Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

Quantification of human immunodeficiency virus type 1 RNA levels in plasma by using small-volume-format branched-DNA assays.

We have developed small-volume (50 or 250 microl)-format branched-DNA assays for human immunodeficiency virus type 1 (HIV-1) RNA for use with specimens in which the volume is limited and/or a high viral load is anticipated. These formats exhibited good correlation with the standard 1-ml format; high specificity, reproducibility, and linearity; and no significant difference in the quantification of HIV-1 subtypes.

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients.

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.

Quantification of cytomegalovirus DNA in peripheral blood leukocytes by a branched-DNA signal amplification assay.

Quantification of cytomegalovirus (CMV) DNA in blood may aid in the identification of patients at highest risk for developing CMV disease, the evaluation of new therapeutics, and the prompt recognition of drug-resistant CMV strains. A branched-DNA (bDNA) assay was developed for the reliable quantification of CMV DNA in peripheral blood leukocytes. The bDNA assay allowed for the highly specific and reproducible quantification of CMV DNA in clinical specimens. Furthermore, the bDNA assay was at least as sensitive as culture techniques and displayed a nearly 3 log10 dynamic range in quantification. Changes in CMV DNA levels measured by the bDNA assay in a human immunodeficiency virus-positive patient undergoing therapy were consistent with CMV culture, antigen, and genotype results and correlated with disease progression and resistance markers. The bDNA assay for the quantification of CMV DNA may provide a useful tool that can be used to aid physicians in monitoring disease progression, evaluating therapeutic regimens, and recognizing viral resistance and drug failure.

Variance of plasma human immunodeficiency virus type 1 RNA levels measured by branched DNA within and between days.

Previous studies have shown that CD4-positive T cells vary in a predictable manner over 24 h. This diurnal variance has significant clinical implications. Recently, viral RNA measurements have been increasingly used as a standard marker in the management of human immunodeficiency virus (HIV)-infected patients. Little detailed analysis of the variability of this marker has been conducted. To define the variance of plasma HIV-1 RNA levels within days, 11 clinically stable patients with established HIV infection and a baseline viral RNA level >40,000 copies/mL were studied. Following the patients' admission to an inpatient research unit, plasma samples were obtained frequently over 48 h and analyzed for HIV-1 RNA levels by use of a quantitative branched chain DNA assay (bDNA). No diurnal pattern was detected. In these clinically stable patients, viral RNA levels exhibited a variance of approximately 0.4 log.

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 qualifications. 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 x 10(6)/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.

Oral histoplasmosis in HIV-infected patients. A report of two cases.

Histoplasmosis is a fungal infection caused by the organism Histoplasma capsulatum. Disseminated disease usually occurs in immunosuppressed patients or in patients with chronic illnesses. Although relatively uncommon, histoplasmosis has been reported in patients with AIDS, and oral lesions have been noted on multiple sites and in various clinical presentations. We present two HIV-positive cases with oral lesions as the initial signs of histoplasmosis. Both patients responded well to IV amphotericin B but later suffered recurrences despite being maintained on systemic antifungal therapy.

Upper and middle lobe bronchoalveolar lavage to diagnose Pneumocystis carinii pneumonia.

Pneumocystis carinii pneumonia (PCP) remains the most common lethal opportunistic pulmonary infection in patients infected with the human immunodeficiency virus (HIV). Although the use of prophylactic inhaled pentamidine has effectively reduced the frequency of primary and recurrent episodes of PCP, the aerosolization of pentamidine may have altered the localization of active PCP, resulting in more upper lobe disease. The distribution of disease may have also affected the diagnostic accuracy of standard bronchoalveolar lavage of the middle lobe, with a reduction in sensitivity from about 90 to 65%. In retrospective surveys of patients from our institution, Steiger and Fahy found that pooled multiple-lobe radiographic site-directed bronchoalveolar lavage resulted in diagnostic sensitivities of 91 and 100%, respectively. We performed a follow-up prospective study of 38 consecutive patients on aerosolized pentamidine in whom we lavaged both the middle lobe and an upper lobe. We found that bilobar lavage including routine lavage of an upper lobe increases the diagnostic sensitivity of bronchoalveolar lavage alone to 95% compared with 65% if lavage is performed only in the middle lobe (p < 0.05). Radiographic studies demonstrate a concordant increase in exclusive or predominant upper lobe disease in patients on aerosolized pentamidine, but our results indicate that PCP is recovered more frequently from the upper lobe regardless of the radiographic appearance. We conclude that all patients on prophylactic inhaled pentamidine should undergo bilobar lavage with the inclusion of an upper lobe in the initial evaluation of possible PCP. The diagnostic sensitivity of 95% makes bilobar bronchoalveolar lavage an acceptable sole initial diagnostic modality without the need for initial transbronchial lung biopsy.

A randomized comparison of once-monthly or twice-monthly high-dose aerosolized pentamidine prophylaxis.

RESULTS: Ten of the 146 (7 percent) evaluable subjects developed PCP during the year study period, and there was no difference in the efficacy of the two regimens. Among patients receiving secondary prophylaxis, the attack rate of PCP at 1 year was 11 percent. This compares favorably with a 1-year attack rate of 19 percent in similar patients receiving standard dose (300 mg) prophylaxis and suggests, but does not prove, a dose-response effect. Concentrations of pentamidine in BAL fluid were not significantly different among the three lobes of the lung. Intrapulmonary pentamidine did not accumulate during the year of study. Aerosolized pentamidine was associated with a marginal but statistically significant increase in the residual volume, decreased flow rates, and increased airway reactivity. OBJECTIVE: The optimal regimen of aerosolized pentamidine in unknown. Published data suggest that there is a dose-response effect and that the occurrence of Pneumocystis carinii pneumonia (PCP) has been associated with prolongation of the interval between doses. The purpose of this study was to compare the efficacy, pharmacokinetics, and physiologic effects of two high-dose regimens of aerosolized pentamidine prophylaxis. DESIGN: Prospective, randomized study of 300 mg twice monthly vs 600 mg once monthly during a 1-year observation period. Pentamidine concentrations in plasma and bronchoalveolar lavage (BAL) fluid were measured and serial pulmonary function was measured. SETTING: A large teaching hospital in San Francisco. PATIENTS: One hundred fifty-one adult (age > 18 years) men with human immunodeficiency virus infection. Of 146 evaluable patients, prophylaxis was primary (no prior PCP) in 108 (75 percent) and secondary (one prior episode of PCP) in 38 (25 percent). MEASUREMENTS: Date and diagnosis of PCP, occurrence of drug toxicity, pulmonary function testing, and concentrations of pentamidine in BAL and plasma. CONCLUSIONS: The data suggest, but do not prove, that a dose-response effect has been demonstrated, and that high-dose aerosolized pentamidine may further reduce the attack rate of PCP. These preliminary observations should be confirmed in a double-blind trial comparing 300 mg with 600 mg administered once monthly. The clinical relevance of the adverse pulmonary effects is unclear and requires further investigation.

Elevated serum concentrations of IgE antibodies to environmental antigens in HIV-seropositive male homosexuals.

Forty-five homosexual male subjects with human immunodeficiency virus (HIV) infection, who received care during a 4-month period in an ambulatory center for acquired immunodeficiency syndrome (AIDS), were classified according to their principal presentation with characteristic secondary infections (CDC group IV C, N = 28), cancers (IV D, N = 10), or limited or no symptoms (groups II, III, IV A, or IV B, N = 7). The incidence of allergic rhinitis and conjunctivitis increased after HIV seroconversion by approximately twofold in patients of groups IV C and IV D. The mean serum concentration of IgE was significantly higher for group IV C than for the other HIV-seropositive groups and for a control group of 45 HIV-seronegative homosexual male subjects from the same community who were studied concurrently. More patients in groups IV C and IV D had positive RASTs for a panel of environmental antigens than patients in the other HIV-seropositive groups and the HIV-seronegative control group. Patients with AIDS presenting with typical secondary infections thus have a high frequency of some clinical and laboratory manifestations of allergic diseases.

Long latency event-related potentials in patients infected with human immunodeficiency virus.

Long latency auditory evoked potentials were recorded in 55 homosexual men infected with human immunodeficiency virus (HIV). Forty-one of these patients were asymptomatic from the infection and 14 had clinical signs of illness. Nine of the symptomatic patients were demented and 8 (6 of whom were demented) met other diagnostic criteria for acquired immunodeficiency syndrome (AIDS). Cerebral responses were recorded from Fz, Cz, and Pz electrode placements referred to linked mastoids and averaged separately to rare (2,000 Hz) and frequent (1,000 Hz) tones presented in a pseudorandom sequence. Electroencephalography (EEG) was performed in 54 of the patients and magnetic resonance imaging (MRI) or computed tomography (CT) was done in 14 (13 of whom were symptomatic from the infection). The latency of N1, P2, N2, and P3 components was delayed in HIV-positive patients compared to normal and this was particularly so for the N1, N2, and P3 components. These changes were more marked in those patients who were symptomatic from their infection, especially in those who were demented. They were, however, present to a lesser degree even in asymptomatic (Class II) patients. Thus, 78% of the demented patients and 28% of nondemented patients had a delay in latency of at least one of the evoked potential components beyond the upper limit of our normal population. By contrast, the EEG was normal in all patients with asymptomatic HIV infection and most symptomatic patients, although 5 patients in this latter group had mild generalized slowing. MRI and CT findings were similarly nonspecific, particularly in the nondemented group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study.

To determine the prevalence of cardiac abnormalities in patients with human immunodeficiency virus (HIV) infection, two-dimensional Doppler echocardiography was performed on 70 consecutive patients with HIV infection, including 51 with acquired immunodeficiency syndrome (AIDS), 13 with AIDS-related complex and 6 with asymptomatic HIV infection. Of the 70 patients, 36% were hospitalized and 64% were ambulatory at the time of evaluation. The average age was 37 years; 93% were homosexual men. Echocardiographic findings included dilated cardiomyopathy in eight patients (11%), pericardial effusions in seven patients (10%) (one with impending tamponade), pleural effusion in four patients (6%) and mediastinal mass in one patient (1%). Among the 25 hospitalized patients, echocardiographic abnormalities were noted in 16 (64%), whereas among the 45 ambulatory patients, the only abnormality noted was mitral valve prolapse in 3 patients (7%) (p less than 0.0001). Dilated cardiomyopathy was the only echocardiographic lesion more common in the 25 hospitalized patients than in 20 hospitalized control patients with acute leukemia. Symptoms of congestive heart failure responded to conventional therapy. Cardiac lesions were associated with active Pneumocystis carinii pneumonia and low T helper lymphocyte counts. Dilated cardiomyopathy of unknown origin may be more common than was previously recognized in hospitalized, acutely ill patients with AIDS, but is uncommon in ambulatory patients with HIV infection. Echocardiography should be considered in the evaluation of dyspnea in hospitalized patients with HIV infection, especially those with dyspnea that is out of proportion to the degree of pulmonary disease.