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.     

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.     

HIV-1 protease inhibitors: effects on HIV-2 replication and resistance

Novel antiretroviral drugs include protease (PR) inhibitors (e.g. atazanavir, tipranavir and darunavir) that block HIV-1 maturation and show remarkable antiviral potency on drug-resistant isolates. However, the strains used as prototypes in the design of the novel drugs belong to a specific clade (i.e. HIV-1 group M subtype B), which is the most prevalent in developed countries. At the same time, there is an increasing concern about the expansion of other HIV-1 clades as well as other related retroviruses, such as HIV-2. The HIV-2 PR is weakly inhibited by some PR inhibitors (e.g. amprenavir), and little is known of the mutational pathways leading to drug resistance in this virus. The design of specific PR inhibitors targeting HIV-2, or potent drugs showing broad specificity on HIV-1 and HIV-2 clades, remains a major challenge for the future.     

Genetic factors that confer sensitivity to HAART in HIV-infected subjects: implication of a benefit of an earlier initiation of HAART

EVALUATION OF: Ahuja SK, Kulkarni H, Catano G et al.: CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nat. Med. 14(4), 413-420 (2008). It is widely accepted that the effect of highly active antiretroviral therapy (HAART) varies widely among HIV-infected individuals. Host genetic factors are thought to be linked to the sensitivity to HAART in HIV-infected individuals. Ahuja et al. attempted to identify the genes that determine the sensitivity to HAART in HIV-infected subjects. Based on the hypothesis that CD4+ depletion and the recovery process in HIV-infected subjects are under the control of specific common genetic pathways, they evaluated the associations of genetic variations, such as CCR5 genotype, CCL3L1 copy number variation and HLA alleles, with the sensitivity to HAART in two cohorts from the USA. They found that the CCL3L1-CCR5 genetic risk status, but not HLA-B*57, is apparently a good predictor of the recovery rate of CD4+ T cells during HAART. In particular, the recovery rate of CD4+ T cells during HAART has the most sensitive association with the copy number of CCL3L1. Furthermore, Ahuja et al. studied the impact of CCL3L1-CCR5 genetic risks in HIV-infected individuals initiating HAART during acute or early infection. They suggested that CCL3L1-CCR5 genetic risk status may be a useful guide in deciding whether to initiate HAART in HIV-infected subjects with a level of 350 CD4+ T cells/mm(3)or more. This study has provided a critical breakthrough in predicting the response to HAART in HIV-infected subjects.     

基因多态性与利福平对依非韦伦的疗效影响

依非韦伦（efavirenz）是中国HIV-1感染者广泛使用的一线抗HIV-1治疗药物。该药的临床标准用量来源于以白种人为主的临床试验,考虑到人种的差异、病理生理及合并用药的不同等对依非韦伦药物动力学的影响,标准剂量的依非韦伦并不适合所有的患者。本文综述依非韦伦血药浓度与其不良反应和疗效的相关性,依非韦伦相关代谢酶的基因多态性、利福平对其血药浓度的影响,并总结了有关中国HIV-1感染者使用依非韦伦的相关研究等,希望为临床及科研工作者提供参考。     

Emerging resistance to antibiotics against respiratory bacteria: impact on therapy of community-acquired pneumonia in children.

Perhaps because of its etiologic complexity, community-acquired pneumonia (CAP) in infants and children remains a significant problem worldwide. Over the last few years, difficulties related to CAP treatment in children have greatly increased because of the emergence of resistance to the most widely used antibiotics against some of the bacterial pathogens involved in the development of the disease. There are few data describing the impact of antibiotic resistance on clinical outcomes in CAP, but many experts believe that the clinical impact is limited. We here discuss the prevalence of different etiologic agents in CAP of children, the diagnostic criteria, problems related to antibiotic resistance, therapeutic strategies, and future implications.     

Virological and clinical implications of resistance to HIV-1 protease inhibitors.

Resistance to HIV-1 protease inhibitors is associated with 25 or more amino acid substitutions in the protease and its cleavage sites. These appear in variable combinations and in different orders, and their effects depend on the combinations in which they occur. Substitutions within and away from the enzyme active site may engender resistance by drug-specific or drug-independent mechanisms. The correlates of resistance to the different protease inhibitors overlap substantially, and each can select for viral variants that are cross-resistant to others. An understanding of protease inhibitor resistance is critical for the appropriate use of these potent inhibitors of viral replication.     

Antihypertensive use before and after initiation of fixed-dose combination products in Australia: a retrospective study

Background National guidelines in Australia advise that patients should be stabilised on both individual antihypertensive medicines before initiating a fixed-dose combination (FDC) product. Objective The aim of this study was to examine the antihypertensive medicines use before and after initiation of four antihypertensive FDC products recently listed under the Australian Pharmaceutical Benefits Scheme—olmesartan or valsartan with hydrochlorothiazide, valsartan with amlodipine and ramipril with felodipine. Setting Australian veteran population Methods This was a retrospective cohort study using Australian Government Department of Veterans’ Affairs pharmacy claims data. Subjects initiating a FDC between 2008 and 2010 were included. Their antihypertensive medicine use was investigated in the 12-months prior to and post FDC product initiation. Main outcome measure Proportions of FDC initiators dispensed one or both of the individual medicines, or who had antihypertensive medicines other than the individual ones were assessed for the 12 months prior to initiation. For the post history, proportions of patients who continued the FDC as a sole therapy, had other antihypertensives co-administered with FDC, or ceased the FDC were established. Results 2,513 participants initiated one of the four FDC products in the study period. Immediately prior to FDC initiation, below 1 % had both individual medicines, 29 % had one of the individual medicines, 58 % had antihypertensive medicines other than the individual ones, and 12 % had no antihypertensive therapy. At 12 months post initiation, 25 % of the FDC initiators continued it as a sole treatment, 35 % required an additional antihypertensive medicine in addition to FDC product, and 40 % ceased the FDC. Conclusion A minority of patients initiated combination products after being stabilised on both individual medicines. Significant number had no prior history of antihypertensive use. One-third of FDC initiators still required additional antihypertensive medication concurrently with the FDC product at 12 months post initiation.     

Genetic polymorphisms in the chemokine and chemokine receptors: impact on clinical course and therapy of the human immunodeficiency virus type 1 infection (HIV-1)

The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-Delta32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX(3)CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.     

Impact of patient attitudes and beliefs to insulin therapy upon initiation,and their attitudinal changes after initiation: the DAWN Japan study

Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients’ attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation.

Methods Insulin-naive patients with type 2 diabetes who were recommended to start insulin therapy (n?=?149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not.

Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. ‘Negative image of injections’ and ‘Positive image toward insulin therapy’ were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32–0.76] and 2.58 [1.51–4.42], respectively). After insulin initiation, ‘Negative image of injections’, ‘Positive image toward insulin therapy’, ‘Feelings of guilt regarding diabetes self-management’, and ‘Negative image toward insulin therapy’ decreased significantly (P?<?0.001 for all). ‘Social/interpersonal effects’ did not change after insulin initiation.

Conclusions This study demonstrated that patients who started insulin therapy were less likely to have negative images of injections and more likely to have positive images toward insulin therapy. Starting insulin therapy did not deteriorate the patient’s overall impression of therapy. The key limitation is the relatively small sample size (n?=?130). The results suggest that education about the benefits of insulin therapy may help patients who are not ready to initiate insulin overcome their barrier to early insulin initiation and practical support may help those who have already started therapy to maintain its use.     

Structural and thermodynamic basis of resistance to HIV-1 protease inhibition: implications for inhibitor design

One of the most serious side effects associated with the therapy of HIV-1 infection is the appearance of viral strains that exhibit resistance to protease inhibitors. At the molecular level, resistance to protease inhibition predominantly takes the form of mutations within the protease molecule that preferentially lower the affinity of protease inhibitors with respect to protease substrates, while still maintaining a viable catalytic activity. Mutations associated with drug resistance occur within the active site cavity as well as distal sites. Active site mutations affect directly inhibitor/protease interactions while non-active site mutations affect inhibitor binding through long range cooperative perturbations. The effects of mutations associated with drug resistance are compounded by the presence of naturally occurring polymorphisms, especially those observed in non-B subtypes of HIV-1. The binding thermodynamics of all clinical inhibitors against the wild type protease, drug resistant mutations and non-B subtype HIV-1 proteases has been determined by high sensitivity isothermal titration calorimetry. In conjunction with structural information, these data have provided a precise characterization of the binding mechanism of different inhibitors and their response to mutations. Inhibitors that exhibit extremely high affinity and low susceptibility to the effects of mutations share common features and binding determinants even if they belong to different chemical scaffolds. These binding determinants define a set of rules and constraints for the design of better HIV-1 protease inhibitors.