New & Investigational Antiretroviral Agents

NEW & INVESTIGATIONAL ANTIRETROVIRAL AGENTS

New therapies are continually being sought that exploit other HIV targets, have activity against resistant viral strains, have a lower incidence of adverse effects, and offer convenient dosing. Newly approved agents and those currently in advanced stages of clinical development include the NRTI agents elvucitabine,racivir, and apricitabine; the NNRTI agent rilpivirine; entryinhibitors such as the CCR5 receptor antagonists vicriviroc and PRO 140, the fusion inhibitor TNX-355 (ibalizumab); and integrase inhibitors such as elvitegravir. In addition, new drug classes such as maturation inhibitors (bevirimat) are under investigation.

ANTIHEPATITIS AGENTS

Several agents effective against HBV and HCV are now available (Table 49–6). Current treatment is suppressive rather than cura-tive and the high prevalence of these infections worldwide, with their concomitant morbidity and mortality, reflect a critical need for improved therapeutics.

INTERFERON ALFA

Interferons are host cytokines that exert complex antiviral, immuno-modulatory, and antiproliferative actions . Interferon alfa appears to function by induction of intracellular signals following binding to specific cell membrane receptors, resulting in inhibition of viral penetration, translation, transcrip-tion, protein processing, maturation, and release, as well as increased host expression of major histocompatibility complex antigens, enhanced phagocytic activity of macrophages, and aug-mentation of the proliferation and survival of cytotoxic T cells.

Injectable preparations of interferon alfa are available for treat-ment of both HBV and HCV infections (Table 49–6). Interferon alfa-2a and interferon alfa-2b may be administered either subcu-taneously or intramuscularly; interferon alfacon-1 is administered subcutaneously. Elimination half-life is 2–5 hours for interferon alfa-2a and -2b, depending on the route of administration. The half-life of interferon alfacon-1 in patients with chronic HCV ranges from 6 to 10 hours. Alfa interferons are filtered at the glomerulus and undergo rapid proteolytic degradation during tubular reabsorption, such that detection in the systemic circula-tion is negligible. Liver metabolism and subsequent biliary excre-tion are considered minor pathways.

A meta-analysis of clinical trials in patients with chronic HBV infection showed that treatment with interferon alfa is associated with a higher incidence of hepatitis e antigen (HBeAg) serocon-version and undetectable HBV DNA levels compared with placebo. The addition of the pegylated moiety results in further increases in the proportion of patients with HBeAg seroconver-sion (∼ 30%) and a decline by approximately 4 log copies/mL (a 99.99% reduction) in HBV DNA after 1 year.

The use of pegylated (polyethylene glycol-complexed) interferon alfa-2a and pegylated interferon alfa-2b results in slower clearance and longer terminal half-lives and steadier concentrations, which allows for less frequent dosing in patients with chronic HCV infec-tion. Renal elimination accounts for about 30% of clearance, and clearance is approximately halved in subjects with impaired renal function; dosage must therefore be adjusted.

The adverse effects of interferon alfa include a flu-like syndrome (ie, headache, fevers, chills, myalgias, and malaise) that typically occurs within 6 hours after dosing; this syndrome occurs in more than 30% of patients during the first week of therapy and tends to resolve upon continued administration. Transient hepatic enzyme elevations may occur in the first 8–12 weeks of therapy and appear to be more common in responders. Potential adverse effects during chronic therapy include neuro-toxicities (mood disorders, depression, somnolence, confusion, seizures), myelosuppression, profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retin-opathy, pneumonitis, and possibly cardiotoxicity. Induction of autoantibodies may occur, causing exacerbation or unmasking of autoimmune disease (particularly thyroiditis). The polyethylene glycol molecule is a nontoxic polymer that is readily excreted in the urine.

Contraindications to interferon alfa therapy include hepatic de-compensation, autoimmune disease, and history of cardiac arrhyth-mia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interac-tions include increased theophylline and methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias.