Household ventilation and tuberculosis transmission in Kampala, Uganda.

OBJECTIVE: To test the feasibility of measuring household ventilation and evaluate whether ventilation is associated with tuberculosis (TB) in household contacts in Kampala, Uganda. DESIGN: Adults with pulmonary TB and their household contacts received home visits to ascertain social and structural household characteristics. Ventilation was measured in air changes per hour (ACH) in each room by raising carbon dioxide (CO2) levels using dry ice, removing the dry ice, and measuring changes in the natural log of CO2 (lnCO2) over time. Ventilation was compared in homes with and without co-prevalent TB. RESULTS: Members of 61 of 66 (92%) households approached were enrolled. Households averaged 5.4 residents/home, with a median of one room/home. Twelve homes (20%) reported co-prevalent TB in household contacts. Median ventilation for all rooms was 14 ACH (interquartile range [IQR] 10-18). Median ventilation was 12 vs. 15 ACH in index cases' sleeping rooms in households with vs. those without co-prevalent TB (P = 0.12). Among smear-positive indexes not infected by the human immunodeficiency virus (HIV), median ventilation was 11 vs. 17 ACH in index cases' sleeping rooms in homes with vs. those without co-prevalent TB (P = 0.1). CONCLUSION: Our findings provide evidence that a simple CO2 decay method used to measure ventilation in clinical settings can be adapted to homes, adding a novel tool and a neglected variable, ventilation, to the study of household TB transmission.

A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/µL.

BACKGROUND: Optimal treatment of human immunodeficiency virus (HIV)-associated tuberculosis in patients with high CD4⁺ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression. METHODS: We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/µL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4⁺ T-cell counts of < 250 cells/µL, AIDS, or death. RESULTS: Intervention and comparison arms had similar median CD4⁺ counts (517 and 534 cells/µL, respectively) and HIV RNA levels (4.6 and 4.7 log10 copies/µL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis. CONCLUSIONS: Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4⁺T-cell counts of >350 cells/µL was safe and associated with clinical benefits.

Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata.

BACKGROUND: The human immunodeficiency virus (HIV) alters the presentation of pulmonary tuberculosis (PTB), but it remains unclear whether alterations occur at a CD4 cell threshold or throughout HIV infection. OBJECTIVE: To better understand the relationship between CD4 count and clinical and radiographic presentation of PTB. SETTING AND DESIGN: Initial presentations of culture-confirmed PTB patients evaluated at a Ugandan national TB referral center and an affiliated research unit were compared by HIV status and across 11 CD4 cell count strata: 0-50 to >500 cells/µl. RESULTS: A total of 873 HIV-infected PTB cases were identified. Among HIV-infected PTB cases with CD4 < 50, 21% had a normal chest X-ray (CXR) vs. 2% with CD4 > 500, with a continuous trend across CD4 strata (test for trend, P < 0.001). All radiographic manifestations of PTB displayed significant trends across CD4 strata. HIV-infected vs. non-HIV-infected patients had no significant difference in CXR findings of miliary patterns or pleural effusion at CD4 > 100, normal CXR or fibrosis at CD4 > 150, adenopathy at CD4 > 250, and cavitation or upper lung disease at CD4 > 300. Twenty-three per cent of co-infected cases with CD4 < 50 and 1% with CD4 > 500 had negative acid-fast bacilli (AFB) smears, with a significant trend between (P < 0.001). CONCLUSION: Variations in CXR appearance and AFB smear correlate with CD4 decline in significant, continuous trends.

It's not just what you say: relationships of HIV dislosure and risk reduction among MSM in the post-HAART era.

In the post-HAART era, critical questions arise as to what factors affect disclosure decisions and how these decisions are associated with factors such as high-risk behaviors and partner variables. We interviewed 1,828 HIV-positive men who have sex with men (MSM), of whom 46% disclosed to all partners. Among men with casual partners, 41.8% disclosed to all of these partners and 21.5% to none. Disclosure was associated with relationship type, perceived partner HIV status and sexual behaviors. Overall, 36.5% of respondents had unprotected anal sex (UAS) with partners of negative/unknown HIV status. Of those with only casual partners, 80.4% had >1 act of UAS and 58% of these did not disclose to all partners. This 58% were more likely to self-identify as gay (versus bisexual), be aware of their status for <5 years and have more partners. Being on HAART, viral load and number of symptoms were not associated with disclosure. This study - the largest conducted to date of disclosure among MSM and one of the few conducted post-HAART - indicates that almost 1/5th reported UAS with casual partners without disclosure, highlighting a public health challenge. Disclosure needs to be addressed in the context of relationship type, partner status and broader risk-reduction strategies.

Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention.

OBJECTIVES: Voluntary counseling and testing (VCT) for the human immunodeficiency virus (HIV) is recommended for persons treated for tuberculosis (TB). Opportunities to diagnose HIV may be missed by limiting HIV testing to only persons diagnosed with TB. Among TB suspects in Uganda, we determined HIV prevalence, risk behaviors, and willingness to refer family for VCT. METHODS: Consenting adult patients presenting for evaluation at a referral TB clinic received same-day VCT. TB diagnosis data were abstracted from clinical records. RESULTS: Among 665 eligible patients, 565 (85%) consented to VCT. Among these, 238 (42%) were HIV-positive. Of the HIV-infected patients, 37% had received a non-TB diagnosis. HIV seroprevalence was higher in patients with a non-TB diagnosis (49%) than those diagnosed with TB (39%) (P = 0.02). Fewer than 6% of HIV-infected patients reported always using condoms with sexual partners. The majority of patients (86%) reported being 'very willing' to refer family members for VCT. CONCLUSIONS: Over 35% of HIV-infected cases in our population would have been undetected if HIV testing was limited to cases with diagnosed TB. The high HIV seroprevalence in both TB and non-TB cases merits HIV testing for all patients evaluated at TB clinics. HIV-infected TB suspects reporting high-risk behavior are at risk for HIV transmission, and should receive risk-reduction counseling.

Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

OBJECTIVE: To evaluate the early bactericidal activity (EBA) of the new fluoroquinolones levofloxacin, gatifloxacin and moxifloxacin in patients with pulmonary tuberculosis (PTB). DESIGN: Randomized, open-label trial. Forty adults with newly diagnosed smear-positive PTB (10 per arm) were assigned to receive isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. Sputum for quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (EBA 0-2) and last 5 days of monotherapy (extended EBA, EBA 2-7). Laboratory staff were blinded to treatment assignment. RESULTS: The EBA 0-2 of INH (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day) (P = 0.14). Bactericidal activity between days 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison, the EBA 2-7 of the fluoroquinolones was greater than for INH. CONCLUSION: Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA. These drugs warrant further study in the treatment of drug-susceptible TB.

Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study.

We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV naïve, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

Modeling the impact of modified directly observed antiretroviral therapy on HIV suppression and resistance, disease progression, and death.

A simulation model that used Markov assumptions with Monte Carlo uncertainty analysis was evaluated 1500 times at 10,000 iterations. Modified directly observed therapy (MDOT) for human immunodeficiency virus was assumed to improve adherence to therapy to 90% of prescribed doses. The impact of MDOT interventions on modeled biological and clinical outcomes was compared for populations with mean rates of adherence (i.e., the mean percentage of prescribed doses taken by each member of the population who had not discontinued therapy) of 40%, 50%, 60%, and 70%. MDOT reduced the risk of virological failure, development of opportunistic infections, and death, yet increased the risk of drug resistance, for each adherence distribution among persons with detectable plasma virus loads. Over 1500 trials, for a population with 50% adherence to therapy and a 12-month period, MDOT increased the median rate of virological suppression from 13.2% to 37.0% of patients, decreased the rate of opportunistic infection from 5.7% to 4.3% of patients, and decreased the death rate from 2.9% to 2.2% of patients. In the same population, however, MDOT increased the rate of new drug resistance mutations from 1.00 to 1.41 per person during the 12-month period. The impact of MDOT was smaller in populations with higher levels of adherence. MDOT interventions will likely improve clinical outcomes in populations with low levels of adherence but may not be effective at preventing drug resistance in treatment-experienced populations. MDOT may be more effective in preventing drug resistance with potent regimens in treatment-naive patients.

Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial.

BACKGROUND: Increasing Plasmodium falciparum resistance to chloroquine in sub-Saharan Africa necessitates use of alternative antimalarial agents. Affordable alternative treatments include sulfadoxine/pyrimethamine and amodiaquine. Combination of antimalarial agents can increase therapeutic efficacy and delay emergence of drug resistance. We compared the efficacy of sulfadoxine/pyrimethamine, amodiaquine, and an amodiaquine/sulfadoxine/pyrimethamine combination for treatment of uncomplicated malaria in a region of high chloroquine resistance. METHODS: Patients with symptoms of uncomplicated falciparum malaria and confirmed disease in Kampala, Uganda, were randomly assigned to receive sulfadoxine/pyrimethamine (25 mg/kg sulfadoxine, and 1.25 mg/kg pyrimethamine) plus placebo; amodiaquine (25 mg/kg) plus placebo; or amodiaquine plus sulfadoxine/pyrimethamine. Patients were followed up for 14 days, and clinical and parasitological outcomes were assessed. FINDINGS: 90% (400/445) of patients enrolled in the study successfully completed 14 days of follow-up. Treatment failure based on clinical criteria occurred in 13 of 131 (10%) patients on sulfadoxine/ pyrimethamine, nine of 131 (7%) on amodiaquine, and four of 138 (3%) on amodiaquine/sulfadoxine/pyrimethamine. Based on parasitological criteria, treatment failed in 26%, 16%, and 10% of these patients, respectively. Amodiaquine/sulfadoxine/pyrimethamine was significantly more effective than sulfadoxine/pyrimethamine alone in children aged younger than 5 years (clinical failure in 3.5% vs 13.9%, respectively, risk difference 10.4% [95% CI, 1.6-19.3] p=0.021; parasitological failure in 12.8% vs 26.4%, risk difference 13.6% [1.2-26.0] p=0.041). INTERPRETATION: Sulfadoxine/pyrimethamine, amodiaquine, and amodiaquine/sulfadoxine/pyrimethamine were all effective for treatment of uncomplicated falciparum malaria in Uganda. The amodiaquine/sulfadoxine/pyrimethamine combination was the most effective, and could be the optimum low-cost alternative to chloroquine in Africa.

Provider assessment of adherence to HIV antiretroviral therapy.

BACKGROUND: Adherence assessment is an essential component of monitoring HIV antiretroviral therapy. Prior studies suggest that medical providers frequently estimate individual patient adherence inaccurately. OBJECTIVE: We compared provider estimates of nonadherence to antiretroviral therapy with unannounced pill counts and structured patient interviews to determine the accuracy of adherence information obtained by providers and patients. DESIGN, SETTING, AND PARTICIPANTS: Comparison of three adherence measures in homeless or marginally housed persons receiving HIV antiretroviral therapy (n = 45) and their providers (n = 35). MEASUREMENTS: Provider estimate of percentage of pills taken; three successive patient structured reports of number of doses missed in the last 3 days; and three successive unannounced pill counts. RESULTS: 13% (95% confidence interval [CI], 4%-22%) of patients were not following their regimen as directed. Provider-adherence estimate explained only 26% (95% CI, 6%-47%) of the variation in pill count adherence, whereas patient report explained 72% (95% CI, 52%-96%). The sensitivity and specificity of provider estimates of nonadherence, defined as <80% of pills taken by pill count, were 40% and 85%, respectively. The sensitivity and specificity of patient interview were 72% and 95%, respectively. CONCLUSIONS: Provider estimate of adherence was inaccurate whereas structured patient report was more closely related to pill count. Structured assessment over several short intervals may improve accuracy of adherence assessment in clinical practice.

Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population.

OBJECTIVE: To examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy. DESIGN AND SETTING: A cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels. PARTICIPANTS: Thirty-four HIV-infected people with a median of 12 months of PI therapy. MAIN OUTCOMES: Adherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance. RESULTS: Median adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36-65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03). CONCLUSION: A substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

Quantitative and cost comparison of ultrasensitive human immunodeficiency virus type 1 RNA viral load assays: Bayer bDNA quantiplex versions 3.0 and 2.0 and Roche PCR Amplicor monitor version 1.5.

Quantification of human immunodeficiency virus type 1 (HIV-1) RNA as a measure of viral load has greatly improved the monitoring of therapies for infected individuals. With the significant reductions in viral load now observed in individuals treated with highly active anti-retroviral therapy (HAART), viral load assays have been adapted to achieve greater sensitivity. Two commercially available ultrasensitive assays, the Bayer Quantiplex HIV-1 bDNA version 3.0 (bDNA 3.0) assay and the Roche Amplicor HIV-1 Monitor Ultrasensitive version 1.5 (Amplicor 1.5) assay, are now being used to monitor HIV-1-infected individuals. Both of these ultrasensitive assays have a reported lower limit of 50 HIV-1 RNA copies/ml and were developed from corresponding older generation assays with lower limits of 400 to 500 copies/ml. However, the comparability of viral load data generated by these ultrasensitive assays and the relative costs of labor, disposables, and biohazardous wastes were not determined in most cases. In this study, we used matched clinical plasma samples to compare the quantification of the newer bDNA 3.0 assay with that of the older bDNA 2.0 assay and to compare the quantification and costs of the bDNA 3.0 assay and the Amplicor 1.5 assay. We found that quantification by the bDNA 3.0 assay was approximately twofold higher than that by the bDNA 2.0 assay and was highly correlated to that by the Amplicor 1.5 assay. Moreover, cost analysis based on labor, disposables, and biohazardous wastes showed significant savings with the bDNA 3.0 assay as compared to the costs of the Amplicor 1.5 assay.

Expanding access to early HIV care: new challenges for federal health policy.

Advances in biomedical research have resulted in new standards for HIV treatment that involve earlier intervention with more complex combination antiretroviral therapy. This article examines the implications of these treatments for federally funded programs that provide HIV care and discusses mechanisms for making Medicaid and the AIDS Drug Assistance Program (ADAP) consistent with the treatment standards. The article provides a rationale for expanding access by expanding entitlement programs (Medicaid) rather than discretionary programs (ADAP). A potential legislative approach to Medicaid expansion is described. Cost projections suggest that this approach is feasible and would constitute a significant step toward increasing access to HIV care.

Limited antibody-dependent cellular cytotoxicity antibody response induced by a herpes simplex virus type 2 subunit vaccine.

The humoral response to a herpes simplex virus (HSV) type 2 subunit vaccine containing recombinant glycoproteins B (gB2) and D (gD2) was tested in 3 groups of patients. These included HSV-seronegative, HSV-1-seropositive, and HSV-2-seropositive individuals. There were excellent antibody responses, as measured by gB2- and gD2-specific ELISAs and HSV-2 neutralization assays. However, in 2 HSV-2 antibody-dependent cellular cytotoxicity (ADCC) assays, there were relatively low antibody responses, especially among HSV-seronegative individuals. The low ADCC responses may be associated with the poor efficacy of this vaccine observed in clinical trials.

Risk factors for early hospital readmission in patients with AIDS and pneumonia.

OBJECTIVE: To determine risk factors for early readmission to the hospital in patients with AIDS and pneumonia. DESIGN: Case-control analysis. SETTING: A municipal teaching hospital serving an indigent population. PATIENTS: Case patients were all AIDS patients hospitalized with Pneumocystis carinii pneumonia or bacterial pneumonia between January 1992 and March 1995 who were readmitted for any nonelective reason within 2 weeks of discharge (n = 90). Control patients were randomly selected AIDS patients admitted during the study period who were not early readmissions (n = 87), matched by proportion of Pneumocystis carinii to bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: Demographics, social support, health-related behaviors, clinical aspects of the acute hospitalization, and general medical status were the main predictors measured. RESULTS: Patients were at significantly increased risk of early readmission if they left the hospital unaccompanied by family or friend (odds ratio [OR] 4.76; 95% confidence interval [CI] 2.06, 11.0; p =.0003), used crack cocaine (OR 3.40; 95% CI 1.02, 11.3; p =. 046), had one or more coincident AIDS diagnoses (OR 3.65; 95% CI 1. 44, 9.26; p =.0065), or had been admitted in the preceding 6 months (OR 2.82; 95% CI 1.21, 6.57; p =.016). Demographic characteristics, alcoholism, intravenous drug use, illness severity on admission, and length of hospitalization did not predict early readmission. CONCLUSIONS: Absence of companion at discharge and crack use were important risk factors for early readmission in patients with AIDS and pneumonia. Additional AIDS comorbidity and recent antecedent hospitalization were also risk factors; however, demographics and measures of acute illness during index hospitalization did not predict early readmission.

Physician-assisted suicide and patients with human immunodeficiency virus disease.

BACKGROUND: Data are limited on the attitudes and practices of physicians regarding assisting the suicide of patients with human immunodeficiency virus (HIV) disease. METHODS: Between November 1994 and January 1995, we used an anonymous, self-administered questionnaire to survey all 228 physicians in the Community Consortium, an association of providers of health care to patients infected with HIV in the San Francisco Bay area. The responses were compared with those in a 1990 survey of consortium physicians. Physician-assisted suicide was defined as "a physician providing a sufficient dose of narcotics to enable a patient to kill himself." Respondents were to "assume that the patient is a mentally competent, severely ill individual facing imminent death." RESULTS: One hundred eighteen of the questionnaires were evaluated. Respondents reported a mean of 7.9 "direct" and 13.7 "indirect" requests from patients for assistance. In responses based on a case vignette, 48 percent of the physicians said they would be likely or very likely to grant the request of a patient with the acquired immunodeficiency syndrome (AIDS) for assistance in a suicide, as compared with 28 percent of the respondents in 1990. Asked to estimate the number of times they had granted the request of a patient with AIDS for assistance in committing suicide, 53 percent said they had done so at least once (mean number of times, 4.2; median, 1.0; range, 0 to 100). In a multivariate analysis, factors positively associated with having, in fact, assisted a suicide were having had a higher number of patients with AIDS who had died, a higher number of indirect requests from patients for assistance, a stated gay, lesbian, or bisexual orientation on the part of the physician, and a higher "intention to assist" score (as calculated from the physician's responses to the case vignette). CONCLUSIONS: Within a group of physicians caring for patients with HIV disease, the acceptance of assisted suicide increased between 1990 and 1995. A majority of respondents in 1995 said they had granted a request for assisted suicide from a patient with AIDS at least once.

Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Pulmonary Complications of HIV Infection Study Group.

The Pulmonary Complications of HIV Infection Study is a prospective, multicenter, observational study evaluating pulmonary disease among HIV-infected persons. For approximately 52 mo, 1,182 HIV-infected subjects were followed. All participants were evaluated for pulmonary disease on a predetermined schedule. There were 145 episodes of Pneumocystis carinii pneumonia (PCP). Low CD4 count correlated with risk of PCP (p < 0.0001); 79% had CD4 counts less than 100/microl and 95% had CD4 counts less than 200/microl. Subtle changes in diffusing capacity for carbon monoxide (DLCO) were associated with PCP. Univariate analysis identified recurrent undiagnosed fevers, night sweats, oropharyngeal thrush, and unintentional weight loss to be associated with risk among persons with CD4 counts above 200/microl. Subjects in whom CD4 counts declined to below 200/microl and who were not receiving preventive therapy were nine times more likely to develop PCP within 6 mo compared with subjects who received such therapy. A strong trend toward differences between the sexes was detected. Black subjects had less than one third the risk of developing PCP as did white subjects (p < 0.0001). There was no significant difference in risk by HIV transmission category, study site, frequency of follow-up, age, education, smoking history, or use of antiretroviral therapy. Multivariable analysis revealed low CD4 lymphocyte count (p < 0.0001), use of prophylaxis (p < 0.0001), racial differences (p < 0.0001), and declining DLCO (p = 0.015) to influence risk. Constitutional signs and symptoms indicate increased risk for PCP among HIV-infected persons with CD4 counts above 200/microl.

Interleukin-12 administered in vivo decreases human NK cell cytotoxicity and antibody-dependent cellular cytotoxicity to human immunodeficiency virus-infected cells.

Persons infected with human immunodeficiency virus (HIV) have cellular cytotoxicity defects. Interleukin (IL)-12 is a potent stimulator of cytotoxicity. Fifteen HIV-infected patients were studied in a phase 1, single-dose escalation trial of human recombinant IL-12. One day after subjects received an IL-12 dose of 300 or 1000 ng/kg, they had a reduction in absolute lymphocyte count and peripheral blood mononuclear cell recovery. In evaluable patients 24 h after IL-12 administration, there was a 31% reduction overall in NK cell cytotoxicity (NKC) to HIV-infected cells at all doses and a 52% reduction in antibody-dependent cellular cytotoxicity (ADCC) at doses of 300 and 1000 ng/kg. In vitro incubation of patients' cells with IL-12 (before IL-12 administration) for 24 h increased NKC but had no effect on ADCC. The paradoxic acute reduction in cell number and cytotoxicity in vivo may be due to NK cell trafficking or regulatory cytokine mechanisms not apparent in vitro.