ABSTRACT In October 2007, raltegravir (Isentress; Merck), a small-molecule drug that inhibits HIV-1 integrase, became the first drug in its class to be approved by the US FDA for the

treatment of HIV-1 infection in combination with other antiretroviral agents. You have full access to this article via your institution. Download PDF MAIN Current therapy for patients with

HIV-1 infection initiating their first regimen is based on combinations of drugs that target two virally encoded enzymes: HIV-1 reverse transcriptase and HIV-1 protease1. Multiple agents in

three classes — nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) — are now available. For those

now harbour difficult-to-treat multidrug-resistant HIV-1. Fortunately, over the past 2 years, several new drugs with clear efficacy in treatment-experienced patients have received regulatory

approval for the management of HIV-1 infection: the PIs tipranavir and darunavir, the chemokine (C-C motif) receptor 5 (CCR5) inhibitor maraviroc and, most recently, the HIV-1 integrase

inhibitor, raltegravir (Fig. 1). BASIS OF DISCOVERY HIV-1 integrase is a virally encoded enzyme that integrates the viral DNA into the genome of the host cell, which is essential for viral

replication2. Integration is a multistep process that involves two steps catalysed by HIV-1 integrase: endonucleolytic processing of the viral DNA to remove the terminal dinucleotide from

each 3′ end, and strand transfer, in which the viral DNA 3′ ends are covalently linked to the cellular DNA2,3. As with HIV-1 reverse transcriptase and HIV-1 protease, the key role of HIV-1

integrase in the viral life cycle makes it an attractive therapeutic target, which has prompted considerable efforts to develop integrase inhibitors2,3,4. The discovery of diketo acids that

selectively inhibit the strand transfer function of HIV-1 integrase and thereby prevent integration and inhibit HIV-1 replication provided proof of concept for this enzyme as a therapeutic

target for HIV-1 infection3. Medicinal chemistry efforts based on an understanding of the mechanism of action of such compounds and the required pharmacophore led to the identification of

raltegravir5 (Fig. 1). DRUG PROPERTIES Raltegravir is an HIV-1 integrase strand-transfer inhibitor with potent _in vitro_ activity against a wide range of wild-type and multidrug-resistant

HIV-1 clinical isolates5,6,7. CLINICAL DATA Evidence for the efficacy and safety of raltegravir is based on analyses of 24-week data from two ongoing, randomized, double-blind,

placebo-controlled trials6. These trials evaluated raltegravir (400 mg twice-daily orally) in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-infected

patients, aged 16 years or older, with documented resistance to at least one drug in each of three antiretroviral drug classes (NNRTIs, NRTIs, PIs)6. After 24 weeks of therapy, for the 436

patients evaluated, the proportion of patients with HIV-1 RNA <400 copies per ml was 76% in the raltegravir arm and 39% in the control arm6. The proportion of patients with HIV-1 RNA

<50 copies per ml was 63% in the raltegravir arm and 33% in the control arm6. The mean changes in plasma HIV-1 RNA from baseline were −1.85 log10 copies per ml for patients receiving

raltegravir compared with −0.84 log10 copies per ml for patients receiving placebo. Also, the mean increase from baseline in CD4+ cell counts was higher in the raltegravir arm (89 cells per

mm3) than in the control arm (35 cells per mm3)6. There was no consistent evidence of any drug-related clinical or laboratory toxicity, and few individuals interrupted therapy due to adverse

events. INDICATIONS Raltegravir is approved by the FDA in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have

evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents6. HIV INTEGRASE INHIBITORS Analysing issues in the pharmacotherapy of HIV-1 is Steven G. Deeks,

M.D., Professor of Medicine at the University of California, San Francisco, USA. At present, for a treatment-naive individual infected with HIV-1 who has access to all 25 or so

antiretroviral drugs currently approved, it should be easy to construct at least three and perhaps four sequential regimens in which there is a high likelihood for complete viral

suppression, even if drug-resistance to each sequential regimen emerges. Therapeutic options are not nearly as robust for patients who have been exposed in the past 15 years to multiple

suboptimal regimens. However, even in this challenging patient population, it is likely that raltegravir and the other recently developed drugs will be effective. One of the most important

questions in the field today is whether the prevalence of multidrug resistance will wane over time as a consequence of raltegravir's approval, or whether in a few years there will be

large numbers of patients who have resistance to all the existing drug classes, including integrase inhibitors. Most patients now entering treatment do well virologically, immunologically

and clinically. The major barrier to success is the inability of some patients to adhere in a durable manner to combination therapy, as incomplete adherence allows the virus to replicate in

the presence of drug, which is the optimal manner in which to select for drug-resistant mutations. Emerging data suggest that raltegravir is well tolerated7,8, which should make long-term

adherence easier. The fact that the drug must be administered twice daily to ensure durable responses is perhaps its major limitation, as clinical experience suggests that once-daily

administration is preferred for drugs that need to be taken indefinitely9. Preliminary data also suggest that the resistance to raltegravir develops rapidly during virological failure, and

that viruses resistant to raltegravir will be cross-resistant to elvitegravir, the only other integrase inhibitor in advanced stages of development. This low genetic barrier to resistance,

which is a controversial but clinically recognized property1, might dampen enthusiasm for the use of raltegravir in a potentially non-adherent population. Another potential limitation of

current treatment strategies is the inability of these drugs to fully reconstitute a normal immune system10. Suboptimal CD4 gains during otherwise effective therapy may result in an

increased risk of both AIDS and non-AIDS associated morbidity11. One potential factor limiting immune reconstitution may be persistent low-level viral replication, which can result in

heightened immune activation and immunological dysfunction12. Again, it remains possible that the potency (and perhaps the favourable pharmacokinetic properties) of raltegravir might make it

an attractive option in such individuals. Some have argued that even with safe, convenient and effective options, many patients will simply not be able to adhere to combination therapy for

decades. This raises what may be the greatest unmet need: the ability to fully eradicate replication-competent HIV from an infected individual. Several research groups in the mid-1990s

attempted this using the regimens available at that time. These efforts failed in part because viral replication was not completely inhibited, although this remains a very controversial

issue. The addition of raltegravir, which is widely thought to be more potent than previous drugs, has quietly generated renewed interest in whether HIV can be fully eradicated using

antiretroviral drugs alone.boxed-text BOX 1 | MARKET FOR INTEGRASE INHIBITORS Analysing the market for integrase inhibitors are Santwana Kar, Business Analyst and Steven I. Gubernick,

Principal, Product and Portfolio Strategy, IMS Health, London, UK. In October 2007, the FDA granted the integrase inhibitor raltegravir (Isentress; Merck) accelerated approval for use in

combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients. The safety and efficacy of raltegravir have not been established in

treatment-naive adult patients or in paediatric patients, although clinical trials in both areas are ongoing. Importantly, drug interaction studies show that raltegravir can be used in

combination with other antiretrovirals without the need for dose adjustment. Moreover, raltegravir has no negative effect on lipids, a significant benefit over many current therapies.

Raltegravir faces future in-class competition from Gilead's investigational integrase inhibitor, elvitegravir. Raltegravir is dosed twice-daily, compared with once-daily for

elvitegravir, but it does not have to be boosted with ritonavir (Norvir; Abbott) as does elvitegravir . Gilead plans to conduct head-to-head Phase III trials versus raltegravir and possibly

versus the CCR5 antagonist, maraviroc (Selzentry, Pfizer). Further competition is anticipated to come in 2008 from Johnson & Johnson's investigational NNRTI etravirine, which is

awaiting FDA and EMEA approval. This drug is the first NNRTI to demonstrate antiviral activity versus documented NNRTI-resistant mutations. Due to its potency, safety, tolerability, and

flexibility, raltegravir has the potential to be a major player in the HIV market in second-line use and beyond. Analysts forecast sales of US $100 million in 2008, rising to $500 million by

2010, and should the drug achieve first-line approval, sales could rise to $1 billion within the next 5 years. REFERENCES * Flexner, C. HIV drug development: the next 25 years. _Nature Rev.

Drug Discov._ 6, 959–966 (2007). Article  CAS  Google Scholar  * Pommier, Y. et al. Integrase inhibitors to treat HIV/AIDS. _Nature Rev. Drug Discov._ 4, 236–248 (2005). Article  CAS 

Google Scholar  * Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. _Science_ 287, 646–650 (2000). Article  CAS  Google

Scholar  * Hazuda, D. J. et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. _Science_ 305, 528–532 (2004). Article  CAS  Google Scholar  *

Summa, V. et al. Discovery of MK-0518 a novel, potent and selective HIV integrase inhibitor in phase III clinical trials. 16th International AIDS Conference Aug 13–18 2006; 16 Abstract No.

ThPe0020. _International AIDS Society web site_ [online], (2006). Google Scholar  * Food and Drug Administration. FDA labelling information [online], (2007). * Grinsztejn, B. et al. Safety

and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. _Lancet_ 369,

1261–1269 (2007). Article  CAS  Google Scholar  * Markowitz, M. et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in

treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. _J. Acquir. Immune. Defic. Syndr._ 46, 125–133 (2007). Article  CAS  Google Scholar  * Claxton, A.J.,

Cramer, J. & Pierce, C. A systematic review of the associations between dose regimens and medication compliance. _Clin. Ther._ 23, 1296–1310 (2001). Article  CAS  Google Scholar  * Panel

on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents (1–143). _Department of Health and Human

Services web site_ [online], (2007). * Moore, D. M. et al. Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological

response. _AIDS_ 20, 371–377 (2006). Article  CAS  Google Scholar  * Hunt, P. W. et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected

patients with sustained viral suppression during antiretroviral therapy. _J. Infect. Dis._ 187, 1534–1343 (2003). Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Steven Deeks is at the University of California, San Francisco, 995 Potrero Avenue, San Francisco, California 94110, USA. [email protected], Steven G. Deeks * Santwana

Kar and Steven I. Gubernick are at IMS Health, 7 Harewood Avenue, London NW1 6JB, UK. [email protected], Santwana Kar & Steven I. Gubernick * Peter Kirkpatrick is at Nature Reviews

Drug Discovery. [email protected], Peter Kirkpatrick Authors * Steven G. Deeks View author publications You can also search for this author inPubMed Google Scholar * Santwana Kar View

author publications You can also search for this author inPubMed Google Scholar * Steven I. Gubernick View author publications You can also search for this author inPubMed Google Scholar *

Peter Kirkpatrick View author publications You can also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS Steven Deeks has served as an ad hoc consultant

for Tibotec and Boehringer Ingelheim, and is the principal investigator on studies partially funded by Merck and Pfizer. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Deeks, S., Kar, S., Gubernick, S. _et al._ Raltegravir. _Nat Rev Drug Discov_ 7, 117–118 (2008). https://doi.org/10.1038/nrd2512 Download citation * Issue Date: February

2008 * DOI: https://doi.org/10.1038/nrd2512 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative