Pegylated interferon-alpha 2a treatment of chronic SIV-infected macaques.

BACKGROUND: In vitro and clinical observations in HIV-infected patients receiving interferon alpha therapy have shown a reduction in HIV loads. Limited investigations have explored the innate or adaptive immune responses of IFN-alpha on SIV replication in vivo. METHODS: Seven chronically infected rhesus macaques were given pegylated IFN-alpha 2a (n = four) or saline (n = three) injections once weekly for 14 weeks. Weekly peripheral blood samples were taken for safety parameters, viral load determinations, and measurements of innate and adaptive immune responses. RESULTS: Pharmacokinetic measurements demonstrated therapeutic peg-IFN-alpha levels for the initial period of therapy and IFN-alpha inducible antiviral molecules were increased sporadically in the PBMC mRNA of the treatment group. Despite the demonstrable effect of the IFN-alpha injections, the treatment had no effect on plasma viral RNA levels. CONCLUSIONS: This work demonstrates that while short term IFN-alpha therapy induces innate antiviral immunity, it does not dramatically enhance or suppress viral replication. However, studies in the SIV model to determine therapeutic potential of chronic IFN-alpha therapy for the treatment of HIV will require macaque specific cytokines.

Low sensitivity of T-cell based detection of tuberculosis among HIV co-infected Tanzanian in-patients.

OBJECTIVE: To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection. DESIGN: Cross-sectional study. SETTING: Two hospitals in Northern Tanzania. SUBJECTS: Eighty three adult male and female inpatients. INTERVENTION: All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG. RESULTS: Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95% CI 12%-34%) of 54 HIV-uninfected and 13 (45%; 95% CI 26%-64%) of 29 HIV-infected subjects (p = 0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95% CI 91%-100%) of 40 HIV-uninfected subjects compared with seven (54%; 95% CI 25%-81%) of 13 HIV-infected subjects (p < 0.0001), and QFTG was positive in 28 (70%; 95% CI 53%-83%) of 40 HIV-uninfected subjects compared with three (23%; 95% CI 5%-54%) of 13 HIV-infected subjects (p = 0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in seven (50%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.0701) and QFTG was positive among two (14%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.7437). CONCLUSIONS: The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p < 0.0001) and QFTG (p = 0.0029) for the diagnosis of active M. tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.

Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy.

OBJECTIVE: To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117). METHODS: A total of 101 HIV-infected adults, with CD4 cell count <300 cells/mm(3) and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored. RESULTS: ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p < 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p = 0.01) and Visual Analogue Scale (VAS) (p = 0.01), sural SNAP amplitude (p < 0.01), and toe cooling (p < 0.01) and vibration (p = 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load. CONCLUSIONS: In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.

HIV neuropathy natural history cohort study: assessment measures and risk factors.

BACKGROUND: Distal sensory polyneuropathy (DSP) is the most common neurologic complication of human immunodeficiency virus (HIV) infection. Risk factors for DSP have not been adequately defined in the era of highly active antiretroviral therapy. METHODS: The authors evaluated 101 subjects with advanced HIV infection over 48 weeks. Assessments included a brief peripheral neuropathy (PN) screen (BPNS), neurologic examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsies with quantitation of epidermal nerve fiber density. Data were summed into a Total Neuropathy Score (TNS). The presence, severity, and progression of DSP were related to clinical and laboratory results. RESULTS: The mean TNS (range 0 to 36) was 8.9, with 38% of subjects classified as PN-free, 10% classified as having asymptomatic DSP, and 52% classified as having symptomatic DSP. Progression in TNS from baseline to week 48 occurred only in the PN-free group at baseline (mean TNS change = 1.16 +/- 2.76, p = 0.03). Factors associated with progression in TNS were lower current TNS, distal epidermal denervation, and white race. As compared with the TNS diagnosis of PN at baseline, the BPNS had a sensitivity of 34.9% and a specificity of 89.5%. CONCLUSIONS: In this cohort of advanced human immunodeficiency virus (HIV)-infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

Hydroxyurea in combination with didanosine and stavudine in antiretroviral-experienced HIV-infected subjects with a review of the literature.

The safety and efficacy of hydroxyurea with didanosine in combination with stavudine in nucleoside reverse-transcriptase inhibitor (NRTI)-experienced patients was investigated. Entry criteria included HIV-1 infected, NRTI-experienced adults, with CD4(+) counts 50-550 cells/mm(3) and viral loads >or=12,500 copies/mL. Subjects were treated with didanosine 200 mg twice a day (BID), stavudine 40 mg BID, and hydroxyurea 1000 mg daily for 16 weeks. Thirty-one HIV-1 subjects with mean bDNA viral load 1x10(5) log(10) copies/mL and mean CD4(+) T-cell counts of 231 cells/mm(3) were enrolled. A 1.3 log(10) decrease in mean viral load was seen at 12 weeks of therapy. Prior didanosine use resulted in a more rapid response to therapy compared with prior zidovudine use. Side effects consisting of neutropenia, pancreatitis, and peripheral neuropathy occurred in four subjects and resolved upon withdrawal of therapy. This non-randomized study in subjects with a mean CD4(+) T-cell count of 230 cells/mm(3) demonstrates the antiviral activity of hydroxyurea+didanosine and stavudine. Toxicities related to therapy need to be followed closely. The results support the need for a randomized, prospective study to determine the safety and efficacy of hydroxyurea plus didanosine in antiretroviral-experienced patients with CD4(+) cell counts below 300 cells/mm(3).

Leukocyte-reduced red blood cell transfusions in patients with anemia and human immunodeficiency virus infection: the Viral Activation Transfusion Study: a randomized controlled trial.

CONTEXT: Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs). OBJECTIVE: To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients. DESIGN AND SETTING: Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors). PATIENTS: A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion). MAIN OUTCOME MEASURES: Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion. RESULTS: At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels. CONCLUSIONS: We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.

Changing patterns of infections in patients with AIDS: a study of 279 autopsies of prison inmates and nonincarcerated patients at a university hospital in eastern Texas, 1984-1993.

Reports on autopsies of 279 persons infected with human immunodeficiency virus (HIV) were reviewed retrospectively to determine changes in survival rates and infections and to identify differences between prison inmates and nonincarcerated patients. The 78 cases from 1984 through 1988 were compared with 201 from 1989 through 1993, on the basis of use of antiretroviral therapy and (after 1988) prophylaxis against Pneumocystis carinii pneumonia (PCP). Risk factors for HIV infection were homosexuality/bisexuality (30%), injection drug use (IDU; 22%), transfusion (5%), heterosexual contact (4%), and combinations of the above or unknown factors (38%); 95% of patients were males and 41% were state prison inmates in Texas. IDU was more common and homosexuality/ bisexuality was less common among inmates than among nonincarcerated patients. Mean survival time was 12 months in the first period studied and 23 months in the later period (P < .05). Cytomegalovirus infection was the most common type in both periods. The number of cases of PCP declined and the number of cases of bacterial infections increased significantly in the later period. Tuberculosis was significantly more common in inmates than in nonincarcerated patients. Tuberculosis and disseminated histoplasmosis (noted at autopsy) and deaths due to disseminated Mycobacterium avium complex and histoplasmosis were significantly more common among injection drug users than among homosexuals/bisexuals. Invasive candidiasis was more common in homosexuals/ bisexuals and in those who survived > 3 years. Antiretroviral therapy, prophylaxis for PCP, and risk factors for HIV infection appear to influence the mortality rate and prevalence of certain infections found at autopsy.

Effects of Clostridium perfringens recombinant and crude phospholipase C and theta-toxin on rabbit hemodynamic parameters.

Clostridium perfringens exotoxins have been implicated as major virulence factors responsible for shock and organ failure in gas gangrene, yet the mechanism(s) by which they mediate cardiovascular dysfunction remain enigmatic. Recombinant (r) phospholipase C (PLC), r theta-toxin, culture supernatant (crude toxin), or 0.9% NaCl was infused intravenously into awake rabbits. Cardiac index (CI), mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), arterial blood gases, and hematocrit were measured 1 h before and for 3 h after toxin infusion. Crude toxin and rPLC decreased CI, MAP, and HR and increased CVP; mortality was 87.5% and 83%, respectively. r theta-toxin did not decrease CI or MAP and mortality was 25%. Further, crude toxin and rPLC but not r theta-toxin inhibited cardiac contractility (dF/dt) in isolated rabbit atrial muscles. These results suggest that PLC-induced myocardial dysfunction contributes to shock in C. perfringens infection.

Clinical features of microsporidiosis in patients with AIDS.

Microsporidia are protozoan parasites responsible for significant gastrointestinal disease in patients infected with human immunodeficiency virus. We report the clinical features of 20 patients with chronic diarrhea for whom microsporidian spores were identified by modified trichrome staining of stool smears and confirmed by biopsy and/or electron microscopy of stool. Of the 18 microsporidian protozoa identified to the species level, 14 (78%) were Enterocytozoon bieneusi and four (22%) were Septata intestinalis. The mean CD4 count in these patients was 35 +/- 29 cells/mm3. Parameters of absorption, specifically absorption of fat and D-xylose, and levels of zinc were strikingly abnormal in patients who were tested. Treatment with albendazole led to clinical responses in six of 10 patients, and dietary manipulation resulted in clinical improvement in eight of nine patients. We recommended that patients with chronic, intermittent diarrhea and CD4 counts of < 100 cells/mm3 be further evaluated for microsporidia by modified trichrome staining of stool and light and electron microscopy of small bowel biopsy specimens. Antiprotozoal therapies are currently experimental, but some patients who have been treated with these therapies have dramatic responses. We also recommend that special attention be paid to the measurement of parameters of absorption with appropriate modification of diet.

Physiological effects of HIV infection on human intestinal epithelial cells: an in vitro model for HIV enteropathy.

OBJECTIVES: To determine the role of direct infection of intestinal cells with HIV-1 in the pathogenesis of HIV-related enteropathy. METHODS: We infected HT-29-18-C1 intestinal cells with the IIIB strain of HIV and examined the physiologic effects of enterocyte function. Dipeptidase-IV, aminopeptidase-N, gamma glutamic transferase, and alkaline phosphatase were measured in HIV-infected and control cultures. The cellular second messengers intracellular calcium and cyclic adenosine monophosphate were also measured in infected and control cultures. RESULTS: A persistent infection was established for > 95 days with peak supernatant reverse transcriptase and HIV p24 antigen levels of 5.17 log10 c.p.m./ml and 45 ng/ml, respectively. Brush-border enzyme activity (nmol of product/min/mg protein) tended to be lower in infected cell cultures compared with controls early in infection (P < 0.02). Baseline second messenger concentrations were similar but infected cultures responded to stimulation with a calcium ionophore with an exaggerated increase in intracellular calcium (P = 0.03). CONCLUSIONS: These results suggest that absorptive and secretory function of enterocytes may be altered by direct HIV infection and that additional physiologic experiments with this in vitro model may lead to a better understanding of the clinical syndrome of HIV enteropathy.