Severe Human Immunodeficiency Virus Infection Research Articles

Nursing and Community Rates of Mycobacterium tuberculosis Infection among Students in Harare, Zimbabwe

African hospitals have experienced major increases in admissions for tuberculosis, but they are ill-equipped to prevent institutional transmission. We compared institutional rates and community rates of tuberculin skin test (TST) conversion in Harare, Zimbabwe. We conducted a cohort study of TST conversion 6, 12, and 18 months into training among 159 nursing and 195 polytechnic school students in Harare. Students had negative TST results (induration diameter, < or =9 mm) with 2-step testing at the start of training. Nursing students experienced 19.3 TST conversions (increase in induration diameter, > or =10 mm) per 100 person-years (95% confidence interval [CI], 14.2-26.2 conversions per 100 person-years), and polytechnic school students experienced 6.0 (95% CI, 3.5-10.4) conversions per 100 person-years. The rate of difference was 13.2 conversions (95% CI, 6.5-20.0) per 100 person-years. With a more stringent definition of conversion (increase in the induration diameter of > or =10 mm to at least 15 mm), which is likely to increase specificity but decrease sensitivity, conversion rates were 12.5 and 2.8 conversions per 100 person-years in nursing and polytechnic school students, respectively (rate difference, 9.7 conversions per 100 person-years; 95% CI, 4.5-14.8 conversions per 100 person-years). Nursing students reportedly nursed 20,868 inpatients with tuberculosis during 315 person-years of training. Both groups had high TST conversion rates, but the extremely high rates among nursing students imply high occupational exposure to Mycobacterium tuberculosis. Intense exposure to inpatients with tuberculosis was reported during training. Better prevention, surveillance, and management of institutional M. tuberculosis transmission need to be supported as part of the international response to the severe human immunodeficiency virus infection epidemic and health care worker crisis in Africa.

A Pilot Study of Sequential Therapy with Zidovudine plus Acyclovir, Dideoxyinosine, and Dideoxycytidine in Patients with Severe Human Immunodeficiency Virus Infection

A pilot study was initiated to explore a sequential combination antiretroviral regimen in 21 patients with AIDS or advanced human immunodeficiency virus (HIV) infection, who had received little or no prior anti-HIV therapy. The mean entry CD4 cell count was 184/mm3. Patients received 3-week cycles consisting of zidovudine plus acyclovir, dideoxyinosine, and dideoxycytidine for 1 week each. Overall, the regimen was well tolerated for up to 3 years. The principal toxicities were anemia, nausea, and vomiting; 1 patient developed retinal lesions. The mean CD4 cell count reached a peak of 64 cells/mm3 above baseline at week 8 (P = .005 compared to baseline) and remained above baseline for > 40 weeks. Patients also gained weight and had decreases in serum HIV p24 antigen. Eight patients developed opportunistic infections or tumors. Only 4 patients died during 3 years of follow-up. This regimen appears to be generally tolerable and to have anti-HIV activity. Additional studies will be needed, however, to learn how to best combine the available agents in patients with HIV infection.

Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy.

To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas. The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma. Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048). HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors.

The expanding challenge of HIV-associated malignancies.

The expanding challenge of HIV-associated malignancies.

Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection [see comments

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.

Subcutaneous Recombinant Granulocyte-Macrophage Colony-Stimulating Factor Used as a Single Agent and in an Alternating Regimen With Azidothymidine in Leukopenic Patients With Severe Human Immunodeficiency Virus Infection

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.

Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection

Erythropoietin (EPO) is a major regulatory factor controlling red blood cell (RBC) production in humans. Although other humoral factors can alter the proliferation of committed early erythroid progenitors in vitro, no factor other than EPO has been clearly shown to induce proliferation of these cells in vivo. In a clinical trail of recombinant granulocyte colony-stimulating factor (G-CSF) and recombinant EPO in patients with advanced human immunodeficiency virus (HIV) infection, we noted reticulocytosis and increases in hemoglobin when G-CSF was administered before the administration of EPO. Subsequent studies demonstrated a significant increase in circulating burst forming unit-erythron (BFU-E) during daily recombinant G-CSF therapy. This increase was both time- and dose-dependent. The magnitude of increase in BFU-E correlated with the magnitude of increase in neutrophils and was associated with a mean increase in reticulocytes of 32,363/microL and a significant increase in mean hemoglobin of 1.04 +/- 0.34 g/dL over an 18-day interval. There was a significant increase in iron binding capacity and decreases in iron saturation and ferritin levels. In patients who were not recently transfused, there was an associated fall in endogenous erythropoietin levels. The increase in RBC production was most marked in patients who were severely anemic, transfusion-dependent, and who had elevated pretreatment EPO levels. There was no correlation between the increase in BFU-E and endogenous EPO levels or the time since last dose of zidovudine. The addition of recombinant EPO therapy three times weekly to patients did not result in further significant increases in BFU-E but did significantly increase hemoglobin. Our data suggest that recombinant G-CSF may be one of the hematopoietic factors that influences production of BFU-E and RBCs in humans.

Pharmacokinetics of 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine in patients with severe human immunodeficiency virus infection

This article describes the pharmacokinetics of 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) as determined during phase I clinical trials in patients with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome-related complex. Drug levels were determined by HPLC in plasma, cerebrospinal fluid, and urine after administration of the drugs either intravenously or as an oral liquid given with antacid. ddA was metabolized rapidly and quantitatively to ddI to such an extent that ddA was undetectable in the plasma even during continuous intravenous administration of ddA. The plasma kinetics of ddI were generally monoexponential and were characterized by a half-life of 38 minutes. This probably does not accurately reflect the kinetics of the active species of ddI, which appears to be 2',3'-dideoxyadenosine triphosphate, formed intracellularly. Oral bioavailability was 38% for oral liquid given with antacid. The total body clearance averaged 1.00 L/kg/hr, with a volume of distribution of 1.01 L/kg. Approximately 36% of the intravenous dose could be recovered unchanged in the urine. The level of ddI in the cerebrospinal fluid 1 hour after drug infusion averaged 21% of that of the simultaneous plasma level. It is concluded that ddI has pharmacokinetic properties that are amenable to its clinical use.