Connection domain mutations in treatment-experienced patients in the OPTIMA trial.

OBJECTIVES: To determine the frequency of mutations in the connection domain (CD) of HIV reverse transcriptase in treatment-experienced patients in the Options in Management with Antiretrovirals trial, their impact on susceptibility to antiretroviral (ARV) drugs, and their impact on virologic outcomes. METHODS: Baseline plasma ARV genotypes and inferred resistance phenotypes were obtained. Frequencies of E312Q, Y318F, G333D, G333E, G335C, G335D, N348I, A360I, A360V, V365I, A371V, A376S, and E399G were compared with a treatment-naive population. The association of CD mutations with inferred IC50 fold changes to nucleos(t)ide reverse transcriptase inhibitors was evaluated. Univariate and multivariate analyses examined the association of CD mutations with a >1 log10 per milliliter decrease in HIV viral load after 24 weeks on a new ARV regimen. RESULTS: Higher CD mutation rates were seen in Options in Management with Antiretrovirals patients (n = 345) compared with a treatment-naive population. CD mutations were associated with increased inferred IC50 fold changes to abacavir, stavudine, tenofovir, and zidovudine. On univariate analysis, A371V was associated with lack of virologic response, as was having any CD mutation on multivariate analysis. CONCLUSIONS: CD mutations are frequent in treatment-experienced populations. They are associated with reduced susceptibility to some nucleos(t)ide reverse transcriptase inhibitors and with a diminished response to ARV therapy.

Novel targets for antiretroviral therapy: clinical progress to date.

The advent of HIV-1 resistance to antiretroviral medications, the need for lifelong antiretroviral therapy (ART) for HIV-infected individuals, and the goal of minimizing ART-related adverse effects and toxicity all drive the need for new antiretroviral drugs. Two new classes of antiretroviral medications for HIV treatment, the CCR5 and integrase inhibitors, have recently been approved for use in patients in whom previous HIV treatment regimens have failed. These new agent classes are a welcome addition to other antiretroviral classes, which include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Maraviroc is a CCR5 co-receptor antagonist that blocks HIV binding to the CCR5 receptor, which is a CD4 co-receptor necessary for cell entry. It is approved for use in ART-experienced patients with CCR5-tropic HIV, and was found to significantly reduce HIV viral load and increase CD4+ cell count when combined with an optimized background ART regimen (OBR). Treatment failure with maraviroc has been described and is primarily associated with the presence of CXCR4-tropic virus. Vicriviroc is another CCR5 co-receptor antagonist that is in late clinical trials. Raltegravir is the first US FDA-approved HIV-1 integrase inhibitor. It is approved for use in ART-experienced patients and was found to significantly reduce HIV viral load and increase CD4+ cell counts compared with placebo in combination with an OBR. Raltegravir has also been studied in treatment-naive patients and was found to be non-inferior to an efavirenz-based regimen. Elvitegravir is another HIV-1 integrase inhibitor in clinical development. Other new antiretroviral agents in clinical development include PRO140, a monoclonal antibody against CCR5, and bevirimat, a maturation inhibitor that prevents late-stage gag polyprotein processing. A number of other drug targets, such as CCR5 co-receptor agonists, CXCR4 co-receptor antagonists, novel fusion inhibitors, and alternative antiretroviral strategies, such as immune stimulation and gene therapy, are under investigation.

Infectious complications in OIF/OEF veterans with traumatic brain injury.

Of veterans from the U.S. Global War on Terrorism who have sought care in the Department of Veterans Affairs, approximately 12% have an infectious disease diagnosis. Infections in those veterans with traumatic brain injury (TBI) include infections associated with blast injuries and burns, such as skin and soft tissue infections; infections as a result of retained bullet or shrapnel fragments; pulmonary infections resulting from lung injury, intubation, or resultant tracheostomy; hospital-acquired infections, such as those associated with methicillin-resistant Staphylococcus aureus and other antimicrobial resistant organisms such as Acinetobacter baumannii; and infections from implanted prosthetic devices, such as metal hardware or skull flaps. Longer-term cognitive impairment may result in behaviors that place veterans with TBI at risk for human immunodeficiency virus or hepatitis C virus infections. Finally, chronic infections acquired abroad, such as cutaneous leishmaniasis or Q-fever, may be diagnosed after veterans return to the United States. These infections present challenges in terms of added morbidity and costs associated with complex antimicrobial management; isolation requirements; and surgical procedures, such as those to remove infected retained fragments or prosthetic devices. In this review, providers will become more familiar with the scope and complexity of infectious disease management in veterans with TBI.

The Relationship Between HIV Infection and Cardiovascular Disease.

Over 30 million people are currently living with human immunodeficiency virus (HIV) infection, and over 2 million new infections occur per year. HIV has been found to directly affect vascular biology resulting in an increased risk of cardiovascular disease compared to uninfected persons. Although HIV infection can now be treated effectively with combination antiretroviral medications, significant toxicities such as hyperlipidemia, diabetes, and excess cardiovascular co-morbidity; as well as the potential for significant drug-drug interactions between HIV and cardiovascular medications, present new challenges for the management of persons infected with HIV. We first review basic principles of HIV pathogenesis and treatment and then discuss relevant clinical management strategies that will be useful for cardiologists who might be involved in the care of HIV infected patients.