Newer Anti-HIV Drugs and How to Use Them: Part 2

Protease Inhibitors (PIs)

The most recently FDA-approved PIs are darunavir (Prezista) in 2005 and tipranavir (Aptivus) in 2006. These 2 drugs were approved for therapy in treatment-experienced HIV patients who have developed resistance to other available PIs.

Tipranavir (Aptivus)

In two Phase 3 trials (the RESIST studies), tipranavir 500 mg boosted with ritonavir 100 mg dosed twice daily in combination with optimized background regimen (OBR), demonstrated significantly greater virological and immunological responses when compared with a investigator-chosen ritonavir-boosted PI with OBR.

Articles on tipranavir posted on HIV and Hepatitis.com

Darunavir (Prezista)

In 2 similar Phase 2 studies, darunavir 600 mg boosted with ritonavir 100 mg twice daily in combination with OBR demonstrated superior virologic responses when compared with an investigator-chosen comparator PI with OBR (POWER 1 and 2 trials).

The FDA has recommended that tipranavir/ritonavir and darunavir/ritonavir with OBR be used in particular with patients with multi-drug resistant virus who have failed prior therapy. Some PI-resistant strains of HIV will be susceptible to these two drugs, as they belong to the existing PI class of drugs.

Darunavir has also been tested in treatment-naive patients. In one Phase 3 trial researchers compared tenofovir/emtricitabine in combination with either darunavir/ritonavir 800/100 mg once daily OR lopinavir/ritonavir (Kaletra) once or twice daily. Following 48 weeks of treatment, darunavir/ritonavir demonstrated non-inferiority to lopinavir/ritonavir in terms of virological response and showed fewer GI side effects and less body fat changes (R Ortiz and others. AIDS 22.2008).

On the basis of these study results, darunavir is regarded as one of the preferred ritonavir-boosted PIs for use in treatment-naive patients. In addition, the FDA has approved once daily dosing of ritonavir-boosted darunavir in treatment-naive patients.

Articles on darunavir posted on HIV and Hepatitis.com

Entry Inhibitors

Enfuvirtide (Fuzeon)

The FDA approved the fusion inhibitor enfuvirtide (Fuzeon) in 2003. It was the first drug approved in a new class since the approval of the PIs. Enfuvirtide blocks HIV fusion into the host cell by binding to a part of the viral envelope, which prevents the process required for viral fusion and entry into CD4 cells.

The FDA indication for use of enfuvirtide is in treatment-experienced patients with virologic failure. As with other antiretrovirals, enfuvirtide should be used with at least one and preferably two other drugs with activity against HIV to reduce the risk of the development of resistance.

Articles on enfuvirtide posted on HIV and Hepatitis.com

Maraviroc (Selzentry)

In order for HIV to enter CD4 cells, the viral envelope interacts with the CD4 molecule of the surface of the cell and, in addition, with one of 2 chemokine coreceptors, CXCRA or CCR5. Individuals can be infected with HIV that utilizes CXCR4 (X4-tropic virus), CCR5 (R5-tropic virus), or both (dual-tropic) for entry. In addition, some patients will have mixtures of viruses that can utilize either CXCR4 or CCR5 (mixed-tropic) for entry.

Approved by the FDA in 2007, maraviroc (Selzentry) was the first CCR5 to be approved in this new class of entry inhibitors. Two Phase 3 trials of the drug found that treatment-experienced patients showed CCR5-tropic virus only, with no detectable CXCR4-tropic virus. Maraviroc appeared very safe, with no signs of risk of malignancies or infections. Some patients had virologic failure with detectable CXCR4-tropic virus, but the study investigators found no signs of increased HIV disease progression.

Maraviroc has demonstrated no evidence of anti-HIV activity in patients with CXCR4-tropic virus. A test has been developed with the sensitivity to detect CXCR4- tropic virus. This improved sensitivity allows for a high level of certainty about which patients would benefit from using maraviroc.

Maraviroc requires dose-adjustment when used with CYP3A inducers, and like other anti-HIV drugs, may have drug-drug interactions that could affect dosing (see maraviroc package insert).

A Phase 3 study compared the efficacy of maraviroc to efavirenz in treatment-naive patients. A recent re-analysis of the results of this study, in which screening samples were retested with the enhanced tropism assay, showed that in the patients without CXCR4-tropic virus, the two drugs had no significant differences in virologic responses.

Articles on Maraviroc posted on HIV and Hepatitis.com

Vicriviroc

The experimental CCR5 antagonist vicriviroc is in testing for use in patients without detectable CXCR4-tropic virus. A Phase 2 study of treatment-experienced patients using OBR with ritonavir-boosted vicriviroc showed significantly greater suppression of the virus compared with the use of OBR alone. All patients had no detectable CXCR4-tropic virus, took OBR that included ritonavir along with either 20 or 30 mg of once-daily vicriviroc or placebo. The percentages of patients with plasma HIV RNA less than 50 copies/mL at 48 weeks were 52%, 56%, and 14%, respectively.

Early testing suggested that vicriviroc was associated with an increased risk for the development of malignancies. Since then, in follow-up testing in the vicriviroc study and in the larger trials of maraviroc, there has been no evidence of increased risk of malignancies in patients using this new class of drugs.

Articles on Vicriviroc Posted on HIV and Hepatitis.com

PRO 140

PRO 140 is a humanized monoclonal antibody that inhibits infection by CCR5-tropic using virus by binding the CCR5 coreceptor. PRO 140 is in early stage testing among patients without detectable CXCR4-tropic virus. Early data show median peak HIV RNA decreases of 1.90 and 2.17 log10 copies/mL, respectively.

Articles on PRO 140 Posted on HIV and Hepatitis.com

Integrase Inhibitors

Raltegravir (Isentress)

The integrase enzyme is necessary for incorporating proviral HIV DNA into the host chromosome. Raltegravir (Isentress) is the first integrase inhibitor approved by the FDA, also in 2007. The studies that led to approval of the drug were conducted in patients with virologic failure who had 3-class drug resistant virus.

In one study, raltegravir 400 mg twice daily with OBR showed superior virologic and immunologic responses compared to OBR with placebo, with no apparent adverse events compared with the control group.

Researchers evaluated raltegravir with tenofovir/emtricitabine (Truvada) compared to efavirenz/tenofovir/emtricitabine in a Phase 3 trial in treatment-naive patients (STARTMRK study).

The raltegravir-based regimen was non-inferior to the efavirenz-based regimen, with 86.1% versus 81.9% achieving HIV RNA levels less than 50 copies/mL, respectively. There were fewer clinical adverse events in the raltegravir arm, including fewer central nervous system side effects and rash, as well as fewer adverse effects on lipids.

A recent analysis of controlled trials and open-label use of raltegravir showed that the rate of malignancies was not increased in patients using the drug compared with other therapies (D Cooper. CROI 2009. Abstract 859).

Articles on Raltegravir Posted on HIV and Hepatitis.com

Elvitegravir

Elvitegravir is a substrate for cytochrome P450 and is in development as a once daily drug boosted by ritonavir. In a Phase 2 study in treatment-experienced patients receiving optimized NRTIs with or without enfuvirtide, researchers determined that elvitegravir at higher doses (50 and 125 mg) with ritonavir 100 mg exhibited more potent viral suppression versus those receiving a PI and a similar OBR.

A Phase 3 noninferiority trial of elvitegravir is ongoing to evaluate ritonavir-boosted elvitegravir versus raltegravir in treatment-experienced patients.

Unfortunately, the resistance mutations of elvitegravir and raltegravir are very similar, which makes it likely that patients developing resistance to one will not have the other drug as an effective treatment option.

Articles on Elvitegravir Posted on HIV and Hepatitis.com

Maturation Inhibitors

Bevirimat

Bevirimat is a maturation inhibitor that blocks Gag processing to inhibit replication of HIV.

Recent studies show that certain resistance mutations (codon Q369, V370, and T371) developed by patients receiving bevirimat result in decreased susceptibility to the drug. In analyzing bevirimat-naïve patients, researchers found that approximately 40% had viruses containing at least one of these polymorphisms. This finding suggests that bevirimat would have only limited anti-HIV activity in these patients.

Increasing the Use of Newer Drugs in Clinical Practice

	There is a growing need for development of new anti-HIV drugs due in part to the increased survival rates in HIV patients many of whom have developed multi-drug resistance to the virus.
	HIV antibody testing should be offered to all patients aged 13- 64 when they present for clinical care.
	HAART should be initiated in HIV patients at higher CD4 T cell levels.

Treatment-naive and Treatment-experienced Patients

	Current treatment options are not ideal for all treatment-naive patients.
	Current first-line NNRTIs may be associated with toxicities (e.g., rash, central nervous system side effects, dyslipidemia) and may have a low barrier to development of resistance.
	Efavirenz should not be used by pregnant women or women expecting to become pregnant.
	Nevirapine cannot be used in women with CD4 T-cell levels greater than 250 cells/mm3
	All the above show the need for new NNRTIs in first-line therapy.
	Rilpivirine has fewer adverse effects than efavirenz and a higher resistance barrier.
	Ritonavir-boosted PIs are good first-line options in treatment-naive patients, but there are concerns about pill burden, GI effects, hypertriglyceridemia, and hyperbilirubinemia (atazanavir).
	Darunavir/ritonavir represents an advance in the PI drug class, with fewer GI side effects, noninferiority to lopinavir/ritonavir, and the option for once-daily dosing.
	The CCR5 antagonist maraviroc with two NRTIs in patients without CXCRA-tropic virus allows for the possibility of saving NNRTIs and PIs for future regimens; In addition, the drug has limited side effects, but is not currently FDA-approved for use in treatment-naive patients.
	The integrase inhibitor raltegravir with 2 NRTIs shows potent response compared with efavirenz and allows for use of NNRTIs and PIs in future regimens; however, raltegravir is not yet FDA-approved for use in treatment-naive patients; also a substantial number of patients will have integrase inhibitor-resistant virus, suggesting that these viruses will not be susceptible to the integrase inhibitor elvitegravir, which is in later stage development.
	Even in highly treatment-experienced patients, adding multiple new active agents to a failing regimen can achieve high levels of viral suppression.
	New treatment regimens in patients with multi-drug resistant virus must be chosen carefully in order to avoid the emergence of resistance to the newer drugs.

Conclusions

The development of increasingly potent, well-tolerated, and conveniently administered antiretrovirals has significantly enhanced the overall efficacy of first-line therapy, according to the study authors. There are now increased treatment options due to the availability of these new drugs, both in existing and new drug classes.

"Ultimately, the key to long-term success is a thorough assessment of a patient's willingness to take medications, as well as the number of fully active drugs available for a given individual," wrote the authors.

In conclusion, they noted, "The goal remains to use two to three fully active drugs to achieve undetectable levels of plasma HIV-1 RNA (<50 copies/mL) in order to enhance the likelihood of durable viral suppression without the emergence of drug resistance to the newer drugs."

Part 1 of this article

6/26/09

Reference

HH Kim and ES Daar. Newer Antiretroviral Agents and How to Use Them. Current HIV/AIDS Reports 6(2): 55-62. May 2009.

Other Citations

1. S Cox, S Moore, J Southby, and others. Safety profile of apricitabine, a novel NRTI, during 24-week dosing in experienced HIV-1 infected patients [abstract TUAB0106]. Presented at the XVII International AIDS Conference. Mexico City, Mexico; August 3-8, 2008.

2. P Cahn P, J Altclas J, M Martins, and others: 24-week data from study AVX-201: a prospective, randomized, double-blind, dose-ranging phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance [abstract 793]. Presented at the 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 3-6, 2008.

3. E DeJesus, D Saple, J Morales-Ramirez J, and others, Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with unique pharmacokinetic profile [abstract H-892]. Presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting. Washington, DC; October 25-28, 2008.

4. Madruga JV, Cahn P, Grinsztejn B, et al.: Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet 2007, 370:29-38.

5. R Haubrich, P Cahn, B Grinsztejn, and others. DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1-infected patients [abstract 790]. Presented at the 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 3-6, 2008.

6. M Satascoy, P Cahn, C Gonsalez, and others. TMC278 (rilpivirine), an investigational next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naive patients: 96-week results of study C204 [abstract TUAB0103]. Presented at the XVII International AIDS Conference. Mexico City, Mexico; August 2-8, 2008.

7. G van’t Klooster, R Verloes, L Baert, and others Long-acting TMC278, a parenteral depot formulation delivering therapeutic NNRTI concentrations in preclinical and clinical settings [abstract 134]. Presented at the 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 3-6, 2008.

8. G Moyle, M Boffito, Z Shen, and others RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor, shows positive outcome in treatment of naive HIV patients [abstract H893]. Presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting. Washington, DC; October 25-28, 2008.

9. CB Hicks, P Cahn, DA Cooper, and others. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in Multi-drug Resistant Patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006, 368:466-475.

10. B Clote, N Bellos, JM Molina, and others. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007, 369:1169-1178.

12. LK Naeger and KA Struble. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS 2007, 21:179-185.

13. R Ortiz R, E Dejesus, H Khanlou, and others. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008, 22:1389-1397.

14. CDC: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

15. RM Gulick, J Lalezari, J Goodrich, and others. Maraviroc for previously treated patients with R5 HIV-1 infection. New England Journal of Medicine 359:1429-1441. 2008.

16. M Saag, P Ive, J Heera, and others. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine/lamivudine), for the treatment of antiretroviral-naïve subjects infected with R4 HIV 1: week 48 results of the MERIT Study [abstract WESS104]. Presented at the 4th International AIDS Society. Sydney, Australia; July 22-25, 2007.

17. RJ Landovitz, B Angel, C Hoffmann C, and others. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. Journal of Infectious Diseases 198:1113-1122. 2008.

18. RT Steigbigel, DA Cooper, PH , and others. Raltegravir with optimized background therapy for resistant HIV-1 infection. New England Journal of Medicine 359:339-354. 2008.

19. J Lennox, E DeJesus, A Lazzarin, and others. STARTMRK, a phase III study of the safety and efficacy of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients [abstract 896a]. Presented at the 48th ICAAC/IDSA 46th Annual Meeting. Washington, DC; October 25-28, 2008.

20. M Witmer, R Danovich, A Day, and others. Cross resistance between HIV-1 integrase strand transfer inhibitors (InSTIs) raltegravir, elvitegravir and second generation InSTIs [abstract H-1232]. Presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting. Washington, DC; October 25-28, 2008.

21. J Lalezari, S McCallister, M Gigliotti, and others. A phase 2 safety and efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients identifies the target phase 3 study profile [abstract 891]. Presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting. Washington, DC; October 25-28, 2008.

22. SM Hammer, JJ Eron Jr, P Reiss, and others. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society--USA panel. Journal of the American Medical Association 300:555-570. 2008.

22. Y Yazpandanah, C Fagard, D Descamps, and others. High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatment-experienced patients with multidrug-resistant virus: results of the ANRS 139 TRIO trial [abstract THAB0406]. Presented at the XVII International AIDS Conference. Mexico City, Mexico; August 3-8, 2008.

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