Elvitegravir (GS 9137)

Elvitegravir (formerly GS 9137 and JTK-303) is a promising integrase inhibitor in late clinical development by Gilead Sciences. When studied in treatment-experienced patients with extensive drug resistance, viral load was more likely to fall below 50 copies/ml in the two higher-dose elvitegravir groups than in the protease inhibitor arm. Elvitegravir was well tolerated and few participants stopped taking the drug due to side-effects.1 2   

Unfortunately, there will probably be cross-resistance of this drug to raltegravir.3 4

In 2008, two phase III multicentre clinical trials began enrolling treatment-experienced individuals into non-inferiority studies comparing elvitegravir to raltegravir, each combined with an optimised treatment regimen. More ambitiously, another study is looking at a once-daily ‘quad’ pill regimen containing elvitegravir, emtricitabine/tenofovir (Truvada), and the PK-enhancer GS-9350 that would compete against Atripla (fixed-dose combination of emtricitabine, tenofovir, and efavirenz) as a first-line regimen.

Elvitegravir's target, the integrase enzyme, is encoded with the pol gene of HIV, as are the other two viral enzymes, reverse transcriptase and protease. Integrase inhibitors block the insertion of viral genomic DNA into host cell DNA.

Effectiveness

Elvitegravir’s efficacy and safety was evaluated in a randomised phase II study comparing boosted elvitegravir to a boosted protease inhibitor. The 278 study participants all had significant prior exposure to antiretroviral therapy, with viral load of at least 1000 copies/ml and at least one major protease inhibitor resistance mutation.5

According to the 24-week analysis of results, the best response to the experimental integrase inhibitor elvitegravir is seen when it is taken with T-20 (enfuvirtide, Fuzeon) and other active drugs, such as boosted protease inhibitors. Elvitegravir induces a swift reduction in HIV levels, but needs an optimised background regimen to keep viral load at an undetectable level.

Study results were confounded by several trial design changes. Due to poor virologic response at week 8, those in the 20mg elvitegravir arm were switched to the 125mg elvitegravir arm. As drug interaction data from other studies became available, showing that protease inhibitors and integrase inhibitors could be safely co-administered, PIs were added to the optimised background regimen. By week 24, 15% of participants on the the elvitegravir arms had added a second-generation PI, either tipranavir (Aptivus) or darunavir (Prezista). Further, 37% of patients on the comparator arm who experienced virologic failure switched to open label elvitegravir. The durability of response in those receiving elvitegravir at 125mg was related to how many active agents were in the optimised background regimen.

A phase 2 study in previously untreated patients, of elvitegravir boosted by a new boosting agent cobicistat, both in combination with tenofovir/emtricitabine (Truvada), demonstrated a very high rate of viral suppresison when the combination was compared to Atripla (90% vs 83% at week 24 by intent to treat analysis). This combination product, the Quad pill, is now being evaluated in phase III studies.6

Resistance

In elvitegravir studies, the E92Q substitution is accompanied by a compensatory mutation at L68V/l that increases the replication capacity of E92Q.7 The primary mutations for eltegravir are Q148R, E92Q, and T66l.3 Additional mutations occur at codons 92, 138, and 147.

Analysis of patients failing therapy in the BENCHMRK phase III studies found mutations at position 143 to be significant.8 9 This mutation seems to arise somewhat later than others and mutations at Y143C/H/R are thought to improve viral fitness. Virus containing raltegravir resistance mutations may have impaired integrase and replicative abilities.10

There is a high degree of cross-resistance between raltegravir and elvitegravir. Elvitegravir seems to be more potent than raltegravir, but resistance to it is generally greater than to raltegravir. Virologic failure is usually marked by at least two mutations. Q148K and T66I provided the highest resistance to either drug, while the S153Y mutation provided greater resistance to elvitegravir.11 To date, a commercial assay for testing resistance to either integrase inhibitor has not found its way to market.

The majority of amino acids on the integrase gene are polymorphic; i.e., there is variability within the amino acids typically found at most of the sites, although some areas of the integrase gene are more conserved than others. This is in contrast to the much more 'conserved' nature of the protease and reverse transcriptase genes. Integrase-inhibitor resistance mutations have been identified, many of which seem to appear among the naturally-occurring variations (polymorphisms) in the integrase gene. These include T97A, K156N, L74M, G163R, and V151I.

Drug interactions

Elvitegravir is metabolised by the liver enzyme pathway CYP3A4. Since the NNRTI etravirine is an inducer of CYP3A, there was a suspected potential for interactions between the two drugs. Elvitegravir is typically dosed with low-dose ritonavir, which also has a very wide range of interactions with other medications.

A small study carried out by Gilead Sciences and Tibotec investigated the pharmacokinetic interactions between elvitegravir and the NNRTI drug etravirine. The study found that there were no significant drug interactions and that dosing levels of either drug would not need to be changed.12

The pharmacokinetics (PK) of tipranavir and darunavir were not altered after co-administration with ritonavir-boosted elvitegravir. Elvitegravir PK was stable with varied ritonavir doses of 100mg once daily, 100mg twice daily, or 200mg twice daily, so elvitegravir can be added to boosted tipranavir or boosted darunavir without dose adjustment.13 

In the phase III studies comparing elvitegravir head-to-head against raltegravir, an elvitegravir dose of 150mg once daily will be used with a selected protease inhibitor. However, due to known pharmacokinetic interactions, those assigned to use of either boosted atazanavir or lopinavir as part of an optimised background regimen will be on a reduced elvitegravir dose of 85mg once daily.

References

  1. Zolopa AR et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 143LB, 2007
  2. DeJesus E 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 Acquir Immune Defic Syndr 43(1): 1-5, 2006
  3. Goethals O et al. Resistance mutations in HIV-1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 82(21):10366-10374, 2008
  4. Serrao E et al. Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 5(6): 25, 2009
  5. Zolopa AR et al. The HIV integrase inhibitor elvitegravir has potent and durable activity in treatment-experienced patients with optimized background therapy. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-714, 2007
  6. Cohen C et al. The single-tablet, fixed-dose regimen of elvitegravir/GS-9350/emtricitabine/tenofovir DF (Quad) achieves a high rate of virologic suppression and GS-9350 is an effective booster. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 58LB, San Francisco, 2010
  7. Goodman D et al. Integrase inhibitor resistance involves complex interactions among primary and secondary resistance mutations: a novel mutation L68V/I associates with E92Q and increases resistance. Seventeenth International HIV Drug Resistance Workshop, Sitges, Spain, abstract 13, 2008
  8. Fransen S et al. Loss of raltegravir susceptibility in treated patients is conferred by multiple non-overlapping genetic pathways. Seventeenth International HIV Drug Resistance Workshop, Sitges, Spain, abstract 7, 2008
  9. Da Silva D et al. Mutational patterns in the HIV-1 integrase related to virological failures on raltegravir-containing regimens. Seventeenth International HIV Drug Resistance Workshop, Sitges, Spain, abstract 12, 2008
  10. Marcelin AG et al. Raltegravir resistance mutations affect strongly the integrase activities and the replicative capacity of viruses harbouring such mutations. Seventeenth International HIV Drug Resistance Workshop, Sitges, Spain, abstract 17, 2008
  11. Marinello J et al. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry 47(36): 9345-9354, 2008
  12. Ramanathan S et al. Lack of clinically relevant drug interactions between ritonavir-boosted elvitegravir and TMC125. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-1049, 2007
  13. Mathias AA et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 49(2):156-162, 2008