Clinicopathologic characterization of squamous-cell carcinoma arising from pilonidal disease in association with condylomata acuminatum in HIV-infected patients: report of two cases.

Pilonidal disease is a common acquired condition believed to arise from penetration of short hairs into the subcutaneous tissue that induces a cyst or sinus formation. Malignant degeneration is rare and is typically seen only after decades of antecedent disease presence. Condylomata acuminatum in association with pilonidal disease have been described in two prior case reports, however, the coexistence of condyloma with pilonidal disease complicated by malignant degeneration has not been previously reported. Condylomata have known potential for malignant degeneration and are correlated with human papilloma virus infection, with certain serotypes of higher oncogenic potential. Coinfection with human immunodeficiency virus and human papilloma virus is associated with higher rates of anal neoplasia. We report two cases of human immunodeficiency virus-infected patients with the constellation of pilonidal disease, condylomata acuminatum, and subsequent malignant degeneration into squamous-cell carcinoma. In contrast to other case reports in the literature, these two patients had considerably shorter antecedent periods of pilonidal disease before malignant degeneration was detected. Both cases also had intractable courses. We conclude that the existence of condylomata acuminatum and pilonidal disease in an immunocompromised patient may represent a more ominous condition than solitary pilonidal disease. Therefore, careful inspection of the pilonidal area in human immunodeficiency virus-infected patients presenting with condylomata is important and earlier intervention should be considered. Moreover, further evaluation of the prevalence of squamous-cell carcinoma arising from pilonidal disease complicated by condylomata, particularly in the immunosuppressed, is warranted.

Bone marrow aspiration, biopsy, and culture in the evaluation of HIV-infected patients for invasive mycobacteria and histoplasma infections.

Bone marrow (BM) aspiration and biopsy are used commonly in clinical practice to diagnose invasive tissue infections caused by Mycobacterium avium intracellulare (MAC), Mycobacterium tuberculosis (TB), and Histoplasma capsulatum (HC) in patients with human immunodeficiency virus-1 (HIV) infection. However, the value of these invasive procedures relative to other diagnostic approaches has not been clearly defined. To determine the value of BM culture and BM histology in the diagnosis of opportunistic MAC/TB and HC infections in immunosuppressed patients with HIV, we retrospectively reviewed the records of 56 adult patients with HIV who underwent a single BM aspiration, biopsy, and culture because of unexplained fever and/or other clinical features suggestive of MAC/TB or HC infection. Thirty-two patients (57%) were ultimately diagnosed with MAC/TB or HC infection by positive cultures of BM, blood, sputum, or bronchoalveolar lavage fluid or by the histologic detection of organisms in biopsies of BM or other tissues. The diagnostic sensitivity of BM cultures was equal to that of blood cultures (20/32, or 63%). Granuloma and/or histologically apparent organisms were seen in BM biopsy specimens in 11 of 32 individuals (34%) ultimately diagnosed with MAC/TB or HC infections. Among these 11 cases, both granuloma and acid-fast staining organisms were found in the BM biopsy specimens of 2 individuals for whom both BM and blood cultures were negative. Certain clinical symptoms and signs at the time of BM examination were found by logistic regression analysis to be significantly associated with a subsequent diagnosis of MAC/TB or HC infections; these included high fever, long duration of febrile days prior to BM examination, and elevated direct bilirubin. In conclusion, while the diagnostic sensitivity of BM cultures was found to be no greater than that of blood cultures in detecting MAC/TB or HC infections in immunosuppressed HIV+ patients, histopathologic examination of BM specimens resulted in the relatively rapid identification of nearly one third of infected patients who underwent BM examination, and also identified infections in some patients who were culture negative. These findings support the continued use of BM aspiration, biopsy, and culture for the diagnosis of opportunistic MAC/TB or HC infections in immunosuppressed HIV+ patients, particularly when selected clinical features are present.

Intracranial mass lesions: sequential thallium and gallium scintigraphy in patients with AIDS.

PURPOSE: To determine the efficacy of sequential thallium and gallium scintigraphy to differentiate intracranial neoplasms (lymphoma and glioma) from other nonmalignant intracranial mass lesions among patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: The authors reviewed the cases of 40 patients with human immunodeficiency virus (HIV) who underwent thallium and gallium scanning to evaluate intracranial mass lesions from October 1991 through November 1997. There was a definitive final diagnosis of the nature of the mass lesions in 21 of these cases. In these 21 cases, the scintigraphic patterns were reviewed and were compared with the final diagnosis. RESULTS: On the basis of results at thallium and gallium scanning, the patients were divided into three groups. Group A included 13 patients (11 with brain tumors [lymphomas and gliomas] and two with progressive multifocal leukoencephalopathy [PML]) with thallium-positive, gallium-positive scans. Group B included five patients with intracranial infections (tuberculosis, Cryptococcus, bacteria) with thallium-negative, gallium-positive scans. Group C included three patients (one with PML and two with infarcts) with thallium-negative, gallium-negative scans. All patients with lymphomas were in group A. The sensitivity and specificity of the thallium-positive, gallium-positive pattern for intracranial malignancy were 100% and 80%, respectively. CONCLUSION: Sequential thallium and gallium scanning helped differentiate tumors from nonmalignant intracranial mass lesions and may help differentiate infections from PML or infarcts.

Meningioma in four patients with human immunodeficiency virus infection.

We describe four patients infected with the human immunodeficiency virus (HIV) who had development of meningiomas. In contrast to those in the general population who have meningiomas, all our patients were young men; the mean age was 40 years (range, 32 to 50). Their risk behavior for HIV was homosexuality (three patients) and intravenous drug use (one patient). The CD4+ cell count in each of the three homosexual men was less than 50/microL and was 280/microL in the drug user. Imaging studies showed enhancing lesions in three of the patients. Although each of these meningiomas could have occurred in otherwise normal young to middle-aged men, we speculate that the meningiomas may have grown in these HIV-infected hosts because of either loss of immune function or dysregulation of cytokines.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.

BACKGROUND: Reduced doses of cytotoxic chemotherapy or standard-dose therapy plus a myeloid colony-stimulating factor decreases hematologic toxicity and its complications in patients with non-Hodgkin's lymphoma associated with infection with the human immunodeficiency virus (HIV). However, the effect of reducing the doses of cytotoxic chemotherapeutic agents on clinical outcome is not known. METHODS: We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkin's lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte-macrophage colony-stimulating factor (GM-CSF; n=94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n=98). RESULTS: A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P= 0.56). There were no significant differences in overall or disease-free survival; median survival times were 35 weeks for patients receiving low-dose therapy and 31 weeks for those receiving standard-dose therapy (risk ratio for death in the standard-dose group=1.17; 95 percent confidence interval, 0.84 to 1.63; P=0.25). Toxic effects of chemotherapy rated grade 3 or higher occurred in 66 of 94 patients assigned to standard-dose therapy (70 percent) and 50 of 98 patients assigned to low-dose treatment (51 percent, P=0.008). Hematologic toxicity accounted for the difference. CONCLUSIONS: As compared with treatment with standard doses of cytotoxic chemotherapy (m-BACOD), reduced doses caused significantly fewer hematologic toxic effects yet had similar efficacy in patients with HIV-related lymphoma. Dose-modified chemotherapy should be considered for most HIV-infected patients with lymphoma.

Kaposi's sarcoma in women with AIDS.

OBJECTIVE: To describe the presentation and incidence of Kaposi's sarcoma (KS) in a cohort of women infected with HIV and to compare their clinical characteristics with men at the same institution. DESIGN: Retrospective chart and database review. SETTING: Adult clinical AIDS program outpatient clinics at a municipal teaching hospital. RESULTS: One hundred and seven people with KS were found of whom twelve (11.2%) were women. The prevalence of KS in women was 3.6% compared with 9.9% among men (P < 0.001). Women born outside the United States were at increased risk of developing KS (P < 0.05). At initial KS presentation, no difference in HIV stage or CD4 count was found between men and women. Women presented with more advanced KS than men, with increased incidence of non-cutaneous disease (P < 0.001), lymphedema (P < 0.0001), lymph-node disease (P < 0.0001) and visceral disease (P = 0.03). Women had decreased survival after KS diagnosis compared to men, although the difference was not significant (P = 0.41). CONCLUSIONS: KS is not a rare diagnosis in HIV-infected women followed at our institution. Although the increased risk of KS in men is most likely to be related to differences in exposure, the sex-related differences in presentation and course may be due in part to delay in diagnosis. KS should be considered in the spectrum of HIV-related complications in women as well as in men.

A phase I/II study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection.

In a phase I/II trial assessing the toxicity, pharmacokinetics, and activity of the (-)enantiomer of 2'-deoxy-3'-thiacytidine (3TC, lamivudine), 97 patients with AIDS or advanced human immunodeficiency virus (HIV) disease were administered 3TC at 0.5-20.0 mg/kg/day. The cohort's median entry CD4 cell count was 128/mm3 (range, 7-357). A toxic dose was not reached, although some patients reported mild headache, insomnia, and abdominal symptoms, and there was a general downward trend in neutrophil counts at the highest doses. Although subjective and difficult to interpret, increases in energy and appetite were noted, particularly in patients receiving > or = 8.0 mg/kg/day. Immunologic and virologic parameters showed evidence of at least transient anti-HIV activity at those higher doses. Although further studies of 3TC as monotherapy are needed, its favorable toxicity profile, evidence of at least transient clinical activity, and results of in vitro resistance experiments support further clinical testing in combination therapy.

Development of HIV-1 resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS or advanced AIDS-related complex.

OBJECTIVE: To determine the rate of development of in vitro HIV resistance to (-)2'-deoxy-3'-thiacytidine (3TC) and relate the effect of dose to emergence of resistance. METHODS: HIV-infected men and non-pregnant women, aged > or = 18 years, with a CD4 count < or = 300 x 10(6)/l cells were followed in a Phase I/II study, in which they were evaluated for tolerance to 3TC and effect of this agent with regard to viral susceptibility. Peripheral blood and plasma samples were collected at regular intervals for analysis. HIV was isolated using umbilical cord blood mononuclear cells as targets. These cells were also used in determinations of median inhibitory drug concentration. Specific amplification of the 184 mutation site, associated with HIV resistance to 3TC, was performed by polymerase chain reaction, using specific primer pairs, on DNA harvested from infected peripheral blood mononuclear cells (PBMC) of donors or, alternatively, on DNA that had been reverse transcribed from plasma-associated HIV RNA. RESULTS: Phenotypic resistance was detected in approximately one-third of individuals studied, who were followed between 8 and 56 weeks. Development of 3TC resistance occurred independently of dose, although time of first appearance of resistant HIV-1 variants appeared reduced at high 3TC doses. Amino-acid changes at codon 184 in HIV-1 reverse transcriptase were associated with, and preceded, the development of phenotypic 3TC resistance. Most commonly, a Met to Ile substitution appeared transiently before being superceded by a Val substitution at codon 184. CONCLUSIONS: In vitro resistance to 3TC developed in a high proportion of subjects who received prolonged monotherapy with this drug. The development of resistance to 3TC was associated with appearance of mutated viral forms and the disappearance of wild-type virus, with regard to codon 184, in both patient plasma and PBMC.

Pulmonary mycobacterial infections in AIDS: characteristic pattern of thallium and gallium scan mismatch.

PURPOSE: To evaluate the diagnostic specificity of thallium and gallium scan mismatch as a sign of mycobacterial infection in immunodeficient patients. MATERIALS AND METHODS: Thallium and gallium scans obtained in 56 immunodeficient patients between January 1989 and March 1994 were retrospectively reviewed, with special attention to the final diagnoses in all patients with thallium-gallium scan mismatch compared with those whose scans showed other scintigraphic patterns. RESULTS: Fourteen patients had focal gallium uptake, but no thallium uptake, in the mediastinum and hilar nodes (thallium-gallium mismatch). Twelve of the 14 had culture-proved mycobacterial infections; one had cryptococcal infection; and in one, the diagnosis was not established. Thirty-seven of the remaining 42 patients who had different scintigraphic patterns on thallium-gallium scans had other complications of acquired immunodeficiency syndrome such as Kaposi sarcoma, non-Hodgkin lymphoma, and bacterial pneumonia. The diagnosis in five of the 42 patients was not known because follow-up data were incomplete. CONCLUSION: The thallium-gallium mismatch pattern in immunodeficient patients is specific for mycobacterial infection.

pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo.

Specific mutations in the human immunodeficiency virus type 1 (HIV-1) pol gene that cause zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI) resistance were studied. The 50% inhibitory concentrations (IC50s) of nucleosides for cloned viruses containing these mutations were compared with the IC50s of the corresponding triphosphate analogs for mutant recombinant-expressed reverse transcriptases (RTs). Changes in ddATP inhibition of RNA-dependent DNA polymerase activity fully accounted for the ddI resistance of the virus caused by a Leu-74-->Val substitution in RT, including an augmentation by the AZT-selected substitutions Thr-215-->Tyr and Lys-219-->Gln in RT. In contrast, the AZT-selected substitutions studied did not cause as great a change in the IC50 of AZT-triphosphate (AZT-TP) for polymerase as they did in the IC50 of AZT for mutant virus. In addition, the mutation at codon 74 suppressed AZT resistance in the virus caused by the mutations at codons 215 and 219 but did not suppress the AZT-TP resistance of enzyme containing these same mutations in RT. The mutation at codon 74 was found in clinical isolates whether or not the patient had received AZT prior to starting ddI therapy. AZT resistance coexisted with ddI resistance following acquisition of Leu-74-->Val in three clinical isolates, indicating that the suppressive effect of Val-74 on the AZT resistance of the virus does not occur in all genetic contexts. When this suppression of AZT resistance was seen in the virus, Val-74 did not appear to cause mutually exclusive changes in AZT-TP and ddATP binding to RT in vitro. The results of the in vitro experiments and characterization of clinical isolates suggest that there are differences in the functional effects of these AZT and ddI resistance mutations.

Relation between plasma concentrations of didanosine and markers of antiviral efficacy in adults with AIDS or AIDS-related complex.

The relation between the average steady-state plasma concentration (Cpss) of didanosine and selected measures of efficacy, such as CD4 cell count, p24 antigenemia, and weight gain, was evaluated in patients participating in a phase 1 safety and pharmacokinetics study. All patients were diagnosed as having AIDS or severe AIDS-related complex. These individuals first received intravenous didanosine for 2 weeks at doses of 0.8-33 mg/(kg.d) and then took the drug orally at twice the intravenous dose. Cpss values were calculated on the basis of apparent oral clearance after 4 weeks of oral administration and average daily dose over the first 12 weeks of the study. These data were available for 61 patients enrolled at three clinical sites. High values for Cpss were strongly correlated with an increase in CD4 count (P = .006), a decrease in serum levels of p24 antigen (P = .006), and weight gain (P = .0001) at week 12. Logistic regression analysis was used to assess the influence of Cpss on response (as judged by the three criteria just mentioned) after adjustment for other potential factors related to infection with human immunodeficiency virus. The baseline CD4 cell count and the status with regard to prior zidovudine therapy were related to the CD4 response. However, the odds that a response would include all three parameters were nearly twice as high when the Cpss value increased by twofold.(ABSTRACT TRUNCATED AT 250 WORDS)

Didanosine in the treatment of AIDS and AIDS-related complex: a critical appraisal of the dose and frequency of administration.

In the summer of 1988, dose-finding phase 1 trials of the efficacy and safety of didanosine were begun by investigators at the National Cancer Institute (NCI), by the AIDS Clinical Trials Group (ACTG) at New York University School of Medicine and the University of Rochester School of Medicine, and by researchers at Boston City Hospital (BCH). The schedules of drug administration studied included once daily (BCH), twice daily (ACTG and NCI), and three times daily (NCI). The total daily dose studied ranged from 0.8 to 66 mg/(kg.d). Significant toxicities developed in more than half of the patients receiving doses of > or = 12 mg/(kg.d). Only 5% of patients given < 10 mg/(kg.d) developed grade 3 or 4 toxicities. Although CD4+ lymphocyte counts increased at doses as low as 1.6 mg/(kg.d), a minimal effective dose could not be determined. An analysis of data on serum levels of p24 antigen suggests that a dose of > or = 5 mg/(kg.d) is superior to lower doses in terms of activity against human immunodeficiency virus. A dose given on a once-daily schedule may exhibit less antiretroviral activity than the same dose given on a twice-daily schedule. Long-term follow-up of the phase 1 trial of the once-daily regimen at BCH has further documented the safety of didanosine given at doses of < 12 mg/(kg.d) for extended periods. A review of these studies suggests that a twice-daily schedule of didanosine administration at a daily dose of 5-10 mg/(kg.d) is safe and is associated with significant antiretroviral activity in vivo.

Longitudinal analysis of responses to oral didanosine therapy following zidovudine therapy in advanced infection with human immunodeficiency virus.

The effect on immunologic and virological parameters of up to 24 weeks of therapy with didanosine at daily oral doses of < or = 12.5 mg/(kg.d) was studied retrospectively in 69 patients with advanced disease due to human immunodeficiency virus--i.e., AIDS or advanced AIDS-related complex--who had previously been treated with zidovudine. Patients entered the study with a low CD4 cell count (median, 39/microL) and with evidence of an ongoing depression of bone marrow function. Didanosine therapy was associated with a significant increase in CD4 counts and a prolonged decrease in serum levels of p24 antigen relative to baseline. These changes were more pronounced in the population with baseline CD4 counts of > or = 100/microL. A beneficial effect of didanosine therapy on hematologic parameters was observed in these patients, with increases during therapy of hemoglobin levels as well as white blood cell, granulocyte, and platelet counts. These responses were maximal at weeks 16-20. Further investigations are needed to establish the clinical correlates of these observations.

Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease.

Myelosuppression is associated with human immunodeficiency virus (HIV) infection and may also be produced by agents used for the treatment of the disease or the treatment of its complications. Didanosine (ddl; 2',3'-dideoxyinosine) is a newer purine nucleoside that has recently become available for therapy for HIV infection. The effects of didanosine on peripheral blood counts have been retrospectively evaluated in the first 170 patients treated with this new agent in four phase I trials. Patients treated with didanosine showed statistically significant improvements in hemoglobin levels, white cell counts, and granulocyte and platelet numbers as compared with baseline values. These changes were seen with or without prior therapy with zidovudine, were somewhat more pronounced at higher doses of didanosine, and persisted for up to 1 year. Reported adverse events included peripheral neuropathy, diarrhea, and most notably, pancreatitis. It is concluded that, while some toxic side effects occur, didanosine therapy in HIV infection is associated with an amelioration of HIV-induced myelosuppression.

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

Pulmonary Kaposi sarcoma in patients with AIDS: scintigraphic diagnosis with sequential thallium and gallium scanning.

Pulmonary Kaposi sarcoma associated with acquired immunodeficiency syndrome (AIDS) is difficult to diagnose because the clinical presentations and radiographic findings are nonspecific. The authors report three proved cases of AIDS-associated pulmonary Kaposi sarcoma diagnosed with sequential thallium and gallium scans. These scans demonstrated abnormal increase of pulmonary thallium uptake, whereas the gallium uptake was negative. In the authors' experience and in reports in the radiology literature, infected areas of the chest are generally thallium-negative on the delayed (3-hour) scans but are gallium-avid, whereas lymphomas are both thallium- and gallium-avid. The authors conclude that sequential thallium and gallium scans can be used to help diagnose pulmonary Kaposi sarcoma and distinguish it from other common AIDS-associated chest complications such as lymphoma and infections.

Treatment of AIDS and AIDS-related complex with 2',3'-dideoxyinosine given once daily.

In a phase I dosage-finding trial, 2',3'-dideoxyinosine (didanosine; ddI) was administered once daily to 36 patients with AIDS or AIDS-related complex for up to 65 weeks (mean, 32.1 weeks) at six dosage levels. Thirteen of 18 patients previously treated with zidovudine had developed hematologic intolerance. The maximal tolerated dosage of ddI was 12 mg/(kg.d); dose-limiting toxicities were pancreatitis and peripheral neuropathy. Other toxicities included elevation in hepatic transaminase levels, rash, cardiac conduction abnormality, and asymptomatic hyperuricemia. Eighty-six percent of patients who completed 6 weeks of treatment showed improvement in constitutional symptoms and significant weight gain. In patients treated with ddI, the mean number of CD4+ lymphocytes increased from 124/mm3 at baseline to 199/mm3 at 24 weeks (P = .0027) and the mean leukocyte count, total lymphocyte count, and hemoglobin level showed increases (all P less than .01) after 12 weeks. Serum levels of viral p24 antigen decreased greater than or equal to 50% in 14 of 19 assessable patients. No differences between the responses of patients previously treated with zidovudine and those of zidovudine-naive patients were observed. These results indicate that ddI has significant antiretroviral activity in vivo and a toxicity profile different from that of zidovudine.

Once-daily administration of 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial.

We conducted a Phase I open-label trial of 2',3'-dideoxyinosine (ddI) for the treatment of the acquired immunodeficiency syndrome (AIDS) and severe AIDS-related complex. A single daily dose of ddI was administered orally to 34 patients (17 with AIDS and 17 with AIDS-related complex) for a median of 12 weeks (range, 2 to 56). We studied six dose levels from 1.6 to 30.4 mg per kilogram of body weight per day. Of the 17 patients previously treated with zidovudine, 13 had had hematologic side effects. The maximal tolerated dose of oral ddI was estimated to be 20.4 mg per kilogram per day. Pancreatitis and peripheral neuropathy were the major dose-limiting toxic effects. Other toxic effects included elevations in hepatic transaminase levels, abnormalities in cardiac conduction, rash, and asymptomatic elevations in serum urate levels and the creatine kinase fraction from skeletal muscle. Treatment with ddI was associated with an increase in the mean number of CD4 lymphocytes from 125 per cubic millimeter at base line to 182 per cubic millimeter after 10 weeks (P = 0.005). There were also increases after 12 weeks in the mean total lymphocyte count (from 0.8 to 1.2 x 10(9) per liter) and the mean hemoglobin level (from 12.9 to 14.1 g per deciliter) (both P less than 0.01). The amount of human immunodeficiency virus p24 antigen decreased by more than 50 percent in 14 of 19 patients with detectable antigen. No differences in response were observed between patients previously treated with zidovudine and those never treated with the drug. We conclude that ddI has antiretroviral activity in patients with AIDS or AIDS-related complex and that the toxicity of ddI differs from that of zidovudine. However, controlled trials are necessary to evaluate the efficacy of ddI.