Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Quantifying the risks and benefits of efavirenz use in HIV-infected women of childbearing age in the USA.

OBJECTIVES: The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz-related teratogenicity) associated with using efavirenz in HIV-infected women of childbearing age in the USA. METHODS: We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz-based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor-based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100,000 women, we incorporated literature-based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women. RESULTS: Survival for HIV-infected women who received an efavirenz-based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non-efavirenz-based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100,000 exposed women, compared with 72.46/100,000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS-related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz-exposed women. CONCLUSIONS: Use of non-efavirenz-based initial ART in HIV-infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision-making regarding efavirenz use presents a trade-off between these two risks; this study can inform discussions between patients and health care providers.

The impact of HIV/HCV co-infection on health care utilization and disability: results of the ACTG Longitudinal Linked Randomized Trials (ALLRT) Cohort.

HIV/hepatitis C virus (HCV) co-infection places a growing burden on the HIV/AIDS care delivery system. Evidence-based estimates of health services utilization among HIV/HCV co-infected patients can inform efficient planning. We analyzed data from the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort to estimate resource utilization and disability among HIV/HCV co-infected patients and compare them to rates seen in HIV mono-infected patients. The analysis included HIV-infected subjects enrolled in the ALLRT cohort between 2000 and 2007 who had at least one CD4 count measured and completed at least one resource utilization data collection form (N = 3143). Primary outcomes included the relative risk of hospital nights, emergency department (ED) visits, and disability days for HIV/HCV co-infected vs HIV mono-infected subjects. When controlling for age, sex, race, history of AIDS-defining events, current CD4 count and current HIV RNA, the relative risk of hospitalization, ED visits, and disability days for subjects with HIV/HCV co-infection compared to those with HIV mono-infection were 1.8 (95% CI: 1.3-2.5), 1.7 (95% CI: 1.4-2.1), and 1.6 (95% CI: 1.3-1.9) respectively. Programs serving HIV/HCV co-infected patients can expect approximately 70% higher rates of utilization than expected from a similar cohort of HIV mono-infected patients.

The prevalence of transmitted antiretroviral drug resistance in treatment-naïve patients and factors influencing first-line treatment regimen selection.

OBJECTIVES: To estimate the prevalence of transmitted antiretroviral (ARV) drug resistance, and to assess whether resistance testing influences first-line ARV regimen selection. METHODS: Data on patients' characteristics were collected through questionnaires. ARV drug resistance was tested by genotypic methods and defined by Quest-Stanford classification rule. Physicians reported the intended and actual treatments and the factors considered in treatment selection. RESULTS: Two hundred and twenty-eight patients were included. The prevalence of ARV drug resistance was 12.1%, with 9.8% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4.5% for nucleoside reverse transcriptase inhibitors and 1.8% for protease inhibitors (PIs). Pill burdens, dosing frequency and physicians' experience with regimens were the major factors considered in treatment selection. The intended and actual treatment differed for 73 and 44% of the patients with and without ARV drug resistance, respectively [odds ratio (95% confidence interval, CI)=3.6 (1.5-9.0), P=0.006]. NNRTI-based regimens were intended for 10 patients with resistance to NNRTIs; these patients were prescribed PI-based regimens after genotypic testing. CONCLUSIONS: Transmitted ARV drug resistance was detected in 12.1% of treatment-naïve patients, with resistance to NNRTIs the most common. Resistance-testing results played a partial role in first-line treatment selection. However, resistance to NNRTIs pre-empted NNRTI use.

The long-term benefits of genotypic resistance testing in patients with extensive prior antiretroviral therapy: a model-based approach.

OBJECTIVES: Resistance testing in HIV disease may provide long-term benefits that are not evident from short-term data. Our objectives were to estimate the long-term effectiveness, cost and cost-effectiveness of genotype testing in patients with extensive antiretroviral exposure. METHODS: We used an HIV simulation model to estimate the long-term effectiveness and cost-effectiveness of genotype testing. Clinical data incorporated into the model were from NARVAL, a randomized trial of resistance testing in patients with extensive antiretroviral exposure, and other randomized trials. Each simulated patient was eligible for up to three sequential regimens of antiretroviral therapy (i.e. two additional regimens beyond the trial-based regimen) using drugs not available at the time of the study, such as lopinavir/ritonavir, darunavir/ritonavir and enfuvirtide. RESULTS: In the long term, projected undiscounted life expectancy increased from 132.2 months with clinical judgement alone to 147.9 months with genotype testing. Median survival was estimated at 11.9 years in the resistance testing arm vs 10.4 years in the clinical judgement alone arm. Because of increased survival, the projected lifetime discounted cost of genotype testing was greater than for clinical judgement alone (euro313,900 vs euro263,100; US$399,000 vs US$334,400). Genotype testing cost euro69,600 (US$88,500) per quality-adjusted life year gained compared with clinical judgement alone. CONCLUSIONS: In patients with extensive prior antiretroviral exposure, genotype testing is likely to increase life expectancy in the long term as a result of the increased likelihood of receiving two active new drugs. Genotype testing is associated with cost-effectiveness comparable to that of strategies accepted in patients with advanced HIV disease, such as enfuvirtide use.

Strategies for management and treatment of dyslipidemia in HIV/AIDS.

With the improved survival of HIV-infected patients, there are increased concerns about the long-term effects of treatment, including protease inhibitor (PI)-related dyslipidemia. Some 50-70% of patients receiving combination antiretroviral therapy (ART) involving PIs develop lipid abnormalities consisting of elevated levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides that are well-known risk factors for cardiovascular disease. Treatment of HIV dyslipidemia should include lifestyle modifications such as a low-fat diet, increased exercise, reduced alcohol consumption and smoking cessation. In many patients, however, these changes alone will not correct lipid levels. In some patients, changing the PI component of ART to another PI or non-PI and/or lipid-lowering drugs has proven successful. Each approach is associated with advantages and limitations and the need to maintain viral suppression must be balanced with the need to treat abnormal lipid levels.

Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Resistance rates in treatment-naive patients.

In a study of newly diagnosed patients in Europe, resistance rates were similar in patients who had been infected in the past year and in those who had been infected longer.

Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. New drugs.

Several industry-supported studies provide information on new drugs in various stages of development, including the PIs tipranavir, TMC-114, and 908 (the amprenavir prodrug), and the NRTI SPD754.

Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Atazanavir in treatment-experienced patients.

Two industry-sponsored prospective studies provide some clarification regarding the optimal use of the new PI atazanavir in PI-experienced patients.

Positive Epstein-Barr virus heterophile antibody tests in patients with primary human immunodeficiency virus infection.

PURPOSE: To describe three cases of primary human immunodeficiency virus (HIV) infection in patients who had laboratory studies consistent with infectious mononucleosis. SUBJECTS: We describe 3 patients who presented with a viral syndrome, had a positive heterophile antibody test, and were diagnosed with primary HIV infection. RESULTS: The results of Epstein-Barr virus serology studies in each of these patients were consistent with chronic, but not acute, Epstein-Barr virus infection. HIV antibody tests were negative, and HIV RNA was >500,000 copies/mL in each patient. CONCLUSIONS: Clinicians should recognize that a positive heterophile antibody test in the setting of an acute viral illness does not exclude the diagnosis of primary HIV infection, although reactivation of latent Epstein-Barr virus infection cannot be ruled out. Patients presenting with nonspecific viral syndromes should be assessed for HIV risk behaviors and tested for primary HIV infection when appropriate.

Opportunistic infections in HIV disease: down but not out.

Despite the marked improvement in patient survival and reduction in the incidence of HIV-related opportunistic infections with the introduction of potent, combination antiretroviral therapy, these infections remain a significant challenge in the management of HIV-infected patients. Ongoing issues that will require further study include a better characterization of immune reconstitution illnesses, other potential alterations in the natural history of opportunistic infections with antiretroviral therapy, and to what degree patients who experience failure of antiviral treatment become susceptible to various opportunistic processes.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif.

Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infection and will play an important part in therapeutic and prophylactic HIV-1 vaccines. The identification of virus-specific epitopes that are efficiently recognized by CTL is the first step in the development of future vaccines. Here we describe the immunological characterization of a number of novel HIV-1-specific, HLA-A2-restricted CTL epitopes that share a high degree of conservation within HIV-1 and a strong binding to different alleles of the HLA-A2 superfamily. These novel epitopes include the first reported CTL epitope in the Vpr protein. Two of the novel epitopes were immunodominant among the HLA-A2-restricted CTL responses of individuals with acute and chronic HIV-1 infection. The novel CTL epitopes identified here should be included in future vaccines designed to induce HIV-1-specific CTL responses restricted by the HLA-A2 superfamily and will be important to assess in immunogenicity studies in infected persons and in uninfected recipients of candidate HIV-1 vaccines.

Paronychia in association with indinavir treatment.

To assess a possible association between antiretroviral treatment and paronychia, we conducted a retrospective cohort study of 288 human immunodeficiency virus-positive protease inhibitor recipients. Indinavir treatment-adjusted for age, sex, CD4 count, diabetes status and other antiretroviral drug exposures-was significantly associated with paronychia of the great toe (hazard ratio 4.7; 95% confidence interval 1.6-13.9).

Central nervous system aspergillosis in patients with human immunodeficiency virus infection. Report of 6 cases and review.

Central nervous system (CNS) aspergillosis is a relatively uncommon complication of human immunodeficiency virus (HIV) infection. We describe 6 patients with the acquired immunodeficiency syndrome (AIDS) who developed CNS aspergillosis, and we review a total of 33 cases of CNS aspergillosis among HIV-infected individuals that were diagnosed by histology and/or culture. All patients were diagnosed with advanced HIV infection. Major risk factors for the disease included neutropenia and corticosteroid use. The most common presenting symptoms were nonspecific neurologic manifestations including headache, cranial or somatic nerve weakness or paresthesia, altered mental status, and seizures. The most common sites of additional Aspergillus involvement were the lungs, sinuses, ears, and orbits, while in one-fourth of the cases CNS was the only site of Aspergillus infection. The final diagnosis of CNS aspergillosis was made on autopsy in more than half the cases, and medical treatment of CNS aspergillosis was unsuccessful in all cases. CNS aspergillosis should be included in the differential diagnosis of HIV-infected patients who present with nonspecific neurologic symptoms and signs. If we take into account the much higher prevalence of invasive aspergillosis of the lungs, the findings in the present report suggest that CNS aspergillosis in HIV-infected individuals occurs more often as a result of direct extension from the sinuses, orbits, and ears than through hematogenous spread from the lungs. Physicians should be aware that the CNS might be the only site of Aspergillus involvement and include CNS aspergillosis in the differential diagnosis of HIV-infected patients presenting with focal neurologic signs and symptoms, especially when the head CT reveals hypodense lesions.

Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents.

The known effects of highly active antiretroviral therapy (HAART) on opportunistic infections (OIs) range from immune restoration disease to remission of specific OIs. In the present study, Mycobacterium avium complex infection recurred in 3 patients receiving antimycobacterial therapy and HAART. At the time of the initial M. avium infection, the mean CD4 cell count was 22.3 cells/mm3, and the HIV viral load was 181,133 copies/mL. Relapse occurred a mean of 14. 3 months after the first episode; the mean follow-up CD4 cell count was 89/mm3 (mean elevation of 66 cells/mm3), and the HIV viral load was <400 copies/mL in each patient. M. avium was isolated from blood (1 patient), blood and lymph node (1), and small-bowel tissue (1). M. avium infection may recur as a generalized or focal disease in those who are receiving antimycobacterial agents but whose HAART-associated CD4 cell recovery, although significant, is not optimal.