Setting Of HIV Coinfection Research Articles

Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection.

Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently reported that accelerated peripheral cell death may contribute to naïve CD4+ T cell loss and that mechanistic relationships between monocyte activation, T cell activation, and soluble inflammatory mediators may also contribute. Chronic HCV infection can be cured by direct-acting anti-viral (DAA) therapy, and success is defined as sustained virological response (SVR, undetectable HCV RNA (ribonucleic acid) at 12 weeks after DAA treatment completion). However, there is no general consensus on the short-term and long-term immunological outcomes of DAA therapy. Here, we consolidate previous reports on the partial normalization of naïve CD4+ lymphopenia and T cell immune activation and the apparent irreversibility of monocyte activation following DAA therapy in HCV infected and HCV/HIV co-infected individuals. Further, advanced age and cirrhosis are associated with delayed or abrogation of immune reconstitution after DAA therapy, an indication that non-viral factors also likely contribute to host immune dysregulation in HCV infection.

Small Animal Model of Post-chemotherapy Tuberculosis Relapse in the Setting of HIV Co-infection.

Tuberculosis relapse following drug treatment of active disease is an important global public health problem due to the poorer clinical outcomes and increased risk of drug resistance development. Concurrent infection with HIV, including in those receiving anti-retroviral therapy (ART), is an important risk factor for relapse and expansion of drug resistant Mycobacterium tuberculosis (Mtb) isolates. A greater understanding of the HIV-associated factors driving TB relapse is important for development of interventions that support immune containment and complement drug therapy. We employed the humanized mouse to develop a new model of post-chemotherapy TB relapse in the setting of HIV infection. Paucibacillary TB infection was observed following treatment with Rifampin and Isoniazid and subsequent infection with HIV-1 was associated with increased Mtb burden in the post-drug phase. Organized granulomas were observed during development of acute TB and appeared to resolve following TB drug therapy. At relapse, granulomatous pathology in the lung was infrequent and mycobacteria were most often observed in the interstitium and at sites of diffuse inflammation. Compared to animals with HIV mono-infection, higher viral replication was observed in the lung and liver, but not in the periphery, of animals with post-drug TB relapse. The results demonstrate a potential role for the humanized mouse as an experimental model of TB relapse in the setting of HIV. Long term, the model could facilitate discovery of disease mechanisms and development of clinical interventions.

Diagnostic Utility and Impact on Clinical Decision Making of Focused Assessment With Sonography for HIV-Associated Tuberculosis in Malawi: A Prospective Cohort Study.

The focused assessment with sonography for HIV-associated tuberculosis (TB) (FASH) ultrasound protocol has been increasingly used to help clinicians diagnose TB. We sought to quantify the diagnostic utility of FASH for TB among individuals with HIV in Malawi. Between March 2016 and August 2017, 210 adults with HIV who had 2 or more signs and symptoms that were concerning for TB (fever, cough, night sweats, weight loss) were enrolled from a public HIV clinic in Lilongwe, Malawi. The treating clinicians conducted a history, physical exam, FASH protocol, and additional TB evaluation (laboratory diagnostics and chest radiography) on all participants. The clinician made a final treatment decision based on all available information. At the 6-month follow-up visit, we categorized participants based on clinical outcomes and diagnostic tests as having probable/confirmed TB or unlikely TB; association of FASH with probable/confirmed TB was calculated using Fisher's exact tests. The impact of FASH on empiric TB treatment was determined by asking the clinicians prospectively about whether they would start treatment at 2 time points in the baseline visit: (1) after the initial history and physical exam; and (2) after history, physical exam, and FASH protocol. A total of 181 participants underwent final analysis, of whom 56 were categorized as probable/confirmed TB and 125 were categorized as unlikely TB. The FASH protocol was positive in 71% (40/56) of participants with probable/confirmed TB compared to 24% (30/125) of participants with unlikely TB (odds ratio=7.9, 95% confidence interval=3.9,16.1; P<.001). Among those classified as confirmed/probable TB, FASH increased the likelihood of empiric TB treatment before obtaining any other diagnostic studies from 9% (5/56) to 46% (26/56) at the point-of-care. For those classified as unlikely TB, FASH increased the likelihood of empiric treatment from 2% to 4%. In the setting of HIV coinfection in Malawi, FASH can be a helpful tool that augments the clinician's ability to make a timely diagnosis of TB.

Markers of Tissue Repair and Cellular Aging Are Increased in the Liver Tissue of Patients With HIV Infection Regardless of Presence of HCV Coinfection.

Liver disease is a leading cause of HIV-related mortality. Hepatitis C virus (HCV)–related fibrogenesis is accelerated in the setting of HIV coinfection, yet the mechanisms underlying this aggressive pathogenesis are unclear. We identified formalin-fixed paraffin-embedded liver tissue for HIV-infected patients, HCV-infected patients, HIV/HCV-coinfected patients, and controls at Duke University Medical Center. De-identified sections were stained for markers against the wound repair Hedgehog (Hh) pathway, resident T-lymphocytes, and immune activation and cellular aging. HIV infection was independently associated with Hh activation and markers of immune dysregulation in the liver tissue.

Nonpathologic Infection of Macaques by an Attenuated Mycobacterial Vaccine Is Not Reactivated in the Setting of HIV Co-Infection

Failure to replace Bacille Calmette-Guerin vaccines with efficacious anti-tuberculosis (TB) vaccines have prompted outside-the-box thinking, including pulmonary vaccination to elicit local immunity. Inhalational MtbΔsigH, a stress-response-attenuated strain, protected against lethal TB in macaques. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV co-infection. Macaques were aerosol-vaccinated with ΔsigH and subsequently challenged with SIVmac239. Bronchoalveolar lavage and tissues were sampled for mycobacterial persistence, pathology, and immune correlates. Only 35% and 3.5% of lung samples were positive for live bacilli and granulomas, respectively. Our results therefore suggest that the nonpathologic infection of macaque lungs by ΔsigH was not reactivated by simian immunodeficiency virus, despite high viral levels and massive ablation of pulmonary CD4+ T cells. Protective pulmonary responses were retained, including vaccine-induced bronchus-associated lymphoid tissue and CD8+ effector memory T cells. Despite acute simian immunodeficiency virus infection, all animals remained asymptomatic of pulmonary TB. These findings highlight the efficacy of mucosal vaccination via this attenuated strain and will guide its further development to potentially combat TB in HIV-endemic areas. Our results also suggest that a lack of pulmonary pathology is a key correlate of the safety of live mycobacterial vaccines.

Drug Interactions Associated with HIV and HCV Medications

The management of HCV in the setting of HIV co-infection has been transformed with the availability of the direct-acting antivirals. Cure rates for HCV in co-infection are greater than 90 % in all genotypes. Even difficult to treat patients with cirrhosis can be successfully treated with newer regimens. Consensus guidelines are available to assist providers in selecting appropriate regimens. Despite their widespread success, drug interactions when combining HIV and HCV medications are complex, but manageable. In this review, an in-depth description of how DAAs and HIV medications are metabolized is provided. Specific guidance around combining DAA regimens with common HIV regimens used in the modern treatment era are reviewed in detail. Tables and figures contained in the review also highlight common interactions encountered with DAA/HIV combinations, route of metabolism, and compatibility for common HIV regimens when combined with DAAs. Providers are encouraged to utilize the information in this article as a guide for treating HIV and HCV co-infection for assistance in selecting regimens that are least likely to interact. Examples of peer reviewed, reputable web, and print references are also provided; these should be utilized prior to initiating therapy as screening tools to assist in managing HIV/DAA drug interactions.

Emerging trends and persistent challenges in the management of adult syphilis.

There are an estimated 10.6 million incident cases of syphilis worldwide each year. We highlight some persistent challenges and emerging trends in the clinical management of syphilis with a particular focus on therapy, serology, diagnostics, and prevention. Decades after the introduction of penicillin, the optimal management of early syphilis continues to be a controversial topic, particularly in the setting of HIV co-infection. Similarly, the need for routine lumbar puncture in HIV co-infected asymptomatic persons is an unanswered question. Despite advances in both automation and point-of-care diagnostics, we continue to rely on indirect measures of disease activity to manage this infection. As syphilis rates in some populations continue to rise, novel and effective prevention strategies are needed.

Acute hepatitis C virus (HCV) infection in the setting of HIV coinfection: a single-centre 10-year follow-up.

IntroductionAcute hepatitis C virus (HCV) infection has emerged as a major cause of morbidity in the HIV-infected population. Most guidelines recommend early treatment with pegylated interferon and ribavirin due to higher cure rates. The impact of acute HCV and its treatment on the outcome of the HIV-infected population is unknown. With new treatment options for HCV, early treatment of acute HCV has to be questioned. Here, we report a long-term analysis on patients with acute HCV.MethodsRetrospective analysis from an outpatient clinic from Berlin. All patients with the diagnosis of acute HCV according to The European AIDS Treatment Network (NEAT) criteria were included in the database at their date of HCV diagnosis and followed-up until the last medical contact. Demographic data was taken from the medical file. A fibrosis estimation was performed using transient elastography (Fibroscan(®). A Fibroscan value above 7 kPa was considered as significant fibrosis, above 12.4 kPa as liver cirrhosis. The following outcomes were documented: (a) liver-related: hepatic decompensation, cirrhosis, hepatocellular carcinoma. (b) non-liver-related: death, myocardial infarction, AIDS-defining event, psychiatric hospitalisation.ResultsA total of 207 cases of acute HCV infection in HIV-infected patients were diagnosed between May 2002 and September 2013. All patients were male and declared homosexual contacts as their risk factor for having acquired HIV. The mean age was 39 years, 162 patients (78%) were on antiretroviral treatment, and the median CD4 cell count was 593/mm3 (IQR 443–749). At HCV diagnosis, the highest median alanine aminotransferase (ALT) level was 408 IU/mL (159–871), the HCV viral load was 800,000 IU/mL (45x103–2.8x106). 22 cases (11%) cleared their infection spontaneously, 161 (77%) underwent interferon-based treatment. Of those treated, 58% had a sustained virological response. 36 cases of HCV reinfection were documented. All patients were followed-up over an interval of 806 patient-years. The median liver stiffness was 5.3 kPa (4–7) after a median interval of 34 months. 33 patients developed significant fibrosis, and 11 patients (6%) developed cirrhosis. Nine (5%) patients died during follow-up, and 11 developed non-liver-related endpoints. All but one deceased patients had interferon-based treatment.ConclusionsSevere hepatic disease and death rarely occurs in a highly treated HCV population. As interferon-based treatment may induce side effects, it is from now on justified to await new HCV treatment options.

Immunopathogenesis of HIV/Hepatitis C Virus Coinfection

As a result of shared infection routes, approximately 25% of individuals infected with HIV in North America are also infected with hepatitis C virus (HCV). In the setting of HIV coinfection, the course of HCV disease is more aggressive, resulting in higher HCV viral loads and a more rapid progression of liver pathology. With the success of HAART, HCV-related end-stage liver disease has become a leading cause of morbidity and mortality in HIV/HCV-coinfected patients. In this article, we will discuss recent studies examining the immune response during HIV and HCV coinfection, focusing on alterations or dysfunctions in virus-specific T-cell responses that may play a role in the immunopathogenesis of HIV/HCV coinfection. Summarizing the impact of HIV coinfection on HCV-specific T-cell immunity and highlighting some of the proposed mechanisms of T-cell dysfunction in HIV/HCV-coinfected individuals may uncover information that could lead to new treatment strategies for these patients experiencing accelerated liver disease and generally poorer outcomes than their HCV-monoinfected counterparts.

HCV‐specific T cells in HCV/HIV co‐infection show elevated frequencies of dual Tim‐3/PD‐1 expression that correlate with liver disease progression

Co-infection of HCV with HIV has been associated with more rapid progression of HCV-related disease. HCV-specific T-cell immune responses, which are essential for disease control, are attenuated in co-infection with HIV. T-cell exhaustion has recently been implicated in the deficient control of chronic viral infections. In the current study, we investigated the role of programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) expression in T-cell exhaustion during HCV/HIV co-infection. We show that in HCV/HIV co-infection, both total and HCV-specific T cells co-express Tim-3 and PD-1 in significantly higher frequencies, compared with HCV mono-infection. Co-expression of these two markers on HCV-specific CD8(+) T cells positively correlated with a clinical parameter of liver disease progression. HCV-specific CD8(+) T cells showed greater frequencies of Tim-3/PD-1 co-expression than HIV-specific CD8(+) T cells, which may indicate a greater degree of exhaustion in the former. Blocking Tim-3 or PD-1 pathways restored both HIV- and HCV-specific CD8(+) T-cell expansion in the blood of co-infected individuals. These data demonstrate that co-expression of Tim-3 and PD-1 may play a significant role in HCV-specific T-cell dysfunction, especially in the setting of HIV co-infection.

Management of HIV and hepatitis virus coinfection

Importance of the field: Liver disease related to infection with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) is a frequent cause of morbidity and mortality in those infected with the human immunodeficiency virus (HIV) in this era of highly active antiretroviral therapy (HAART). Although progress has been made in the treatment of HBV and HCV in the setting of HIV-coinfection, there is a lack of data in certain areas and several aspects of the management are unclear at this time.Areas covered in this review: Available data on the treatment of HBV and HCV infections, especially in the HIV-coinfected patient, are presented. Practical aspects of the management of these patients are reviewed, including diagnosis, treatment indications, monitoring, and toxicities. The impact of HAART on liver disease, end-stage-liver disease, and new therapeutic approaches are also reviewed.What the reader will gain: There are two modalities for the treatment of chronic HBV infection: interferon and nucleos(t)ide reverse transcriptase inhibitors (NRTI). The latter is the mainstream of therapy for HIV–HBV-coinfected patients. The double antiviral activity of NRTI requires coordination and careful selection of treatment for both viruses to avoid selection of resistance mutations and toxicity. Combination of pegylated interferon and ribavirin, the current standard treatment for chronic hepatitis C, has significant toxicity and limited efficacy in HIV–HCV-coinfected individuals. Oral anti-HCV treatments are currently under development and need to be studied in the HIV-coinfected population. Liver transplantation has a better outcome in HBV- than in HCV-HIV-coinfected patients. HAART seems to have a positive impact on the liver disease of HBV- and/or HCV-coinfected subjects but the CD4 threshold above which the benefit might take place is unknown at this time.Take home message: Anti-HBV treatment in the HIV-coinfected patient relies on the available NRTIs with activity against both viruses. Whereas HBV suppression can be achieved with this approach, toxicities and the selection of HBV-resistant variants result in challenging clinical scenarios. Current anti-HCV treatment (pegylated interferon and ribavirin) has limited efficacy in the HIV-coinfected patient, and STAT-C drugs are eagerly awaited.

Profile of Patients Triply Infected with HIV and the Hepatitis B and C Viruses in the HAART Era

HIV-HCV-HBV-coinfected patients were assessed to characterize the viral interactions in the setting of HIV coinfection and in the HAART era. All positive anti-HCV antibody and HBs antigen-positive HIV-infected patients were identified at five HIV clinics. Antihepatitis delta (HDV) antibody, serum HIV RNA, HCV RNA, and HBV DNA quantification and genotype determinations were performed. Out of 67 patients identified 47 (70%) were receiving anti-HBV therapy. HCV RNA and HBV DNA were detectable in 52.5% and 37% of patients, respectively. All possible patterns were found, regardless of anti-HBV therapy. HDV coinfection was associated with undetectable HCV RNA [RR 9.52 (95% CI 1.85-49.01); p = 0.007]. Independent factors predicting undetectable HBV DNA lacked HBeAg [RR 13.94 (95% CI 3.05-63.72); p = 0.001] and use of anti-HBV therapy [RR 11.42 (95% CI 2.43-53.54); p = 0.002]. Replication and genotypes of HCV or HBV had no impact on the replication of the other virus. In conclusion, in this cohort of triple infection (HBV/HCV/HIV) various viral patterns were identified. Spontaneous HCV clearance was frequent, and it was independently associated with HDV coinfection. In the absence of HBV therapy, HBV most often actively replicates. HBV/HCV replication or genotypes were not related to the replication of the other virus.

Treatment of cryptococcosis in the setting of HIV coinfection

The HIV pandemic has been associated with a rise in the prevalence of primary and recurrent cryptococcosis. Evidence-based treatment algorithms exist for the use of antifungal drugs and maintaining normal intracranial pressure in HIV-infected hosts with cryptococcal meningitis. Further investigation is needed for the treatment of cases with refractory infections and cryptococcosis-related immune reconstitution syndrome, along with the optimal use of adjuvant therapies. Primary and secondary prevention strategies remain at the crux of global control strategies for cryptococcal disease.

Hepatitis C and HIV coinfection

Coinfection with hepatitis C virus (HCV) and HIV is common. Studies conducted prior to the advent of highly active antiretroviral therapy reported increased HCV liver disease severity in coinfected persons compared with those infected with HCV alone. In the current era, the influences of HIV and highly active antiretroviral therapy on the natural history of HCV liver disease are less well defined. Peginterferon alfa and ribavirin are the current standard of care in treating HCV, but HIV coinfection is associated with lower response rates to treatment. Further research is needed to enhance our understanding of the natural history and pathogenesis of HCV liver disease in the setting of HIV coinfection and to identify more effective HCV treatments.

Major Causes of Antiviral drug Resistance and Implications for Treatment of Hepatitis B virus Monoinfection and Coinfection with HIV

The two key events in the life-cycle of the hepatitis B virus (HBV) involve (1) the generation from viral genomic DNA of the covalently closed circular DNA transcriptional template, and (2) the reverse transcription of the viral pregenomic RNA to form the HBV DNA genome. Diversity in the HBV genome is ensured by the low fidelity of the viral reverse transcriptase (rt). Particular selection pressures such as antiviral therapy readily select out escape mutants from this pre-existing quasispecies pool. Antiviral drug resistance in chronic hepatitis B can be caused by many factors, including the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, the genetic barrier of the &gt;compound and the availability of replication space. In the setting of HIV coinfection, the rate of replication is increased by one to two orders of magnitude, accelerating the emergence of drug resistance in this setting. The HBV genome is arranged into frame-shifted and overlapping reading frames in such a manner that antiviral drug-resistance-associated changes in the rt can result in changes in the viral envelope protein. These HBV isolates with altered surface antigens exhibit reduced binding of specific and neutralizing antibody and so have diagnostic and public health implications, especially in the setting of HIV coinfection where the risk of transmission is increased. Thus, prevention of resistance requires the adoption of strategies that effectively control virus replication, including the use of combination chemotherapy.

Challenges in the HIV patient coinfected with hepatitis C

Hepatitis C infection (HCV) in HIV-infected individuals is prevalent. HCV-mediated hepatic disease is clearly exacerbated in the setting of HIV disease and is of increasing concern as coinfected patients live longer on highly active antiretroviral therapy (HAART). Treatment for HCV in the setting of HIV coinfection is rapidly evolving. Complex treatment issues arise in patients requiring the multiple antiviral therapies that target HCV and HIV. This review focuses on the major issues involved in the pathogenesis and treatment of coinfected patients in the era of HAART.

Human T-Cell Lymphotropic Virus Type I (HTLV-I)-Associated Adult T-Cell Leukemia-Lymphoma in a Patient Infected with Human Immunodeficiency Virus Type 1 (HIV-1)

A patient had adult T-cell leukemia-lymphoma in the unusual setting of coinfection with human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus type I (HTLV-I). The leukemic cells were CD4 positive and showed clonal genetic rearrangement of the T-cell receptor complex. Cytogenetic analysis showed three clonal karyotypic abnormalities: trisomy 3 and two translocations [t(1;15), (X;1)]. The patient was seropositive for HIV and HTLV-I; HTLV-I and HIV-1 DNA sequences were detected in peripheral blood leukocytes by the polymerase chain reaction. The HTLV-I sequences were detected in a relatively high proportion of mononuclear cells (at least 1 in 30 cells), whereas HIV-1 sequences were detected in a smaller proportion of cells (at least 1 in 3000 cells). Clinical remission was achieved after chemotherapy. There was a decrease in the proportion of HTLV-I positive mononuclear cells (at least 1 in 1000 cells), whereas the proportion of HIV-1 positive cells was relatively unchanged (at least 1 in 1000 cells). Adult T-cell leukemia-lymphoma in the setting of HIV coinfection may become increasingly common because asymptomatic retroviral coinfections are frequent.