John C. Pottage

Blastomycosis in Patients with the Acquired Immunodeficiency Syndrome

OBJECTIVE To describe the clinical, demographic, radiographic, diagnostic, and therapeutic aspects of blastomycosis in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN A retrospective survey. SETTING Ten university medical centers and community hospitals, six in geographic areas endemic for Blastomyces dermatitidis, and four outside the endemic area. PATIENTS We identified 15 patients with blastomycosis and positive serologic test results for human immunodeficiency virus (HIV). MEASUREMENTS A diagnosis of blastomycosis was based on a positive culture (14 patients) or typical histopathologic features (one patient) for B. dermatitidis in clinical specimens. RESULTS Twelve of 15 patients had a previous or concomitant AIDS-defining illness at the time of diagnosis of blastomycosis, and only one patient had a CD4 lymphocyte count of greater than 200 cells/mm3. Two patterns of disease emerged: localized pulmonary involvement (seven patients), and disseminated or extrapulmonary blastomycosis (eight patients). Central nervous system involvement was common (40%). Six patients died within 21 days of presentation with blastomycosis, including four patients with disseminated and two with fulminant pulmonary disease. Among the nine patients who survived longer than 1 month, all received amphotericin B as initial antifungal therapy, and most received subsequent therapy with ketoconazole. Only two of these nine patients died with evidence of progressive blastomycosis. CONCLUSIONS Blastomycosis is a late and frequently fatal infectious complication in a few patients with AIDS. In these patients, overwhelming disseminated disease including involvement of the central nervous system is common, and it is associated with a high early mortality. Initial therapy with amphotericin B is appropriate in patients with AIDS and presumptive blastomycosis.

Early reduction of immune activation in lymphoid tissue following highly active HIV therapy.

Objective:To evaluate immune reconstitution within HIV-infected lymphoid tissue during highly active antiretroviral therapy (HAART). Design and methods:In situ cellular responses were studied in sequential tonsillar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 × 106/l) antiretroviral treatment-naive volunteers enrolled in a clinical trial to determine the early effect of HAART. Computerized image analysis was used to study immunohistochemically stained sequential tonsil sections for the patterns of local cytokine production, chemokine receptor expression and cellular distribution. Replicate quantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation of drug effects and compared with four uninfected controls. Tonsillar HIV proviral-DNA was determined by fluorescent in situ 5′-nuclease assay. Results:HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine expression. A five- to 15-fold elevation of interleukin (IL)-1α, IL-12, IL-2 and interferon (IFN)-γ protein expression was found compared with controls, and each encompassed a mean of at least 4.5% of the tissue compartment. This was reduced by 20–90% in all individuals after 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, IL-10), plus tumour necrosis factor (TNF)-α, remained low throughout the study. HAART reduced, by 40%, the expression of HIV co-receptors, CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory proteins, CD68 and calprotectin, diminished by 26–83% after therapy. The HIV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2–7%), remained HIV DNA positive after 4 weeks of therapy. Conclusions:Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitution begins with a reduction in inflammatory cytokine production which precedes the elimination of local proviral reservoirs.

Immunologic and virologic evaluation after influenza vaccination of HIV-1-infected patients

Objective: The present study was designed to determine the effect of immune activation, achieved by influenza vaccination, on plasma HIV RNA levels and immunological parameters including CD4 cell levels, antigen‐stimulated T‐cell function and apoptotic death of peripheral blood mononuclear cells. Design and methods: Thirty‐four HIV‐infected individuals and nine uninfected controls were immunized with influenza vaccine and blood was collected at weeks 0, 2, 4 and 16. Plasma was isolated and used for HIV RNA and influenza‐specific antibody quantifications. CD4 cell counts, activation and maturation markers of T‐lymphocyte subsets were determined by flow cytometry. In vitro T‐helper responses, spontaneous‐ and activation‐induced cell death assays were also performed. Results: Influenza‐specific humoral and cellular immune responses correlated with CD4 count. Only in patients with CD4 counts > 300 × 106/l there was a modest increase in T‐cell responses to influenza virus, which was less than control subjects, observed after vaccination. Immunization had no significant effect on CD4 counts or plasma viral levels in the HIV‐positive patients. Baseline apoptosis inversely correlated with CD4 counts and directly correlated with viral load. Activation‐induced apoptosis did not change appreciably after vaccination and spontaneous apoptosis increased only in the < 300 CD4 group. Conclusion: These results indicate that immune stimulation resulting from influenza vaccination did not significantly change the levels of plasma virus, CD4 cell counts, or activation‐induced apoptosis in HIV‐infected individuals, although an increase in the T‐cell response to influenza and spontaneous apoptosis was observed in the > 300 and < 300 CD4 groups, respectively.

Maximum suppression of Hiv replication leads to the restoration of Hiv-specific responses in early Hiv disease

ObjectivesIt is predicted that HIV-infected individuals in early HIV disease are the most likely group to achieve immune reconstitution following highly active antiretroviral treatment. We assessed whether suppression of HIV replication in this group would improve immune function. MethodsSeventeen antiretroviral-naïve patients in early HIV disease were evaluated for immune function and lymphocyte phenotyping using standard immunological assays. ResultsAbsolute CD4+ T-cell number increased from a median of 550 to 800 × 106 cells/l while CD8+ T-cell numbers were reduced. The decrease in CD8+ cells correlated with a decrease in the CD8+ memory phenotype. Kinetics of CD4+ naïve and memory T-cell rise indicated that 80% of the maximum CD4+ naïve increase was achieved within 18 weeks whereas maximum CD4+ memory T-cell rise was achieved within 36 weeks. Activation markers (HLA-DR, CD38) and an apoptosis-related marker (CD95) were reduced on CD4+ and CD8+ T cells. Lymphocyte proliferation responses to tetanus toxoid, alloantigen, and anti-CD3/CD28 were restored in patients that were initially unresponsive. At baseline, 31% of the patients responded to HIV p24, which increased to 69% post-therapy. The inducible RANTES response was normalized following therapy whereas inducible interferon-γ, interleukin (IL)-12, and MIP1β were elevated. The depressed inducible IL-10 response, however, was not altered after therapy. ConclusionsThis is one of the first studies to demonstrate the restoration of HIV-1 specific responses in non-acute HIV infection, suggesting early intervention with potent antiretroviral therapy may reverse immune-mediated damage not seen with treated patients who have more advanced disease.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals : Selection of thymidine analog regimen therapy (START II)

ObjectiveComparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DesignRandomized, open-label. SettingFourteen HIV Clinical Research Centers. PatientsTwo-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts ⩾ 200 × 106/l and plasma HIV-1 RNA levels ⩾ 10 000 copies/ml. InterventionsStavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. Main outcome measuresThe proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and ⩽ 50 copies/ml and changes in CD4 cell counts were compared. ResultsIn an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7–30.3%;P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, −1.4% to 25.7%;P = 0.068). At 48 weeks 41% and 35% were ⩽ 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 × 106/l cells for the d4T arm and 106 × 106/l cells for the ZDV arm (P = 0.001). The occurrence of serious adverse events was not significantly different between arms. ConclusionThe combination of stavudine, ddI and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

CANDIDA KRUSEI FUNGEMIA : REPORT OF 4 CASES AND REVIEW OF THE LITERATURE

Candida krusei has recently been increasingly recognized as a pathogen in immunocompromised patients with malignancies. We report four immunocompromised patients with C. krusei fungemia and review the literature. Including our 4 cases, 62 cases of C. krusei fungemia were identified in the literature. Detailed information was available for only 25 patients. The clinical features of patients with C. krusei fungemia are similar to those reported for Candida tropicalis. Most patients were neutropenic and more than one half of the patients had received antifungal therapy and had evidence of gastrointestinal mucosal breakdown before the development of C. krusei fungemia. The overall mortality was 48%. Patients treated with regimens containing amphotericin B had improved survival over patients who received no therapy. Favorable response rates were higher in patients receiving high-dose amphotericin B or high-dose amphotericin B plus flucytosine when compared to patients treated with low-dose amphotericin B.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex

Zidovudine is a nucleoside analog that reduces progression of human immunodeficiency virus type 1 (HIV)-associated disease and prolongs survival [1-3]. The use of this drug at high doses in patients with advanced disease has been limited by hematologic toxicity [4-6]. Initial studies of another nucleoside analog, 2,3-dideoxycytidine (ddC), have shown that it is a potent inhibitor of HIV replication; therapy with ddC results in both the rapid suppression of serum p24 antigen levels and increases in CD4 cell counts [7, 8]. The principal dose-limiting toxicity of ddC is sensory peripheral neuropathy, which is related to both dose and duration of therapy [7-10]. Both zidovudine and ddC have been studied at lower doses to construct a tolerable monotherapy regimen [2, 6, 9, 11]. Alternating courses of zidovudine and ddC have been studied in an attempt to reduce dose-limiting toxicity. By limiting the continuous administration of each drug, the use of alternating therapy may allow any short-term toxicity from one drug to resolve during the administration of the other, and cumulative toxicity may be avoided. In addition to a reduction in toxicity, several other benefits of alternating therapy have been suggested. First, such combination therapy may have a synergistic or additive effect on virologic and immunologic markers; preliminary studies in vitro and in vivo suggest that alternating regimens have an enhanced antiretroviral effect [7, 12]. Concurrent zidovudine and ddC therapy has shown similar in vitro and in vivo effects and has recently been approved for use by the Food and Drug Administration [13, 14]. Second, it may be possible to maintain continuous high-dose therapy, thereby maximizing central nervous system concentrations. Third, in limiting the time of exposure to each drug, the sequential use of two agents may reduce or retard the emergence of drug-resistant isolates. We evaluated monthly and weekly alternating schedules of zidovudine and ddC to determine whether a reduction in toxicity or an enhanced antiretroviral effect, or both, could be achieved by this method of administration of the two agents. Intermittent zidovudine and ddC limbs were included to assess the relative contribution of each of the components to the overall effect. Continuous zidovudine, 1200 mg/d, served as the control treatment regimen. Methods Patients The study sample consisted of patients with AIDS-related complex or AIDS. We defined AIDS-related complex as the documented presence of one of the following: weight loss exceeding 15 pounds or 10% of body weight within 120 days before entry; a temperature greater than 38.5 C that persisted for more than 14 consecutive days or was documented on more than 15 days in a 30-day interval; diarrhea (three or more liquid stools per day) for at least 30 days without a definable cause; recurrent oral candidiasis; hairy leukoplakia; or a history of herpes zoster. We defined AIDS according to Centers for Disease Control criteria [15]. All study patients had circulating serum p24 antigen levels of 70 pg/mL or more on two occasions before enrollment. No restriction was placed on entry CD4 cell count. Patients were excluded from the study if they met any of the following criteria: a hemoglobin concentration of less than 95 g/L; transfusion dependence; an absolute granulocyte count less than 1.2 109/L; a platelet count less than 100 109/L; a calculated creatinine clearance rate of 50 mL/min per 1.73 m2 body surface area or less; transaminase levels 5 or more times the upper limit of normal; a Karnofsky performance score of less than 60; pregnancy or lactation; significant malabsorption; cardiac or liver disease; or AIDS-defining conditions requiring systemic maintenance chemotherapy. Patients with evidence of preexisting peripheral neuropathy and those who had had previous ddC treatment were also excluded. We encouraged all patients with less than 200 CD4 cells/mm3 to undergo aerosolized pentamidine prophylaxis (300 mg every month) for Pneumocystis carinii pneumonia. Study Design An unblinded, randomized trial (Protocol 047) was conducted at 12 AIDS Clinical Trials Units. Seven regimens were tested (Figure 1). At the time the study began, the standard zidovudine dose was 200 mg every 4 hours. Figure 1. The seven treatment regimens. Randomization was stratified by center and according to CD4 cell count (> 200 cells/mm3 or 200 cells/mm3). At least 16 patients were assigned to each limb. Patients who did not complete the first 8 weeks of therapy for any reason other than toxicity were replaced. All study patients gave informed consent and institutional review board approval was obtained at each institution. Study medication was to be administered for up to 49 weeks, with an additional follow-up period of 3 weeks. Study patients being treated with an intermittent regimen who had less than a 50% reduction in the serum p24 antigen level at 6 months had the option to change to an alternating regimen. Patients who completed 49 weeks of therapy and showed evidence of a beneficial response (defined as a 50% reduction in p24 antigen level or an improvement in CD4 cell count) had the option to continue therapy past 52 weeks. For the present analyses, only the first 48 weeks of data were used. Patient Evaluation Pretreatment evaluations included a medical history, physical examination, weight measurement, Karnofsky score, complete blood count, hepatic and renal function studies, T-cell subset analysis, and serum p24 antigen determination (Abbott Laboratories, North Chicago, Illinois). Follow-up evaluation was done weekly for the first 8 weeks and every 4 weeks thereafter. Serum specimens for p24 antigen determination were collected weekly for the first 8 weeks and then 3 of every 4 weeks thereafter. An evaluation for peripheral neuropathy was done on enrollment and was repeated as follows: neuropathy symptom questionnaire every 2 weeks, peripheral neurologic examination every 4 weeks, and quantitative sensory testing of vibration every 8 weeks [10]. Signs or symptoms suggestive of opportunistic infection or malignancy were evaluated according to standard AIDS Clinical Trials Group guidelines [15]. Hematologic toxicity for patients being treated with a zidovudine-containing regimen was defined and managed as follows: Transfusion was allowed for symptomatic grade 2 anemia (hemoglobin, 80 to 94 g/L) and for grade 3 (hemoglobin, 65 to 79 g/L) or grade 4 anemia (hemoglobin < 65 g/L). Study drug dosage was reduced or held in cases of grade 3 or 4 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; or in cases of grade 3 (granulocyte count, 500 to 750; leukocyte count < 1.5 109/L) or grade 4 (granulocyte count >500, leukocyte count < 1.0 109/L) granulocyte-leukocyte toxicity. Patients were removed from the study if they developed grade 3 or 4 anemia or granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred. Patients treated with intermittent ddC were removed from the study for the following reasons: a first episode of grade 3 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; grade 3 granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred; or a first episode of grade 4 anemia or granulocyte-leukocyte toxicity. Dose-limiting peripheral neuropathy was defined by the occurrence of bilateral burning or shooting pains in the lower extremities that were of moderate (grade 2) intensity and persisted for 72 hours or more; a symptom of severe (grade 3) intensity of any duration; or a symptom of moderate intensity of any duration plus either a supporting abnormality in the affected limb on standardized peripheral nerve examination or a supporting abnormality in the affected limb on quantitative sensory testing. Statistical Analysis Data from all enrolled patients were used in the analyses; however, data collected beyond the point at which patients switched from their initially assigned therapy were not included in the analysis. The Fisher exact test and chi-square tests were used to compare subgroups when the data were discrete [16] and Wilcoxon-Mann-Whitney tests were used for continuous data [17]. The Kaplan-Meier method and log-rank tests were used to analyze time-to-event data [18]. All P values were two-sided. The area under the curve (AUC) of absolute CD4 cells/mm3 was calculated, and the resulting total area was divided by time on therapy (T) to derive AUC/T [19]. The baseline CD4 count was subtracted from AUC/T to obtain the average change in CD4 cell count from baseline. A linear regression model was then calculated, with the average change in CD4 cell count as the dependent variable and both the baseline CD4 cell count and the assigned treatment limb as the independent variables. Results Patients One hundred thirty-one patients were enrolled in the study between 24 June 1988 and 17 October 1989 (Table 1). Most patients were male (96%) and white (76%) and had not received zidovudine within 90 days of study entry (96%). Seventy-seven percent had AIDS-related complex and 23% had AIDS. The median CD4 cell count at entry was 142 cells/mm3, and the median serum p24 antigen level was 257 pg/mL. Table 1. Patient Characteristics at Study Entry* The median follow-up for the entire study group was 40 weeks. Fifty-nine patients (45%) completed 48 weeks of therapy (Table 2). Twenty patients were withdrawn from the study because of toxicity related to ddC or zidovudine. Twenty-eight patients were removed because of AIDS-related opportunistic infection, malignancy, or dementia; 13 of these patients were removed from the study before completing 8 weeks of therapy. These 13 patientsalong with 4 patients who voluntarily withdrew from the study, were lost to follow-up, or were removed from the study for protocol violations in the first 8 weekswere

Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy.

&NA;Although significant progress has been made in understanding immune reconstitution in peripheral blood following highly active antiretroviral therapy (HAART), less is known about immune changes in lymphoid tissue. Here, the expression of cytokine proteins (interferon gamma [IFN‐&ggr;], interleukin [IL]‐2, IL‐4, IL‐10, IL‐1&agr;, and IL‐1&bgr;) and surface antigens (CD4, CD8, CD1a, CD68) as well as cellular proviral HIV‐1 DNA were determined in sequential tonsil biopsies before and at 4, 12, and 48 to 56 weeks posttherapy by quantitative in situ image analysis and fluorescent in situ 5′‐nuclease assay (FISNA). Despite plasma virus suppression, a fraction of tonsil cells harbored pro‐viral DNA for up to 1 year. A fourfold to eightfold increase in CD8+ T cells in tissue compared with seronegative controls and an increased frequency of CD1a+ dendritic cells prior to HAART reached control levels at week 56. The frequency of IFN‐&ggr; expressing cells was 10‐ to 15‐fold higher than controls before therapy and was comparable with findings in seronegative controls by week 56. Elevated baseline expression of IL‐1&agr; and IL‐1&bgr; was reduced by week 4 but IL‐1&agr; levels remained elevated in 1 of 3 patients at week 56. These findings suggest that with effective viral suppression the immune system in tissue may return to a more resting state.

Recombinant interferon alpha-2a for treatment of herpes zoster in immunosuppressed patients with cancer

PURPOSE Acyclovir and high doses of intramuscular leukocyte interferon have been shown to prevent dissemination of herpes zoster in cancer patients with localized herpes zoster. With the availability of recombinant interferon, we decided to conduct a multicenter, placebo-controlled, double-blind trial of intramuscular recombinant interferon alpha-2a to assess its efficacy and safety in the treatment of localized herpes zoster in immunosuppressed patients with cancer. PATIENTS AND METHODS Immunosuppressed cancer patients with localized herpes zoster were randomly assigned to receive placebo, 36 X 10(6) units of recombinant interferon alpha-2a per day, or 68 X 10(6) units of recombinant interferon alpha-2a per day. Due to frequent adverse effects, the 68 X 10(6) unit dose of interferon was discontinued prior to conclusion of the trial. RESULTS Dissemination of herpes zoster occurred in 14 of the 24 patients (58 percent) who received placebo but in only four of 24 recipients (17 percent) of 36 X 10(6) units of interferon per day (p = 0.003). Adverse effects (fever, chills, headaches, gastrointestinal irritability, fatigue, and myalgias) were more common or severe in interferon-treated patients. CONCLUSION These results suggest that interferon modifies the severity of herpes zoster in immunosuppressed patients with cancer but is associated with frequent side effects.

HIV infection in women: an observational study of clinical characteristics, disease progression, and survival for a cohort of women in Chicago.

To further characterize the natural history of HIV infection in women in the antiretroviral era, we performed a longitudinal, descriptive analysis of demographic features, clinical characteristics, patterns of antiretroviral and prophylactic therapy, disease progression, and survival in a cohort of women followed at a university medical center from 1986 to 1992. Eighty-two women (39 white [non-Hispanic], 33 African-American, 10 Hispanic) were followed for a median of 13 months (range 3-61 months). Sixty-two women received antiretroviral therapy, 34 through participation in a clinical trial. Candida esophagitis and Pneumocystis carinii pneumonia were the most common AIDS-defining conditions, accounting for 77% of all initial AIDS-defining diagnoses. Gynecologic complications affected 34 women (41%) and included recurrent Candida vaginitis in 26, abnormal PAP smears/cervical intraepithelial neoplasia in 10, and recurrent genital herpes simplex virus disease in seven. Median survival (Kaplan-Meier) from the time of HIV serodiagnosis was > 59 months; median survival following an AIDS diagnosis was 27 months. No survival differences were detected based on race, insurance status, or mode of HIV transmission. Women who participated in antiretroviral therapy clinical trials had a statistically significantly longer duration of survival compared with nonparticipants. Candida infections and gynecologic diseases were common in this population. Overall survival was similar to that reported for men.