Cellular factors: targets for the treatment of HIV infection

On 19-20 April 1998, researchers and clinical investigators from around the world gathered in Pavia, Italy, for Cellular Factors: Targets for the Treatment of HIV Infection, a comprehensive 2 day meeting designed to share the most recent findings in human immunodeficiency virus (HIV) and AIDS treatment research. Because viral replication is dependent on the host cell machinery, many researchers are seeking new treatment strategies that control HIV by limiting the availability of cellular proteins and metabolic functions. Other approaches, such as gene therapy, seek to confer cellular resistance to the effects of viral gene products. Conference participants discussed a range of new therapeutic approaches, as well as new research into the workings of the cells that are targets of HIV infection. The meeting was sponsored by the Research Institute for Genetic and Human Therapy (RIGHT), with the support of Bristol-Myers Squibb Immunology and Policlinico San Matteo. Established in 1994 and codirected by Drs Julianna Lisziewicz and Franco Lori, RIGHT is a non-profit organization dedicated to translating basic research into clinical trials. With laboratories at Georgetown University in Washington, DC, and at the Policlinico San Matteo in Pavia, Italy, RIGHT works with an international research network of molecular biologists, virologists and immunologists to understand how diseases might be attacked at the molecular level. Current research focuses on prevention and treatment of HIV infection. Several clinical studies are now underway. Hydroxyurea, which targets a cellular enzyme, is being tested in combination with antiretroviral drugs to inhibit HIV-1 replication and control the onset of resistance. In gene therapy pilot studies, a novel antiviral gene is being tested for its ability to confer cellular resistance to HIV.     

Atazanavir sulfate + cobicistat for the treatment of HIV infection

Introduction: During last two decades several drugs were developed to offer long-term benefits in terms of virologic efficacy, favourable tolerability and toxicity profiles in treatment of HIV infection. Pharmacokinetics boosting of protease inhibitor allows a higher genetic barrier, as few or no drug-resistant mutations are detected in patients with virologic failure.

Areas covered: Atazanavir sulfate + cobicistat (ATV/c) was recently approved for the treatment of HIV-1 infection. Bioequivalence between cobicistat (COBI) and ritonavir (RTV) as a pharmacoenhancer of ATV was established. Additionally, randomized clinical trials demonstrated that ATV/c and ATV/ritonavir had comparable efficacy and safety profiles. Low rates of virologic failure and no ATV resistance mutations were observed in these clinical trials. Therefore, COBI shows increased advantages over RTV, such as no activity against HIV, fewer drug-drug interactions and better solubility, which promotes coformulation strategies with less pill burden, better tolerability, and, potentially, higher life-long treatment adherence.

Expert commentary: ATV/c regimen supports its useas an effective treatment option for HIV-1 infected patients with increased cardiovascular disease and chronic kidney disease risk associated with aging. In addition, ATV/c is a new opportunity to expand the strategy of switch to a dual therapy to lower the risk of long-term toxicities as well as the advantage of its cost-benefit.     

Pediatric HIV infection and treatment

Knowledge regarding the basic mechanisms of pediatric HIV infection and its prevention and treatment has expanded greatly in the last decade. Significant questions remain and have been largely refocused to the complexities of a chronic disease process. Management invariably requires specialists who must keep abreast of a rapidly evolving information base.     

CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection

The human chemokine receptors, CCR5 and CXCR4, are potential host targets for exogenous, small-molecule antagonists for the inhibition of HIV-1 infection. HIV-1 strains can be categorised by co-receptor tropism - their ability to utilise CCR5 (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual-tropic) as a co-receptor for entry into susceptible cells. CCR5 may be the more suitable co-receptor target for small-molecule antagonists because a natural deletion in the CCR5 gene preventing its expression on the cell surface is not associated with any obvious phenotype, but can confer resistance to infection by CCR5-tropic strains - the most frequently sexually-transmitted strains. The current leading CCR5 antagonists in clinical development include maraviroc (UK-427,857, Pfizer), aplaviroc (873140, GlaxoSmithKline) and vicriviroc (SCH-D, Schering-Plough), which have demonstrated efficacy and tolerability in HIV-infected patients. Pharmacodynamic data also suggest that these compounds have a long plasma half-life and/or prolonged CCR5 occupancy, which may explain the delay in viral rebound observed following compound withdrawal in short-term monotherapy studies. A switch from CCR5 to CXCR4 tropism occurs spontaneously in approximately 50% of HIV-infected patients and has been associated with, but is not required for, disease progression. The possibility of a co-receptor tropism switch occurring under selection pressure by CCR5 antagonists is discussed. The completion of ongoing Phase lib/Ill studies of maraviroc, aplaviroc and vicriviroc will provide further insight into co-receptor tropism, HIV pathogenesis and the suitability of CCR5 antagonists as a potent new class of antiyirals for the treatment of HIV infection.     

Progress and prospects: RNA-based therapies for treatment of HIV infection

The current treatment regimen for HIV-infected individuals combines two or more drugs targeting different viral proteins such as RT and gag. Resistance to conventional drugs can develop quickly, and typically persists. The prospect of longer, continuous antiretroviral therapy brings with it the need for new antiretroviral drugs and approaches. In this context, gene therapies have the potential to prolong life and quality of life as an additional therapeutic class and may serve as an adjuvant to traditional treatments. This review focuses on RNA-based hematopoietic cell gene therapy for treatment of HIV infection. Recent advances in our understanding of RNA interference (RNAi) make this an especially attractive candidate for anti-HIV gene therapy although ribozyme and RNA decoy/aptamer approaches can be combined with RNAi to make a combinatorial therapy akin to highly active anti-retroviral therapy.     

Hydroxyurea for HIV infection

Hydroxyurea, an inhibitor of DNA synthesis, is used to treat HIV infection. By inhibiting ribonucleotide reductase, hydroxyurea depletes the pool of deoxynucleoside triphosphates, particularly dATP, available for DNA synthesis. Hydroxyurea may be a candidate for use with nucleoside analogs, particularly ddI. Hydroxyurea's use in treating HIV infection with and without ddI, with ddI and without d4T, and with ddI plus a protease inhibitor are discussed. Studies using hydroxyurea with ddI and d4T have shown clinical promise and could be a viable antiretroviral strategy in some patients, especially in countries with limited resources. A regimen containing hydroxyurea, ddI, and a protease inhibitor could be used in aggressive initial or salvage antiretroviral therapy. It is also possible that during acute HIV infection, hydroxyurea's cytostatic properties could contribute to the ultimate preservation of normal immunologic function. Hydroxyurea's dosage level is still uncertain; 500 mg twice daily has been used most often.     

Update on antiretroviral treatment during primary HIV infection

Primary HIV-1 infection covers a period of around 12 weeks in which the virus disseminates from the initial site of infection into different tissues and organs. In this phase, viremia is very high and transmission of HIV is an important issue. Most guidelines recommend antiretroviral treatment in patients who are symptomatic, although the indication for treatment remains inconclusive in asymptomatic patients. In this article the authors review the main virological and immunological events during this early phase of infection, and discuss the arguments for and against antiretroviral treatment. Recommendations of different guidelines, the issue of the HIV transmission and transmission of resistance to antiretroviral drugs, as well as recently available information opening perspectives for functional cure in patients treated in very early steps of HIV infection are also discussed.