Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals

Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.     

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.     

Identification of human immunodeficiency virus-infected individuals by delayed type hypersensitivity skin testing

This article presents issues surrounding nursing research, education, and practice as they relate to the changing demographics in American society. The authors suggest that cultural diversity should be a key element in all components of nursing. They present challenges to nurse researchers, educators, and practitioners regarding the essential need to be sensitive about cultural diversity. They further suggest that the 21st century will emerge with demographic shifts that include larger groups of ethnic individuals and families. These ethnic groups will be both care providers and recipients of care. Recommendations are suggested to prepare for diversity in America health care systems.     

Highly active antiretroviral therapy decreases the incidence of bacteremia in human immunodeficiency virus-infected individuals

Dandruff is a clinical alteration of the skin that consists histologically of orthokeratotic clumps with minute parakeratotic foci found in inflammatory pathologies such as seborrheic dermatitis and psoriasis. Therefore, some nucleated cells should be found in dandruff and hence there is a possibility that forensically typeable DNA could be extracted from dandruff. Because of a particular case in which we were involved, a study was carried out to determine whether or not DNA could be extracted from dandruff, and if the two most widely used extraction techniques (Chelex and organic) would be applicable. Results show that sufficient quantities of DNA (more than 30 to 40 ng) can be obtained from as little as 1.0 to 1.5 mg of dandruff. Both methods yield DNA, although the organic procedure seems to yield more (72.5 ng Chelex vs. 183.3 ng organic). All the DNA samples extracted were typed correctly for the loci HUMTH01 and HUMvWA. Therefore, dandruff can be considered a potential source of DNA for forensic identification.     

Cancers in human immunodeficiency virus-infected children

Although the exact incidence of cancers in human immunodeficiency virus (HIV)-infected children is not clear, an excess of non-Hodgkin's lymphomas and soft tissue tumors as well as a multitude of otherwise rare tumors in childhood, such as cervical, thyroid, or pulmonary carcinoma, has been reported. In contrast to the findings in HIV-infected adults, Kaposi's sarcoma is rare in children in industrialized countries but not in children living in the sub-Saharan area. Treatment of the neoplastic disease is often complicated by multiple HIV-associated organ dysfunctions as well as drug interactions and infectious complications secondary to severe immunosuppression. Nonetheless, preliminary results with dose-intensive, but brief, chemotherapeutic regimens have been encouraging, and HIV-infected children who develop cancer are likely to benefit from aggressive treatment combined with adequate supportive care. Furthermore, insights gained from the study and treatment of this very challenging group of patients may benefit other immunocompromised hosts as well as increase our understanding of oncogenesis in general.     

Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men

Herpes simplex virus (HSV) infection is common in persons coinfected with human immunodeficiency virus (HIV). In a prospective study, daily viral cultures of the mouth, genitals, and rectum were collected from 68 HIV-positive and 13 HIV-negative men who have sex with men. Subjects completed a median of 57 days of follow-up. Anogenital HSV-2 cultures were positive on 405 (9.7%) of 4167 days for HIV-positive men and on 24 (3.1%) of 766 days for HIV-negative men. Most reactivations were perirectal and subclinical. Risk factors for increased HSV-2 shedding among HIV-positive men were low CD4 cell count (odds ratio, 2.5; 95% confidence interval, 1.2-5.4) and antibodies to both HSV-1 and HSV-2 versus HSV-2 only (odds ratio, 1.9; 95% confidence interval, 1.0-3.7). Three isolates obtained from 3 separate subjects were resistant to acyclovir. Thus, subclinical HSV-2 reactivation is an important opportunistic infection in persons with HIV infection. Further studies are necessaryto determine the impact of subclinical HSV-2 reactivation on the natural history of HIV infection.     

Syphilitic uveitis in human immunodeficiency virus-infected patients

Congenital cystic adenomatoid malformation of the lung (CCAM) is characterized by an adenomatoid proliferation of bronchiole-like structures and cysts formation. The condition is most commonly found in newborns and children and it may be associated with other malformations; rarely, the presentation is delayed until adulthood. This paper presents a case of CCAM in a 62-year-old male, who presented with recurrent bacterial pneumonias and breathlessness one exertion. The chest X-rays and CT scan revealed a patchy opacity in the right lower pulmonary zone. Bronchoscopic examination was normal. At surgery, a mass involving the right lower and middle lobes, and enlargement of hilar lymph nodes were found. A bilobectomy was performed without complications. Examination of the gross specimen showed a lesion characterised by multiple small cysts, all less than 1 cm in diameter; they were lined predominately by columnar epithelium, occasionally by ciliated epithelium. Rare cysts were lined by foreign body giant cells. Elastic fibers and smooth muscle were present within the cysts wall. Peripherally, there were normal alveoli and bronchioli mixed with cysts, and plasmalymphocytic infiltrates. The final diagnosis was Stocker's Type II CCAM of the lung. CCAM of the lung is a rare development lesion of the lung and it has no sexual predilection. It is usually unilateral and sublobar or lobar in size, but occasionally it can be multilobar. Typical histologic feature of CCAM are adenomatoid proliferation of bronchiole-like structures and macro- or microcysts lined by columnar or cuboidal epithelium and absence of cartilage and bronchial glands. Inflammatory changes are not found in infants, but may be present in adult patients. Based on the size of the cysts, CCAM may be classified into three different types: type I characterised by multiple cysts, over than 1 cm in diameter; type II with smaller cysts, less than 1 cm in diameter; type III that shows solid lesions composed of bronchiole-like structures. Type II is commonly found in childhood, but is occasionally seen in adult patients, as that one in our report. The insult probably occurs between 4th and 7th week of fetal life. The etiologic agent is unknown. The histologic diagnosis of CCAM is difficult in adult patient, perhaps because of supervening infections that sometimes distort the underlying diagnostic pathologic appearances and make them difficult to recognise, as happened in our case. From the clinical point of view, most of the lesions cause severe respiratory failure; in adult individuals the diagnosis is difficult, since there are very few relevant symptoms and signs. The patients can present with fever, recurrent infections, breathlessness and haemoptysis. The chest X-rays abnormalities are not specific and include homogeneous or multicystic opacities. Similarly, other diagnostic methods add no further useful informations. Surgical treatment is necessary also in adult patients, because of the risk of recurrent pulmonary infections and malignancies associated with CCAM. Lobectomy is the treatment of choice, but sometimes a larger resection is required, when the lesion involves more than one lobe.     

Management of cervical neoplasia in human immunodeficiency virus-infected women

The existence of cervical neoplasia in women with human immunodeficiency virus (HIV) represents one of the most serious challenges in the oncologic care of immunosuppressed patients. While the development of most cancers in the immunosuppressed patient can be attributed solely to immune deficiency, the relationship between squamous cell neoplasia of the cervix and HIV is quite unique because of common sexual behavioral risk factors. Screening strategies in HIV-positive women must take into account the high prevalence of cervical dysplasia in this subgroup as well as the limitations of cytologic screening. Cervical dysplasia in HIV-positive women may be of higher grade than in HIV-negative patients, with more extensive involvement of the lower genital tract with HPV-associated lesions. The presence and severity of cervical neoplasia in HIV-positive women correlate with both quantitative and qualitative T-cell function. Standard therapies for preinvasive cervical disease have yielded suboptimal results with high recurrent rates. While poor treatment results of standard ablative and excisional therapies warrant unique therapeutic strategies, one must recognize that close surveillance and repetitive treatment have been successful in preventing progressive neoplasia and invasive cervical carcinoma. The disease characteristics of invasive cervical carcinoma may take a more aggressive clinical course in HIV-infected women. HIV-positive women with cervical cancer have higher recurrence and death rates with shorter intervals to recurrence and death than do HIV-negative control subjects. CD4 status does influence subsequent outcome. In general, the same principles that guide the oncologic management of cervical cancer in immunocompetent patients should be applied. However, extremely close monitoring for both therapeutic efficacy and unusual toxicity must be instituted.     

Long-term tolerance and efficacy of 3'-azidothymidine and 3'-fluorothymidine treatment of asymptomatic monkeys infected with simian immunodeficiency virus

Macaques chronically infected with simian immunodeficiency virus were treated with zidovudine (20 mg/kg of body weight per day for 9 weeks) or 3'-fluorothymidine (5 mg/kg of body weight per day for 9 weeks or three doses of 2 mg/kg per day for 24 days). Hematological changes in the treated animals included macrocytic anemia and leukopenia. Determination of antiviral effects in this model requires improved assay methods.     

Population pharmacokinetics of rifabutin in human immunodeficiency virus-infected patients

Rifabutin pharmacokinetics were studied by the population approach (NONMEM) with 40 human immunodeficiency virus-infected patients receiving rifabutin at different doses for prophylaxis or therapy of mycobacterial infections. A two-compartment open model with first-order absorption was used as the structural pharmacokinetic model. Parameter estimates were the absorption rate constant (0. 201/h), clearance/bioavailability (CL/F; 60.9 liters/h), volume of the central compartment/bioavailability (231 liters), intercompartmental clearance (60.3 liters/h), and volume of the peripheral compartment/bioavailability (Vp/F; 1,050 liters). The distribution and elimination half-lives were 1.24 and 25.4 h, respectively. The covariates tested for influence on CL/F and Vp/F were sex, age, weight, height, body surface area, tobacco smoking, drug addiction, alanine aminotransferase levels, creatinine clearance, total protein, bilirubin, numbers of CD4(+) cells, presence of diarrhea, cachexia index, rifabutin use (prophylaxis versus therapy), rifabutin dose, study site, and the concomitant administration of clarithromycin, fluconazole, phenobarbital, ciprofloxacin, azithromycin, or benzodiazepines. The only statistically significant effects on rifabutin pharmacokinetic parameters were a 27% decrease in Vp/F due to the concomitant administration of azithromycin and a 39% increase in Vp/F due to tobacco smoking. Such effects may be considered clinically unimportant. Our results confirm the lack of a correlation of rifabutin pharmacokinetic parameters with parameters of disease progression and gastrointestinal function. Also, the lack of a correlation with covariates which were previously found to be significant, such as concomitant fluconazole and clarithromycin use, may suggest that the effect of such covariates may be less important in the real clinical setting, in which several concomitant factors may influence pharmacokinetic parameters, with an overall effect of no apparent correlation.     

Oral manifestations of human immunodeficiency virus-infected patients in Taiwan

To understand the characteristic clinical features of human immunodeficiency virus (HIV)-related oral lesions and determine the prevalence of various oral lesions in HIV-infected patients in Taiwan, we conducted a cross-sectional study of 207 HIV-infected patients at the Taipei Municipal Institute for Venereal Disease Control. Overall, 108 (52.2%) patients had at least one oral lesion. The most common oral manifestation of HIV infection among these 207 patients was oral hairy leukoplakia (OHL, 29.5%), followed by candidiasis (12.1%), xerostomia (10.6%), aphthous ulcers (8.7%), and linear gingival erythema (5.8%). Less frequently encountered oral lesions included leukoplakia (1.9%), papilloma (1.4%), necrotizing ulcerative periodontitis (1.0%), Kaposi's sarcoma (1.0%), herpes simplex (0.5%), Burkitt's lymphoma (0.5%), and parotid gland enlargement (0.5%). Thirty-one (15%) patients had multiple oral lesions. Patients with oral candidiasis or multiple oral lesions had significantly lower mean CD4 lymphocyte counts and CD4/CD8 lymphocyte ratios than those without any oral lesions (p < 0.05). Chi-square analysis revealed that patients with CD4 lymphocyte counts below 200 cells/mm3 were more prone to have OHL (p < 0.002), oral candidiasis (p < 0.001) and multiple oral lesions (p < 0.001). Those with CD4/CD8 lymphocyte ratios below 0.4 were more likely to have OHL (p < 0.02), oral candidiasis (p < 0.01) and multiple oral lesions (p < 0.02) than those with higher counts. In conclusion, the occurrence of oral lesions, especially OHL and oral candidiasis, is fairly common in Taiwanese HIV-infected patients.     

Ineffective platelet production in thrombocytopenic human immunodeficiency virus-infected patients

Thrombocytopenia has been characterized in six patients infected with human immunodeficiency virus (HIV) with respect to the delivery of viable platelets into the peripheral circulation (peripheral platelet mass turnover), marrow megakaryocyte mass (product of megakaryocyte number and volume), megakaryocyte progenitor cells, circulating levels of endogenous thrombopoietin (TPO) and platelet TPO receptor number, and serum antiplatelet glycoprotein (GP) IIIa49-66 antibody (GPIIIa49-66Ab), an antibody associated with thrombocytopenia in HIV-infected patients. Peripheral platelet counts in these patients averaged 46 +/- 43 x 10(3)/microL (P = . 0001 compared to normal controls of 250 +/- 40x 10(3)/microL), and the mean platelet volume (MPV) was 10.5 +/- 2.0 fL (P > 0.3 compared with normal control of 9.5 +/- 1.7 fL). The mean life span of autologous 111In-platelets was 87 +/- 39 hours (P = .0001 compared with 232 +/- 38 hours in 20 normal controls), and immediate mean recovery of 111In-platelets injected into the systemic circulation was 33% +/- 16% (P = .0001 compared with 65% +/- 5% in 20 normal controls). The resultant mean peripheral platelet mass turnover was 3.8 +/- 1.5 x 10(5) fL/microL/d versus 3.8 +/- 0.4 x 10(5) fL/microL/d in 20 normal controls (P > .5). The mean endogenous TPO level was 596 +/- 471 pg/mL (P = .0001 compared with 95 +/- 6 pg/mL in 98 normal control subjects), and mean platelet TPO receptor number was 461 +/- 259 receptors/platelet (P = .05 compared with 207 +/- 99 receptors/platelet in nine normal controls). Antiplatelet GPIIIa49-66Ab levels in sera were uniformly increased in HIV thrombocytopenic patients (P < .001). In this cohort of thrombocytopenic HIV patients, marrow megakaryocyte number was increased to 30 +/- 15 x 10(6)/kg (P = .02 compared with 11 +/- 2.1 x 10(6)/kg in 20 normal controls), and marrow megakaryocyte volume was 32 +/- 0.9 x 10(3) fL (P = .05 compared with 28 +/- 4.5 x 10(3) fL in normal controls). Marrow megakaryocyte mass was expanded to 93 +/- 47 x 10(10) fL/kg (P = .007 compared with normal control of 31 +/- 5.3 x 10(10) fL/kg). Marrow megakaryocyte progenitor cells averaged 3.3 (range, 0.4 to 7.3) CFU-Meg/1,000 CD34(+) cells compared with 27 (range, 0.1 to 84) CFU-Meg/1,000 CD34(+) cells in seven normal subjects (P = .02). Thus, thrombocytopenia in these HIV patients was caused by a combination of shortening of platelet life span by two thirds and doubling of splenic platelet sequestration, coupled with ineffective delivery of viable platelets to the peripheral blood, despite a threefold TPO-driven expansion in marrow megakaryocyte mass. We postulate that this disparity between circulating platelet product and marrow platelet substrate results from direct impairment in platelet formation by HIV-infected marrow megakaryocytes.     

Association between an early humoral response to Mycobacterium tuberculosis antigens and later development of tuberculosis in human immunodeficiency virus-infected individuals

We describe four cases of inflammatory pseudotumor seen at our institution in the past 4 years. Four children were each found to have a large extraperitoneal mass on imaging studies, three of which were in the pelvis. Malignant sarcomatous tumors were suspected. Surgical biopsy of each mass, however, revealed inflammatory pseudotumor.     

Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients

The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h] alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (Cmax) of ZDV plasma decreased from 748 +/- 375 (mean +/- standard deviation) to 546 +/- 296, and area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased from 3,052 +/- 1,007 to 2,261 +/- 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide Cmax and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3'-amino-3'-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.     

T cell subsets and cytomegalovirus retinitis in human immunodeficiency virus-infected patients

A case-control study was done to investigate the relationship between T cell subsets and cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected subjects with or without CMV retinitis and CD4+ cell counts of <0.050 x 10(9)/L. Cell surface markers on peripheral blood lymphocytes were evaluated using flow cytometry. Patients with CMV retinitis had significantly lower levels of CD8+ cells (median: 0.152 x 10(9)/L) compared with levels for controls (median: 0.296 x 10(9)/L, P < .001). Significant down-regulation of costimulatory molecule CD28+ and lymphocyte function-associated antigen-1 (LFA-1) expression was observed in patients versus controls (CD28+: 0.048 x 10(9)/L vs. 0.143 x 10(9)/L, P < .001; LFA-1: 0.238 x 10(9)/L vs. 0.400 x 10(9)/L, P < .001), but no significant differences were noted for NK cells. We propose that progressive loss of the CD3+ CD8+ cell subset and down-regulation of CD28 and LFA-1 accessory molecules are associated with an increased risk of CMV retinitis in HIV-infected patients.     

Simultaneous Pneumocystis carinii and pneumococcal pneumonia in human immunodeficiency virus-infected children

Three children with acquired immunodeficiency syndrome who had pneumonia develop were infected simultaneously with Pneumocystis carin?i and Streptococcus pneumoniae. Such coexistence has not been previously reported in children. One patient received prophylactic treatment against Pneumocystis carin?i before his illness.