HIV-1 integrase inhibitors: a review of their chemical development

Highly active antiretroviral therapy (HAART) significantly decreases plasma viral load, increases CD4+ T-cell counts in HIV-1-infected patients and has reduced progression to AIDS in developed countries. However, adverse side effects, and emergence of drug resistance, mean there is still a demand for new anti-HIV agents. The HIV integrase (IN) is a target that has been the focus of rational drug design over the past decade. In 2007, raltegravir was the first IN inhibitor approved by the US Food and Drug Administration for antiretroviral combination therapy, while another IN inhibitor, elvitegravir, is currently in Phase III clinical trials. This article reviews the development and resistance profiling of small molecule HIV-1 IN inhibitors.     

HIV-1 reservoirs

In most infected individuals, HIV-1 replicates high levels throughout the duration of infection, including the clinically quiescent phase of disease. The level of this active viral replication correlates directly with disease progression and survival. The advent of combination therapeutics for HIV-1 (i.e., highly active antiretroviral therapy [HAART]) has led to dramatic reductions in viral replication in vivo and morbidity and mortality, at least in the developed world.     

高效抗逆转录病毒疗法对艾滋病的治疗效果及其耐药情况

目的评价高效抗逆转录病毒疗法（highly active antiretroviral therapy,HAART）对艾滋病患者的疗效,并观察其耐药情况。方法 2008年11月,对23例接受免费HAART治疗1～3年的艾滋病患者的HIV-RNA病毒载量、HIV-1耐药、CD4＋T淋巴细胞绝对计数、常规生化检测结果进行分析。结果 23例艾滋病患者在HAART治疗1～3年后有6例（26.1%）患者HIV-RNA载量在水平线以下,17例（73.9%）HIV-RNA载量未达到检测线以下。5例患者（21.7%）的HIV-1发生了耐药,服药依从性良好的患者仅9例（39.1%）。结论 HAART对艾滋病患者的疗效较差、耐药率高、服药依从性差。     

Analysis of CCR5, CCR2, SDF1 and RANTES gene polymorphisms in subjects with HIV-related PML and not determined leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), a human polyomavirus that can lytically infect and destroy the oligodendrocites in immunosuppressed individuals. After the introduction of highly active antiretroviral therapy (HAART) for AIDS treatment, a PML-like leukoencephalopathy, known as non-determined leukoencephalopathy (NDLE), has also been observed. Since a number of host genetic factors have been identified as having an impact on susceptibility to HIV-1 infection and in the progression to AIDS and death, in this work we analysed the pattern of distribution of different chemokine and chemokine receptor polymorphisms that seem to be involved in HIV+ neurological diseases. The CCR5, RANTES, CCR2 and SDF1 genes were molecularly analysed in 84 HIV+ HAART treated subjects: 55 without neurological disorders (HIV+), 12 HIV+ NDLE and 17 HIV+ PML patients. The RANTES -403 G/A polymorphism was significantly associated with NDLE. These data suggest that mutation of the RANTES allele can predispose to the induction of demyelination similarly to what has been observed in Multiple Sclerosis (MS) and may suggest a possible explanation for the development of leukoencephalopathy without detection of JCV.     

The roles of HIV-1 proteins and antiretroviral drug therapy in HIV-1-associated endothelial dysfunction

Since the emergence of highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1)-infected patients have demonstrated dramatic decreases in viral burden and opportunistic infections, and an overall increase in life expectancy. Despite these positive HAART-associated outcomes, it has become increasingly clear that HIV-1 patients have an enhanced risk of developing cardiovascular disease over time. Clinical studies are instrumental in our understanding of vascular dysfunction in the context of HIV-1 infection. However, most clinical studies often do not distinguish whether HIV-1 proteins, HAART, or a combination of these 2 factors cause cardiovascular complications. This review seeks to address the roles of both HIV-1 proteins and antiretroviral drugs in the development of endothelial dysfunction because endothelial dysfunction is the hallmark initial step of many cardiovascular diseases. We analyze recent in vitro and in vivo studies examining endothelial toxicity in response to HIV-1 proteins or in response to the various classes of antiretroviral drugs. Furthermore, we discuss the multiple mechanisms by which HIV-1 proteins and HAART injure the vascular endothelium in HIV-1 patients. By understanding the molecular mechanisms of HIV-1 protein- and antiretroviral-induced cardiovascular disease, we may ultimately improve the quality of life of HIV-1 patients through better drug design and the discovery of new pharmacological targets.     

Treatment of HIV infection in the older patient

The number of HIV patients over the age of 50 years is increasing due to increased longevity in patients treated with highly active antiretroviral therapy (HAART), in addition to new primary infections in older patients. Numerous studies have demonstrated worse HIV disease progression and mortality in older HIV patients compared with younger patients. While HAART therapy has been shown to be effective at reducing HIV-1 RNA, the immunologic benefits in older patients may be reduced compared to younger patients. Older patients are more likely to suffer comorbidities requiring concomitant medications than younger patients. Toxicities from HAART, particularly dyslipdemia, insulin resistance, and pancreatitis may also be worse in older HIV patients. Controlled trials on epidemiology, pathogenesis, and therapeutic and clinical outcomes in the elderly are needed. As the HIV-infected population ages, there is a growing need to better determine the efficacy of HAART in older patients, and to investigate factors associated with a more rapid course of HIV infection in patients over the age of 50 years.     

HIV-associated nephropathy: epidemiology, pathogenesis, diagnosis and management

HIV-associated nephropathy (HIVAN) is the most well-known and aggressive kidney disease in HIV-1-infected patients. A variant of focal segmental glomerulosclerosis, it is characterized by the collapse of the glomerular tuft with podocyte hypertrophy/hyperplasia and foot process effacement, often with concurrent tubular microcystic dilation and tubulointerstitial nephritis. The disease has been intimately linked to the direct effect of HIV-1 on the kidney. It affects patients of African descent exclusively and is manifested by an acute decline in kidney function, most often in conjunction with high-grade proteinuria and uncontrolled HIV-1 infection. With the widespread use of highly active antiretroviral therapy (HAART), its prevalence is declining in Western countries. However, the epidemiology of the disease is not well defined in the poorest areas of the world, which bear a disproportionate share of the HIV-1 epidemic burden. Scientific evidence suggests that HAART can prevent the development of HIVAN. Furthermore, HAART, corticosteroids and inhibition of the renin-angiotensin axis are potentially helpful in delaying disease progression, as well as the need for renal replacement therapy.     

中国高效抗逆转录病毒治疗中HIV检测技术的支撑作用与发展

高效抗逆转录病毒治疗(HAART)是目前治疗AIDs行之有效的方法.但是,作为遏制MIDS的一项公共卫生策略,涉及到政府行为.自2003年以来我国政府积极响应联合国的号召,做出了政府的承诺,制定了"四免一关怀"的政策,全面开展全国性的HAART治疗工作.HIV及相关的检测技术是HAART治疗推广和应用的重要技术保障,包括HIV感染者和AIDS病例的确诊、治疗的准入、药物疗效和毒副反应的观察、药物的置换、HIV耐药的发现和变化,均以HIV检测技术为基础,当然也包括了有关研究.本期刊载的6篇有关HAART治疗及其相应检测技术的研究,有力地证明我国HIV检测技术在为国家免费MDS治疗中发挥的作用,也在服务中对发现的问题加强研究,又促使HIV检测技术本身的不断开拓与创新,为进一步完善HAART治疗的发展,提供了科学依据.     

An overview of the human immunodeficiency virus featuring laboratory testing for drug resistance.

The human immunodeficiency virus (HIV) pandemic is unique in human history in its rapid spread, its persistence, and the depth of its impact. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that approximately 65 million people have been infected with HIV since the beginning of the epidemic. During this time, approximately 25 million people have died from acquired immune deficiency syndrome AIDS. HIV-associated morbidity and mortality was substantially reduced during the last decade following the introduction of highly active antiretroviral therapy (HAART). In spite of the striking success of HAART in treating HIV infection, many patients experience treatment failure as genetic changes emerge in the virus leading to drug resistance. Laboratory testing for drug resistance in HIV strains is now used in combination with other methods to guide antiretroviral therapy. The purpose of this report is to review the background information on HIV with the focus on the problem of drug resistance and to describe the laboratory methods of testing for drug resistance in HIV strains.     

Current progress in the development of RNAi-based therapeutics for HIV-1

Highly active antiretroviral therapy (HAART) treatment for HIV has changed the course of AIDS in societies in which the drugs are readily available. Despite the great success of HAART, drug resistance and toxicity issues still remain a concern for some individuals. Thus, a number of investigators have been exploring other approaches for inhibiting HIV-1 replication. One of the most potent of these is the use of RNA interference (RNAi). This review will focus solely on the use of RNAi for the treatment of HIV-1 infection, including the problems, progress and future prospects.     

Immunosuppressive drugs as an adjuvant to HIV treatment

Although highly active antiretroviral therapy (HAART) has dramatically changed the epidemiological impact of HIV infection, many problems with currently used antiretroviral therapy have underscored the urgent need for additional therapeutic approaches. Structured treatment interruption trials, which can be considered an immune-based therapy with an autologous virus, have failed to control viral replication in most chronically HIV-1-infected patients. Alternative approaches could be the use of immunosuppressive drugs to enhance the control of viral replication mediated by their immune and antiviral properties. The use of immunosuppressive drugs may reduce the number of activated CD4 cells that support massive virus production and may prevent sequestration of CD4 T cells into lymphoid tissue, which is the place of antigen presentation and productive HIV infection. The strategy of using drugs that interfere with the HIV life-cycle, acting on the target cells of HIV rather than on viral enzymes, offers the advantage of avoiding the development of antiretroviral drug-resistant HIV mutants. However, it is not known if these approaches will clinically benefit long-term infection, by establishing a new immunological set-point that may affect the rate of disease progression. Caution is required when using HAART in combination with cytostatic drugs in HIV-1 infection until their impact and long-term safety have been investigated further in larger clinical trials.     

Therapeutic anti-HIV vaccine

Highly active antiretroviral therapy (HAART) of HIV-infected people results in viral control. When HAART is interrupted, however, HIV-infected individuals lose viral control and show reappearance of plasma viremia. Thus, they need to continue HAART almost forever for prevention of AIDS progression. Cytotoxic T lymphocyte (CTL) responses play an important role in viral suppression but are mostly reduced during HAART. There have been many attempts to develop therapeutic vaccines inducing CTL responses during HAART toward better control, although none of them has yet shown sufficient efficacy.     

The use of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection: impact on medical, palliative care, and quality of life outcomes

The effect of highly active antiretroviral therapy (HAART) in the treatment of HIV infection is usually measured by survival, CD4 lymphocyte counts, HIV-1 RNA viral load testing, and the occurrence of opportunistic infections. This pilot study sought to measure the impact of HAART treatments on a wide range of clinical outcomes and psychological variables in a sample of patients with advanced HIV infection. Seventy patients with advanced AIDS who were protease inhibitor na?ve were started on HAART regimens. Patients were admitted to an AIDS inpatient unit of a long-term care facility that provides treatment and palliative care. All patients were diagnosed with AIDS, had CD4 cell counts below 300/cc(3), and had a projected survival of greater than one month. Patients were started on triple-drug HAART regimens with daily medical supervision and observation. In addition to standard clinical and laboratory markers, a series of observer-rated and self-report instruments were used to measure various physical and psychological factors (e.g., pain and symptom distress, psychological well-being, depression). Data were collected at baseline and after 1 and 3 months of HAART therapy. As expected, the CD4 count increased and viral load levels decreased significantly over the 3-month study period. In addition, patients improved significantly in body weight, and serum albumin and ferritin levels. The only psychosocial measure that improved significantly with treatment was depression. Ratings of pain intensity, physical and psychological symptom distress, and overall quality of life did not change. Of the 70 patients studied, 84.3% were still alive after the 3-month study period. Of these, 6 (8.6%) were discharged to community. However, 17 surviving patients (24.3%) had HAART regimens discontinued due to drug intolerance and 11 patients (15.7%) expired during the study period. While these data are preliminary, HAART regimens appear to have positive effects on CD4 count, HIV viral load, and several other measures of physical well-being in patients with advanced AIDS. Despite these improvements, the benefits of treatment on pain and symptom distress, and psychological well-being were less clear. In addition, treatment failure (mortality and intolerance) were not uncommon in this sample (40%). Further research is clearly necessary to better understand the benefits of HAART therapy in patients with advanced HIV infection.     

Anti-IFN alpha immunization raises the IFN alpha-neutralizing capacity of serum--an adjuvant to antiretroviral tritherapy.

HAART (highly active antiretroviral therapy) suppresses but does not eradicate HIV-1 infection. However, since the antiretroviral agents used in HAART may also be toxic in the long-term, immunotherapies which correct HIV-1 immunosuppression or the cytokine dysregulation associated with it may be beneficial. In this respect, a double blind multicentric placebo-controlled phase II/III anti-IFN alpha vaccine trial has been carried out on 242 HIV-1 patients, the majority of whom were undergoing HAART treatment. In vaccinated patients (vaccinees) who responded to immunization by increased levels of IFN alpha Abs (whether under HAART or not) when compared to placebo or non-responder vaccinees, a strong correlation was found between an increased IFN alpha neutralizing capacity and the reduction of clinical manifestations.     

Combinatorial approaches to the prevention and treatment of HIV-1 infection

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.