STRATEGIC PLAN OF STUDY

Strategic Plan of Study



Strategic Plan of Study

Background

The successful use of highly active antiretroviral therapy (HAART) can dramatically suppress human immunodeficiency virus (HIV)-1 viral replication and effect significant immune reconstitution. However, despite full access to antiretroviral agents, the emergence of antiretroviral-resistant HIV-1 strains and/or drug toxicities can derail effective treatment. A prospective study of patients in a New York City cohort with acute and early HIV-1 infection found the prevalence of transmitted resistance to at least one antiretroviral agent to be 24.1%.5 Consequently, the need to develop antiretroviral agents with novel mechanisms of action persists for the treatment of both antiretroviral-experienced and antiretroviral-naïve patients. In October 2007, the United States Food and Drug Administration (FDA) approved the first drug in the integrase-inhibitor class for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients, adding to the available chemotherapeutic agents for the effective treatment of HIV/AIDS.

Description of Study

Successful HIV-1 replication requires the use of 3 enzymes: reverse transcriptase, integrase, and protease. The HIV-1 life cycle initiates with viral entry into host immune cells that express surface CD4. After viral entry, HIV-1 reverse transcriptase converts its single-stranded RNA into double-stranded DNA (dsDNA), at which time integrase assembles in a stable complex with viral DNA—the pre-integration complex—and is chaperoned into the nucleus.10 Subsequent integration of HIV-1-complementary DNA (cDNA) into the host genome is a two-step process catalyzed by the HIV-1 integrase enzyme. Initially, 2 nucleotides are excised from the 3 ends of the nascent HIV-1 DNA. This is followed by the irreversible, covalent insertion of HIV-1 viral genomic DNA into the host chromosome. While the HIV-1 virus is known to preferentially target sites within transcribed host genes for integration—so called “hot spots”—the factors underlying these preferences are not entirely clear. When integrase is inhibited, host enzymes circularize the viral cDNA, and 2-long terminal repeat (LTR) circles accumulate in the nucleus. Inhibiting integrase from performing its essential functions therefore blocks stable integration of HIV-1 DNA into the host genome and prohibits the establishment of viral latency within the host cell, preventing high-level HIV-1 replication and infection of new cells by competent virus.

In-vivo and in-vitro studies demonstrate that raltegravir is mainly eliminated via a uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)-mediated hepatic glucuronidation metabolic pathway. Glucuronosyltransferase inhibitors, as well as inducers of the enzyme, have the mechanistic potential to increase or decrease raltegravir concentrations, respectively. The elimination of raltegravir via the UGT1A1 metabolic pathway suggests caution be used in the coadministration of raltegravir with strong inducers of this pathway, such as rifampin, which could theoretically reduce raltegravir concentrations. The impact on UGT1A1 of other strong inducers of drug-metabolizing enzymes, such as phenytoin and phenobarbital, is unknown. Other less-strong inducers (eg, efavirenz, nevirapine, rifabutin, St. John's wort) may be used with the recommended dose of raltegravir. Finally, unlike the PIs, raltegravir has no apparent effect on the cytochrome P450 3A4 (CYP3A4) system, and therefore has a low propensity to alter the pharmacokinetics of agents metabolized by ...