti-HIV activity of the candidate microbicide Maraviroc, a CCR5 receptor antagonist. International Microbicides Conference, Pittsburgh, PA.

  3. Evans A. (Presented 2010, May 22-25). Abstract: Protease inhibitors Darunavir, Lopinavir and Ritonavir as potential microbicides. International Microbicides Conference. Pittsburgh, PA.

  4. Armanasco N, Fletcher P, Harman S, Herrera C, Nuttall J, Romano J, Shattock RJ (Presented 2010, May 23). Abstract: L644, a cholesterol derivatized version of the gp41 fusion peptide C34, provides superior activity in preclinical microbicide assays. International Microbicides Conference. Pittsburgh, PA.

  5. International Microbicides Conference. (2010, May 25). Lubricant use may raise HIV infection risk during anal sex. [Press Release].