Immune recovery following antineoplastic chemotherapy and highly active antiretroviral therapy (HAART) in a child with HIV-1 infection previously unresponsive to HAART

We report the case of a perinatally HIV-1-infected child, previously immunologically unresponsive to antiretroviral treatments (including the highly active antiretroviral therapy), who instead developed a vigorous and long-lasting immune response after the highly active antiretroviral therapy was associated with antineoplastic chemotherapy undertaken for a B-cell non-Hodgkin bone lymphoma.     

Antiretroviral compounds: mechanisms underlying failure of HAART to eradicate HIV-1

During the past decade, combined highly active antiretroviral therapy (HAART) consisting of the nucleoside, non-nucleoside and protease inhibitors has improved the outlook for HIV-infected individuals. However, despite the clinical improvement associated with HAART, current antiviral drug regimens are not able to eradicate HIV due to the persistence of virus in cellular reservoirs (predominantly long-lived memory CD4+ T cells and cells of the macrophage lineage) and anatomical sanctuary sites (brain and possibly testis). Detailed knowledge of viral reservoirs is essential for the effective design of therapeutic eradication strategies such as immunostimulation of virus-persistent reservoirs and better penetration of antiretroviral drugs into sanctuary sites. The recent therapeutic approaches undertaken thus far, including immune activation, intensification protocols combined with HAART, antiretroviral treatment during seroconversion, structured treatment interruptions, activation of latent infection or targeted killing of viral reservoirs have failed to completely eradicate the virus. This review provides an evaluation of the current HAART regimens exploring the reasons for their inability to eradicate HIV from cellular reservoirs and anatomical sanctuary sites. We also provide examples of therapeutic strategies that aim to eradicate the virus, flush out reservoirs and increase antiretroviral drug concentration in these cells and tissue compartments.     

Darunavir: in the treatment of HIV-1 infection

Darunavir (TMC114) is a nonpeptidic peptidomimetic HIV protease inhibitor (PI), with a high binding affinity and a close fit within the substrate envelope. Darunavir shows potent in vitro activity against a broad range of clinical isolates of HIV type 1 (HIV-1), including those with decreased susceptibility to most available PIs. The bioavailability of oral darunavir is increased when it is coadministered in combination with low-dose (100mg) ritonavir. In the POWER 1 and POWER 2 trials, two 144-week randomised phase IIb trails, a reduction in plasma HIV-1 RNA levels of > or = 1 log10 copies/mL (primary endpoint) occurred in 77% and 62% of treatment-experienced recipients of darunavir plus ritonavir (darunavir/ritonavir) 600mg/100mg twice daily (in combination with an optimised background regimen) [vs 25% and 14% of control PI (CPI) recipients; p < 0.001] at week 24. Results are from primary analyses (n = 301 and 201). In a pooled subgroup analysis of data from the POWER 1 and 2 trials, reductions in HIV-1 RNA levels of > or = 1 log10 copies/mL were achieved in 61% of patients treated with darunavir/ritonavir 600mg/100mg twice daily verus 15% of CPI recipients (p < 0.0001) at week 48. Darunavir/ritonavir 600mg/100mg was generally well tolerated in the POWER 1 and 2 trials, with a tolerability profile similar to that of comparator CPIs.     

Vector therapies for malignant glioma: shifting the clinical paradigm

BACKGROUND: Malignant glioma represents one of the most aggressive and devastating forms of human cancer. At present, there exists no successful treatment for this disease. Gene therapy, or vector therapy, has emerged as a viable experimental treatment method for intracranial malignancies. OBJECTIVE: Vector therapy paradigms that have entered the clinical arena have shown adequate safety; however, the majority of the studies failed to observe significant clinical benefits. As such, researchers have refocused their efforts on developing novel vectors as well as new delivery methods to enhance the therapeutic effect of a particular vector. In this review, we discuss common vector therapy approaches used in clinical trials, their drawbacks and potential ways of overcoming these challenges. METHODS: We focus on the experimental evaluation of cell-based vector therapies and adenoviral and herpes simplex virus type 1 vectors in the treatment of malignant glioma. CONCLUSION: Vector therapy remains a promising treatment strategy for malignant glioma. Although significant questions remain to be answered, early clinical data suggest safety of this approach and future studies will likely address the efficacy of the proposed therapy.     

Mitochondrion-mediated apoptosis in HIV-1 infection

Acquired immunodeficiency syndrome (AIDS), which is caused by human immunodeficiency virus (HIV-1), involves the apoptotic destruction of lymphocytes and, in the context of AIDS-associated pathologies, of neurons and myocytes. Several proteins encoded by HIV-1 trigger apoptosis by inducing permeabilization of the mitochondrial membrane. Several nucleoside analogs used clinically in the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA) and/or increase the frequency of mtDNA mutations. These cause severe mitochondriopathy and might contribute to lipodystrophy, the complication associated with HIV-1 therapy. HIV-1 protease inhibitors can inhibit apoptosis at the mitochondrial level, which might help to alleviate lymphopenia. Thus, it appears that the pathogenesis of AIDS, and the pharmacological interventions and complications associated with this disease, affect the mitochondrial regulation of apoptosis, which, therefore, largely determines the outcome of HIV-1 infection.     

Atazanavir: in pediatric patients with HIV-1 infection

Atazanavir is a selective and potent inhibitor of the HIV-1 protease. The drug is administered in combination with low-dose ritonavir, to boost atazanavir pharmacokinetics (i.e. ritonavir-boosted atazanavir), and other antiretroviral agents. The efficacy of once-daily ritonavir-boosted atazanavir plus background therapy (BT) in establishing virologic suppression in treatment-naive pediatric patients (aged 6 to <18 years) infected with HIV-1 was demonstrated in an ongoing, open-label, multicenter, phase I/II trial (PACTG 1020A). HIV-1 RNA levels of <50 or <400 copies/mL were achieved by the majority of patients (>70%) after 24 weeks' therapy, with these benefits maintained at week 48. Some treatment-experienced pediatric patients (aged 6 to <18 years) also achieved HIV-1 RNA levels of <50 or <400 copies/mL in the PACTG 1020A trial after 24 (≤45% of patients) and 48 (≤32%) weeks of treatment with ritonavir-boosted atazanavir plus BT, although the benefits of the regimen in this patient population appeared to be limited by as few as one or two protease inhibitor resistance mutations. Treatment-experienced pediatric patients (aged 10-19 years) infected with HIV-1 had mixed success in establishing/maintaining virologic suppression when they were switched from their current antiretroviral treatment regimen to once-daily ritonavir-boosted atazanavir plus BT in a small, single-center, observational study. However, some patients may have received atazanavir at a suboptimal dosage or had suboptimal susceptibility to BT agents. In the PACTG 1020A trial, use of atazanavir (with or without ritonavir) in pediatric patients aged 6 to <18 years was associated with a similar safety profile to that reported in adults.     

Particle-based vaccines for HIV-1 infection

The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in pre-clinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.     

Chemokine receptors in HIV-1 and SIV infection

Seven transmembrane segment (7TMS) receptors for chemokines and related molecules have been demonstrated to be essential, in addition to CD4, for HIV and SIV infection. The β-chemokine receptor CCR5 is the primary, perhaps sole, coreceptor for HIV-1 during the early and chronic phases of infection, and supports infection by most primary HIV-1 and many SIV isolates. Late-stage primary and laboratory-adapted HIV-1, HIV-2, and SIV isolates can use other 7TMS receptors. CXCR4 appears especially important in late-stage HIV infection; several related receptors can also be used. The specificity of SIV viruses is similar. Commonalities among these receptors, combined with analyses of mutated molecules, indicate that discrete, conformationally-dependent sites on the chemokine receptors determine their association with the third variable and conserved regions of viral envelope glycoproteins. These studies are useful for elucidating the mechanism and molecular determinants of HIV-1 entry, and of inhibitors to that entry.     

CCR5 chemokine receptors: gatekeepers of HIV-1 infection

With the discovery that CCR5 is the critical protein required for infection by M-tropic HIV, has come huge research efforts, both in academia and industry, to try to exploit this finding. Thus, research advances in the fields of virology, structural protein chemistry, and receptor pharmacology have combined to add a new understanding to the process of HIV fusion and possible mechanisms to prevent HIV entry. This review will approach this field from a receptor pharmacology viewpoint and outline some concepts of receptor allosterism and protein-protein interaction which may be relevant to CCR5 blockade. Many of these ideas may be explored in a practical sense with the advent of new small molecule CCR5 inhibitors currently entering the clinic.     

Sedation for critically ill or injured adults in the intensive care unit: a shifting paradigm

As most critically ill or injured patients will require some degree of sedation, the goal of this paper was to comprehensively review the literature associated with use of sedative agents in the intensive care unit (ICU). The first and selected latter portions of this article present a narrative overview of the shifting paradigm in ICU sedation practices, indications for uninterrupted or prolonged ICU sedation, and the pharmacology of sedative agents. In the second portion, we conducted a structured, although not entirely systematic, review of the available evidence associated with use of alternative sedative agents in critically ill or injured adults. Data sources for this review were derived by searching OVID MEDLINE and PubMed from their first available date until May 2012 for relevant randomized controlled trials (RCTs), systematic reviews and/or meta-analyses and economic evaluations. Advances in the technology of mechanical ventilation have permitted clinicians to limit the use of sedation among the critically ill through daily sedative interruptions or other means. These practices have been reported to result in improved mortality, a decreased length of ICU and hospital stay and a lower risk of drug-associated delirium. However, in some cases, prolonged or uninterrupted sedation may still be indicated, such as when patients develop intracranial hypertension following traumatic brain injury. The pharmacokinetics of sedative agents have clinical importance and may be altered by critical illness or injury, co-morbid conditions and/or drug-drug interactions. Although use of validated sedation scales to monitor depth of sedation is likely to reduce adverse events, they have no utility for patients receiving neuromuscular receptor blocking agents. Depth of sedation monitoring devices such as the Bispectral Index (BIS?) also have limitations. Among existing RCTs, no sedative agent has been reported to improve the risk of mortality among the critically ill or injured. Moreover, although propofol may be associated with a shorter time to tracheal extubation and recovery from sedation than midazolam, the risk of hypertriglyceridaemia and hypotension is higher with propofol. Despite dexmedetomidine being linked with a lower risk of drug-associated delirium than alternative sedative agents, this drug increases risk of bradycardia and hypotension. Among adults with severe traumatic brain injury, there are insufficient data to suggest that any single sedative agent decreases the risk of subsequent poor neurological outcomes or mortality. The lack of examination of confounders, including the type of healthcare system in which the investigation was conducted, is a major limitation of existing pharmacoeconomic analyses, which likely limits generalizability of their results.     

Prevention of HIV-1 infection by phthalocyanines

The ability of selected phthalocyanines and metallophthalocyanines to block HIV infection has been evaluated in an epithelial HeLa-CD4 cell line with an integrated LTR-beta-galactosidase gene. Sulfonated phthalocyanine itself (PcS), as well as its copper, nickel, and vanadyl chelates, were the most effective in blocking viral infection. These compounds were also very effective in blocking the fusion activity of the viral Env proteins. All of these compounds are expected to bind axial ligands weakly or not at all. In contrast, sulfonated phthalocyanines bearing metals expected to bind axial ligands more tightly (aluminum, cobalt, chromium, iron, silicon, and zinc) were less effective in blocking HIV infection and also less effective at inhibiting fusion. A number of active compounds were found to block binding of gp120 to CD4. Selected cationic and carboxy phthalocyanines, as well as porphyrazines, were also evaluated. Our results indicate that at least some of the compounds render the virus noninfectious, i.e. that they are virucidal. These compounds have potential as microbicides that might be used to provide protection against sexually transmitted HIV.