Public health consequences of screening patients for adherence to highly active antiretroviral therapy.

Improvements in HIV antiretroviral therapy (ART) have been accompanied by increasing recognition of the importance of adherence to treatment regimens for maximizing patient benefits while minimizing the emergence of drug-resistant virus. Whether clinicians should screen patients for adherence and only administer therapy to those believed likely to adhere has not been resolved. We first examine the implications of data drawn from a recent study reporting physicians' ability to predict whether patients will adhere to highly active antiretroviral therapy (HAART) or not. We then extend previously developed mathematical models of ART to include screening for adherence and focus on resulting drug resistance as well as on HIV and AIDS incidence at the population level. We show that although screening for adherence is likely to reduce the level of drug resistance compared with a policy of treating all HIV patients with HAART, rates of new HIV infections and AIDS cases in the population would likely increase unless screening accuracy is extremely (perhaps implausibly) high.

Evaluating plasma holds in the presence of multiple infections.

To protect plasma supplies, donors are screened for infectious diseases. As an added measure of protection, donations are identified and stored for a period of time to allow future discard in the event that an identified donor subsequently tests positive for some screened disease. Previous models for evaluating such plasma holds have only addressed the case of a single infectious disease. This paper extends the analysis to the case of multiple infections. Given knowledge of the marginal incidence rates for those infections checked, upper and lower bounds for important quantities such as the probability of interdicting an infectious but undetected donation, the expected number of infections interdicted per donation, and the net economic benefits of the holding policy are developed. Several examples are developed, illustrating how the models can be used to evaluate the consequences of a plasma hold.

Repeat screening for HIV: when to test and why.

This paper presents models for repeat HIV screening under conditions of constant low HIV incidence. The models reveal a direct link between the prevalence of undetected HIV infection and the screening interval between repeat HIV tests. We show how to select screening intervals that either achieve a given HIV prevalence level, or optimally balance the cost of repeat HIV testing against the cost of HIV infection. Alternatively, given an existing repeat screening program, the model implies that cost of infection for which the given screening interval is optimal. The method also suggests how to select an HIV testing technology. The models are applied to existing repeat testing programs in the U.S. Army and among legal commercial sex workers in the state of Nevada in the Far West of the United States.

New approaches to HIV surveillance: means and ends. Summary report of conference held at Yale University, 21-22 May 1998, by the Law, Policy and Ethics Core, Center for Interdisciplinary Research on AIDS, Yale University.

A system of HIV surveillance based on AIDS case reporting is no longer adequate to monitor the epidemic of HIV/AIDS in the U.S. We are now faced with the challenge of designing an effective system of HIV surveillance. The "New Approaches to HIV Surveillance: Means and Ends" conference emphasized that there are several alternatives, each with strengths and limitations. The CDC has recommended that all states adopt a system of HIV surveillance based on case reporting. Although it has not specified that such systems need be name-based, CDC appears to reward states that adopt name-reporting systems. The rationale for this stance should be reviewed and made explicit. Name reporting may be superior in some respects to a system of case reports based on unique identifiers (UIs), especially in its greater ability to link surveillance activities to follow up at the individual level. Neither a name-reporting nor a UI approach to case reporting would provide HIV incidence data. The only currently envisioned means of providing incidence data is statistical estimation based on "snapshot estimates" of HIV incidence in sample cohorts. Calibration of this new instrument for HIV incidence estimation against existing data or through field trials is of critical importance.

Accidental, intravenous infusion of a peanut oil-based medication.

OBJECTIVES: To describe a case of fat embolus syndrome with lipoid pneumonia resulting from intravenous infusion of lipid and to illustrate the potential for accidental intravenous administration of vegetable oil-based progesterone preparations in the treatment of oncology patients. CASE REPORT: A patient with recurrent ovarian carcinoma accidentally received approximately 20 mL (0.29 mL/kg) of a peanut oil-based methylprogesterone product intravenously via infusion pump over 24 hours. The patient developed a lipoid pneumonia with dyspnea, cough, hypoxia, radiographic infiltrates, and a pleural effusion. She was hospitalized for 4 days, and signs and symptoms resolved over 2 weeks following steroids and supportive care. DISCUSSION: Experience with accidental or intentional intravenous lipid overdose in humans is limited. Typical findings of fat embolus syndrome are similar to lipid aspiration, with respiratory distress, hypoxia, and pulmonary infiltrates. In contrast to aspiration, however, fat embolus syndrome results in lipogranulomas surrounding blood vessels, rather than air passages, and potentially produces cerebrovascular, accident-like symptoms. Management of fat embolus syndrome is similar to that for lipid aspiration. However, as seen in this case, fat embolus syndrome typically resolves over several weeks as opposed to the 3-month to 1-year period seen with aspiration lipoid pneumonias. CONCLUSIONS: Accidental intravenous infusion of vegetable oil-based products is a potential complication of the increased use of intravenous progesterones.

The cost-effectiveness of HIV testing: accounting for differential participation rates.

OBJECTIVE: To understand the impact of differences in participation rates between infected and uninfected individuals on estimates of the cost-effectiveness of HIV screening. METHODS: Costs per infection detected are modeled as function of both prevalence and serostatus-dependent testing rates. Data from national surveillance surveys, seroprevalence studies, and other sources are employed to suggest the magnitude of results. RESULTS: Differential participation produces a near-doubling in the estimated cost per infection identified. This result is sensitive to assumptions regarding the benefits of screening for seronegatives. CONCLUSIONS: Voluntary HIV screening programs may incur prohibitive costs by over-recruiting people at little risk of infection. Failure to account for differential participation can result in over-optimistic cost-effectiveness estimates. However, the relevance of this result--and the significance of both prevalence and participation as cost drivers--is overwhelmed by what is assumed about the benefits conferred to uninfected people by HIV screening.

Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study.

PURPOSE: A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS: Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS: Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION: Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm.

Cutaneous T-cell lymphomas.

Cutaneous T-cell lymphoma, which usually presents as mycosis fungoides or Sézary syndrome, remains a mostly incurable, yet highly treatable group of diseases. The myriad of active therapies continues to grow, and new insights into the mechanism of systemic and topical therapies are being elucidated. Multimodality treatment initiated for early-stage disease may help improve long-term survival. The need for randomized prospective trials is obvious and should become a priority. Further development of molecular genetic techniques and cell-surface phenotyping has enhanced our understanding of these diseases and will hopefully allow for the development of more effective and specific treatments.

Immunoscintigraphy performed with In-111-labeled CYT-103 in the management of colorectal cancer: comparison with CT.

Immunoscintigraphy performed after intravenous administration of indium-111-labeled CYT-103, an immunoconjugate of monoclonal antibody B72.3, was evaluated in patients with suspected primary or recurrent colorectal cancer at 25 centers in the United States. Gamma camera imaging, computed tomography (CT), and confirmatory surgical exploration were completed in 169 of 227 patients who received single infusions of In-111 CYT-103. Eight patients (3.5%) had reversible, nonserious adverse reactions, and 39% developed antimurine antibodies. Surgery revealed that 155 of 169 patients had colorectal carcinoma. In these 155 patients, immunoscintigraphy and CT demonstrated similar sensitivity (69% and 68%, respectively) and specificity (77%). However, immunoscintigraphy had greater sensitivity in detection of pelvic tumors (74% vs 57%, P = .035) and extrahepatic abdominal tumors (66% vs 34%, P less than .001); CT enabled detection of a greater proportion of liver metastases (84% vs 41%, P less than .001). These results indicate that In-111 CYT-103 can be administered safely and that immunoscintigraphy performed with this agent frequently enables identification of extrahepatic abdominal sites of disease not visualized with CT.

Modeling zidovudine therapy: a cost-effectiveness analysis.

Zidovudine (ZDV), the first FDA-approved therapy for HIV/AIDS, poses a dilemma to the policymaker. On the one hand, ZDV extends the life of HIV-infected persons, producing a clear benefit. On the other hand, some fear that prolonging the lives of infected individuals may contribute to the increased spread of the virus and to a steep rise in the overall costs of AIDS to society. To address this issue, we present a simple model of ZDV therapy against a backdrop of HIV transmission in a population of sexually active, gay men. We find no basis for the fear of dramatic increases in the incidence of AIDS or its associated costs among gay men due to widespread ZDV distribution. On the contrary, our analysis suggests that ZDV therapy is cost-effective, particularly when it is accompanied by modest efforts to promote behavior change and prevention.

Phase II study of recombinant human interferon gamma for treatment of cutaneous T-cell lymphoma.

Recombinant human interferon gamma (rIFN-gamma) was used for the treatment of 16 patients with various stages of cutaneous T-cell lymphoma (CTCL). All patients had been previously treated with standard topical and/or systemic therapies, and some had received experimental treatment with retinoids, recombinant human interferon alfa-2a (rIFN-alpha 2a), or radiolabeled monoclonal antibodies; most patients had an advanced stage of disease. Objective partial responses (PRs) were noted in five patients (31%) and lasted 3 months to greater than 32 months (median, 10 mo). One of these five patients had previously had disease progression after an initial PR with rIFN-alpha 2a. Six other patients (38%) showed minor or mixed responses. The most common side effects of rIFN-gamma included fever, weight loss, mild neutropenia, elevated lactate dehydrogenase, and elevated hepatic transaminases. Additionally, one episode of nephrotic syndrome and one cutaneous allergic reaction were noted. None of the toxic effects were life threatening, and all were reversible. These results suggest that rIFN-gamma has efficacy in the treatment of CTCL refractory to rIFN-alpha 2a.

Modeling HIV infectivity: must sex acts be counted?

The simplest models of HIV infectivity treat the HIV transmission process as a series of independent Bernoulli trials over sex acts or sex partners. In this paper, an approximate maximum likelihood estimator of the transmission probability is derived for such models, and applied to two data sets. Nonparametric models of HIV infectivity are constructed as alternatives for comparison to the simple models. The results suggest that while HIV infectivity can be modeled as a Bernoulli process with a constant infection probability per partner, the Bernoulli model may not be appropriate at the level of sexual contacts. Probabilistic arguments consistent with these findings are proposed and discussed.

Needles that kill: modeling human immunodeficiency virus transmission via shared drug injection equipment in shooting galleries.

Case notification data from the U.S. Centers for Disease Control imply that AIDS has spread rapidly among intravenous drug users in the northeastern United States. These data determine a doubling time for AIDS cases of 5-6 months for this population early in the epidemic. A new mathematical model of transmission of human immunodeficiency virus (HIV) via shared drug injection equipment in "shooting galleries" is developed to understand the rapid spread of HIV and AIDS among drug users. The model depends on quantities such as rates of sharing injection equipment, the ratio of addicts to injection equipment in the population, the infectivity of HIV transmitted by shared injection equipment, the likelihood that infectious equipment is "flushed" by the blood of an uninfected user, and the duration of needle-sharing activity by HIV-infected addicts. The model is extended to incorporate the impact of cleansing or bleaching of injection equipment. Also, the model is reformulated to account for the inactivation of HIV infectiousness over time. The models demonstrate that policies such as the distribution of cleansing solutions and/or injection equipment among drug addicts could slow or stop the intravenous transmission of HIV in shooting galleries.

The diagnostic and therapeutic use of monoclonal antibodies in colorectal cancer.

Preliminary trials have illustrated that monoclonal antibodies can be administered safely, tumor binding can be achieved, and sensitive radioimaging may be possible. Additionally, clinical responses in patients with colorectal carcinoma can occur. The limitations of murine monoclonal therapy are now being addressed and in time will be overcome. Monoclonal antibodies offer great promise in the diagnosis and therapy of malignant disease. Further investigation using innovative approaches and in combination with other therapies may help to reach this goal.

Long-term persistence of human anti-murine antibody responses following radioimmunodetection and radioimmunotherapy of cutaneous T-cell lymphoma patients using 131I-T101.

Five cutaneous T-cell lymphoma (CTCL) patients have been imaged and treated with radiolabeled murine monoclonal antibody 131I-T101 in our laboratory. All patients developed human anti-murine antibody responses (HAMA) 14 days after the primary antibody infusion. HAMA responses could still be detected more than 22 months after T101 treatment. A substantial proportion of HAMA was crossreactive with any IgG2a antibody tested, although there did exist a specific anti-idiotypic component to HAMA. HAMA were of both IgM and IgG isotype. We also analyzed the effects of plasmapheresis on the specific HAMA isotypes in three patients who were retreated at the time of disease progression.

Radioimmunotherapy of patients with cutaneous T-cell lymphoma using an iodine-131-labeled monoclonal antibody: analysis of retreatment following plasmapheresis.

Radioimmunotherapy retreatment of patients receiving radiolabeled murine monoclonal antibodies is difficult because of human antimurine antibody (HAMA) formation. Retreatment therapy was initiated in three patients at the time of disease progression using a radioiodinated monoclonal antibody (T101). The clinical protocol consisted of a two day plasma exchange (4-6 L) to reduce HAMA titers. Immunoimaging was performed with 5 mCi 131I-T101 (10 mg). Gamma scintillation images were obtained 18 hr postinfusion, and radiation dosimetry estimates were performed. At 24 hr postinfusion, each patient received a 100-mCi 131I-T101 (10 mg) therapy dose. Results obtained after plasmapheresis showed a significant reduction, ranging from 28%-61%, in HAMA titers. Blood clearances were markedly different between initial therapy and retreatment therapy for patient with high HAMA titers, reflecting immune complex formation. Two patients responded to retreatment therapy with responses lasting 1 to 2 mo. Minimal acute and no chronic toxicities were observed during the retreatment protocol.

Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council Study.

A radiolabeled murine monoclonal antibody (T101) was used for imaging and therapy of six patients with cutaneous T cell lymphoma (CTCL). Radioimmunodetection was performed with a 5.6 to 13.1 mCi 131I-T101 preparation (9.6 to 10.5 mg). A therapeutic dose of 100.5 to 150.1 mCi 131I on 9.9 to 16.9 mg of antibody was administered to five patients, with subsequent retreatment following plasmapheresis in three patients at the time of disease progression. All patients responded to their initial therapy and two patients responded to retreatment. Regression of skin lesions and peripheral adenopathy was witnessed. All patients reported resolution of their chronic pruritus. The duration of response ranged from 3 weeks to 3 months. Acute toxicity included fevers, pruritus, and mild dyspnea in two instances. Myelosuppression was seen in patients receiving the 144.7 mCi, 145.0 mCi, and 150.1 mCi 131I-T101 doses. Radioimmunodiagnostic and therapy studies included gamma scintigraphy, plasma, urinary, and wholebody antibody clearances, and biodistribution determined from skin, bone marrow, and liver biopsies. Immunologic studies included immunoperoxidase staining of target tissues, immunofluorescent flow cytometric analysis on peripheral blood and bone marrow, assays for serum blocking factors, determination of a human antimouse antibody (HAMA) response, and quantitation of circulating T101 levels. These preliminary data suggest that 131I-T101 has therapeutic potential in CTCL and that myelosuppression will be the limiting toxicity.

Estramustine affects bone mineral metabolism in metastatic prostate cancer.

A patient with metastatic prostate cancer is described where treatment with Adriamycin (doxorubicin) and estramustine produced severe hypophosphatemia (serum phosphate level, 1.2 mg/dl), which was reversible when treatment was discontinued. Previous studies have shown no effect of Adriamycin on serum phosphate levels. A retrospective study of serial serum chemistry values was done in 15 patients treated with estramustine. A significant fall in the serum phosphate level (mean, 0.8 +/- 0.3 mg/dl) was observed during the first 6 weeks of treatment. When compared with similar patients treated with bilateral orchiectomy, estramustine-treated patients had lower levels of serum calcium, fractional excretion of calcium, serum phosphate, and renal tubular threshold for phosphate reabsorption (TmPO4/GFR). Qualitatively similar but quantitatively smaller effects were also seen in a group of patients treated with diethylstilbestrol (DES) in a dose of 1 to 3 mg daily. Estramustine appears to have significant effects on bone mineral metabolism, particularly on renal phosphate handling resulting in significant hypophosphatemia. This is probably due to an estrogenic effect.