The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir.

OBJECTIVES: HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy-experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long-term adverse events (AEs). This open-label, multicentre, noninferiority study enrolled HIV-1-infected, treatment-experienced adults with confirmed HIV-1 RNA ≤ 75 HIV-1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC + ATV/r) for ≥ 6 months with no reported history of virological failure. METHODS: Participants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Endpoints included the proportion of participants with HIV-1 RNA < 50 copies/mL by time to loss of virological response (TLOVR), AEs, fasting lipids, and inflammatory, coagulation, bone and renal biomarkers. RESULTS: After 48 weeks, 76% (152 of 199) of ABC/3TC + ATV-treated and 79% (77 of 97) of TDF/FTC + ATV/r-treated participants had HIV-1 RNA < 50 copies/mL (TLOVR; P = 0.564). Other efficacy analyses yielded similar results. Rates of new grade 2-4 AEs were 45% in both groups, but an excess of hyperbilirubinaemia made the rate of treatment-emergent grade 3-4 laboratory abnormalities higher with TDF/FTC + ATV/r (36%) compared with ABC/3TC + ATV (19%). Most fasting lipid levels remained stable over time; high-density lipoprotein (HDL) cholesterol increased modestly in ABC/3TC + ATV-treated participants. Bone and renal biomarkers improved significantly between baseline and week 48 in participants taking ABC/3TC + ATV and were stable in participants taking TDF/FTC + ATV/r. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. CONCLUSIONS: The ABC/3TC + ATV treatment-switch group had similar viral suppression rates up to 48 weeks to the TDF/FTC + ATV/r comparator group, with lower rates of moderate- to high-grade hyperbilirubinaemia and improvements in bone and renal biomarkers.

In vivo and in vitro studies on Anaplasma phagocytophilum infection of the myeloid cells of a patient with chronic myelogenous leukaemia and human granulocytic ehrlichiosis.

AIMS: The occurrence of human granulocytic ehrlichiosis (HGE) in a patient with chronic myelogenous leukaemia (CML) provided an opportunity to study whether Anaplasma phagocytophilum, the aetiological agent of HGE, infects mature or immature cells, both in vivo and in vitro. METHODS: Diagnosis of HGE was confirmed by culture, polymerase chain reaction (PCR), detection of intragranulocytic inclusions, and serology. The infection rates of different myelogenous stages of granulocytic differentiation were determined by microscopy. Anaplasma phagocytophilum infection of the bone marrow was analysed by PCR, culture, and microscopy. In addition, the in vitro growth of A phagocytophilum in the patient's granulocytes and in HL-60 cells (a promyelocytic leukaemia cell line) was compared. RESULTS: Pretreatment blood smears showed that mature granulocytic cells had a higher infection rate with A phagocytophilum than did immature cells. In the original inoculation of the patient's cells into HL-60 cells to isolate A phagocytophilum, the bacterium grew faster in the patient's leukaemic cells than in HL-60 cells. Anaplasma phagocytophilum inclusions were rarely seen in bone marrow granulocytes and PCR was negative. In vitro, two A phagocytophilum isolates grew faster in the patient's granulocytes than in HL-60 cells. CONCLUSIONS: The superior growth in CML cells compared with HL-60 cells suggests that A phagocytophilum preferentially infects mature granulocytes. The higher infection rate of the patient's mature versus immature granulocytes before treatment and the minimal level of infection of the patient's bone marrow support this. It is possible that the primary site of infection in HGE is the peripheral mature granulocytic population.

Serum IgE levels in patients with human immunodeficiency virus infection.

BACKGROUND: Increased serum IgE levels are associated with advanced HIV infection. The magnitude of the increase has varied greatly between studies which generally did not assess potential confounding factors. OBJECTIVE: To determine whether the increased serum IgE levels reported with HIV infection is affected by demographic or behavioral factors, we studied injection drug users, women, and minority ethnic and racial groups with HIV infection, for whom little data now exist. METHODS: A prospective cross-sectional study of ambulatory patients with or at risk for HIV infection was performed. We enrolled 83 injection drug users and 56 non-drug users seropositive for HIV and 43 seronegative at-risk individuals from an Infectious Diseases clinic and a longitudinal study of HIV infection in injection drug users in the Bronx, New York City. Fifteen HIV-seronegative non-atopic controls were also studied. Total serum IgE levels were measured by a solid phase fluorescent assay and lymphocyte phenotypes were measured by monoclonal antibodies. RESULTS: On multiple linear regression analysis, HIV infection (P=.01) and advanced HIV disease (P < or =.01) were independently associated with increased serum IgE levels, controlling for gender, race, age, and use of injection drugs. In both HIV-seronegative and seropositive individuals, female gender was independently associated with lower IgE levels (P < or = .001). We did not find an independent effect of race or injection drug use on IgE levels. CONCLUSIONS: Increased serum IgE levels were associated with HIV infection, the highest levels existing in those with advanced HIV disease. Women had lower IgE levels than men, independent of HIV status. Active or past drug use, race, and age were not found to be independently associated with serum IgE levels. Further studies are necessary to elucidate the mechanisms underlying the increased serum IgE levels seen with HIV infection and its associated immunodeficiency, and to substantiate and explore the decreased levels found in women.

Effect of prior hepatitis B infection on serum IgE levels in patients with human immunodeficiency virus infection.

BACKGROUND: Advanced HIV infection is associated with increased serum IgE levels, which in turn have been associated with a poor prognosis. Our preliminary data revealed that serum IgE levels were significantly elevated in HIV seropositive injection drug users compared with HIV seropositive non-injection drug users. Since viral hepatitis is common among injection drug users and is itself associated with elevated serum IgE levels, we studied whether there was an association between increased serum IgE levels and positive hepatitis serology in HIV-seropositive patients. METHODS: A retrospective cross-sectional analysis was performed. The medical records of ambulatory HIV-infected patients in an ongoing study were reviewed. Forty-five patients had hepatitis A, B, and C serology performed. The associations between serum IgE levels and hepatitis A, B and C antibodies, CD4 and CD8 lymphocyte percentages, injection drug use, and sex were analyzed by univariate and multiple regression analyses. RESULTS: On univariate analyses, hepatitis B antibody was significantly associated with increased serum IgE levels in HIV-infected subjects (P = .013), especially in those with AIDS (P = .015). Multiple regression analyses controlling for CD4 lymphocyte percentages, sex, and drug use, confirmed that hepatitis B antibody status remained significantly associated with increased serum IgE levels (P = .05). There was no association of serum IgE levels with hepatitis A or C serology. CONCLUSION: Prior hepatitis B infection is significantly associated with increased serum IgE levels in advanced HIV infection. The clinical implications of this finding deserve further study.

Mucociliary clearance abnormalities in the HIV-infected patient: a precursor to acute sinusitis.

An increasing number of patients with human immunodeficiency virus (HIV) suffer from acute infectious sinusitis, and many suffer recurrent episodes at a higher rate than their non-HIV counterparts. This study investigates a mechanism underlying the increased incidence of sinusitis, that of prolonged mucociliary transport time (MTT). Nasal mucociliary clearance was examined in 30 HIV-infected patients and 30 matched, non-HIV controls using a nasal saccharin transport test. MTTs for the study group and the controls were 11.9 +/- 5.9 minutes and 7.4 +/- 3.7 minutes, respectively. This difference attained statistical significance (P < .05). Study group patients with a history of sinusitis had a mean MTT of 13.7 +/- 6.8 minutes. Those with complaints of "new onset" nasal obstruction since HIV conversion had a mean MTT of 13.5 +/- 6.8 minutes. Statistical significance (P < .05) was found comparing these times to controls, as well as to study patients without these symptoms. These data support an inherent delay of mucociliary clearance in HIV-infected patients which is chronic, possibly irreversible, and, in association with nasal obstruction, represents a major mechanism of both the high acute and recurrent sinusitis rate in this population. The cause of the mucociliary delay is still unclear and needs to be further investigated.

Sinusitis in human immunodeficiency virus infection: typical and atypical organisms.

The majority of patients with human immunodeficiency virus (HIV) infection will develop acute sinusitis. This may be a single episode, or may be the beginning of a long course of recurrent sinusitis, of which the etiology is not yet well understood. A retrospective study of cultures from antral washings was conducted to determine the organisms that were more commonly isolated in patients with HIV infection and sinusitis. Forty-seven organisms were isolated from the sinus cultures of 41 HIV-positive patients. The most common organisms isolated were Streptococcus pneumoniae (19%), Streptococcus viridans (19%), and Pseudomonas aeruginosa (17%). Pseudomonas aeruginosa is an atypical cause of acute sinusitis in the general population but was found to be an important pathogen in our HIV-infected patients. Other atypical organisms were also isolated, including Listeria monocytogenes and Candida albicans. It is important to recognize that atypical organisms must be considered if an HIV-infected patient with sinusitis does not respond to initial antibiotic therapy. A discussion follows emphasizing the need for prompt diagnosis and treatment of sinusitis in HIV infection.

Sinusitis and atopy in human immunodeficiency virus infection.

Sinusitis is increased in patients with human immunodeficiency virus (HIV) infection. To determine the underlying mechanism(s), 37 HIV-positive patients were evaluated. HIV-negative controls included 21 with rhinosinusitis, 32 with atopy, and 16 without sinusitis. Twenty-two HIV-positive patients (59%) had sinusitis; 14 of them had AIDS. There was a significant association between sinusitis severity and stage of HIV infection (P < .05). IgE levels were higher in the HIV-positive patients, increased with disease progression, and were strongly correlated with sinusitis severity (P < .01). Of HIV-positive patients, 72% exhibited more than two positive skin tests compared with 24% of HIV-negative rhinosinusitis patients and 12.5% of controls (P < .05). Sinusitis is common in HIV-positive patients, especially those with AIDS. HIV causes an allergic diathesis with increased IgE levels and allergic reactivity. There is a significant correlation between IgE levels and sinusitis severity, suggesting sinusitis is part of this acquired atopic state.

Pneumocystis carinii pneumonia presenting as asthma: increased bronchial hyperresponsiveness in Pneumocystis carinii pneumonia.

Two male patients presented with clinical and laboratory findings consistent with typical bronchial asthma and subsequently developed Pneumocystis carinii pneumonia (PCP). Only on subsequent questioning did both admit to homosexuality and behavior associated with a high risk of HIV-infection. In order to determine how frequently reversible airway obstruction is seen in patients with PCP, we measured peak expiratory flow rates (PEFR) before and after bronchodilator administration in 37 of these patients. Initial PEFR measurements revealed a significant decrease in PEFR (< 80% predicted) in 84%, with 54% of these exhibiting a significant bronchodilator response (> or = 15% increase). For comparison, peak flow measurements were made in a control group of 31 HIV-infected patients without acute PCP, divided between those with asymptomatic HIV-infection, AIDS-related complex (ARC), and AIDS, (including patients with previous PCP). Only 23% of these individuals had low PEFR, and only 3% exhibited bronchodilator responses. In order to confirm the existence of bronchial hyperreactivity in patients with PCP, another 16 patients with PCP were tested by methacholine bronchial challenge and 50% were found to have positive responses. These findings suggest that both reversible airway obstruction and airway hyperreactivity are found in association with acute PCP and that as a result some patients with PCP may present with symptoms of asthma. It is important for physicians to have a high degree of suspicion to avoid missing a diagnosis of PCP in a patient presenting with apparent asthma.

Increased urine interleukin-1 levels in aging.

Our laboratory previously noted an increase in thymocyte mitogenic activity in the urine of many elderly patients. The present study was performed to verify this finding and to determine if this activity was actually due to an increase in interleukin-1 (IL-1). IL-1 levels were measured in the urine of 33 healthy, ambulatory, elderly subjects (ages 83-95 years), using both a murine thymocyte bioassay, measuring activation by the incorporation of tritiated thymidine and an MTT dye reduction assay. There was a significant increase in urine IL-1 in 85% of elderly individuals. In the MTT dye reduction assay, mean elderly urine IL-1 levels were 0.88 U/ml, in comparison with a young control group (ages 23-37 years) in which urine IL-1 levels were very low (mean IL-1 < or = 0.05 U/ml). Urine levels of IL-1 beta were also measured by using a sensitive immunoassay (ELISA) and were found to be significantly increased in the elderly (mean = 57.4 pg/ml), compared to the young (mean = 2.5 pg/ml). In contrast, IL-2 levels in urine were very low, with no difference between the young and the elderly. Mean urine protein and creatinine levels did not differ significantly between young and old, and did not account for the increase in urine IL-1 levels. Although its immunologic significance is not yet understood, this striking increase in IL-1 is an unusual and interesting finding that merits further investigation.

Periodontal disease in heterosexuals with acquired immunodeficiency syndrome.

We studied the prevalence and severity of periodontal disease among 181 heterosexual men and women with AIDS. Included were 167 (92%) intravenous drug users (IVDU) and 14 sexual partners of persons at risk for AIDS. Periodontal disease was seen in 71 of 78 (91%) women compared to 75 of 103 (73%) men. Gingivitis was the most severe form of periodontal disease in 7 (9%) women and 15 (15%) men. Increased severity of periodontal disease was seen in women as compared with men (P less than .001); among subjects with periodontitis, 48 (75%) of 64 women had moderate to advanced disease compared to 32 (53%) of 60 men. For individuals with periodontitis, the extent of involvement was associated with severity; 90% of subjects with advanced periodontitis had all 4 quadrants affected. Concurrent oral manifestations of AIDS, including candidiasis, hairy leukoplakia, ulcers and Kaposi's sarcoma were present in 167 (92%) subjects. We conclude that HIV-associated gingivitis and HIV-associated periodontitis are common in heterosexual men and women with AIDS and are often accompanied by other oral manifestations of AIDS. The reason periodontal disease is more severe in women is not known. Clinicians should be aware that these disorders occur in heterosexuals as well as in homosexual men. Further study will be necessary to delineate the pathogenesis of these disorders.

Salmonella meningitis and infection with HIV.

Patients infected with HIV demonstrate increased susceptibility to serious infections with non-typhoidal salmonellae. However, no cases of salmonella meningitis have been reported in this population. We now report three cases of salmonella meningitis which occurred in a population of 1800 patients with AIDS or AIDS-related complex at our hospitals. The incidence of meningitis complicating salmonella infection in our HIV-infected population appears to be much higher than that reported in non-AIDS patients (7.5 versus 0.15%). All had cerebrospinal fluid parameters consistent with bacterial meningitis, and two of three revealed organisms on cerebrospinal fluid Gram stain. Two presented with a fulminant illness and died despite therapy; the third developed a brain abscess associated with a relapse of meningitis. Salmonella meningitis should be considered as a cause of acute neurological deterioration in patients at risk for HIV-related disease. Relapses may occur, and mortality is high.

Zidovudine therapy in an inner city population.

To determine the compliance and tolerance with zidovudine (azidothymidine or AZT) therapy among poor, minority, and intravenous drug-using patients, data were collected on all AIDS and ARC patients followed for at least 4 weeks in a New York City Human Immunodeficiency Virus clinic. Ninety-nine patients received zidovudine, of whom 75% were males, 92% were minorities, and 59% had a history of intravenous drug use. Of the 99 patients, 72 had AIDS and 27 had ARC with T-helper (CD4) lymphocytes less than or equal to 500 mm3. Eighty-seven of the 99 patients (88%) were compliant with zidovudine therapy. Fifty-seven percent of these had at least one adverse drug reaction requiring dose reduction (44%) or cessation (13%). Adverse reactions were similar to those reported in other populations with HIV-related illness, although headache and nausea were less common. Twenty opportunistic infections (OIs) or HIV-related malignancies occurred in 15 of 82 (18%) patients who were on zidovudine for at least 4 weeks (7.6 OIs/1,000 patient weeks). Seven of the 82 died (9%), compared to 9 of the 17 patients (53%) who did not complete 4 weeks of zidovudine therapy (p less than 0.05). There were no significant differences in any of these measures when intravenous drug users were compared with other risk groups. We conclude that zidovudine can be administered to intravenous drug users and others in an inner city clinic with acceptable compliance and tolerance.

Multifocal cytomegalovirus encephalitis in AIDS.

A 43-year-old man with the acquired immunodeficiency syndrome had clinical evidence of multifocal disease of the brain, but computed tomography was negative. Magnetic resonance imaging revealed multifocal lesions, histologically proven to be caused by cytomegalovirus. Therapy with 9[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (BW B759U) resulted in stabilization of the patient's clinical disease and radiographic improvement of the lesions.

Serologic, immunologic, and clinical features of parenteral drug users from contrasting populations.

We screened inpatient and outpatient parenteral drug users with no clinical evidence of AIDS for immunodeficiency and antibodies to HTLV-III by ELISA. Among 20 outpatient drug users, 5 (25%) were seropositive. Three of these (and 2 who were seronegative) had low T-cell ratios. Over 6 months, 1 seropositive patient with a low ratio developed oral thrush and weight loss. We also studied 13 parenteral drug users hospitalized for conditions other than AIDS. Eight had low T-cell ratios, and at least 6 of these developed AIDS or ARC within 4 months. Serum from 8 of 13 inpatients was available for HTLV-III testing: 6/8 were seropositive and 3 of these 6 were among those developing AIDS or ARC. Abnormal T-cell ratios among all patients were associated with abnormal HTLV-III serology (p = .02). Of the 7 patients who developed AIDS or ARC, 4 were tested for both antibodies and T-cell ratios: all 4 were seropositive and had low ratios. A low ratio (p = .0004), a positive ELISA (p = .014), and abnormalities of both tests (p = .001) were associated with the development of AIDS or ARC. Of the 26 patients without AIDS or ARC, 3 were lost to follow-up and 23 did not develop AIDS or ARC. Six of these 26 had abnormal ratios. Of the 21 patients who did not develop AIDS or ARC and who were tested for HTLV antibodies, 2 were lost to follow-up. Seven of 21 were seropositive and 2/21 were both seropositive and had a low ratio. One of these 2 seropositive patients with low ratios also had lymphadenopathy, but he was lost to follow-up. The other had no adenopathy and remained well until her death from trauma a year later. This study found two populations with very different risks. Six of 13 hospitalized parenteral drug users and only 1 of 20 healthy outpatients developed AIDS or ARC.

The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.

Forty-four episodes of Pneumocystis carinii pneumonia (PCP) occurred in 36 of 70 patients with the acquired immunodeficiency syndrome. Thirty-four patients with 40 episodes of PCP were treated with trimethoprim-sulfamethoxazole. Therapy was successful in 18 episodes (45%), but was unsuccessful in 15 episodes (37.5%). In the latter cases, two patients died within 72 hours; 13, of whom nine died, had therapy changed to pentamidine. In seven additional episodes (17.5%), trimethoprim-sulfamethoxazole was changed to pentamidine due to adverse reactions; all patients survived. Seven patients (26% of survivors) developed recurrent PCP. Twenty-two patients (65%) developed adverse reactions to trimethoprim-sulfamethoxazole, including leukopenia (20), hepatotoxicity (12), fever (eight), rash (six), and immediate reactions (two). Reactions were most common during the second week of therapy. Patients with the acquired immunodeficiency syndrome who have PCP have a high trimethoprim-sulfamethoxazole failure rate, due either to adverse reactions or unresponsive infection. Late recurrence is common.

Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome.

We studied the frequency with which unexplained oral candidiasis led to unequivocal acquired immunodeficiency syndrome (AIDS) in patients at risk. Twenty-two previously healthy adults with unexplained oral candidiasis, of whom the 19 tested had a reversed T4/T8 ratio and 20 had generalized lymphadenopathy, were compared with 20 similar patients with a reversed T4/T8 ratio and generalized lymphadenopathy who did not have oral candidiasis. All were intravenous-drug abusers, homosexual or bisexual men, or both. Thirteen of the 22 patients with oral candidiasis (59 per cent) acquired a major opportunistic infection or Kaposi's sarcoma at a median of three months (range, 1 to 23) as compared with none of 20 patients with generalized lymphadenopathy and immunodeficiency but without candidiasis who were followed for a median of 12 months (range, 5 to 21) (P less than 0.001). AIDS developed in 12 of 15 patients with candidiasis and T4/T8 ratios less than or equal to 0.51, as compared with none of four with ratios equal to or greater than 0.60 (P less than 0.01). We conclude that in patients at high risk for AIDS, the presence of unexplained oral candidiasis predicts the development of serious opportunistic infections more than 50 per cent of the time. Whether the remainder will have AIDS is not yet known.

Group B streptococcal arthritis in adults.

Group B streptococcal arthritis in adults is uncommon. This report describes seven cases seen at these institutions over the past five years and reviews the previous 17 documented cases. Of seven adults, three were diabetics, three had prosthetic hips, and one had undergone splenectomy. Six had undergone no prior dental, genitourinary, or gastrointestinal procedures. The most common clinical presentation was fever and acute joint pain. Five patients had monoarticular arthritis; two had multiple joint involvement. Underlying joint abnormalities included osteoarthritis (two), prosthetic hip (three), and neuropathic joint (one). Bacteremia was documented in three and suspected in the remaining four patients, often without a primary source. Therapy included parenteral antibiotics, usually penicillin G, and drainage of the involved joint. Two of three patients with prosthetic implants required Girdlestone procedures; the third was apparently cured. The three diabetic patients died, one with resolution of group B streptococcal arthritis. The seventh patient was cured. Group B streptococcal arthritis is a serious infection in adults with diabetes and late prosthetic hip infections.