Abstract
Currently, there are 19 antiretroviral drugs approved for the treatment of HIV infection, in 3 mechanistic classes: HIV reverse transcriptase inhibitors, HIV protease inhibitors and HIV entry inhibitors. The standard of care for the treatment of HIV infection has evolved from the use of single-drug therapy, to dual-nucleoside analogue therapy to the current standard of care, 3-drug therapy with 2 nucleoside analogues in combination with a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. The impact of 3-drug combination antiretroviral therapy is dramatic, with up to 80% reductions in HIV-related mortality and morbidity since 1995. Future directions in antiretroviral therapy include the refinement of simpler, less-toxic regimens; the development of new antiretroviral agents in current or newer mechanistic drug classes with activity against resistant virus or better side effect profiles; the development of additional diagnostic tools to improve the management of antiretroviral therapy; and the expansion of the availability and benefits of antiretroviral therapy to all HIV-infected people worldwide. Antiretroviral therapy has changed and improved profoundly the clinical management of HIV infection.
Abstract
Highly active antiretroviral therapy (HAART) can suppress HIV viral replication and partially restore immunodeficiencies caused by the virus. However, complete viral eradication has not yet been achieved, and immune restoration is incomplete in many patients. Furthermore, effective lifelong HAART may not be a practical goal as a result of toxicities, complexity of regimens, and development of viral resistance. Therefore, immune based therapies which are directed at the host immune system are being developed as adjunctive therapy to antiretrovirals. Numerous cytokines and immunosuppressants have been investigated, but the clinical efficacy of these strategies remains to be proven.
Abstract
Although highly active antiretroviral therapy suppresses HIV replication resulting in extraordinary clinical benefits, difficulties with toxicity, adherence, and the monetary cost of medications limit the long-term effectiveness and availability of therapy for many HIV-infected individuals. Strategies to interrupt therapy have been proposed as a means to enhance the sustainability of antiretroviral treatment. Several different approaches with varied patient populations, theoretical concepts and clinical designs are frequently merged together as "treatment interruptions". This chapter summarizes the latest developments concerning the potential risks and benefits of treatment interruptions in the management of HIV infection. Currently, none of the strategies can be recommended in standard clinical care.
Abstract
Since the beginning of the AIDS pandemic in the early 1980's nearly 50 million people have been infected and over 16 million of those have died of AIDS. One of the most important reasons for the failure to control this epidemic is the extensive genetic variation observed in HIV-1. This high variability is responsible for biological differences among HIV-1 strains and for allowing the virus to escape the host immune response and multiple antiretroviral treatments. Here we discuss the implications of HIV-1 evolution and high mutation frequency in drug resistance, viral fitness and its potential use as a novel antiretroviral therapy.
Abstract
Drug resistance of human immunodeficiency virus presents a major obstacle to long-term effective antiretroviral therapy. One important indicator of emerging drug resistance is a quantifiable increase in plasma viral RNA levels in patients undergoing treatment. Phenotypic and genotypic assays have been developed to monitor viral resistance by measuring viral susceptibility to a certain inhibitor in vitro and/or the presence of viral genetic mutations associated with drug resistance. Drug-resistance testing, particularly genotypic resistance data, improves the response to therapy during treatment of HIV-infected patients. Several different phenotypic and genotypic assays are available for monitoring drug resistance, however, some assays are more sensitive than others for determining the presence of resistant viruses.
Abstract
Highly active antiretroviral therapy have been shown to drastically reduce mortality and morbidity in HIV-infected patients. Until recently, because of high cost and complexity of administering them, these drugs were mostly limited to treating HIV-infected patients in the developed world. Because prices of antiretroviral drugs have fallen sharply, treatment is becoming widely available in developing countries. However, multiple practical challenges remain in implementing antiretroviral programs in developing countries. If not managed and implemented carefully, these challenges may results in widespread occurrence of drug resistance. In this chapter, we examine logistical challenges of implementing antiretroviral therapy in developing; discuss how best antiretroviral therapy programs may be implemented effectively, and review some antiretroviral programs that have successfully occur in developing countries. We conclude that although implementing antiretroviral programs in a developing country is a challenge, it is feasible and an effective program may directly benefit infected persons, and should be expected to strengthen HIV prevention efforts.
Abstract
Each year more than 2 million babies are born to HIV-1-infected women worldwide. Without intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 ranges between about 15 and 40 percent, with the highest rates seen in breastfeeding populations. This chapter summarizes recent advances in MTCT prevention with a focus on implementation of antiretroviral prophylaxis in high-prevalence, resource-limited settings. In the United States and other industrialized nations, remarkable progress has been made since 1994 toward maximally reducing MTCT. Short-course peripartum antiretrovirals, in particular the two-dose intrapartum and neonatal nevirapine (NVP) regimen, can substantially reduce perinatal transmission in resource-limited settings in the developing world where >98% of all infant HIV infections occur. Research studies are focusing on the potential adverse impact of NVP drug resistance. Because safe and acceptable alternatives to breastfeeding are not currently a viable option for many HIV-infected women, particularly in sub-Saharan Africa, it is critical to identify interventions to maximally reduce postnatal HIV transmission through breast milk. Novel trials are investigating potential vaccine strategies, highly active antiretroviral therapy (HAART) to the mother, and/or antiretroviral prophylaxis to the infant, followed by early weaning. An urgent task now is to translate promising clinical trial results into an effective global campaign.
Abstract
In the last few years, HIV entry inhibitors have moved rapidly from the laboratory to the clinic. Inhibitors that target each step in the entry pathway, from attachment to membrane fusion, are currently in various stages of clinical development. The FDA has approved the fusion inhibitor Enfuvirtide, and inhibitors that block receptor binding continue to show promise in phase I/II clinical trials. Entry inhibitors are unique in that they block molecular interactions that take place on the cell surface, obviating the need for transport across the cell membrane. Furthermore, these inhibitors can be used synergistically to target different stages of entry or combined with other inhibitor classes to lessen the potential for cross-resistance. In addition to entry inhibitors, viral integration has become a promising target for drug development, and the discovery of drugs that target virus assembly and release is ongoing. As our understanding of each step of the viral life cycle continues to mature, novel inhibitors will be developed to bolster the armamentarium against HIV.
Abstract
In addition to virus-specific enzymes, such as reverse transcriptase and protease, several cellular factors are required for replication of human immunodeficiency virus type 1 (HIV-1). The best example is the chemokine receptors CCR5 and CXCR4 acting as coreceptors for HIV-1 entry (see the chapter of entry inhibitors). Although the viral transactivator protein Tat plays a critical role in HIV-1 replication, the cellular cofactors cyclin-dependent kinase 9 and cyclin T1 are indispensable for Tat-dependent transactivation of viral genome. In addition, proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1β, are known to enhance HIV-1 replication by activating the cellular transcription factor nuclear factor κB, which interacts with the HIV-1 long terminal repeat promoter and enhances HIV-1 gene expression. Furthermore, certain cellular enzymes are also involved in viral maturation. Since the emergence of drug-resistance would not be avoidable with current highly active antiretroviral therapy with inhibitors of viral proteins, inhibitors of cellular factors should be extensively studied as alternative approach to effective anti-HIV-1 chemo-therapy.
Abstract
RNA interference is a powerful and highly specific mechanism for gene silencing that uses small double-stranded RNAs (small interfering RNAs or siRNA) to target mRNA with sequence homology for degradation. The RNA interference machinery is conserved throughout evolution and exists in all cells. It is used to protect plants and lower organisms from viral infection. HIV replication can be inhibited in vitro by silencing the expression of viral genes, as well as host genes required for HIV infection, such as the coreceptors CCR5 and CXCR4. This review will discuss the attractive features and obstacles to harnessing RNA interference for therapy and prevention of HIV infection. One of the main obstacles is delivery since siRNAs do not pass through the cell membrane unaided. One delivery strategy involves a gene therapy approach to use viral vectors to express short hairpin sequences processed within cells into siRNAs; another approach involves devising methods to deliver siRNAs as small molecule drugs. Strategies to address anticipated problems arising from the sequence variability and high mutation rate of HIV are discussed.
Abstract
One of the main obstacles inhibiting HIV eradication is a population of latently infected T cells. Although small, the latent population is extremely stable and, due to the lack of viral replication, resistant to current antiretroviral therapies. It has become evident that long-term therapy with current regimens will not successfully eliminate infection. Upon the withdrawal of therapy, virus derived from the latent reservoir is able to rekindle infection and renew progression to AIDS. Consequently, viral eradication will be dependent on the implementation of therapeutic strategies to specifically target and clear the reservoir. This chapter will define latent infection of T cells relative to other cellular reservoirs and detail the cellular and molecular mechanisms responsible for its generation, persistence and induction. We will then describe the conceptual strategies that could be implemented to induce latent viral gene expression and render these cells sensitive to the host immune response and/ or antiviral agents. Past and future therapeutic approaches to eradicate the latent reservoir will additionally be discussed. Any strategy to clear the latent reservoir will also likely affect other aspects of immune physiology and thus, potential pitfalls and benefits of these approaches will be summarized. Ultimately, this chapter will inform the reader of the current knowledge concerning the latent HIV reservoir and present past and potential future strategies to eliminate it.
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