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.

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.

Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.

Virus-specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. In individuals who control viremia in the absence of antiviral therapy, polyclonal, persistent, and vigorous HIV-1-specific CD4+ T cell proliferative responses were present, resulting in the elaboration of interferon-gamma and antiviral beta chemokines. In persons with chronic infection, HIV-1-specific proliferative responses to p24 were inversely related to viral load. Strong HIV-1-specific proliferative responses were also detected following treatment of acutely infected persons with potent antiviral therapy. The HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.

Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients.

BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.

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.

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.

Clinical, echocardiographic and Doppler correlates of clinical instability with onset of atrial fibrillation.

To identify clinical and Doppler echocardiographic correlates of instability with the onset of atrial fibrillation (AF), 87 consecutive patients with new-onset AF who had echocardiograms recorded during that hospital admission while in sinus rhythm were studied. Reviewers who were blinded to echocardiographic and Doppler data classified 51 patients (59%) as unstable because of the development of angina, congestive heart failure, syncope or hypotension with the onset of AF. Echocardiographic and Doppler data on transmitral blood flow velocity were analyzed by a single reviewer who was blinded to other clinical data. Multiple logistic regression analysis identified 3 variables as independent predictors of clinical instability with the onset of AF: (1) history of prior myocardial infarction (p less than 0.02); (2) echocardiographic evidence of left ventricular dysfunction (p less than 0.03); and (3) Doppler evidence of increased atrial filling fraction (p less than 0.0001). An atrial filling fraction threshold of 0.40 had a sensitivity for predicting clinical instability of 80% and a specificity of 72%. These data are consistent with the hypothesis that patients who are more dependent on the atrial contribution to ventricular filling are at increased risk of instability with AF due to the loss of atrial systole.

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.

Cytologic detection of microsporidia spores in bile. A comparison of stains.

OBJECTIVE: To compare stains in preparations of bile in a patient with AIDS and microsporidial cholangitis. STUDY DESIGN: Bile was obtained from a 30-year-old male with AIDS and symptoms of cholangitis. Comparative staining of the specimen was performed using a formalin-fixed preparation stained with Chromotrope 2R stain and with alcohol-fixed preparations stained with Gram and Giemsa stain and Diff-Quik. An alcohol-fixed ThinPrep slide was stained with Papanicolaou stain. RESULTS: Diagnostic microsporidia spores were detected under oil immersion using Papanicolaou, Chromotrope 2R, Giemsa and Gram stain. The Diff-Quik-stained preparation also revealed microsporidia but with suboptimal morphology. CONCLUSION: Detection of microsporidia in bile can be achieved using several different stains routinely available to cytologists, most optimally with alcohol-fixed Papanicolaou- or Giemsa-stained preparations or with Chromotrope 2R stain, which is available in parasitology laboratories. These findings should be applicable to fluids from other body sites with this emerging pathogen in AIDS.

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.

Viral load and perinatal transmission.

AIDS: Two recent studies show a maternal viral load is the leading predictor of viral perinatal HIV transmission. In Pediatric ACTG Study 185, none of the women with viral loads below 500 copies/ml transmitted the virus to their infant. In the Women and Infants Transmission Study (WITS), women with viral loads below 1,000 did not transmit the virus to their babies. The WITS study also correlated increased rates of transmission with an increased maternal viral load. In general, even when viral loads are below detectable limits, infant infections occur, although with lowered frequency.^ieng

Single-dose Nevirapine during pregnancy.

AIDS: The recommended three-part antiretroviral therapy featuring AZT to reduce perinatal transmission is not feasible in developing countries because of cost and other barriers to health care delivery. The HIVNET 012 study in Uganda shows that single-dose Nevirapine for the woman in labor followed by a single dose for the infant is more effective in reducing the risk of transmission than the AZT regimen. A cost-effectiveness study using data from HIVNET 012 shows that treatment with Nevirapine costs much less than the $50 threshold widely used for public health intervention in poorer countries. Though studies on the long-term safety and efficacy of the Nevirapine therapy have not been done, Nevirapine therapy appears to be the best current method for the prevention of perinatal transmission of HIV.^ieng

More on stopping antiretroviral therapy.

AIDS: Isolated reports have occurred of patients whose viral loads remained under control even when antiretroviral therapy was discontinued. The cases of three such patients are described. The patients were part of a small clinical study with six participants; the other three experienced viral rebounds. Study results are preliminary, and there is little information on how these patients were selected. More research is needed to learn how to induce this same positive immune response in other patients.^ieng

AIDS deaths decline.

AIDS: A recent report from the Centers for Disease Control and Prevention (CDC) announced a marked decline for the first time in total U.S. AIDS deaths. This decline was due to recent improvements in medical care for HIV-positive patients. The primary reason for the decline was attributed to treatments that slow progression of AIDS and prevent opportunistic infections. The present use of protease inhibitors should contribute to this trend in the future. However, the number of AIDS deaths in women and those infected heterosexually rose. Efforts are being made to target groups lacking accessibility to health care, such as blacks and Hispanics, who have a higher incidence of opportunistic infections than whites. Finally, preventing perinatal transmission of HIV by using AZT has been successful, and has lowered transmission rates to 10 percent and lower.^ieng

Aspergillus sinusitis in two HIV-infected men.

AIDS: A case report of two HIV-infected men diagnosed with aspergillus sinusitis is provided. Despite aggressive treatment with antifungal agents, such as amphotericin B and itraconazole, the sinusitis would not resolve. Both protease inhibitor-naive patients were treated with the same antiretroviral regimen. Only one of the patients had a dramatic drop in viral load; the other patient succumbed to neurologic deficits and respiratory failure. Many patients who are using protease inhibitors continue to have good clinical status despite rising viral loads. The availability of antiretroviral therapy has changed the outlook for opportunistic infections, such as severe intestinal cryptosporidiosis, PML, and azole-resistant oral candidiasis. The key role in recovery is successful treatment with antiretroviral therapy to enable the body to fight such infections.^ieng

Should we argue with success?

AIDS: A case study is presented of a man who was diagnosed with HIV several years ago, and who has been responding well to a d4T/3TC regimen. Dr. Steven Deeks and Dr. Paul Sax both describe possible treatment options and present their opinions of the different options. Both conclude that if the patient is doing well on the current dual nucleoside analogue regimen, it may be best to continue with that treatment, even if it is not the current recommended therapy.^ieng