Symptomatic Human Immunodeficiency Virus Infection Research Articles

Retrovir Therapy in Hemophilic Children with Symptomatic Human Immunodeficiency Virus Infection

In desperation, we have used retrovir in five hemophilic children (10-16 years old) over the past 22 months. All had presented with various clinical manifestations of acquired-immune-deficiency-syndrome (AIDS)-related complex or AIDS. Our decision to treat with retrovir was based on clinical manifestations and very low numbers of CD4 cells (less than 200). The most common clinical presentation was recurrent oral moniliasis. Other significant findings included recurrent herpes zoster, thrombocytopenia, growth failure, and biliary tract infection. Initially, all five children received the full adult dosage of retrovir (200 mg q 4 h x 6 doses/day). This dosage had to be reduced in four children because of toxicity. The most commonly observed toxic side effects were anemia and neutropenia. Alanine aminotransferase (ALT) levels rose to 4-10 times the upper limit of normal in four of five children. One was on concomitant ketokonazole prior to the rise in ALT level. Myalgia and headache were reported by two patients. Improvement in clinical and immunological status was observed in all children initially. After 12-18 months of retrovir therapy, infectious complications secondary to prolonged neutropenia were seen in these immunocompromized children. However, compared to historic controls, these children have had fairly stable disease. We feel that all hemophilic children with symptomatic human immunodeficiency virus infection should be offered this drug, even though the optimal dosage for children is not yet established.

Characterization of the serologic profile of children with human immunodeficiency virus infection: Correlation with clinical status

Serum samples from 28 children with symptomatic human immunodeficiency virus (HIV) infection were studied for the presence of HIV antigen. Their humoral immune response profile, including anti-HIV specific isotypic responses and neutralizing titers was characterized. Additionally, serum specimens from 12 of these children were tested for their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) against HIV envelope antigens. Analysis of our results showed that children with acquired immuno-deficiency syndrome (AIDS) were much more likely to have serum antigenemia and an absence of anti-p24 antibodies than those with AIDS-related complex (ARC). A significant association was also noted between a more stable clinical status and a strong anti-p24 antibody response with detectable antibodies to other HIV antigens in multiple antibody subclasses. This suggests that the longitudinal evaluation of antigen/antibody profiles may aid in the assessment of prognosis for children with HIV infection. Sera from 6 6 patients with ARC and 4 6 patients with AIDS were able to mediate ADCC. No correlation was found between clinical status and the titers of neutralizing antibodies.

Pharmacokinetics of azidothymidine during late pregnancy in Long-Evans rats

Azidothymidine (Zidovudine) is used to treat symptomatic human immunodeficiency virus infection. It has the ability to reverse seropositivity as well as decrease serum viral titers, and perhaps decrease potential for transmission of the virus. An animal model (pregnant Long-Evans rats) was used to investigate the potential for placental transmission of azidothymidine. The drug crosses the placenta to reach concentrations in the placenta and fetus that are comparable to 75% and 58%, respectively, of those in the maternal serum by 2 hours after administration. By 4 to 6 hours after administration azidothymidine concentrations in the placenta and fetal liver significantly exceed maternal concentrations.

The Influence of HIV Infection on Antibody Responses to a Two-Dose Regimen of Influenza Vaccine

We studied whether a two-dose regimen of inactivated influenza virus vaccine was more effective than a single dose in inducing protective hemagglutination-inhibition antibody responses in patients infected with human immunodeficiency virus (HIV). Participants included subjects with acquired immunodeficiency syndrome, subjects with acquired immunodeficiency syndrome-related complex, and HIV-seropositive individuals with either lymphadenopathy only or no symptoms. Control subjects were HIV-seronegative heterosexuals and HIV-seronegative homosexuals. Two doses of inactivated influenza vaccine containing 15 micrograms of the hemagglutinin of influenza A/Taiwan/1/86(H1N1), A/Leningrad/360/86(H3N2), and B/Ann Arbor/1/86 were administered intramuscularly in the deltoid region 1 month apart. The second dose of vaccine did not significantly increase the frequency or magnitude of antibody responses of either HIV-seropositive or HIV-seronegative subjects over that achieved by a single dose. The two-dose regimen induced a protective level (greater than or equal to 1:64) of hemagglutination-inhibition antibody to influenza A(H1N1) or (H3N2) virus less often in subjects with symptomatic HIV infection than in uninfected control subjects (39% vs 87% or 46% vs 97%, respectively). Our results suggest that a substantial proportion of individuals with symptomatic HIV infection might remain unprotected from influenza, even after immunization with a two-dose regimen.

Pharmacokinetics of rifabutin

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

Pharmacokinetics of orally administered zidovudine among patients with hemophilia and a symptomatic human immunodeficiency virus (HIV) infection

Zidovudine (formerly azidothymidine, AZT) is used to treat certain patients infected with the human immunodeficiency virus (HIV). However, the clinical use of zidovudine (ZDV) in hemophilia patients may be complicated by the high incidence of chronic hepatitis in this patient population. To examine the pharmacokinetics of ZDV eight asymptomatic HIV-infected hemophilia patients received a single oral dose (300 mg). ZDV and its glucuronide metabolite (GZDV) were measured in serum by HPLC. ZDV was rapidly absorbed with a wide range of peak serum concentrations (2052 ± 970 ng/ml) at 0.5 h. Peak GZDV serum concentrations were 4751 ± 2269 ng/ml at 1 h. Both ZDV and GZDV declined in a biexponential manner over 4 h. After 4 h, the ZDV serum concentration decay in three patients continued a log-linear decline, while five patients demonstrated a tri-exponential curve which had a mean terminal elimination half-life of 4.8 ± 2.8 h. No relationship between ZDV or GZDV kinetics and the degree of hepatic enzyme elevation was observed. Although a therapeutic window for ZDV has yet to be described, the wide range of serum concentrations that result from a standard dose suggests that clinical monitoring of ZDV levels may be of value in certain patients. In addition, the prolonged elimination half-life of ZDV in the present study may provide a rationale for less frequent dosing in certain patients.

The Pharmacokinetics of Zidovudine Administered by Continuous Infusion in Children

To define the pharmacokinetics of zidovudine (azidothymidine) in children with human immunodeficiency virus infection. Plasma, urine, and cerebrospinal fluid were obtained following a single 80 mg/m2 body surface dose infused over 1 hour (n = 9), and during a continuous infusion of 0.5 (n = 3), 0.9 (n = 8), 1.4 (n = 7), or 1.8 (n = 3) mg/kg body weight per hour. Outpatient clinic and inpatient ward of the Pediatric Branch of the National Cancer Institute. Twenty-one children (seventeen boys) ranging in age from 14 months to 12 years with symptomatic human immunodeficiency virus infection who were being treated on a phase I-II study of continuous intravenous infusion zidovudine. Zidovudine disappearance following bolus administration was rapid and biexponential with half-lives of 9.6 and 92 minutes, and a total clearance of 705 +/- 330 mL/min.m2. Zidovudine remained above 1 mumol/L, the optimal virostatic concentration in vitro, for only 1.5 hours. In contrast, with continuous infusion steady-state plasma zidovudine concentrations (Css) were maintained above 1 mumol/L continuously, even at the lowest infusion rate. At steady state the ratio of cerebrospinal fluid zidovudine concentration to plasma was 24% +/- 9%. Patients who developed severe neutropenia (absolute neutrophil count less than 0.5 X 10(9)/L) on the continuous infusion regimen had significantly higher plasma Css. Six of eight had a Css greater than 3.0 mumol/L. Pharmacokinetic parameters show that continuous infusion is better than an intermittent schedule in maintaining minimal virostatic concentrations of the drug with a lower daily dose.

Fungal and mycobacterial infections in patients infected with the human immunodeficiency virus.

Fungal and mycobacterial infections are among the most common opportunistic infections in patients infected with human immunodeficiency virus (HIV). Candida infections are the bell-wether of progression to symptomatic HIV infection and candida oesophagitis often marks the onset of the acquired immunodeficiency syndrome (AIDS). More than 80% of AIDS patients have candida disease. Candida infections remain local and respond to treatment but tend to recur. Cryptococcal infections initially affect few HIV positive patients but involve 10-30% with AIDS. Meningitis is the usual presentation and dissemination is common. Amphotericin usually produces improvement but cure is infrequent, and maintenance therapy is advisable. Mycobacteria cause intracellular infections increasing in parallel with immunodeficiency. Mycobacterium avium-intracellulare is predominant, occurring with other opportunistic pathogens causing systemic and local symptoms with high bacterial density in infected cells. Multidrug treatment is best, but the results are disappointing. Tuberculosis is prevalent in certain groups of patients. It often presents with atypical clinical and pathological features. Anti-tuberculous treatment is effective and prophylaxis should be considered. Endemic fungi with mycobacteria cause sporadic infections. Opportunistic infections are the lethal arm of HIV infection. Diligent diagnosis and persistent treatment offer benefit to HIV-infected patients.

Thrombocytopenia and Human Immunodeficiency Virus in Children

Thrombocytopenia occurs in 13% of children with symptomatic human immunodeficiency virus (HIV) infection. The clinical and laboratory course of 19 children infected with HIV with thrombocytopenia is described. Bone marrow aspirates showed normal to increased numbers of megakaryocytes. Levels of antiplatelet antibodies were increased in 80% of the children and circulating immune complexes were found in 74%. Clinically significant hemorrhage leading to anemia occurred in five patients, and CNS bleeding led to a fatal outcome in an additional three children. Spontaneous remission of thrombocytopenia occurred in three of the 19 subjects. High-dose IV gamma-globulin was effective in increasing the platelet counts of six of 15 patients (40%) but resulted in a sustained remission in only one subject. Oral prednisone was effective in increasing the platelet count of two thirds of those whose platelet counts could not be controlled by IV gamma-globulin. Bleeding manifestations were eliminated in all patients whose platelet counts increased significantly. Of the 11 children whose counts increased either spontaneously or as a result of therapy, eight remain alive (72%). In contrast, all of the eight patients whose platelet counts did not improve have died. Thrombocytopenia in children with HIV disease is engendered by immune mechanisms and is a major cause of morbidity and mortality. High-dose IV gamma-globulin and/or corticosteroids are temporarily effective in increasing the platelet count and reducing bleeding in about half of thrombocytopenic patients and are recommended for use. The ability to respond to therapy correlates with improved survival.

Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection.

To produce concentrations of zidovudine (AZT) in plasma and cerebrospinal fluid that would provide constant inhibition of the replication of human immunodeficiency virus (HIV), we gave AZT by continuous intravenous infusion to 21 children ranging in age from 14 months to 12 years who had acquired HIV infection through transfusions or perinatally. All patients were symptomatic before AZT treatment (Class P2 of the Centers for Disease Control); 13 (62 percent) had evidence of neurodevelopmental abnormalities. The mean CD4/CD8 ratio was 0.18; 11 patients had CD4 counts below 0.2 x 10(9) per liter. We administered AZT at four dose levels: 0.5, 0.9, 1.4, and 1.8 mg per kilogram of body weight per hour. The plasma drug concentrations achieved at the respective dose levels were 1.9 +/- 0.3, 2.8 +/- 1.4, 3.1 +/- 1.1, and 4.5 +/- 1.0 microM. The steady-state cerebrospinal fluid:plasma ratio was 0.24 +/- 0.07. The only evidence of toxicity was bone marrow suppression. Transfusion was required in 14 patients because of low levels of hemoglobin (5 mmol per liter [less than 8 g per deciliter]). Dose-limiting neutropenia (less than 0.5 x 10(9) polymorphonuclear leukocytes per cubic millimeter) occurred in most patients who received doses of 1.4 mg per kilogram per hour or more. Improvement in neurodevelopmental abnormalities occurred in all 13 children who had presented with encephalopathy before treatment. Serial measurements of IQ before therapy and after three and six months of continuous therapy with AZT showed that IQ scores, including those for verbal and performance IQ, rose in these 13 patients and in 5 other children who had no detectable evidence of encephalopathy before treatment. Most patients also had increased appetite and weight, decreased lymphadenopathy and hepatosplenomegaly, decreased immunoglobulin levels, and increased numbers of CD4 cells. In some patients the improvement in the features of encephalopathy occurred despite the absence of immunologic improvement. We conclude that AZT is beneficial in children with symptomatic HIV infection, especially those with encephalopathy (which may be subclinical), and that the optimal continuous intravenous dose of AZT in children is between 0.9 and 1.4 mg per kilogram per hour.

Gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus.

Gastrointestinal viruses, predominantly rotaviruses and adenoviruses, were detected by enzyme-linked immunosorbent assay, electron microscopy, or cell culture in >50% of two groups of homosexual men with symptomatic human immunodeficiency virus (HIV) infection, who did (54%) or did not (50%) have diarrhea. Lower detection rates were observed in HIV-seronegative (15%) and asymptomatic HIV-seropositive (16%) men. In the patients with diarrhea, 95% of the isolates of virus were found in the most immuno suppressed patients, those patients with AIDS-related complex or opportunistic infections associated with AIDS. High excretion rates of these viruses are probably associated with both anal-oral transmission and immunosuppression. These viruses apparently cause acute episodes or relapses of diarrhea in some patients but may be co-pathogens or noncontributory to chronic diarrhea in others.

Unrecognized human immunodeficiency virus infection in emergency department patients.

To determine the extent of unrecognized human immunodeficiency virus (HIV) infection, we examined blood samples drawn from patients presenting to an inner-city emergency department. We found 119 of 2302 consecutive adult patients (5.2 percent) to be seropositive for HIV. Although 27 patients presented with known symptomatic HIV infection, 92 of the remaining 2275 patients (4.0 percent) had unrecognized HIV infection. The highest seroprevalence rate (11.4 percent) was found among black men 30 to 34 years of age. Blacks, other nonwhites, and patients under the age of 45 had high rates of unrecognized infection. The clinical team established risk-factor status in only 29.0 percent of the patients. Of the 276 patients with identified risk factors, 13.0 percent were seropositive, whereas 3.1 percent of the 1616 patients with unknown risk-factor status were seropositive. None of the 102 patients who reported no risk factors were seropositive. Although penetrating trauma (seroprevalence, 13.6 percent) was the only clinical presentation associated with an increased seroprevalence rate independent of other known predictors of infection (P = 0.02), seropositive patients were found in all categories of clinical condition. These data, although based on observations in one emergency department setting, support the concept of universal blood and body-fluid precautions by all health care workers whether or not HIV infection is known.

Intravenous immune globulin in symptomatic paediatric human immunodeficiency virus infection.

Seven paediatric patients with symptomatic human immunodeficiency virus (HIV) infection were prospectively studied for 6-24 months after the start of intravenous immune globulin (IVIG) therapy. There was substantial clinical benefit during IVIG treatment with marked reduction of febrile and infectious episodes, normalization of physical and psychomotor development, and absence of mortality. The immunologic monitoring revealed some discrete objective improvements. The results of this study favourably compare to previous reports. It is concluded that IVIG should be standard therapy for symptomatic childhood HIV infection.

Pediatric Acquired Immunodeficiency Syndrome

Central nervous system (CNS) dysfunction was documented in 61 of 68 infants and children with symptomatic human immunodeficiency virus infection. The most frequent manifestations included acquired microcephaly, cognitive deficits, and bilateral pyramidal tract signs. Lymphoma of the CNS, cerebrovascular accidents, and CNS infection caused by conventional pathogens were documented in only ten children (15%). Neurologic deterioration in 11 children was subacute but steadily progressive; in 31 the course was more indolent and began with a plateau. Of these 31 children, 13 had further neurologic deterioration and the conditions of three improved. Seventeen children had a static course with cognitive deficits (seven children) or cognitive plus neurologic impairment (ten children). Neuroradiologic studies in the children with a subacute progressive or plateau course disclosed cerebral atrophy, white matter abnormalities, and calcification of the basal ganglia. Postmortem findings included variable degrees of inflammatory response, multinucleated cells, calcific vasculopathy, and pyramidal tract degeneration. Computed tomographic studies of the children with a static course were normal or showed mild atrophy, but poor brain growth was documented by serial head circumference measurements.

Cytological and immunoglobulin findings in cerebrospinal fluid of symptomatic and asymptomatic human immunodeficiency virus (HIV) seropositive patients.

Immunostimulation in the central nervous system (CNS) measured as abnormal intrathecal immunoglobulin production or activated lymphocytes in the cerebrospinal fluid (CSF), was found in 22 of 25 HIV seropositive patients. All of 11 patients with symptomatic HIV infection and nine of 14 asymptomatic patients had an increased IgG index or a Tourtellotte's production number indicating CNS infection. The amount of intrathecal immunoglobulin was not correlated to the severity of disease since five of six AIDS patients had only slightly elevated values, while some patients without AIDS had a high intrathecal immunoglobulin production. Activated lymphocytes and plasma cells in CSF were frequently found in symptomatic HIV patients without AIDS as well as in asymptomatic HIV seropositive patients. Macrophages and activated monocytes were observed in CSF from AIDS patients. The results indicate that HIV has a high neurotropicity and is spread to CNS in all stages of the infection.

Symptomatic HIV infection of the CNS in a patient without clinical evidence of immune deficiency

Major depression with psychotic features, dementia, and focal neurologic abnormalities appeared in a Haitian man without AIDS or other syndromes of immune compromise. Neurologic evaluation, including brain biopsy, was nondiagnostic, but CSF culture revealed human immunodeficiency virus (HIV).

1986 update of HIV seroprevalence, seroconversion, AIDS incidence, and immunologic correlates of HIV infection in patients with hemophilia A and B

A cohort of 181 patients with hemophilia A (149) and hemophilia B (32) cared for at the Hemophilia Center of Western Pennsylvania was followed to determine human immunodeficiency virus (HIV) seroprevalence, seroconversion rate, and clinical and immunologic correlates of HIV infection. By December 1986, 82 (45%) were HIV seropositive, and of these, ten (12%) had developed AIDS, 28 (34%) had symptomatic HIV infection (CDC class III, IV), of whom 14 (17%) had AIDS-related complex (ARC), and 44 (54%) had asymptomatic HIV infection (CDC class II). The HIV seropositive group included 82% of those treated with factor VIII concentrate (97% severe, 5% moderate), 48% of those treated with factor IX concentrate (92% severe, 8% moderate), 10% of those treated with cryoprecipitate (67% severe, 33% moderate), and none of those treated with fresh frozen plasma. Based on 77 serially sampled HIV seropositive hemophiliacs (1977 to 1986), peak seroconversion occurred in 1982, with 14% (11 of 77) occurring since 1984. With increasing time from seroconversion, both T4 lymphocyte number and function (the latter measured by growth in soft agar [T colony assay]) progressively declined; T4 number declined to 135 +/- 26/mm3 (SEM), and colony count declined 1193 +/- 537 (control 3851 +/- 387) by 5 years after seroconversion. In those developing AIDS, total T4 fell below 100/mm3 (33 +/- 8/mm3) at diagnosis. In this cohort, the overall AIDS incidence is 5.5% (12% among the HIV seropositive) and in those seropositive 5 or more years, the AIDS incidence approaches 32%.

1986 Update of HIV Seroprevalence, Seroconversion, AIDS Incidence, and Immunologic Correlates of HIV Infection in Patients With Hemophilia A and B

A cohort of 181 patients with hemophilia A (149) and hemophilia B (32) cared for at the Hemophilia Center of Western Pennsylvania was followed to determine human immunodeficiency virus (HIV) seroprevalence, seroconversion rate, and clinical and immunologic correlates of HIV infection. By December 1986, 82 (45%) were HIV seropositive, and of these, ten (12%) had developed AIDS, 28 (34%) had symptomatic HIV infection (CDC class III, IV), of whom 14 (17%) had AIDS-related complex (ARC), and 44 (54%) had asymptomatic HIV infection (CDC class II). The HIV seropositive group included 82% of those treated with factor VIII concentrate (97% severe, 5% moderate), 48% of those treated with factor IX concentrate (92% severe, 8% moderate), 10% of those treated with cryoprecipitate (67% severe, 33% moderate), and none of those treated with fresh frozen plasma. Based on 77 serially sampled HIV seropositive hemophiliacs (1977 to 1986), peak seroconversion occurred in 1982, with 14% (11 of 77) occurring since 1984. With increasing time from seroconversion, both T4 lymphocyte number and function (the latter measured by growth in soft agar [T colony assay]) progressively declined; T4 number declined to 135 +/- 26/mm3 (SEM), and colony count declined 1193 +/- 537 (control 3851 +/- 387) by 5 years after seroconversion. In those developing AIDS, total T4 fell below 100/mm3 (33 +/- 8/mm3) at diagnosis. In this cohort, the overall AIDS incidence is 5.5% (12% among the HIV seropositive) and in those seropositive 5 or more years, the AIDS incidence approaches 32%.

Investigation of a Health Care Worker with Symptomatic Human Immunodeficiency Virus Infection: An Epidemiologic Approach

Investigation of a Health Care Worker with Symptomatic Human Immunodeficiency Virus Infection: An Epidemiologic Approach

Obstetric and perinatal consequences of human immunodeficiency virus (HIV) infection: a review.

Pediatric acquired immune deficiency syndrome (AIDS) was known to be a new disease that could be acquired from the mother even before human immunodeficiency virus (HIV) was identified. The suggested routes of transmission of infection are intrauterine, perinatal--from contact with infected maternal genital secretions, or through breastfeeding. At this time the problem in Europe concerns primarily women in high-risk groups: intravenous drug abusers, prostitutes, women from countries where the prevalence of HIV is high, and women whose sexual partners are in a high-risk group. In the future, the infection may extend beyond women in high-risk groups as the disease becomes more prevalent in the community. It has been claimed that pregnancy accelerates symptoms in women who are HIV positive, yet this is based on only a series of case reports of severe infection in pregnancy and on the development of AIDS in asymptomatic women in pregnancy subsequent to the birth of an AIDS child. The only data capable of shedding some light on this issue would be a prospective followup of both pregnant and nonpregnant HIV-positive women from similar high-risk groups. Such a study is ongoing in the US. An increasing number of case reports suggest intrauterine transmission of infection. The following 3 case reports provide clear evidence of intrauterine transmission. Sprecher et al. (1986) detected HIV antigen in amniotic fluid and fetal tissues from a pregnancy termination at 15 weeks gestation in a woman with stage IV AIDS and Kaposi sarcoma. Lapointe et al. (1985) reported an infant born by cesarean section at 28 weeks gestation to a mother with terminal aids. A new dysmorphic syndrome recently has been described in children with symptomatic HIV infection (Marion et al., 1986). HIV has been isolated from cervical secretions (Fogt et al., 1986; Wofsy et al., 1986), which suggests that this cold be another source of infection. There is 1 report of isolation of HIV from the noncellular fraction of breast milk (Thirty et al., 1985). Several case reports have described acquired immunodeficiency in infants for whom the only known risk factor was neonatal transfusion from an individual later found to be suffering from AIDS. The risk of transmission from an infected mother to her infant is unknown, but the best available evidence comes from a study of children born to women who had previously given birth to a child with AIDS (Scott et al, 1985). Of 12 children, 4 developed AIDS or Aids-related complex. Clinical problems among children with AIDS or AIDS-related complex have been fully described. The fatality rate of children with AIDS is high, but the ultimate progress of children with less severe disease or who have asymptomatic infection is known.