Showing papers in "Current Opinion in Hiv and Aids in 2011"
TL;DR: Recent studies support current recommendations to begin ART early in the course of HIV infection in order to limit progression of liver disease in coinfected patients.
Abstract: PURPOSE OF REVIEW Up to one-third of HIV-infected patients is infected with hepatitis C virus (HCV). It is now widely accepted that HIV accelerates the course of HCV-related chronic liver disease. The improved survival of HIV patients after successful antiretroviral therapy (ART) has led to a significant decline in HIV-related morbidity, and liver disease caused by HCV infection has emerged as a major threat to the survival of HIV patients. HIV/HCV coinfected patients have a more rapid progression to cirrhosis and its complications than HCV monoinfected patients. Even though the effect of HCV on HIV infection and disease progression is less clear, most advocate early anti-HCV treatment to reduce the risk of chronic liver disease. RECENT FINDINGS Recent studies support current recommendations to begin ART early in the course of HIV infection in order to limit progression of liver disease in coinfected patients. HIV coinfection has a negative impact on HCV pathogenesis, and despite increased risk of drug-related hepatotoxicity, successful response to ART might lessen progression of chronic liver disease and improve response to anti-HCV therapy. SUMMARY HIV infection affects rate of liver disease progression in those with HCV coinfection. Treatment of HIV may result in slower rates of progression and liver mortality.
180 citations
TL;DR: Strategies to purge the latent proviral pool require nontoxic activator molecules and it is suggested that proviral reactivation will not be achieved when only a single reactivation step is targeted but will require both removal of epigenetic blocks and the activation of P-TEFb.
Abstract: Purpose of reviewDespite the remarkable success of intensive antiretroviral drug therapy in blocking the HIV replication, the virus persists in a small number of cells in which HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mec
172 citations
TL;DR: The multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have.
Abstract: Purpose of Review—Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important non-infectious chronic co-morbidity among antiretroviral (ARV)-treated HIV-infected persons. Recent Findings—HIV infection can impact CVD and co-morbidiities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons. Summary—HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV-infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARV’s can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV-infected persons.
171 citations
TL;DR: The mechanisms underlying elite control are aggressively being sought to guide vaccine development and novel therapeutic strategies and to distinguish and further characterize elite controllers with long-term clinical success from those with HIV disease progression.
Abstract: Purpose of reviewRecent studies have been published characterizing the epidemiology of elite controllers. The demographic features, clinical characteristics, and HIV disease outcomes of elite controllers are summarized.Recent findingsElite controllers are defined by the ability to spontaneously supp
145 citations
TL;DR: A better understanding of relevant mechanisms of latency in vivo, and better tools to translate this knowledge into therapies are needed are needed.
Abstract: Purpose of reviewInterest has re-emerged in approaches to eradicate HIV infection. A series of modifications of nucleosomal histones within chromatin are a key mechanism of HIV gene regulation that alters the recruitment of transcription factors to viral DNA. The balance of these histone modificatio
120 citations
TL;DR: This review examines whether the exceptional HIV-infected elite controllers, who spontaneously and durably maintain extremely low virus replication, might be considered as a model for a functional cure and whether the mechanisms identified in these exceptional individuals might serve to identify therapeutic or vaccine strategies.
Abstract: Purpose of reviewThe limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remission of HIV replication without treatment. This concept requires an understanding of the
105 citations
TL;DR: Investigation of the PD-1, IL-10, and Tim-3 pathways provided insight into mechanisms of HIV-specific CD4 T-cell exhaustion and new evidence that manipulation of these networks may restore immune functions.
Abstract: Purpose of review To understand the role of HIV-specific CD4 T cells in viral control and highlight recent progress in the field. Recent findings HIV-specific CD4 T cells show higher functional avidity in elite controllers than in patients with progressive infection. There is an attrition of the HIV-specific CD4 T-cell population in the digestive mucosa of antiretroviral therapy (ART)-treated patients that contrasts with robust responses in individuals with spontaneous viral control. Secretion of the cytokine IL-21, by HIV-specific CD4 T cells, is associated with disease control and enhances the capacity of HIV-specific CD8 T cells to suppress viral replication. Studies of the PD-1, IL-10, and Tim-3 pathways provided insight into mechanisms of HIV-specific CD4 T-cell exhaustion and new evidence that manipulation of these networks may restore immune functions. Robust, polyfunctional CD4 T-cell responses can be elicited with novel HIV and simian immunodeficiency virus (SIV) vaccines. Summary These observations show that HIV-specific CD4 T-cell responses are different in elite controllers and individuals with progressive disease. Evidence suggests that HIV-specific CD4 T cells will be an important component of an effective HIV vaccine and significant efforts need to be made to further our understanding of HIV-specific CD4 T-cell functions in different body compartments.
104 citations
TL;DR: How histone modifications and chromatin remodeling affect the transcriptional activity of the HIV promoter in the context of HIV latency is reviewed.
Abstract: Purpose of reviewA reservoir of latently infected cells remains in HIV-infected patients treated with highly active antiretroviral therapy treatment. Persistence of HIV in this latent reservoir has prevented full viral eradication. In order to understand and develop rational therapeutics to flush ou
100 citations
TL;DR: ART will serve as a cornerstone of combination prevention of HIV-1 and continued research will be essential to measure anticipated benefits and to detect implementation barriers and untoward consequences of such a program, especially increases in primary ART resistance.
Abstract: Purpose of review This work focuses on the use of antiretroviral agents to prevent the sexual transmission of HIV-1. Recent findings Two randomized clinical trials demonstrated that antiretroviral agents provided before exposure to HIV-1 offer substantial protection, ostensibly directly proportional to the concentration of antiretroviral therapy (ART) in the genital secretions. Intense focus on the use of HIV treatment as prevention has led to publication of modeling exercises, ecological studies, and observational studies, most of which support the potential benefits of ART. However, the logistical requirements for successful use of ART for prevention are considerable. Summary ART will serve as a cornerstone of combination prevention of HIV-1. Continued research will be essential to measure anticipated benefits and to detect implementation barriers and untoward consequences of such a program, especially increases in primary ART resistance.
92 citations
TL;DR: Investigation from multiple groups has now focused upon HIV-specific CD8+ T-cell granule-exocytosis-mediated cytotoxicity as a correlate of immunologic control of HIV.
Abstract: Purpose of reviewOver the past 2 years, a clearer picture has emerged regarding the properties of HIV-specific CD8+ T cells associated with immunologic control of HIV replication. These properties represent a potential mechanism by which rare patients might control HIV replication in the absence of
88 citations
TL;DR: Interactions between Th17 cells, T-reg, and cells of the innate immune system influence the course of HIV and SIV infection from its earliest stages, even before the appearance of adaptive immunity.
Abstract: Purpose of reviewWe present current findings about two subsets of CD4+ T cells that play an important part in the initial host response to infection with the HIV type 1: those producing IL-17 (Th17 cells) and those with immunosuppressive function (CD25+FoxP3+ regulatory T cells or T-reg). The role o
TL;DR: Recent developments in humanized mouse models have facilitated preclinical studies that have demonstrated the ability of CCR5-targeted ZFNs to suppress HIV-1 in vivo, when used to modify human T cells or HSCs.
Abstract: Purpose of Review
Individuals homozygous for a deletion in the CCR5 gene (CCR5Δ32) are almost completely resistant to HIV-1 infection. A recent report that transplantation of hematopoietic stem/progenitor cells (HSC) from a CCR5Δ32 homozygous donor effectively cured an HIV patient has increased interest in the development of strategies that could be used to recreate this phenotype using a patient’s own cells. This review will focus on recent developments to disrupt CCR5 expression in both autologous T cells and HSC.
TL;DR: Novel strategies to enhance assessment, uptake and response to treatment should be evaluated among IDUs to elucidate mechanisms to enhance care for this underserved population.
Abstract: Purpose of review Despite a high burden of hepatitis C virus (HCV) and HIV infection among IDUs and the advent of effective therapies, assessment and treatment remain limited. The current review focuses on the management of HCV and HIV among IDUs, focusing particularly on recent strategies to enhance assessment, uptake and response to HCV and HIV treatment. Recent findings There are compelling data demonstrating that with the appropriate programs, treatment for HIV and HCV among IDUs is successful. However, assessment and treatment for HCV and HIV lags far behind the numbers of IDUs who could benefit from therapy, related to systems, provider and patient-related barriers to care. Strategies for enhancing assessment and treatment for HCV and HIV have been developed, including novel models integrating HCV/HIV care within existing community-based and drug and alcohol clinics, innovative methods for education delivery (including peer-support models) and directly observed therapy. Summary As we move forward, research must move beyond demonstrating that HCV and HIV infections can be successfully treated among IDUs. There is clear evidence that this is both feasible and effective. Novel strategies to enhance assessment, uptake and response to treatment should be evaluated among IDUs to elucidate mechanisms to enhance care for this underserved population.
TL;DR: Because memory CD4+ T cells are critical for appropriate immune defense, targeted approaches are needed to interfere only with the long-term survival of discrete fractions of memory T cells carrying proviral DNA.
Abstract: Purpose of reviewThe present review summarizes the current challenges for the design of new therapeutic strategies toward HIV eradication in individuals receiving suppressive highly active antiretroviral therapy (HAART). We will focus on the experimental evidence suggesting that immunological mechan
TL;DR: Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis, and the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.
Abstract: Purpose of review
Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/SIV infections, innate and adaptive antiviral immune responses contribute to the chronic immune activation. In contrast, non-pathogenic SIV infections of natural hosts such as sooty mangabeys (SMs) and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection.
TL;DR: Recent findings highlight both the antagonistic and agonistic effects of the NF-κB signaling pathway on HIV-1 latency, which might be useful for flushing of latent virus from reservoirs in infected patients.
Abstract: Purpose of reviewTo discuss recent advances in our understanding of the diverse roles of NF-κB/Rel family members in HIV-1 latency.Recent findingsVarious NF-κB/Rel family members can reinforce maintenance of HIV-1 latency. For example, p50 recruits histone deacetylase 1 to the HIV-1 long terminal re
TL;DR: It is suggested that multipotent hematopoietic progenitor cells and possibly tissue mast cells may constitute significant reservoirs for HIV that must be addressed in order to eliminate HIV infection.
Abstract: PURPOSE OF REVIEW Although latent HIV-1 infection in CD4+ T cells contributes to HIV persistence, there is mounting evidence that other viral reservoirs exist. Here, we review recent data suggesting that the infection of hematopoietic progenitor cells creates additional reservoirs for HIV in vivo. RECENT FINDINGS New studies suggest that some types of hematopoietic progenitor cells have the potential to generate reservoirs for HIV. This review focuses on two types that can be infected by HIV in vitro and in vivo: multipotent hematopoietic progenitor cells in the bone marrow and circulating mast cell progenitors. Of these two types, only CD34+ bone marrow cells have been shown to harbor latent provirus in HIV-positive individuals with undetectable viral loads on highly active antiretroviral therapy (HAART). Latent infection of these long-lived cell types may create a significant barrier to HIV eradication; the infection of hematopoietic stem cells in particular could lead to an HIV reservoir that does not appreciably decay over the lifespan of the host. SUMMARY To eradicate HIV infection, it will be necessary to purge all viral reservoirs in the host. The findings highlighted here suggest that multipotent hematopoietic progenitor cells and possibly tissue mast cells may constitute significant reservoirs for HIV that must be addressed in order to eliminate HIV infection. Future studies are needed to determine which types of CD34+ cells are infected in vivo and whether infected CD34+ cells contribute to residual viremia in people with undetectable viral loads on HAART.
TL;DR: Innate responses are pivotal determinants of events at all stages of AHI and increased understanding of mechanisms involved in innate control of HIV-1 and pathways regulating innate activation during HIV- 1 infection could facilitate development of novel approaches to combating this infection.
Abstract: Purpose of review: Acute HIV-1 infection (AHI) is composed of the eclipse phase, during which the transmitted virus struggles to avoid eradication and achieve amplification/spread; the expansion phase when virus disseminates and undergoes exponential replication associated with extensive CD4 T-cell destruction; and the containment phase when set-point levels of viremia and immune activation are established. The importance of interactions between HIV-1 and innate responses in determining events throughout AHI is increasingly recognized, and is reviewed here. Recent findings: During the eclipse phase, HIV-1 subverts dendritic cell functions to promote its replication at mucosal sites and employs multiple strategies to minimize control by type 1 interferons. Systemic virus dissemination is associated with widespread activation of innate responses which fuels HIV-1 replication. To minimize the protective effects of innate responses, HIV-1 resists control by natural killer cells and may impair innate regulation of adaptive responses. Innate responses remain chronically activated after HIV-1 containment which is thought to drive HIV-1 pathogenesis. Summary: Innate responses are pivotal determinants of events at all stages of AHI. Increased understanding of mechanisms involved in innate control of HIV-1 and pathways regulating innate activation during HIV-1 infection could facilitate development of novel approaches to combating this infection. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
TL;DR: The current epidemiology of HCV in HIV infection is outlined, focusing on the recent changes and factors which have been related to the increase in HCV transmission in HIV-infected men who have sex with men (MSM).
Abstract: Purpose of reviewThe epidemiology of hepatitis C virus (HCV) in HIV has changed significantly over the past decade. This review will outline the current epidemiology of HCV in HIV infection, focusing on the recent changes and factors which have been related to the increase in HCV transmission in HIV
TL;DR: The SIV model reproduces latency in memory CD4+ T cells throughout the body and indicates that the CNS contains a stable SIV DNA reservoir, which is required to study therapeutic approaches for a functional HIV cure.
Abstract: Purpose of reviewHere, simian immunodeficiency virus (SIV) macaque models are examined for their strengths in identifying in-vivo sites of HIV latency and persistent virus replication during highly active antiretroviral treatment (HAART) The best characterized HIV reservoir in HAART-treated persons
TL;DR: Large-scale longitudinal clinical studies are needed to confirm the importance of microbial translocation in promotion of hepatic fibrosis, and targeted interventions against microbial products may improve clinical outcomes.
Abstract: Purpose of reviewHuman immune deficiency virus (HIV)-1 and hepatitis C virus (HCV) coinfected individuals progress more rapidly to fibrosis than their HCV mono-infected counterparts. Increased microbial translocation in HIV-1/HCV coinfection may play an important role.Recent findingsThe mechanisms o
TL;DR: Renal transplantation has emerged as a feasible and successful modality of management of end-stage renal disease (ESRD) in HIV-infected individuals and questions remain regarding the pathophysiology of HIVAN.
Abstract: Purpose of review Highly active antiretroviral therapy (HAART) has resulted in a marked decrease in AIDS-related conditions and death. With improved survival, cardiovascular disease, hepatic, renal disease, and non-AIDS-related cancers represent an increasing burden for HIV-infected individuals. Recent findings HIV-associated nephropathy (HIVAN), acute renal injury, HAART, and comorbid conditions such as hepatitis C, hypertension, and diabetes are among the multiple causes of renal disease. In HIVAN there is incomplete understanding of the interaction of the virus with renal cells and the host genetics leading to susceptibility to this form of renal dysfunction. There is agreement that a baseline estimated glomerular filtration should be obtained and that renal function should be monitored during antiretroviral therapy. There is, however, no agreement as to the most accurate method of estimating GFR. Renal transplantation has emerged as a feasible and successful modality of management of end-stage renal disease (ESRD) in HIV-infected individuals. Summary Kidney disease represents an increasing concern in the care of HIV-infected persons, although there are questions remaining regarding the pathophysiology of HIVAN. Transplantation, however, can be carried out safely in infected persons with ESRD.
TL;DR: Recent developments in epidemiological and incidence assay-based methods of measuring incidence have been substantial and are likely to eventually lead to a revolution in the way that worldwide HIV epidemics are routinely tracked.
Abstract: Purpose of reviewTo describe the needs for information on the rate of new HIV infections (incidence) in epidemics and review developments in various methods for its estimation.Recent findingsEpidemiological methods for estimating incidence with models using prevalence data have been useful, but the
TL;DR: Even nef-defective HIV-1 can lead to sufficient replication in vivo to enable viral evolution and eventual progression to immunodeficiency, as exemplified by the unique patient C135.
Abstract: Purpose of review The Sydney Blood Bank Cohort comprised eight individuals who were infected with an attenuated, nef/LTR-deleted strain of HIV-1 from a single donor. All six recipients with sufficient follow-up, as well as the donor, were long-term nonprogressors. Only three recipients have maintained undetectable plasma viral loads, allowing investigation of factors that determined elite control of attenuated HIV-1 infection. Recent findings Follow-up of recipients showed that infection with this attenuated HIV-1 strain resulted in either low or absent viral replication in vivo for up to 29 years. The three patients without detectable viraemia have been studied for virological, genetic and immunological correlates of elite control. CD4 proliferation in vitro in response to p24 provided the clearest distinction of elite controllers from the slow progressors. Host factors are believed to differentiate the three elite controllers; only one, C135, has identifiable genetic polymorphisms that probably contributed to nonprogression: Δ32 CCR5 heterozygosity, HLA-B57 and HLA-DR13 alleles, in addition to infection with nef-defective HIV-1. Summary Even nef-defective HIV-1 can lead to sufficient replication in vivo to enable viral evolution and eventual progression to immunodeficiency. Host factors modified the outcome of infection with attenuated HIV-1, as exemplified by the unique patient C135.
TL;DR: Current data on factors contributing to liver disease in HIV-monoinfected as well as in HIV/viral hepatitis-coinfected patients are reviewed, highlighting the role of ART, HIV itself, immunodeficiency, patient characteristics, and lifestyle risk factors.
Abstract: Purpose of reviewLiver disease is a major cause of morbidity and mortality in HIV-infected persons. The long-term beneficial versus potentially harmful influence of antiretroviral therapy (ART) on the liver is debated. We review current data on factors contributing to liver disease in HIV-monoinfect
TL;DR: In this article, the authors discuss new insights into HIV-1 infection in macrophages and the effect of infection on immune function and pathology, and suggest that macrophage play an important role in HIV- 1 pathogenesis and contribute to the establishment of the viral reservoir responsible for continuous virus production.
Abstract: Purpose of review Macrophages play an important role in HIV-1 pathogenesis and contribute to the establishment of the viral reservoir responsible for continuous virus production. This review will discuss new insights into HIV-1 infection in macrophages and the effect of infection on immune function and pathology. Recent findings New cellular factors interacting with various steps of the HIV-1 replication cycle, such as entry, integration, transcription, and assembly of new viral progeny, have been identified. Cellular and viral microRNAs have been shown to regulate virus replication, promote viral latency, and prolong cell survival. Interference with innate immune functions, like phagocytosis, autophagy, cytokine production, and T-cell activation by HIV-1 has been found to contribute to virus replication and latency. Growing evidence indicates an important role of infected macrophages in a variety of HIV-1-associated diseases, including neurocognitive disorders. Summary Under combined antiretroviral therapy (cART), HIV-1 continues to persist in macrophages. Better understanding of HIV-1 infection in macrophages may lead to new adjunctive therapies to improve cART, specifically targeting the viral reservoir and ameliorating tissue-specific diseases.
TL;DR: A combination of good, anti-HIV-1 host genetics along with infection by a ‘whimpy’ HIV-1 strain may be necessary for elite suppression, whereas only one of these may lead to slow progression and viremia.
Abstract: Purpose of review Differential rates of disease progression are obviously multifactorial, but the virulence of the actual infecting virus is most frequently ignored as potential source of slow or rapid disease progression. In this review, the argument will be made that nearly all elite suppressors are infected by weak HIV-1 strain (in terms of replicative capacity). Whether this poor virus replication is the cause of elite suppression or the consequence of a strong immune response remains a leading question in the field. Recent findings Although numerous research studies have related HIV-1 replicative capacity/fitness in tissue culture to virulence within patients, this review will focus on several recent and key discoveries on the important role of HIV-1 fitness in elite suppression. First, elite suppressors appear to harbor HIV-1 variants that encode Gag, Pol, and Env proteins that are less efficient than their counterparts of HIV-1 in typical/chronic progressors. Second, the actual HIV-1 clone(s) that establish acute infection may be less fit in patients who become elite controllers as compared with typical progressors. Finally, the fitness costs of cytotoxic T lymphocyte escape in HIV-1 may be easily compensated by secondary mutations if the infecting strain is capable of high replication kinetics and rapid evolution. A strain with weak replicative capacity might not compensate for fitness loss or even generate the initial escape mutations. Summary A combination of good, anti-HIV-1 host genetics (e.g. HLA-B*57) along with infection by a 'whimpy' HIV-1 strain may be necessary for elite suppression, whereas only one of these may lead to slow progression and viremia.
TL;DR: Genetic and functional data confirm the importance of KIR-HLA interactions and provide new understanding of the role of innate restriction factors in resistance to HIV-1 and disease progression.
Abstract: Purpose of reviewOur understanding of the early events in HIV-1 infection continues to grow, along with the heightened recognition of the important contribution that innate immunity plays in response to HIV-1. Here, we review the epidemiological and functional studies of genetic polymorphisms associ
TL;DR: This review aims to provide a comprehensive summary of DDI with the recently licensed DAAs, including pharmacokinetic data and current recommendations made by the manufacturers and with particular reference to antiretrovirals.
Abstract: Purpose of review Boceprevir and telaprevir are directly acting antivirals (DAAs) that have recently been licensed for treatment of hepatitis C virus (HCV) infection. Data in both untreated and previously treated patients indicate a significantly increased sustained virological response (SVR) compared with that observed with conventional therapy. However, the advent of DAA therapy poses specific challenges for HCV treatment in terms of managing drug–drug interactions (DDIs). This review aims to provide a comprehensive summary of DDI with the recently licensed DAAs, including pharmacokinetic data and current recommendations made by the manufacturers and with particular reference to antiretrovirals. Potential for DDIs with the DAAs in clinical development and the mechanisms of interaction are also discussed. Recent findings Targeted pharmacokinetic drug interaction studies have demonstrated that both boceprevir and telaprevir are potent inhibitors of the metabolic enzyme cytochrome P4503A4, making them perpetrators of interactions with co-administered medications which are metabolized by this enzyme. In addition, co-administered medications may affect plasma levels of boceprevir and telaprevir via various mechanisms, some of which remain to be fully elucidated. Summary As a result of DDIs, the concomitant use of some medicines with DAA will be contraindicated, whereas other combinations may require caution, monitoring, or dose modification of the co-administered drug. Management of DDIs with these novel agents will pose a new challenge, and prescriber awareness of the potential for DDIs is fundamental for safe prescribing. Online resources are likely to play a key role in prescriber education and clinical decision-making.
TL;DR: Development of DAA therapy will lead to a major shift in HCV clinical management, particularly with the potential for interferon (IFN)-free DAA-based combination therapy.
Abstract: Purpose of review The landscape of hepatitis C virus (HCV) therapy will change considerably over the next decade with the probable licensure of many HCV direct-acting antiviral (DAA) therapy agents. This review will outline the data on the initial two DAA agents licensed (protease inhibitors telaprevir and boceprevir) and cover potential future therapeutic strategies and challenges for DAA-based therapy, including in the context of HIV/HCV coinfection. Recent findings Phase III trials evaluating the addition of telaprevir or boceprevir to pegylated interferon and ribavirin in both HCV treatment naive and experienced populations with chronic HCV genotype 1 have demonstrated considerable improvements in sustained virological response, with many patients able to shorten total treatment duration from 48 to 24-36 weeks. Although these initial DAA-based treatment results are encouraging, additional toxicity, problematic dosing schedules, and potential drug-drug interactions pose challenges for clinical management, particularly in HIV/HCV coinfection. Phase II trials with telaprevir and boceprevir in HIV/HCV populations are underway. Subsequent DAA agents appear to have improved tolerability and dosing schedules and open the door for interferon (IFN)-free DAA-based combination therapy. Summary Development of DAA therapy will lead to a major shift in HCV clinical management, particularly with the potential for IFN-free combination therapy.