Category Archives: 6.3. ART 2011/2012: The Horizon and Beyond

6.3. Art 2011/2012: The Horizon and Beyond

– Christian Hoffmann –

Over the past few years, several important new drugs have been licenced, namely the PI darunavir, the NNRTIs etravirine and rilpivirine, the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc. Almost all HIV-infected patients can now be treated with a virologically successful regimen, even those with multiple resistance mutations. There are hardly anymore “untreatable” patients. However, despite this considerable progress, there is an urgent need for new drugs. This is not just true for patients with multiresistant viruses awaiting new treatment options. Significant problems related to long-term toxicity and adherence are anticipated for all therapies that will presumably need to span decades, as eradication of HIV is still out of reach. As a result, new drugs are needed that are easier to take, with high genetic barriers to development of resistance, and above all less toxic. To reach the goal of eradication, new drugs need to be more potent than those available today. The following overview of agents that could make it to the clinic based on current data (April 2011) does not claim to be complete.

New Pharmacoenhancers (PKEs)

Many antiretroviral agents, among them almost all PIs, but also some new drugs such as vicriviroc or elvitegravir, have to be boosted in order to enhance their pharmacokinetics. For more than a decade, ritonavir has been the only reliable option for boostering. At CROI in February 2009, new pharmacoenhancers were introduced for the first time that could challenge ritonavir’s booster monopoly. The advantages of these new agents inhibiting the CYP3A system is that they have no antiviral effect and thus cannot cause resistance. Obviously, there are no reports yet about long-term side effects and the effects of such a total inhibition of enzyme systems.

Cobicistat (GS-9350) is a PKE developed by Gilead, which showed similar booster effects to ritonavir in first clinical PK studies (German 2009). In a randomized Phase II trial with 79 ART-naive patients who had received atazanavir along with TDF+FTC, effects were comparable to ritonavir (Cohen 2011). Cobicistat has also been developed in a QUAD pill which contains the four Gilead agents tenofovir, FTC, the integrase inhibitor elvitegravir and cobicistat. In a first Phase II double-blind trial the QUAD pill was tested in 71 therapy-naïve patients with Atriplaâ. The results showed similar effects after 24 weeks (Cohen 2011). Cobicistat seems to be well-tolerated, however a slight increase of creatinine was noted. This may only be explained by a lessened tubular creatinine secretion and may not indicate an impairment of renal function. However, problems with regard to management of the creatinine levels under the QUAD pill may still occur, as it also contains the potentially nephrotoxic tenofovir. Nevertheless, Gilead, being experienced in matters concerning nephrotoxicity, is moving forward with Phase II trials.

SPI-452 is a PKE developed by Sequoia that does not have any anti-HIV effect (Gulik 2009). In a first clinical study, different doses plus various PIs were given to 58 healthy volunteers. Tolerance was good. The levels of darunavir (37-fold) and atazanavir (13-fold) significantly increased as well. The booster effect lasted for a long time. Sequioa will continue research with SPI-452 as an individual agent and in fixed combinations. Use with HCV protease inhibitors will also be investigated. A look at the website makes one wonder, as there seems to be no news since February 2009.

PF-03716539 is a PKE from Pfizer. Studies with healthy volunteers regarding its effects on midazolam, maraviroc and darunavir were concluded in October 2009. The results have not yet been officially released.

TMC-558445 manufactured by Tibotec pharmaceuticals is currently being tested in a phase-I study. Results are not available yet.

New formulations  

Currently available drugs are in further development, the most important goals being a reduction in pill burden, easier dosing and fewer side effects. Several such agents that have entered the market already include Invirase 500®, Truvada®, Kivexa® and Atripla® as well the new Norvir® tablets.

Viramuneâ(Extended-Release) is an improved version of the otherwise available nevirapine formulation (Battegay 2009). It allows a once-daily dosing of nevirapine in one pill. Presently, Boehringer is conducting several studies. First data of the VERxVE study were released in the end of 2010. In this study 1,011 treatment naïve patients were treated with either the standard nevirapine or the extended release formulation in addition to TDF+FTC. After 48 weeks, 81% of patients were under detection level in the once-daily-arm compared to 76% in the standard-arm (Gathe 2010). Licensing for viramune XR® has been applied for and is expected by the end of 2011.

Nelfinavir 625 mg – this newer formulation was approved in the US in April 2003. It reduces the nelfinavir dose to 2 tablets BID. One study has shown that this formulation is better tolerated, particularly with respect to gastrointestinal side effects – despite the fact that plasma levels are around 30% higher (Johnson 2003). In Europe, where nelfinavir is produced and sold by Roche instead of Pfizer, the 625 mg tabletwill not be available for the time being. .

Zerit PRC® (PRC = “prolonged release capsule” or XR = “extended release”) is a capsulated once-daily formulation of d4T (Baril 2002). d4T XR was approved in Europe in 2002, but never made it to market – apparently d4t is “out”.  There are attempts underway to improve d4T through minor modifications to its molecular structure. OBP-601 (4’-Ed4T) is a novel nucleoside analog with potent anti-HIV-1 activity and limited cellular toxicity with a unique in vitro resistance profile. The company BMS is apparently working on this substance under the name festinavir (Weber 2008).

Generics are not so difficult to produce as shown by experiences from Africa, India or Thailand. In many cases, bioequivalence has been demonstrated (Laurent 2004, Marier 2007). In developing countries many fixed drug combinations (FDC) are often used. The most frequently used FDC is d4T+3TC+nevirapine which exists as Triomune (Cipla), GPO-vir (GPO), Triviro LNS (Ranbaxy) or Nevilast (Genixpharma). FDCs also exist for AZT+3TC+nevirapine such as Duovir N (Cipla) or Zidovex-LN (Ranbaxy). Patent rights for generics have often been ignored making these preparations insignificant in industrial countries.


Baril JG, Pollard RB, Raffi FM, et al. Stavudine extended/prolonged release (XR/PRC) vs. stavudine immediate release in combination with lamivudine and efavirenz: 48 week efficacy and safety. Abstract LbPeB9014, 14th Int AIDS Conf 2002, Barcelona.

Battegay ME, Arasteh K, Plettenb erg A. Assessment of the steady-state PK parameters of two extended release (XR) nevirapine (NVP) tablets 400 mg and 300 mg QD compared with immediate release (IR) NVP tablets 200 mg BID in HIV-1-infected patients – the ERVIR study. Abstract PE 4.1/2, 12th EACS 2009, Cologne.

Cai Y, Klein C, Roggatz U, et al. Bioequivalence of pilot tablet formulations of ritonavir to the marketed soft gel capsule at a dose of 100 mg. Abstract 52LB, 14th CROI 2007, Los Angeles.

Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011, 25:F7-12.

Gathe J, Knecht G, Orrell C, et al. 48 week (Wk) efficacy, pharmacokinetics (PK) and safety of once a day (QD) 400 mg nevirapine (NVP) extended release formulation (XR) for treatment of antiretroviral (ARV) naive HIV-1 infected patients (Pts) [VERxVE]. Abstract H-1808, 50th ICAAC 2010, Boston.

German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J AIDS 2010, 55:323-9.

Gulnik S, Eissenstat M, Afonina E, et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. Abstract 41, 16th CROI 2009, Montréal.

Johnson M, Nieto-Cisneros L, Horban A, et al. Viracept (Nelfinavir) 625 mg film-coated tablets: investigation of safety and gastrointestinal tolerability of this new formulation in comparison with 250 mg film-coated tablets (Viracept) in HIV patients. Abstract 548, 2nd IAS 2003, Paris.

Klein CE, Chiu YL, Causemaker SK, et al. Lopinavir/ritonavir (LPV/r) 100/25 mg tablet developed for pediatric use: bioequivalence to the LPV/r 200/50 mg tablet at a dose of 400/100 mg and predicted dosing regimens in children Abstract P4.1/01, 11th EACS 2007, Madrid.

Laurent C, Kouanfack C, Koulla-Shiro S, et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004, 364:29-34.

Marier JF, Dimarco M, Guilbaud R, et al. Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formula-tion versus coadministration of the individual products. J Clin Pharmacol 2007;47:1381-9.

Ramanathan S, Warren D, Wei L, Kearney B. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir.  Abstract A1-1301/34, 49th ICAAC 2009, San Francisco.

Weber J, Weberova J, Vazquez A, et al. Drug susceptibility profile of OBP-601, a novel NRTI, using a comprehensive panel of NRTI- or NNRTI-resistant viruses. Abstract 726b, 15th CROI 2008, Boston

New nucleoside analogs

Since the development of dexelvucitabine came to a halt, hopes are now limited that there will be new nucleoside analogs on the market in the near future. Developing NRTIs with strong potency against NRTI-resistant viruses thatat the same time showless mitochondrial toxicity appears to be difficult. It is unlikely that and of the following substanecd will ever make it to the market. Many of them have already disappeared.

Amdoxovir (DAPD) is a novel dioxolane guanosine NRTI which is converted in vivo to the highly efficient DXG. DAPD has good efficacy against viruses resistant to AZT/3TC and against hepatitis B virus (Corbett 2001). When patients showed changes of the ocular lenses during early clinical trials (Thompson 2003), development was halted in 2004 and Gilead withdrew its licensing agreement with two US universities. However, there is still hope for DAPD. Supported by RFS Pharma from Georgia (US), development is ongoing. In this program, DAPD is combined with AZT to use the distinct resistance profiles of both compounds. In the first double-blind, randomized study in 24 patients, the viral load declined by an impressive 1.97 logs after 10 days on 500 mg DAPD + 200 mg AZT BID. There are obviously synergistic effects (Murphy 2010) that can not be explained by interactions alone (Hurwitz 2010). The question will be how to avoid the toxicity of DAPD. Phase II studies are ongoing.

Apricitabine (ATC, AVX-754, formerly SPD-754) is a heterocyclic cytidine analog that was sold by Shire Biochem to Avexa in 2005. ATC chemically resembles 3TC but has in vitro activity against a broad spectrum of TAMs. Up to 5 nucleoside mutations do not significantly impair its activity (Gu 2006). However, susceptibility to ATC is reduced when the K65R is present (Frankel 2007). A first placebo-controlled study in 63 HIV-infected patients treated with ATC monotherapy showed decreases in viral load of between 1.2-1.4 logs depending on the dose – good potency for an NRTI (Cahn 2006). In 50 patients harbouring the M184V mutation there was a reduction of 0.7-0.9 log after three weeks on ATC (Cahn 2010). ATC-specific resistance mutations were not observed after 48 weeks and could not be selected during in vitro experiments (Oliveira 2009). Cephalgia and rhinitis are most frequent, otherwise tolerability of ATC seems to be good (Gaffney 2009). What about long-term toxicity? In monkeys, there were minor skin problems, usually hyperpigmentation, after 52 weeks of exposure. ATC was thus significantly less toxic than BCH-10652, which caused severe degenerative dermatopathy in all exposed monkeys (Locas 2004). 3TC and FTC significantly and competitively lower intracellular levels of ATC. Combination with other cytidine analogs is a problem. After negotiations with large pharmaceutical companies had failed in May 2010, further development was discontinued and it is questionable if it will be resumed.

Dioxolanthymidine (DOT) is a new thymidine analog – one of the few new agents in this subgroup. Dioxolane appeared to be relatively good in preclinical trials (Chung 2005, Liang 2006). Presently, prodrugs are being tested, however, clinical studies have yet to be conducted (Liang 2009).

EFda or 4-ethynol-2-fluor-deoxyadenosine seems to be one of the most effective NRTIs according to the results of animal testing on monkeys. The SIV virus load decreased after 7 days by 2-3 logs (Parniak 2009). It is also being evaluated as a potential microbicide.

Elvucitabine (ACH-126,443) is a cytidine analog developed by Achillion Pharmaceuticals. It is an enantiomer of dexelvucitabine and is also effective against HBV. In vitro studies show potency even in the presence of numerous resistance mutations (Fabrycki 2003). It is also of interest as it seems to have an extremely long half-life of up to 150 hours – this may allow once-weekly dosing (Colucci 2005).

A small, double-blind study showed a reduction in viral load of between 0.7 and 0.8 logs after 28 days in HIVpatients with the M184V mutation. However, this study had to be prematurely terminated, as 6/56 patients developed leucopenia or rash on a dose of 100 mg (Dunkle 2003). It seems that mitochondrial toxicity is lower than that of dexelvucitabine. On the other hand, this lower toxicity may also lower the efficiency of incorporation by drug-resistant forms of HIV-1 RT (Murakami 2004). Less toxicity at the expense of less efficacy? In a smaller Phase II study in 77 therapy naïve patients (with efavirenz and tenofovir), elvucitabine was comparable to 3TC at 96 weeks (DeJesus 2010). There appear to be problems in interactions with ritonavir, which may be due to ritonavir inhibiting an efflux gut transporter with activity present at various levels in subjects (Colucci 2009).

Fosalvudine is an NRTI by the company Heidelberg Pharma, which is a prodrug of the fluorothymidine alovudine. The active part is released only after enzymatic cleavage in the tissue. It is hoped that the toxicity commonly seen with flurothymidines can thus be reduced. In a Phase II trial with 43 ART-naïve HIV+ patients, fosalvudine was well-tolerated and after 2 weeks of monotherapy with 5-40 mg viral load decreased by up to 1 log (Cahn 2007). Trials with pretreated patients are being conducted in Russia as well as in Argentina. Animal testing on rats, however, indicate high mitochondrial toxicity (Vennhoff 2009). Further development is questionable.

Fozivudine is another NRTI developed by Heidelberg Pharma according to the “enhanced pro-drug-principle”. In Phase I/II trials (Bogner 1997, Girard 2000), fozivudine was well-tolerated, but only moderately effective – after 4 weeks, a decrease in viral load at the highest doses of approximately 0.7 logs was reached (Girard 2000). According to the company’s website, they are looking for partners to be able to conduct further trials. It has been silent for a while – no one seems to be very interested in a new AZT.

GS-7340 is a derivative of tenofovir which enables higher tenofovir concentrations in peripheral blood mononuclear cells. GS-7340 has been tested in different doses against tenofovir in 30 HIV-infected patients. After 2 weeks viral load decreased to 1,71 logs in comparison to 0,94 logs. It seems that a very promising tenofovir backup is developing here with better efficacy at an altogether lower systematic tenofovir exposure (Markowitz 2011). However, due to the success of tenofovir, the company will be in no hurry to develop a competition all too quickly.

Phosphazide (Nicavir) is a nucleoside analog that was developed (and is marketed) in Russia, which is very similar to AZT (Skoblov 2003). After 12 weeks of phosphazide monotherapy (400 mg), viral load in a small group of patients dropped by median 0.7 logs. Since phosphazide is a prodrug of AZT, it requires an additional activation step. The D67N mutation seems to reduce efficacy (Machado 1999). A small study has shown potency in combination with ddI and nevirapine (Kravtchenko 2000), another with ddI and saquinavir (Sitdykova 2003). It is still hard to see the advantage over AZT – although better tolerability was presumed, this has not been shown.

Racivir is a cytidine analog produced by Pharmasset. It is a mixture of FTC and its enantiomer. Possibly, both enantiomers have different resistance profiles so that, theoretically, the development of resistance is impeded (Hurwitz 2005). It has shown good antiviral activity in combination with d4T and efavirenz after two weeks (Herzmann 2005). In a double blind randomized study in 42 patients harbouring the M184V mutation, viral load declined by 0.4 logs after 28 days (Cahn 2007). There has been no news since then. There seems to be little interest for larger companies to further develop racivir.

Stampidine is a nucleoside analog developed by the Parker Hughes Institute. It resembles d4T and is apparently 100 times more potent than AZT in vitro (Uckun 2002). It also has activity against HIV mutants with up to 5 TAMs (Uckun 2006). It has been discussed also as a potential microbicide (D’Cruz 2004).

Out of sight, out of mind: the following NRTIs are not being pursued:

  • Adefovir dipivoxil (bis-POM PMEA) from Gilead, low activity against HIV, nephrotoxicity, has an indication in hepatitis B
  • Dexelvucitabine (DFC or Reverset) from Incyte, stopped in 2006 due to several cases of pancreatitis
  • dOTC from Biochem Pharma, stopped due to toxicity in monkeys
  • FddA (Lodenosine) from US Bioscience, stopped in 1999 due to severe liver/kidney damage
  • KP-1461 from Koronis, stopped in June 2008 due to no efficacy
  • Lobucavir from BMS, stopped due to carcinogenicity
  • MIV-210 from Medivir/Tibotec, currently being developed for HBV
  • MIV-310 (alovudine, FLT) from Boehringer Ingelheim, stopped in March 2005 due to a disappointing Phase II study
  • SPD-756 (BCH-13520) and SPD-761    


Bogner JR, Roecken M, Herrmann DB, Boerner D, Kaufmann B, Gurtler L, Plewig G, Goebel FD. Phase I/II trial with fozivudine tidoxil (BM 21.1290): a 7 day randomized, placebo-controlled dose-escalating trial. Antivir Ther 1997, 2:257-64.

Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 2006, 20:1261-8.

Cahn P, Schürmann D, Reuss F, et al. A phase-II study of 14 days monotherapy with the nucleoside-analogue Fosalvudine Tidoxil in treatment-naïve HIV-1 infected adults. WEPEB114LB, 4th IAS 2007, Sydney.

Cahn P, Sosa N, Wiznia A, et al. Racivir demonstrates safety and efficacy in patients harbouring HIV with the M184V mutation and > 3 TAM. Abstract 488, 14th CROI 2007, Los Angeles.

Cahn P, Altclas J, Martins M, et al. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected patients with M184V who are failing combina-tion therapy. HIV Med 2010 Nov 3. [Epub ahead of print]

Chung KC, Yadav V, Rapp K, Chong Y, Schinazi R. Dioxolane thymine nucleoside is active against a variety of NRTI-resistant mutants. Abstract 554, 12th CROI 2005, Boston.

Cihlar T, Laflamme G, Fisher R, et al. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother 2009, 53:150-6.

Cihlar T, Ray AS, Boojamra CG, et al. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother 2008;52:655-65.

Colucci P, Pottage J, Robison H, et al. The different clinical pharmacology of elvucitabine (beta-L-Fd4C) enables the drug to be given in a safe and effective manner with innovative drug dosing. Abstract LB-27, 45th ICAAC 2005, Washington.

Colucci P, Pottage JC, Robison H, et al. Multiple-dose pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, adminis-tered over 21 days with lopinavir-ritonavir in human immunodeficiency virus type 1-infected subjects. Antimicrob Agents Chemother 2009, 53:662-9.

Corbett AH, Rublein JC. DAPD. Curr Opin Investig Drugs 2001, 2:348-53.

D’Cruz OJ, Uckun FM. Stampidine is a potential nonspermicidal broad-spectrum anti-HIV microbicide. Fertil Steril 2004, 1:831-41.

DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. Abstract H-892, 48th ICAAC 2008, 2008.

DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs lamivudine with tenofovir and efavirenz in antiretroviral-treatment-naïve HIV-1 infected patients: 96 week final results. Abstract 511, 17th CROI 2010, San Francisco.

Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: potent antiviral activity demonstrated in multidrug-resistant HIV infection. Antiviral Therapy 2003, 8:S5.

Fabrycki J, Zhoa Y, Wearne J, et al. In vitro induction of HIV variants with reduced susceptibility to elvucitabine (ACH-126,443,beta-L-Fd4C). Antiviral Therapy 2003, 8:S8.

Frankel F, Xu H, Coates J, Wainberg M. In vitro investigation of the resistance profile of apricitabine. Abstract 581, 14th CROI 2007, LA.

Gaffney MM, Belliveau PP, Spooner LM. Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infection. Ann Pharmacother 2009, 43:1676-83

Girard PM, Pegram PS, Diquet B, et al. Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection: pharmacokinetics, tolerability, and efficacy. J AIDS 2000, 23:227-35.

Gu Z, Allard B, de Muys JM, et al. In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcrip-tase inhibitor for treatment of human immunodeficiency virus infection. Antimicrob Agents Chemother 2006, 50:625-31.

Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res 2005, 67:1-9.

Herzmann C, Arasteh K, Murphy RL, et al. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine with efavirenz and stavudine in antiretroviral-naive HIV-infected patients. Antimicrob Agents Chemother 2005, 49:2828-33.

Hurwitz SJ, Asif G, Fromentin E, Tharnish PM, Schinazi RF. Lack of pharmacokinetic interaction between amdoxovir and reduced- and standard-dose zidovudine in HIV-1-infected individuals. Antimicrob Agents Chemother 2010, 54:1248-55.

Hurwitz SJ, Otto MJ, Schinazi RF. Comparative pharmacokinetics of Racivir, (+/-)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans. Antivir Chem Chemother 2005, 16:117-27.

Kravtchenko AV, Salamov GG, Serebrovskaya LV, et al. The first experience of HAART with phosphazid + didanosine + nevirapine in HIV-infected patients in Russia. Abstract 3, 5th Int Conf Drug Therapy 2000, Glasgow, Scotland.

Liang Y, Narayanasamy J, Schinazi RF, Chu CK. Phosphoramidate and phosphate prodrugs of (-)-beta-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies. Bioorg Med Chem 2006, 14:2178-89.

Liang Y, Sharon A, Grier JP, et al. 5′-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): synthesis, anti-HIV activity, cytotoxicity and stability studies. Bioorg Med Chem 2009, 17:1404-9.

Locas C, Ching S, Damment S. Safety profile of SPD754 in cynomolgus monkeys treated for 52 weeks, Abstract 527, 11th CROI 2004, San Francisco.

Machado J, Tsoukas C, Salomon H, et al. Antiviral activity and resistance profile of phosphazid – a novel prodrug of AZT. Abstract 594, 6th CROI 1999, Chicago.

Markowitz M, Zolopa A, Ruane P, et al. GS-7340 Demonstrates Greater Declines in HIV-1 RNA than TDF during 14 Days of Monotherapy in HIV-1-infected Subjects. Abstract 152LB, 18th CROI 2011, Boston.

Murakami E, Ray AS, Schinazi RF, Anderson KS. Investigating the effects of stereochemistry on incorporation and removal of 5-fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D- and L-D4FC-TP. Antiviral Res 2004, 62:57-64.

Murphy RL, Kivel NM, Zala C, et al. Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals. Antivir Ther 2010, 15:185-92.

Oliveira M, Moisi D, Spira B, Cox S, Brenner BG, Wainberg MA. Apricitabine does not select additional drug resistance mutations in tissue culture in human immunodeficiency virus type 1 variants containing K65R, M184V, or M184V plus thymidine analogue mutations. Antimicrob Agents Chemother 2009, 53:1683-5.

Parniak MA, Murphey-Corb M, Nyaundi J, et al. Highly potent in vivo activity of QD administration of 4′-ethynyl-2-fluoro-deoxyadenosine in SIV-infected rhesus macaques. Abstract H-926/409. 49th ICAAC 2009.

Ray AS, Vela JE, Boojamra CG, et al. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother 2008, 52:648-54.

Sitdykova YR, Serebrovskaya LV, Kravchenko AV. Immune reconstitution on treatment of HIV-infected patients with phosphazid, didanosine and saquinavir/ritonavir once daily in russia. Abstract 2.7/1. 9th EACS 2003, Warsaw, Poland.

Skoblov Y, Karpenko I, Shirokova E, et al. Intracellular metabolism and pharmacokinetics of 5´-hydrogenphosphonate of 3´-azido-2´,3´-dideoxythymidine, a prodrug of 3´-azido-2´,3´-dideoxythymidine. Antiviral Res 2004;63:107-13.

Thompson M, Richmond G, Kessler M, et al. Preliminary results of dosing of amdoxovir in treatment-experienced patients. Abstract 554, 10th CROI 2003, Boston.

Uckun FM, Pendergrass S, Venkatachalam TK, Qazi S, Richman D. Stampidine is a potent inhibitor of zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical HIV type 1 isolates with thymidine analog mutations. Antimicrob Agents Chemother 2002, 46:3613-3616.

Uckun FM, Venkatachalam TK, Qazi S. Potency of stampidine against multi-nucleoside reverse transcriptase inhibitor resistant human immunodefi-ciency viruses. Arzneimittelforschung 2006, 56:193-203.

Venhoff AC, Lebrecht D, Reuss FU, et al. Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcrip-tase inhibitor prodrug. Antimicrob Agents Chemother 2009, 53:2748-51.


In 2008, etravirine was the first second-generation NNRTI to be licenced. Encouraged by this success, many pharmaceutical companies have NNRTIs in their pipeline again.

GSK-2248761 (GSK 761, formerly IDX-899) is an NNRTI developed by ViiV Healthcare. The resistance profile in vitro has no cross-resistance with efavirenz (Richman 2008). In vivo the viral load decreased by 1.8 logs at 8 days (Zala 2008). The half-life is long (Zhou 2009).  Early 2011, the FDA interrupted ongoing clinical studies after cerebral seizures had been observed. Further development is questionable, despite assertions by ViiV that the issue is not yet closed.

Lersivirin (UK 453,061) is another new NNRTI by ViiV Healthcare with good efficacy against classic NNRTI resistances (Corbeau 2010). Healthy volunteers had tolerated the substance well over 28 days (Davis 2010). In HIV-infected patients, a decrease of viral load up to 2,0 logs was observed under 10-750 mg after 7 days of monotherapy (Fätkenheuer 2009).

RDEA806 is an NNRTI by Ardea Bioscience. The resistance barrier is very high and the potential for interaction low (Hamatake 2007). Monotherapy trials with HIV-infected patients showed a reduction of over 1.8 logs at 7 days with excellent tolerability (Moyle 2010). The data seem promising enough to start Phase IIb trials. However, the company’s website is strangely blank on the topic.

Out of sight, out of mind, the following NNRTIs are no longer being developed:

  • Atevirdine – Upjohn is concentration on delavirdin (a good idea?)
    • BIRL355BS from Boehringer Ingelheim, in 2007 due to toxicity/metabolites
    • Calanolide A from Sarawak due to poor efficacy
    • Capravirin (AG1549) from Pfizer, limited activity
    • DPC 083 (BMS-561390), May 2003, poor PK/secure data
      • DPC 961 due to suicidal thoughts in healthy volunteers; DPC 963
      • Emivirine (EMV, MKC-442, coactinone) from Triangle, due to limited activity
      • GW420867X from GSK, due to being too much of a me-too drug
      • GW8248 and GW5624 from GSK, due to poor bioavailability
      • HBY-097 from Hoechst-Bayer, due to unfavorable side effects
      • Loviride,  Janssen pharmaceuticals, due to limited activity in the  CAESAR-study
        • MIV-150 from Medivir/Chiron, due to poor bioavailability, is now being developed as a microbicide
        • PNU 142721, Pharmacia & Upjohn, too similar to efavirenz  (Me-too)
          • TMC120 (dapivirine) from Tibotec, due to poor oral bioavailability, now being studied as a microbicide


Cohen C, Molina JM, Cahn P et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised phase III trials comparing TMC278 versus efavirenz in treatment-naïve HIV-1-infected patients. Abstract THLBB206, 18th IAC 2010, Vienna.

Corbau R, Mori J, Phillips C, et al. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2010, 54:4451-63.

Crauwels H, Vingerhoets J, Ryan R. Pharmacokinetic parameters of once-daily TMC278 following administration of EFV in healthy volunteers. Abstract 630, 18th CROI 2011, Boston.

Davis J, Hackman F, Ndongo MN, et al. Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28-day, randomized, placebo-controlled, Phase I clinical study in healthy male volunteers. Clin Ther 2010, 32:1889-95.

Desmidt M, Willems B, Dom P, et al. Absence of a teratogenic potential from a novel next-generation NNRTI, TMC278. Abstract PE7.1/4, 12th EACS 2009, Cologne.

Fätkenheuer G, Staszewski S, Plettenberg A, et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV infected patients. Abstract WESS202, 4th IAS 2007, Sydney.

Goebel F, Yakovlev A, Pozniak A, et al. TMC278: Potent anti-HIV activity in ART-naive patients. Abstract 160, 12th CROI 2005, Boston.

Hamatake R, Zhang Z, Xu W, et al. RDEA806, a potent NNRTI with a high genetic barrier to resistance. Abstract 1662, 47th ICAAC 2007, Chicago.

Hoetelmans R, van Heeswijk R, Kestens D, et al. Pharmacokinetic interaction between TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), and lopinavir/ritonavir (LPV/r) in healthy volunteers. Abstract PE4.3/1, 10th EACS 2005, Dublin.

Janssen PA, Lewi PJ, Arnold E, et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 2005, 48:1901-9.

Langdon G, Davis J, Layton G, et al. Pharmacokinetic interaction of the next generation NNRTI UK-453,061 with other antiretrovirals and assessment of safety and tolerability in healthy male subjects.  Abstract 763, 15th CROI 2008, Boston.

Moyle G, Boffito M, Manhard K, et al. Antiviral activity of RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor in treatment naive HIV patients. Abstract THAB0403, XVII IAC 2008, Mexico City.

Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC 278 demonstrates potent and sustained efficacy in ART naive patients. Abstract LB144 LB, 14th CROI 2007. Los Angeles.

Richman D, Jakubik J, Chapron C, et al. Genotypic resistance and phenotypic cross-resistance profile in vitro for a novel NNRTI: IDX899. Abstract 729, 15th CROI 2008, Boston.

Vanveggel S, Buelens A, Crauwels H, et al. TMC278 25mg QD has no effect on corrected QT interval in a study in HIV-negative volunteers. Abstract PE7.1/2, 12th EACS 2009, Cologne.

Verloes R, van’t Klooster G, Baert L, et al. TMC278 long acting – a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers. Abstract TUPE0042, 17th IAC 2008, Mexico City.

Zala C, Murphy R, Zhou XJ, et al. IDX899, a novel HIV-1 NNRTI with high barrier to resistance, provides suppression of HIV viral load in treatment-naive HIV-1-infected subjects. Abstract THAB0402, XVII IAC 2008, Mexico City.

Zhou XJ, Pietropaolo K, Damphousse D, et al. Single-dose escalation and multiple-dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob Agents Chemother 2009, 53:1739-46.

New protease inhibitors (PIs)

Even among PIs, many agents have been lost along the way. Following the licensing of darunavir, not much can be expected from PIs in the near- to mid-term. This may also be due to the high bar on new PIs in view of the existing results within this group (Review: Pokorná 2009).

DG17 is a prodrug of DG35 and has been under clinical testing for some time. A recent study showed a clear boosting effect with ritonavir and significant pharmacoenhancement reliving further clinical development of the drug (Cherry 2008).

PL-100 (MK8122) is a PI from the Canadian company Ambrilia Biopharma cooperating with Merck. The prodrug PPL-100 is metabolized to the active agent PL-100 which is believed to act against a broad range of PI-resistant viruses (Dandache 2007). PK data on healthy individuals look good. Moreover, the long half-life of 30-37 hours is of note. However, in 2008, clinical development was halted as Merck wants to concentrate more on prodrugs.

SM-309515 is a new PI from Sumitomo Pharmaceuticals and has apparently entered Phase I studies. Earlier versions failed due to the short half-life, and attempts are now being made to improve this (Mimoto 2008). The drug remained effective against mutations such as S37N, I47V, R57K, and I84V. Ritonavir boosting is now being tested in humans.

SPI-256 from Sequioa Pharmaceuticals is effective in vitro against PI-resistant isolates (Gulnik 2006). Healthy individuals have tolerated it well.

TMC-310911 is a new PI from Tibotec which is currently being examined with the booster-drug TMC-558445 in a Phase I-study. Data is not yet available.

Out of sight, out of mind the following PIs are no longer being developed:

  • AG-001859 – from Pfizer
  • Brecanavir – from GSK stopped in 2006 due to poor PKdata
  • DPC 684/681 –  narrow therapeutic range due to cardiotoxicity
  • GS 9005 – previously GS 4338, from Gilead
  • JE-2147, AKA AG1776, KNI-764 – from Pfizer, no news since 1999
  • KNI-272, Kynostatin – due to poor PK data
  • Mozenavir, DMP-450 – from Gilead, me-too drug, not offering anything new or better
  • RO033-4649 – from Roche, probably too similar to saquinavir
  • SC-52151 and SC-55389A – poor bioavailability
  • TMC-126 – Tibotec concentrated on TMC-114 (darunavir)


Cherry CL, Hoy JF, Rowe JS, Krum H, Mills J, Lewin SR. Phase 1 single dose studies to optimize the pharmacokinetics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir. Curr HIV Res 2008, 6:272-5.

Dandache S, Sevigny G, Yelle J, et al. In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2007;51:4036-43.

Gulnik S, Afonina E, Eissenstat M, Parkin N, Japour A, Erickson J. SPI-256, a highly potent HIV protease inhibitor with broad activity against MDR strains. Abstract 501, 13th CROI 2006, Denver.

Hammond J, Jackson L, Graham J, et al. Antiviral activity and resistance profile of AG-001859, a novel HIV-1 protease inhibitor with potent activity against protease inhibitor-resistant strains of HIV. Antiviral Therapy 2004; 9:S17.

Mimoto T, Nojima S, Terashima K. Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure. Bioorg Med Chem 2008, 16:1299-308.

Pokorná J, Machala L, Řezáčová P Konvalinka J. Current and Novel Inhibitors of HIV Protease. Viruses 2009, 1:1209-1239.

Wu JJ, Stranix B, Milot G, et al. PL-100, a next generation protease inhibitor against drug-resistant HIV: in vitro and in vivo metabolism. Abstract H-253, 46th ICAAC 2006, San Francisco.

New entry inhibitors

With T-20 and maraviroc two entry inhibitors have already been licenced (see Chapter 2). Even if the antiviral effects of the drugs are not overwhelming, the concept is intriguing and entry inhibitors could open up new possibilities for the treatment of HIV infection in the coming years. On the other hand, a lot of the data does not go beyond basic science at this stage and many of the drugs discussed below may eventually disappear. Most significantly, coreceptor antagonists have had to bear several bitter setbacks.

New attachment inhibitors

Attachment of the viral glycoprotein gp120 to the CD4 receptor is the first step in the entry of HIV into the target cell. In theory, this step can be inhibited at least by two different mechanisms, namely blocking either gp120 or CD4. Both modes of action are currently under investigaton. Consequently, attachment inhibitors are very heterogeneous, so it is not possible to speak of a single drug class.

Since the beginning of the nineties, there have been a number of investigations into soluble CD4 molecules that prevent the attachment of HIV to the CD4 cell (Daar 1990, Schooley 1990). But, after disappointing results (probably due to the very short half-life of soluble CD4), this approach was abandoned for several years. With the growing knowledge of the mechanism of HIV entry into the cell, as well as following the success of T-20 as the first entry inhibitor, the development of attachment inhibitors has been reinvigorated. However, most drugs are not yet far advanced, often have problematic PK data and are therefore still in the proof-of-concept stage.

BMS-663068 is an attachment inhibitor from BMS. As a small molecule it binds very specifically and reversibly to HIV gp120 and thereby prevents attachment of HIV to the CD4 cell Thus, it does not bind to CD4 like ibalizumab (see below). The substance drew a lot of attention in the CROI study (Nettles 2011). 50 treatment naïve patients received different doses once or twice daily over 8 days. Viral load decreased by 1,2 and 1,8 logs – the maximum reduction in both arms was achieved a few days after treatment had concluded. Unfortunately no doses related dependence was observed and interindividual bioavailability was high. Headaches (44%) and rash (16%, mostly mild) were most frequent. Nevertheless, it is considered a promising revival of a new substance group. BMS-663068 is a prodrug of BMS-62659, with a broad range of efficacy against several HIV isolates (Nowicka-Sans 2011). It is the replacement for BMS-488043, stopped in 2004 after first clinical data were released (Hanna 2004). resistance occurs quickly as the binding site of gp120 is one of the most variable gene regions of all (Madani 2010).

Ibalizumab (formerly TNX-355 or HU5A8) is a monoclonal antibody that binds to the CD4 receptor preventing entry of HIV. The mechanism of action has not been clearly described. In contrast to other attachment inhibitors, ibalizumab does not seem to prevent binding of gp120 to CD4, but rather through conformational changes and thereby the binding of gp120 to CXCR4. Some experts therefore describe it as a coreceptor antagonist. It can be administered intravenously. Following the initial early data (Jacobsen 2004+2009, Kuritzkes 2004), data from a placebo-controlled Phase II trial were very encouraging (Norris 2006). In this study, extensively pretreated patients received ibalizumab as an infusion every two weeks for a year in two different doses (10 mg/kg or 15 mg/kg) or placebo in addition to an optimized ART regime. This study showed a long-lasting decrase in viral load of approximately one log after 48 weeks in both arms.

According to these data, ibalizumab appears to be one of the more promising agents in HIV medicine. There seems to be an inverse correlation between the sensitivity for ibalizumab and soluble CD4, which does not work on its own, as shown above (Duensing 2006). Resistances cause a higher sensitivity towards soluble CD4 and the gp120 antibody VC01, which is why attempts are made to administer ibalzumab in a cocktail of CD4 and VC01 (Pace 2011). First data on resistances have been published recently (Toma 2011). However, one issue will be whether binding to CD4 will affect the functionality of the CD4 T cells. There have been no negative affects reported so far and it seems that the binding site for ibalizumab to CD4 receptors is localized differently from the molecules. The CD4 T cells may be able to employ its normal functions, even if ibalizumab occupies the HIV binding site.

Origially ibalizumab was developed by Tanox Biosystems (Houston, Texas) and later taken over by the biotechnology company Genentech in 2007. In mid-2007 Genentech sold the license for ibalizumab to TaiMed Biologics, a Taiwanese biotech company – they are presently planning Phase IIb trials in Europe and the USA. The continuing research with this agent can be ascribed to the dedication of David Ho, Taiwanese himself and director of the Aaron Diamond AIDS Research Center. They have started to work on a subcutaneous version that quite possibly will take longer to develop.


Daar ES, Li XL, Moudgil T, Ho DD. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A 1990, 87:6574-6578.

Duensing T, Fung M, Lewis S, Weinheimer S. In vitro characterization of HIV isolated from patients treated with the entry inhibitor TNX-355. Abstract 158 LB,  13th CROI 2006, Denver.

Hanna G, Lalezari L, Hellinger J, et al. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. Abstract 141, 11th CROI, 2004, San Francisco.

Jacobson JM, Kuritzkes DR, Godofsky E, et al. Phase 1b study of the anti-CD4 monoclonal antibody TNX-355 in HIV-infected subjects: safety and antiretroviral activity of multiple doses. Abstract 536, 11th CROI 2004, San Francisco.

Jacobson JM, Kuritzkes DR, Godofsky E, et al. 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. Antimicrob Agents Chemother 2009, 53:450-7.

Kuritzkes DR, Jacobson J, Powderly WG, et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004, 189:286-91.

Madani N, Princiotto A, Schön A, et al. Binding requirements for the entry inhibitor BMS-806. Abstract 65, 17th CROI 2010, San Francisco.Norris D, Morales J, Godofsky E, et al. TNX-355, in combination with optimized background regimen, achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. Abstr. ThLB0218, XVI IAC 2006, Toronto.

Nettles R, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: A potentially first-in-class oral HIV attachment inhibitor. Abstract 49, 18th CROI 2011, Boston.

Norris D, Morales J, Godofsky E, et al. TNX-355, in combination with optimized background regimen, achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. Abstr. ThLB0218, XVI IAC 2006, Toronto

Nowicka-Sans B, Gong YF, Ho HT, et al. Antiviral Activity of a New Small Molecule HIV-1 Attachment Inhibitor, BMS-626529, the Parent of BMS-663068. Abstract 518, 18th CROI 2011, Boston.

Pace G, Fordyce M, Franco D. Anti-CD4 monoclonal antibody ibalizumab exhibits exceptional breadth and potency against HIV, which adopts a unique pathway to resistance. Abstract 585, 18th CROI 2011, Boston.

Schooley RT, Merigan TC, Gaut P, et al. Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1990, 112:247-253.

Toma J, Weinheimer SP, Stawiski E, et al. Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab. J Virol 2011, 85:3872-80.

New co-receptor antagonists

In addition to CD4 receptors, HIV also requires so-called co-receptors to enter the target cell. The two most important ones, CXCR4 and CCR5, were discovered in the mid-90s (see Chapter 2). Both receptors can be blocked (antagonized). In 2007, maraviroc was licenced as the first CCR5 antagonist. These small molecules are given orally and bind allosterically to the receptor. Beside these allosteric inhibitors there are monoclonal antibodies binding directly to the receptor. Below we will discuss those agents with published data.

New CCR5 antagonists (small molecules)

Vicriviroc (SCH-D, or 417690) is or was a CCR5 antagonist from Schering-Plough. Clinical development of this promising substance was halted in July 2010    after a pooled analysis of two Phase III trials, VICTOR E3 and E4 (Gathe 2010). A total of 721 pretreated patients received 30 mg vicriviroc or placebo in an optimized therapy containing mainly darunavir/r and/or raltegravir. No difference was observed between vicriviroc and placebo after 48 weeks (64% versus 62% below 50 copies/ml). Despite obvious differences in patients who were down to a maximum of two active drugs (70% versus 55%) the company decided to stop development of vicriviroc. Why this is mentioned here? Because this example clearly shows the problems new agents will face in the future. With the improvement of therapies over time, it is becoming more and more difficult to show effects – background therapies have become “too” good.

Cenicrivoc (TBR-652 or formerly TAK-652) is a new orally available CCR5 antagonist by the Japanese company Takeda, that has now been bought by Tobira. Laboratory data demonstrated that several mutations in the V3 region (and in the env gene) must exist for complete resistance towards TAK-652. Tropism does not seem to change when resistance happens (Baba 2007). Oral bioavailability is good and with 35-40 hours half-life a once daily dosage is possible. The oral availability is improved with food intake. TBR-652 also seems to be effective against CCR2, a receptor seated on moncytes, dendritic and memory T cells. Despite this, there are no concerns regarding its safety and the substance has shown good tolerability in healthy volunteers (Palleja 2009). In a first double-blind study of 10 days monotherapy and different doses in 54 patients, the viral load decreased by a maximum of 1.5-1.8 logs (Lalezari 2011, Marier 2011).

INCB9471 is an orally available CCR5 antagonist by the company Incyte. In a small study with 21 HIV-infected patients, who had received it or placebo over 14 days (Cohen 2007), the lowest viral load reduction was reached at -1.82 logs at 16 days. Due to the long half-life of 60 hours, effects continued until day 20, 6 days after therapy was stopped. Incyte stopped working on the agent in March 2008 to be able to focus on other products – they are looking for a buyer, and further development may be questionable.

PF-232798 is an orally available CCR5 antagonist by Pfizer (now ViiV Healthcare) and probably a maraviroc backup. It has a long half-life and can probably be administered once daily. In vitro it reacts well to maraviroc resistance. In healthy volunteers, it was well tolerated (Dorr 2008).

SCH-532706 is a new CCR5 antagonist from Schering. At first sight, there seems to be no advantage of this agent over vicriviroc. A total of 12 patients receiving 60 mg SCH-532706 (with 100 mg ritonavir) showed a reduction of viral load of up to 1.62 logs at 15 days (Pett 2009). A once-daily administration seems possible. There may be a positive effect on immune activation (Pett 2010) – however, it seems unlikely that this substance will be further pursued after the end of vicriviroc.

Other innovative CCR5 blockers

HGS004 (CCR5mAb004) developed by Human Genome Sciences is a monoclonal antibody showing a high resistance barrier in vitro (Giguel 2006). The half-life is approximately 5-8 days, and 80% of the receptors are occupied over a period of up to 4 weeks after a single dose. In an initial trial, 54 ART-naïve patients received a single infusion between 0.4 and 40 mg/kg HGS004 or placebo (Lalezari 2008). More than half the patients in the higher dose arms showed a reduction of at least one log at 14 days. Possibly, the company has now turned their attention to HGS101 which is even more effective in vitro and in addition effective against maraviroc resistances (Latinovic 2011).

PRO 140 is a monoclonal antibody by the company Progenics, directed against human CCR5 receptors (Trkola 2001). It is not a chemokine derivative like maraviroc or vicriviroc and even seems to have a synergistic effect (Murga 2006). The resistance barrier is probably high (Jacobsen 2010). PRO 140 must be administered parenterally. The normal function of CCR5 receptors should not be interfered with, at least not in the required dosages for inhibition of HIV replication (Gardner 2003). Healthy patients showed excellent tolerability to intravenous single administration of the drug and dose-dependent concentrations were measured (Olson 2005). What was particularly surprising was the extended effect – CCR5 receptors were occupied for up to 60 days and more (Olson 2006). In a trial with 39 HIV-infected patients treated with intravenous single doses of between 0.5 and 5.0 mg/kg, viral load decreased with the highest doses by 1.83 logs with a nadir at day 10 (Jacobson 2008). A higher dosage does not seem to achieve more (Jacobsen 2010). Comparable effects are reached with weekly subcutaneous administration (Jacobson 2010). If the so far excellent tolerability of PRO 140 is confirmed, it may develop to become  the first therapy on a weekly  basis.

ESN-196 is a pilot agent developed by Euroscreen, which does not block the coreceptor, but is agonistic, like the chemokine RANTES, causing internalization of the receptor (Ferain 2008). This CCR5 agonist reduces the receptor density on the cell surface. Therefore, it is as effective as maraviroc in vitro. As an agent with an extended effect, it could become an alternative, even with CCR5A resistant viruses, if proven safe in clinical trials.

Aprepitant (Emend®) is approved as a neurokinin-1 receptor antagonist and as an antiemetic in patients receiving highly emetogenous chemotherapy. It apparently has an effect on R5-tropic viruses caused by a down-regulation of the CCR5 receptors. Lab data showed dose-dependent effects on HIV replication (Wang 2007, Manak 20010). It is alleged that studies with HIV-infected patients are being run.

CXCR4 antagonists

In the early stages of infection, the R5 virus is found in most patients; X4 virus appears at later stages. X4 viruses are found in approximately 50% of cases in intensely pre-treated patients (Hoffmann 2007). This is why theoretically the blocking of CXCR4 receptors seems so attractive, as those patients with limited options would benefit most from it. The combination with CCR5 antagonists seems to be an interesting option. However, the development of CXCR4 antagonists is less advanced than that of the CCR5 antagonists (Khan 2007). This is mainly because theoretically, less clinical consequences are feared with the CCR5 blockade – individuals with a CCR5 genetic defect are healthy. In contrast, an inherent and mostly harmless defect with CXCR4 in humans has not been recorded. CXCR4 blockade had severe consequences in animal testing, for example in angiogenetic haematopoiesis or brain development (Tachibana 1998, Nagasawa 1998, Zou 1998). Years of basic research will certainly be necessary until large clinical studies can be attempted. Nevertheless, several chemically-different substances are in preclinical testing (Jenkinson 2010, Miller 2010, Skerl 2010, Steen 2010, Thakkar 2010). Despite the hurdles, CXCR4 antagonists seems to be a promising class. Research has shown an interesting side-effect that some agents are able to mobilize stem cells. This is why one of the pilot drugs, AMD 3100, presently under the name plexifor, is being further developed as a growth factor for leukocytes as well as a G-CSF alternative (Uy 2008). Such an effect, however, is obviously not desired in permanent HIV therapy. CXCR4 antagonists are also being discussed with regard to lupus erythematodes (Chong 2009).

AMD 11070 is a CXCR4 antagonist developed by AnorMED. Healthy volunteers showed excellent tolerability with AMD 070, but often developed leukocytosis (Stone 2004). The efficacy in HIV-infected patients with dual-tropic viruses was validated in two pilot studies (Moyle 2007, Saag 2007). The viral load decreased by at least one log in 7/15 patients on 10 days of monotherapy. However, in 2007, development was preliminarily stopped because of a liver toxicity. Binding to the X4 receptor is localized differently than the precursor agent AMD 3100, so there may be some scope for the development of new, more potent and less toxic CXCR4 antagonists (Wong 2007) – at least a start was made with AMD 11070 and evidence of efficacy was found. Presently AMD 3465 seems to be another possibility (Bodart 2009).

KRH-3955 and KRH-3140 are two new CXCR4 antagonists that have proven effective in mouse models (Tanaka 2006). According to preclinical data, KRH-3955 seems especially promising (Murakami 2009) and bioavailability is good (in dogs). Likewise, POL3026 is still preclinical and may help inhibit selected X4 shifts while on CCR5 antagonists (Moncunill 2008).


Baba M, Miyake H, Wang X, Okamoto M, Takashima K. Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother 2007;51:707-15.

Bodart V, Anastassov V, Darkes MC, et al. Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4. Biochem Pharmacol 2009, 78:993-1000.

Chong BF, Mohan C. Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus. Expert Opin Ther Targets 2009, 13:1147-53.

Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Abstract TUAB106, 4th IAS 2007, Sydney.

Dorr P, Westby M, McFadyen L, et al. PF-232798, a Second Generation Oral CCR5 Antagonist. Abstract 737, 15th CROI 2008, Boston.

Ferain O, Schols D, Bernard J, et al. ESN-196, a novel, small-molecule CCR5 agonist inhibits R5 HIV infection. Abstract 738, 15th CROI 2008, Boston.

Gardner J, Cohen M, Rosenfield SI, Nagashima KA, Maddon PJ, Olson WC. Immunotoxicology of PRO 140: a humanized anti-CCR5 monoclonal antibody for HIV-1 therapy. Abstract 876, Abstract 444, 43rd ICAAC 2003, Chicago.

Gathe J, R Diaz R, Fätkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. Abstract 54LB, 17th CROI 2010, San Francisco.

Giguel F, Beebe L, Migone TS, Kuritzkes D. The anti-CCR5 mAb004 inhibits hiv-1 replication synergistically in combination with other antiretroviral agents but does not select for resistance during in vitro passage. Abstract 505, 13th CROI 2006, Denver.

Hoffmann C. The epidemiology of HIV coreceptor tropism. Eur J Med Res 2007;12:385-90.

Jacobson J, Thompson M, Fischl M, et al. Phase 2a study of PRO 140 in HIV-infected adults. Abstract HG-1220, 49th ICAAC 2009, San Francisco.

Jacobson JM, Lalezari JP, Thompson MA, et al. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob Agents Chemother 2010, 54:4137-42.

Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 2008, 198:1345-52.

Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a  CCR5 monoclonal antibody. J Infect Dis 2010, 201:1481-7.

Jenkinson S, Thomson M, McCoy D, et al. Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist. Antimicrob Agents Chemother 2010, 54:817-24.

Khan A, Greenman J, Archibald SJ. Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates. Curr Med Chem 2007;14:2257-77.

Lalezari J, Gathe J, Brinson C, et al. Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naïve Subjects. J AIDS 2011 Feb 11. [Epub ahead of print]

Lalezari J, Yadavalli GK, Para M, et al. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 2008, 197:721-7.

Latinovic O, Reitz M, Le NM, Foulke JS, et al. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells. Virology 2011, 411:32-40.

Manak M, Moshkoff D, Nguyen L, et al. Anti-HIV activity of aprepitant and synergistic interactions with other ARVs. Abstr. 750, 15th CROI 2008, Boston.

Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and Pharmacodynamics of TBR-652, a Novel CCR5 Antagonist, in HIV-1-Infected, Antiretroviral Treatment-Experienced and CCR5 Antagonist-Naïve Patients. Antimicrob Agents Chemother 2011 Apr 12. [Epub ahead of print]

Moncunill G, Armand-Ugon M, Clotet I, et al. Anti-HIV Activity and Resistance Profile of the CXCR4 Antagonist POL3026. Mol Pharmacol 2008.

Moyle G, DeJesus E, Boffito M, et al. CXCR4 antagonism: proof of activity with AMD 11070. Abstract 511, 14th CROI 2007, Los Angeles.

Murakami T, Kumakura S, Yamazaki T, et al. The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100. Antimicrob Agents Chemother 2009, 53:2940-8.

Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2006, 50:3289-96.

Nagasawa T, Tachibana K, Kishimoto T. A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol 1998, 10:179-85.

Olson W, Doshan H, Zhan C et al. First-in-humans trial of PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Abstract WePe6.2C04, 3rd IAS 2005, Rio de Janeiro.

Olson WC, Doshan H, Zhan C. Prolonged coating of CCR5 lymphocytes by PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Abstract 515, 13th CROI 2006, Denver.

Palleja S, Cohen C, J Gathe J, et al. Safety and efficacy of TBR 652, a chemokine receptor 5 (CCR5) antagonist, in HIV 1-infected, antiretroviral (ARV) treatment-experienced, CCR5 antagonist–naïve patients. Abstract 53, 17th CROI 2010, San Francisco.

Pett SL, McCarthy MC, Cooper DA, et al.  A phase I study to explore the activity and safety of SCH532706, a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients. Antivir Ther 2009, 14:111-5.

Pett SL, Zaunders J, Bailey M, et al. A novel chemokine-receptor-5 (CCR5) blocker, SCH532706, has differential effects on CCR5+CD4+ and CCR5+CD8+ T cell numbers in chronic HIV infection. AIDS Res Hum Retroviruses 2010, 26:653-61.

Saag M, Rosenkranz S, Becker S, et al. Proof of concept of ARV activity of AMD 11070 (an orally administered CXCR4 entry inhibitor): results of the first dosing cohort A studied in ACTG protocol A5210). Abstract 512, 14th CROI 2007, Los Angeles.

Skerlj RT, Bridger GJ, Kaller A, et al. Discovery of Novel Small Molecule Orally Bioavailable C-X-C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication. J Med Chem. 2010 Mar 19. [Epub ahead of print]

Steen A, Schwartz TW, Rosenkilde MM. Targeting CXCR4 in HIV Cell-Entry Inhibition. Mini Rev Med Chem. 2010 Jan 21. [Epub ahead of print]

Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998, 393:591-4.

Tanaka Y, Okuma K, Tanaka R, et al. Development of novel orally bioavailable CXCR4 antagonist, KRH-3955 and KRH-3140: binding specificity, pharmacokinetics and anti-HIV activity in vivo and in vitro. Abstract 49 LB, 13th CROI 2006, Denver.

Thakkar N, Pirrone V, Passic S, et al. Persistent interactions between the biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother. 2010 Mar 15. [Epub ahead of print]

Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibition of HIV type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 2001, 75:579-88.

Tsibris AM, Paredes R, Chadburn A, et al. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211. Clin Infect Dis 2009, 48:642-9.

Tsibris AM, Sagar M, Su Z, et al. Emergence in vivo of vicriviroc resistance in HIV-1 subtype C: role of V3 loop and susceptibility to other CCR5 antagonists. Abstract 870, 15th CROI 2008, Boston.

Uy GL, Rettig MP, Cashen AF. Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther 2008, 8:1797-804.

Wang X, Douglas SD, Lai JP, Tuluc F, Tebas P, Ho WZ. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J Neuroimmune Pharmacol 2007;2:42-8.

Wong R, Bodard V, Metz M, et al. Understanding the interactions between CXCR4 and AMD 11070, a first-in-class small-molecule antagonist of the HIV coreceptor. Abstract 495, 14th CROI 2007, Los Angeles.

Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998, 393:595-599.

New fusion inhibitors

Although the fusion inhibitor (FI) T-20 was the first entry inhibitor, there has been little development in this field (Review: Eggink 2010). Subcutaneous injection required for many FIs is unappealing for patients and clinicians. It still needs to be demonstrated, whether small molecule FIs, a new group of FIs with oral bioavailability, are effective (Jiang 2004,+ 2005). Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor may dramatically increase its antiviral potency (Ingallinella 2009).

Sifuvirtide is an FI developed in China. In animal testing with monkeys a longer half-life (39 hours) and a higher affinity towards gp41 rather than towards T-20 was observed (Dai 2005). Sifuvirtide was well-tolerated in healthy patients (He 2008) and interesting synergetic effects were reported with T-20 (Pan 2009). However, there seem to be some cross-resistances (Liu 2010).

SP01A from Samaritan Pharmaceuticals is especially interesting because its effects are different from other entry inhibitors. As a procaine hydrochloride, SP01A reduces the expression of key enzyme HMG-CoA reductase, removes cholesterol from the cell membrane and seems to inhibit, not only in vitro, the fusion of virus and cell. The efficacy of this agent, which has been repeatedly tested in HIV+ patients for years, has been shown in three Phase II trials so far. Results were moderate, showing that only 50% of patients have a reduction of viral load at the highest doses of 800 mg. After 10 days of monotherapy, viral load fell by 0.4 logs and after 28 days by 0.5 logs. These results were published in July 2007 on the company’s website (

TR-999 and TR-1144 are two new generation fusion inhibitors, developed by Trimeris in cooperation with Roche (Delmedico 2006). According to studies in monkeys, the potency, duration of action and pharmacokinetics of these peptides are much improved in comparison to T-20. Although administration is still by injection, it may be possible to limit this to once a week. They have only been involved in one clinical trial since 2007, with data due in 2008. There has been no update on their website.

Virip blocks entry of HIV-1 into the cell by interacting with the gp41 fusion peptides. It is also called an anchor inhibitor. Researchers from Ulm, Germany, discovered the peptide in hemofiltrate, the liquid that is filtered out of the blood of dialysis patients, when replacing it with electrolytic solution. Thus virip is a “natural” entry-inhibitor whose antiretroviral activities can significantly be increased by slight modifications or replacement of some amino acids (Munch 2007). In a first study with HIV-infected patients, continuous infusion with the highest dosage led to a reduction of approximately 1 log at 10 days (Forsmann 2010). Tolerability was good and a subcutaneous application is presently being evaluated.

Out of sight, out of mind, entry inhibitors not moving forward:

  • AMD 3100 (CXCR4A) from AnorMed, due to cardiotoxicity
  • Aplaviroc, (CCR5A), from GSK, due to hepatotoxicity
  • BMS 806, BMS-488043  an attachment inhibitor, due to poor PK data
  • FP-21399 (FI) from Lexigen/Merck, due to low potency
  • PRO 542, an attachment inhibitor from Progenics, to focus on PRO 140
  • SCH-C (CCR5A) from Schering-Plough, due to cardiac arrhythmia
  • T-1249  and T-649 (FIs) from Roche/Trimeris, due to little prospect of success
  • TAK-779, TAK-220 (CCR5A) from Takeda, replaced by TAK-652


Dai SJ, Dou GF, Qiang XH, et al. Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro. Acta Pharmacol Sin 2005, 26:1274-80.

Delmedico M, Bray B, Cammack N, et al. Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. Abstract 48, 13th CROI 2006, Denver.

Eggink D, Berkhout B, Sanders RW. Inhibition of HIV-1 by fusion inhibitors. Curr Pharm Des 2010, 16:3716-28.

Forssmann WG, The YH, Stoll M, et al. Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci Transl Med 2010, 2:63re3.

He Y, Xiao Y, Song H, et al. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 2008, 283:11126-34.

Ingallinella P, Bianchi E, Ladwa NA, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc Natl Acad Sci U S A 2009 Mar 18.

Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 2004, 48:4349-59.

Jiang S, Lu H, Liu S, et al. Small molecule HIV entry inhibitors targeting gp41. Abstract TuOa0201. 3rd IAS 2005, Rio de Janeiro.

Liu Z, Shan M, Li L, et al. In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 2011, 286:3277-87.

Munch J, Standker L, Adermann K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 2007;129:263-75.

Pan C, Lu H, Qi Z, Jiang S. Synergistic efficacy of combination of enfuvirtide and sifuvirtide, the first- and next-generation HIV-fusion inhibitors. AIDS. 2009 Feb 24.

New integrase inhibitors

The integration of viral DNA, enabled by the HIV enzyme integrase into the host DNA, is a major step for the replication cycle of HIV. In 2007, raltegravir, the first integrase inhibitor for treatment of HIV infection, was licenced (see Chapter 2). On account of its great success, it can be expected that clinical research will focus on this class for the next few years. One major problem seems to be cross-resistance, which makes it necessary to find new integrase inhibitors that will interact differently to the enzyme than raltegravir – me-too integrase inhibitors that are marginally different in their efficacy and pharmacokinetics are not needed (Serrao 2009).

Dolutegravir (GSK-1349572 or DTG)  is a new integrase inhibitor which initially emerged via Shinogi cooperating with GSK and is now being developed by ViiV Healthcare. As an integrase inhibitor of the second generation it shows improvements, especially with regard to pharmacokinetics (once daily unboosted administration will be possible) and resistance profile. In a Phase IIa study with 35 patients, a reduction of 2.5 logs to below 50 mg/ml was observed and 70% achieved a viral load below 50 (Lalezari 2009). In SPRING-1, a Phase IIb study, 200 treatment naïve patients received different doses of either dolutegravir (10,25 or 50 mg) or efavirenz in addition to 2 NRTIs (Arribas 2010). After an interim analysis at week 16, 90-96% of patients were under detection level of 50 copies/ml in the dolutegravir-arm compared to 60% in the efavirenz-arm. Tolerability was very convincing in SPRING-1 and in all other studies so far (Lou 2009). Cross-resistance with other integrase inhibitors do not seem to be a problem (Underwood 2009, Seki 2010). An important resistance appears to exist with T124A,  as well as mutations typical for raltegravir with Codon 148. Efficacy seems to decline with the existence of further mutations (Garrido 2011). Preliminary clinical data of the VIKING-study show, that higher dosage may help to overcome raltegravir resistances. In VIKING II, 13 out of 24 patients with raltegravir resistances reached a viral load of 400 copies/ml under 10 days monotherapy with 100 mg dolutegravir. The results were better than in VIKING I with 50 mg dolutegravir (Eron 2011). There are no interactions with boosted PIs. However, etravirine reduces the GSK-1349572 levels significantly (Song 2011). This also applies for antacids and it is recommended not to administer them simultaneously (Patel 2011). Dolutegravir is currently being tested in the 50 mg dosage in combination with ABC+3TC. Several studies are ongoing. Taken together, dolutegravir seems to be one of the agents that will make it to the market over the next few years.

Elvitegravir (GS-9137, formerly JTK-303) is an integrase inhibitor developed by Gilead, with a biochemical similarity to chinolone antibiotics (Sato 2006). Like raltegravir, elvitegravir inhibits the strand transfer. Individual doses were orally bioavailable, safe and well tolerated (Kawaguchi 2006). In a study with 40 patients (ART-naïve and pre-treated), viral load decreased by 2 logs at 10 days of monotherapy (DeJesus 2006). A disadvantage is that elvitegravir must be boosted with 100 mg ritonavir (Kearney 2006), but on the other hand a single administration per day seems possible.

A Phase II study, in which 28 patients received either three boosted doses (20, 50 and 125 mg) of elvitegravir or of a new ritonavir-boosted PI, was well-tolerated (Zolopa 2010). One 20 mg arm was prematurely stopped due to a high failure rate, but in the higher dose arms more patients showed a viral load below 50 copies/ml (approximately 40% versus 30%) after 16 weeks. One must be warned against premature comparisons with data from raltegravir, as this study was differently designed – it was compared to an active PI and not a placebo (Zolopa 2010). Like with raltegravir, tolerance was excellent. The dose for future studies is 125 mg.

In vitro resistance mutations can be selected with elvitegravir, too, and there seems to be at least two resistance pathways at T661 or E92Q  (Shimura 2008). Especially E92Q requires a high resistance (36-fold). In the case of Y143, a raltegravir resistance, efficacy seems to persist (Métifiot 2011).  Resistance of elvitegravir and raltegravir overlap to a great extent, thus cross-resistance seems possible (Kodama 2006). No virological response was observed in a small clinical study with patients who changed from elvitegravir to raltegravir (DeJesus 2007).

Major interactions with elvitegravir are not expected, at least not with NRTIs, darunavir, tipranavir, fosamprenavir or etravirine. However, the doses of maraviroc must be halved (Mathias 2007, Ramanathan 2008).

To avoid dependancy on ritonavir as a booster agent, Gilead is presently investigating combinations of elvitegravir with cobicistat (GS-9350), a new pharmacoenhancer (PKE). Encouraging PK data were obtained from healthy volunteers (German 2010), and they are now developing a QUAD pill consisting of a combination of tenofovir, FTC, cobicistat and elvitegravir. In a first Phase II trial, the QUAD pill was tested on therapy-naïve patients double-blind versus Atripla® with comparable effects after 24 weeks (Cohen 2010).

GSK-774 is probably a backup for dolutegravir, but not less effective. In a first double-blind randomized study with 48 volunteers the substance showed good tolerability over 14 days. Under the 13 HIV-infected patients the viral load was reduced by 2.6 logs (Min 2009).

Out of sight, out of mind, recently stopped integrase inhibitors:

  • BMS-707035, probably no advantage over raltegravir
  • GSK-364735, due to liver toxicity in monkeys, stopped in Phase I in 2007
  • S-1360 (Shionogi/GSK), stopped in 2005 due to toxicity
  • L-870810 (Merck), due to liver toxicity seen in dogs


Arribas J, Lazzarin A, Raffi F, et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral-naive adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). Abstract THLBB205, XVIII IAC 2010, Vienna.

Bar-Magen T, Sloan RD, Donahue DA, et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 2010, 84:9210-6.

Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011, 25:F7-12.

DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J AIDS 2006, 43:1-5.

DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0158) use after virologic rebound on elvitegravir (EVT, GS 9137). Abstract TUPEB032, 4th IAS 2007, Sydney.

Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. Abstract 151LB, 18th CROI 2011, Boston.

Garrido C, Soriano V, Geretti AM, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients – Impact of HIV subtypes and prior raltegravir experience. Antiviral Res 2011, 90:164-167.

German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J AIDS 2010, 55:323-9.

Goethals O, Vos A, Van Ginderen M, et al. Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles. Virology 2010, 402:338-46.

Kawaguchi I, Ishikawa T, Ishibashi M, Irie S, Kakee A. Safety and pharmacokinetics of single oral dose of JTK-303/GS 9137, a novel HIV integrase inhibitor, in HIV healthy volunteers. Abstract 580, 13th CROI 2006, Denver.

Kearney B, Mathias A, Zhong L, et al. Pharmacokinetics/pharmacodynamics of GS-9137 an HIV integrase inhibitor in treatment-naive and experienced patients. Abstract 73, 7th Int Workshop Clin Pharm HIV Therapy 2006, Lisbon, Portugal.

Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. Abstract H-254, 46th ICAAC 2006, San Francisco.

Lalezari J, Sloan L, DeJesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. Abstract TUAB105, 5th IAS 2009, Cape Town.

Lou Y, Min S, Chen S, et al. Meta-analysis of safety for short-term dosing of an HIV integrase inhibitor, S/GSK1349572, from seven clinical studies. Abstract H-931/414, 49th ICAAC 2009, San Francisco.

Mathias A, Hinkle J, Enejosa J, et al. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Tipranavir/r. Abstract TUPDB06, 4th IAS 2007, Sydney.

Mathias A, Shen G, Enejosa J, et al. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Darunavir/r. Abstract TUPDB03, 4th IAS 2007, Sydney.

Mathias AA, West S, Hui J, Kearney BP. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther 2009, 85:64-70.

Métifiot M, Vandegraaff N, Maddali K, et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 2011 Apr 18. [Epub ahead of print]

Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor. Abstract H-1228, 49th ICAAC 2009, San Francisco.

Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother 2011 Apr 28. [Epub ahead of print]

Ramanathan S, Kakuda TN, Mack R, West S, Kearney BP. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008, 13:1011-7.

Ramanathan S, Mathias AA, Shen G, et al. Lack of clinically relevant drug-drug interaction between ritonavir-boosted GS-9137 (elvitegravir) and fosamprenavir/r. Abstract WEPEB014, 4th IAS 2007, Sydney.

Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney BP. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J AIDS 2007;46:160-6.

Ramanathan S, West S, Abel S, et al. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir plus maraviroc. Abstract H-1425, 47th ICAAC 2007, Chicago.

Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 2006, 49:1506-8.

Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is a potent next generation HIV Integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. Abstract 555, 17th CROI 2010, San Francisco.

Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogravir: the birth of “me-too” HIV-1 integrase inhibitors. Retrovirology. 2009 Mar 5;6:25.

Shimura K, Kodama E, Sakagami Y, et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008;82:764-74.

Song I, Borland J, Chen S, et al. Effect of Atazanavir and Atazanavir/Ritonavir on the Pharmacokinetics of the Next-Generation HIV Integrase Inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011 Feb 22. [Epub ahead of print]

Song I, Borland J, Min S, et al.  The effect of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother 2011 May 9. [Epub ahead of print]

Song I, Min S, Borland J, et al. The effect of ritonavir-boosted protease inhibitors (PIs) on the HIV integrase inhibitor, S/GSK1349572, in healthy subjects. Abstract A1-1304/37, 49th ICAAC 2009, San Francisco.

Song I, Patel A, Min S, et al. Evaluation of antacid and multivitamin (MVI) effects on S/GSK1349572 pharmacokinetics (PK) in healthy subjects. Abstract A1-1305/38, 49th ICAAC 2009, San Francisco.

Underwood M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. Abstract WEPEA098, 5th IAS 2009, Cape Town.

Van Wesenbeeck L, Rondelez E, Feyaerts M, et al. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 2011, 55:321-5.

Zolopa AR, Berger DS, Lampiris H, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV Type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis 2010, 201:814-22.

New maturation inhibitors

The so-called maturation inhibitors inhibit HIV replication in a very late phase of the HIV reproduction cycle, i.e., at the budding or maturation of new virions. As is the case for integrase inhibitors, 2005 can be seen as the introductory year: this was the first time an agent was shown to have an antiviral effect on HIV-infected patients. Maturation inhibitors are, without a doubt, an interesting class of new drugs. Whether any of the agents will make it as far the clinic remains uncertain, as several problems have surfaced during the development of the prototype, bevirimat.

Bevirimat (MPC-4326, formerly PA-457) is a derivative of betulinic acid, which is isolated as triterpene carbonic acid from birch bark. It was produced by Panacos, which was sold to Myriad Pharmaceuticals. Bevirimat inhibits budding or maturation of new virions (Li 2003) by inhibiting the transition of the capsid precursor (p25) into the mature capsid protein (p24). This prevents the production of infectious viruses. Its long half-life allows once daily dosing (Martin 2007, Smith 2007). Tolerability of bevirimat which up to now has been tested in more than 650 patients has been good, including in the presence of atazanavir (Martin 2008). However, interactions seem to exist with darunavir (reduces bevirimat levels) and raltegravir (raltegravir levels increase) (Beelen 2010).

Data of a placebo-controlled Phase IIa trial was published in autumn 2005, in which patients received an oral once daily monotherapy of bevirimat for 10 days (Beatty 2005). In the highest dose group (200 mg) viral load decreased by 1.03 logs (median); in the 100 mg group it was just 0.48 logs. However, some patients showed no effect on the viral load, which can be ascribed to “natural” polymorphisms in the gag gene (van Baelen 2009, Lu 2011). Patients harbouring viruses with no gag polymorphisms (mutations) on the positions Q369, V370 or T371 before therapy, responded better to bevirimat. In a more recent monotherapy study with 32 patients receiving higher dosage, a reduction of viral load of 0.54 and 0.7 logs respectively, was observed with 200 or 300 mg after 14 days. Without the polymorphism, effects were greater than the one log level, those with the polymorphism had a drop of only 0.2 logs (Bloch 2009). Only about 50-70% of all individuals tested, seemed to be without gag polymorphisms. There appears to be no difference between treatment-naïve and pre-treated patients, nor is there any influence due to the degree of the underlying immunodeficiency (Margot 2009, Knapp 2009, Seclén 2010). However, there seems to be a strong correlation with PI resistance (Verheyen 2010).

This shows clearly the need for tests on these gag polymorphisms before starting therapy with bevirimat and possibly with other maturation inhibitors – not unlike the tropism test with CCR5 antagonists. In June 2010, Myriad announced that they would not continue to develop bevirimat – it remains unclear how and if development will proceed.

PA1050040 is similar to bevirimat, working in the same way, but seems to be effective against bevirimat-resistant viruses (with L363M). PK data appear to be better, while the potential for interactions is less. According to Panacos, a Phase I study has been initialized (Kilgore 2007).

UK-201844 is a maturation inhibitor developed by Pfizer. It was detected after screening over a million agents (Blair 2007). The method of efficacy seems to lie in the interaction with gp160 processing resulting in the production of non-infectious viruses.

BIT-225 by the Australian company Biotron is a specific HIV replication inhibitor in macrophages, but not in T cells (Khoury 2007). It works with a different mechanism than the Vpu ion channel inhibitor and inhibits the release of viral particles from macrophages. BIT-225 could play a role in eradication from latent cell reservoirs. According to Biotron, a successful Phase I study ended in September 2007, showing no relevant toxicity with 40 healthy volunteers receiving doses of 35-400 mg and providing acceptable PK data.

MPC–9055 is, like bevirimat, a maturation inhibitor by Myriad Pharmaceuticals in Salt Lake City. The agent demonstrated good tolerance and acceptable pharmacokinetics with 55 healthy volunteers (Beelen 2009). After the end of bevirimat, develpmet of MPC-9055 seems unlikely.


Beatty G, Jacobson J, Lalezari J, et al. Safety and Antiviral Activity of PA-457, the First-In-Class Maturation Inhibitor, in a 10-Day Monotherapy Study in HIV-1 Infected Patients. Abstract Abstract H-416D, 45th ICAAC 2005, Washington.

Beelen A, Balch A, Swabb E. MPC-4326 drug-drug interaction profile. Abstract 615, 17th CROI 2010, San Francisco.

Beelen A, Otto J, Fidler M, et al. Phase 1, single ascending oral dose study of the safety, tolerability, and pharmacokinetics of a novel HIV-1 maturation inhibitor in HIV- healthy volunteers. Abstract 570, 16th CROI 2009, Montréal.

Blair W, Cao J, Jackson L, et al. Execution of a high throughput HIV-1 replication screen and the identification of a novel small molecule inhibitor that targets HIV-1 envelop maturation. Abstract 50LB, 13th CROI 2006, Denver.

Bloch M, Bodsworth N, Fidler M, et al. Efficacy, safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. Abstract H-1230, 49th ICAAC 2009, San Francisco.

Khoury G, Ewart G, Luscombe C, et al. The antiretroviral efficacy of a novel compound BIT225: inhibition of HIV-1 release from human macrophage reservoirs. Abstract MOPDX06, 4th IAS 2007, Sydney.

Kilgore N, Reddick M, Zuiderhof M, et al. Characterization of PA1050040, a second generation HIV-1 maturation inhibitor. Abstract MOPDX05, 4th IAS 2007, Sydney.

Knapp D, Huang S, Harrigan R. Stable prevalence of bevirimat-related HIV gag polymorphisms both before and after HAART exposure. Abstract 636, 16th CROI 2009, Montréal.

Lalezari J, Richmond G, Thompson M, et al. Pharmacokinetics and safety of a novel 100 mg tablet formulation of MPC-4326 in subjects with HIV-1 infection. Abstract H-1309/42, 49th ICAAC 2009, San Francisco.

Li F, Goila-Gaur R, Salzwedel K, et al. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci U S A 2003, 100:13555-60.

Lu W, Salzwedel K, Wang D, Chakravarty S, Freed EO, Wild CT, Li F.A Single Polymorphism in HIV-1 Subtype C SP1 is Sufficient to Confer Natural Resistance to the Maturation Inhibitor, Bevirimat. Antimicrob Agents Chemother. 2011 Apr 18. [Epub ahead of print]

Margot N, Gibbs C, Miller M. Phenotypic susceptibility to bevirimat among HIV-infected patient isolates without prior exposure to bevirimat. Abstract 637, 16th CROI 2009´, Montréal.

Martin DE, Blum R, Wilton J, et al. Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers. Antimicrob Agents Chemother 2007;51:3063-6.

Martin DE, Galbraith H, Schettler J, Ellis C, Doto J. Pharmacokinetic properties and tolerability of bevirimat and atazanavir in healthy volunteers: an open-label, parallel-group study. Clin Ther 2008, 30:1794-805.

Salzwedel K, Martin DE, Sakalian M. Maturation inhibitors: a new therapeutic class targets the virus structure. AIDS Rev 2007;9:162-72.

Seclén E, González Mdel M, Corral A, et al. High prevalence of natural polymorphisms in Gag (CA-SP1) associated with reduced response to Bevirimat, an HIV-1 maturation inhibitor. AIDS 2010, 24:467-9.

Smith PF, Ogundele A, Forrest A, et al. Phase I and II study of the safety, virologic effect, and PKs/pharmacodynamics of single-dose 3-o-(3´,3´-dimethylsuccinyl)betulinic acid (bevirimat) against HIV infection. Antim Ag Chemoth 2007;51:3574-81.

Van Baelen K, Salzwedel K, Rondelez E, et al. HIV-1 Susceptibility to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag SP1. Antimicrob Agents Chemother. 2009 Feb 17.

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In recent years, in addition to ART, immunomodulatory treatment strategies have been investigated. Although repeatedly discussed as an alternative or supplemet, these therapies still lack proof of clinical benefit. The most recent example is the failure of the two large IL-2-studies (see below). Some approaches are nevertheless addressed here briefly (in alphabetic order) below.

Cyclosporin A (Sandimmune®) – Immune activation may lead to increased HIV replication, and a treatment hypothesis has been to suppress the immune system in an attempt to slow down viral replication. This is the rationale behind studies investigating the use of cyclosporin A, a drug which is normally used for prophylaxis of transplant rejection after allogenic organ transplantation. However, results of clinical trials have been disappointing. Cyclosporin A had no effect on CD4 or CD8 count, nor on expression of activation markers (Calabrese 2002, Lederman 2006). This was not only the case in chronically but also in acutely infected patients (Miro 2009, Markowitz 2010). Cyclosporin A therefore probably has a limited future in the therapy of HIV infection.

G-CSF (granulocyte colony-stimulating factor) is available as filgastrim (Neupogen®), lenogastrim (Granocyte®) and most recently as the less expensive biosimilars. It is also licensed for permanent neutropenia in advanced HIV infection to avoid bacterial infection. In a randomized study with 258 HIV+ patients with CD4 T cells under 200/µl, the rate of severe neutropenia was 2% versus 22% in the control group after 24 weeks (Kuritzkes 1998). Incidence of bacterial infection was reduced by 31% and the number of inpatient days by 45%. No effects on viral load were detected. Patients with CMV retinitis showed a large survival benefit on G-CSF (Davidson 2002). Although severe neutropenia has become rare on ART, G-CSF can be useful today, especially in chemotherapy, with interferon or other myelo-suppressive drugs such as valgancyclovir.

GM-CSF (granulocyte macrophage colony-stimulating factor) is available as molgramostim (Leucomax®) or sargramostim (Prokine®). Three double-blind, randomized studies showed a slight effect on viral load (Angel 2000, Skowron 1999, Brites 2000). However, in one study in patients with uncontrolled infection, there was a slight increase of viremia (Jacobsen 2003). GM-CSF seems to prevent significant loss of CD4 T cells during treatment interruptions (Fagard 2003). Given the side effects and significant cost of GM-CSF, it cannot be recommended outside of clinical studies. GM-CSF is not licensed in Europe.

Hydroxyurea (HU, Litalir®)) is an old chemotherapeutic agent with relatively low toxicity still being used today in hematology (mostly in chronic myelogenous leukemia). It inhibits DNA synthesis via the ribonucleotide reductase, and leads to an intracellular shortage of deoxynucleotide triphosphates. A synergistic effect on HIV replication in combination with ddI was demonstrated in 1994 (Lori 1994). A Swiss study, in which 144 patients were treated with hydroxyurea (HU) or placebo in addition to d4T+ddI, attracted attention in 1998 (Rutschmann 1998). After 12 weeks, 54% (versus 28% in the placebo group) demonstrated a viral load below 200 copies/ml. Was this the discovery of a new cheaper option for HIV treatment? Hydroxyurea became even more fashionable after publication of the “Berlin Patient”, a patient who had been treated with hydroxyurea in addition to indinavir and ddI during acute infection, had stopped all therapy after a few months and subsequently showed no detectable plasma viremia (Lisziewicz 1999). Was this unexpected outcome due to hydroxyurea? Several smaller studies from the US and Argentina seemed to confirm these positive results. Many treating physicians added the drug to ART and many started to dream of a cheap combination of ddI+HU for Africa. These initial hopes subsided rapidly. In particular, the combination with ddI and d4T in particular is toxic: severe polyneuropathy (Moore 2000) and fatal pancreatitis were reported (Havlir 2001). Three randomized studies failed to show any effect, except for high rates of toxicity (Blanckenberg 2004, Stebbing 2004, Swindels 2005). Even in patients with acute HIV infection there was no effect. Thus, further Berlin patients could not be “reproduced” (Zala 2002). Hydroxyurea should not be used in antiretroviral therapy.

Interferons have an antiretroviral effect which has been known for years (Mildvan 1996). The antiviral effect of 3 million IU daily or under pegylated interferon weekly  is about 0.5-1 log (Haas 2000, Hatzakis 2001, Asmuth 2010). Higher dosing may increase this effect (Hatzakis 2001). We have seen patients coinfected with HIV/HCV, who achieved an undetectable HIV RNA during hepatitis C therapy with interferon and ribavirine only. However, an in-depth investigation of the antiviral activity of interferon was not conducted, because of the subcutaneous delivery route and its not insignificant side effects. Whether pegylation of interferone will change circumstances, remains uncertain.

Interleukin-2 (IL-2, aldesleukin, Proleukin®) is a cytokine produced by activated T cells which induces proliferation and cytokine production in T cells, B cells and NK cells. It has been employed in oncology for years and is now usually administered subcutaneously. The most important effect of IL-2 in HIV medicine is the increase in CD4 and CD8 T cells, which may be quite impressive in individual cases. CD45RO memory cells initially increase, followed by naive CD45RA T cells (Chun 1999, Carcelain 2003). This effect is mainly due to a reduced T cell turnover (Kovacz 2005, Sereti 2005, Vento 2006).

The question, whether the CD4 T cells generated by IL-2 were would lead to a clinical benefit, was answered by two large randomized studies, ESPRIT and SILCAAT in 2009 (Abrams 2009). In the ESPRIT study, 4131 patients with at least 300 CD4 T cells/µl were treated with and without IL-2 in addition to ART. SILCAAT had a similar concept, but enrolled 1695 patients with 50-299 CD4 T cells/µl. The results were very disappointing. Although supplementation of ART with IL-2 resulted in a statistically significant increase in CD4 T cell count (ESPRIT: +160, SILCAAT: +59 CD4 T cells/µl), it did not lead to a clinical benefit. Despite improved CD4 T cells under IL-2, patients did not develop less opportunistic infections and mortality was not reduced. Moreover, serious adverse events (including fever, malaise, injection site reactions and deep-vein thrombosis) were more likely to occur among patients receiving IL-2 in the ESPRIT study. Another randomized study (STALWART) provided similar results (Tavel 2011).  Conclusion: SILCAAT, ESPRIT and STALWART have shown that IL-2 as a supplementary therapy in HIV-infected patients is no longer viable, even in patients without immunological response on ART.

Interleukin-7 seems to be more promising. This cytokine plays a fundamental role in T cell homeostasis and is implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes (Review: Chahroudi 2010). Two small randomized placebo-controlled pilot trials with 6 and 16 HIV+ patients, respectively, demonstrated a good increase of CD4 T cells with different subcutaneous doses. The tolerability was good and side effects typical for interleukin-2 were not observed (Levy 2009, Sereti 2009). If these results are confirmed, interleukin-7 may become a good option for patients whose immune constitution remains poor despite good viral load suppression on ART. It remains to be seen how things will develop after the end of interleukin-2.

Interleukin-12 stimulates T lymphocytes and NK cells to generate a Th1-type immune response. In a randomized Phase I study with rhIL-12 100 ng/kg 2 x week, the drug was well tolerated but had no effect on lymphocyte subpopulations, antigen-specific immune response or viral load (Jacobson 2002). Further development is therefore uncertain. The same would appear to be true for interleukin-10 (Angel 2000) or interleukin-15 (Ahmad 2005). In the age of highly effective antiretroviral therapies, such experimental therapies have to meet ever-increasing standards.

Corticosteroids have been pushed by some HIV clinicians. However, such treatment does not stand the test of controlled studies. In a placebo-controlled study with 0.5 mg prednisone/kg over 8 weeks, there were no effects on CD4 T cells or viral load (McComsey 2001). In ACTG 349, 24 patients were treated with 40 mg prednisone daily or not in a double-blind randomized design (Wallis 2003). After 8 weeks, there was a trend towards higher levels of CD4 T cells in the prednisone arm, but there were no effects on activation markers or apoptosis. Two patients on prednisone developed necrosis of the femoral head. This study should advise caution before considering steroids for immunological reasons.

Murabutide is a synthetic muramyldipeptide with a variety of effects on the immune system. It can raise unspecific resistance to infection, induce anti-inflammatory cytokines and growth factors, and strengthen the antiviral effects of cytokines such as IL-2 or interferon. In HIV+ patients, a team in France has used it mainly as an immune modulator, although only in small studies, and at the most, with moderate effect (Bahr 2003).

Mycophenol (Cellcept®) has a theoretical concept similar to that of hydroxyurea and cyclosporin A. Mycophenol inhibits inosine monophosphate (IMP) dehydrogenase and is normally used for prophylaxis of acute transplant rejection in patients with allogenic kidney, heart or liver transplantations, as well as for some autoimmune diseases. Inhibition of lymphocyte proliferation and the subsequent reduction of target cells should theoretically inhibit replication of HIV. Initial reports seem to demonstrate an effect on viral load at least in some patients (Margolis 2002, Press 2002). Whether this will be confirmed by randomized trials seems uncertain. Current data suggest that this is unlikely (Sankatsing 2004, Margolis 2006).

Remune®, the prototype of therapeutic vaccination, has gone from disaster to disaster. Developed by a team headed by the since-deceased Jonas Salk, Remune® was a therapeutic vaccine comprised of an envelope-depleted (gp120) virus which, although indeed immunogenic, does not seem to provide any clinical benefit (i.e., prolongation of life and delay of disease progression). A large trial was interrupted prematurely in May 1999. More than 2500 patients had taken part for a mean of 89 weeks in this study, which was designed to evaluate the addition of Remune® to ART. As well as the lack of clinical benefit, not even advantages with respect to CD4 T cell counts or viral loads could be shown (Kahn 2000).

THC, cannabinoids have no anti-HIV effect. A controlled, randomized study, in which patients could either smoke marijuana or receive THC (dronabinol, Marinol®) or placebo in addition to ART, showed no effects on lymphocyte subpopulations, lymphocyte function or viral load after three weeks (Bredt 2002). THC, which is metabolized via the cytochrome P450 system, had no detrimental effects on PI plasma levels (Abrams 2003). More recently, a randomized study showed that smoked cannabis was well-tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings were comparable to oral drugs used for chronic neuropathic pain (Abrams 2007).


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