Michael A. Polis

The University of Texas at Austin

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Henry Masur

National Institutes of Health Clinical Center

Shyam Kottilil

University of Maryland, Baltimore

Joseph A. Kovacs

National Institutes of Health Clinical Center

Richard T. Davey

National Institute of Allergy and Infectious Diseases

H. Clifford Lane

National Institutes of Health

Judith Falloon

Horizon Therapeutics (United States)

Julia A. Metcalf

National Institute of Allergy and Infectious Diseases

Robert Walker

Boston University

Anu Osinusi

Gilead Sciences (United States)

Richard A. Lempicki

Leidos (United States)

Cooperative Institutions

National Institutes of Health

318

National Institute of Allergy and Infectious Diseases

239

National Cancer Institute

131

National Institutes of Health Clinical Center

Frederick National Laboratory for Cancer Research

Johns Hopkins University

University of Maryland, Baltimore

Leidos (United States)

Science Applications International Corporation (United States)

Université des Sciences, des Techniques et des Technologies de Bamako

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Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients

Antimicrobial Agents and Chemotherapy (1996)

Richard T. Davey Doreen Chaitt G. F. Reed William W. Freimuth Betsey Herpin

Delavirdine mesylate (DLV) is a potent nonnucleoside reverse transcriptase inhibitor with activity specific for human immunodeficiency virus type 1. In the present phase I/II study we evaluated the safety, toxicity, pharmacokinetics, and antiretroviral activities of two-drug and three-drug combinations of DLV and conventional doses of nucleoside analogs compared with those of both DLV monotherapy and two-drug nucleoside analog therapy. A total of 85 human immunodeficiency virus type 1 infected patients with CD4 counts of 100 to 300 cells per mm3 were enrolled in two periods: in the first period patients were randomized to receive either zidovudine (ZDV) plus didanosine (group 1) or ZDV plus didanosine plus escalating doses (400 to 1,200 mg/day) of DLV (group 2). In the second period, patients were randomized to receive either 1,200 mg of DLV alone per day (group 3) or ZDV plus 1,200 mg of DLV per day (group 4). DLV demonstrated good oral bioavailability at all five doses tested. The major toxicity was a transient mild rash which appeared in 44% of all DLV recipients. Overall, group 2 patients demonstrated more sustained improvements in CD4 counts, percent CD4 cells, branched DNA levels, p24 antigen levels, and virus titers in plasma than group 1, 3, or 4 patients. The magnitude of the response correlated with the intensity of prior nucleoside analog treatment, the non-syncytium-inducing or syncytium-inducing viral phenotype at baseline, and the presence of a wild-type codon at amino acid position 215 in the baseline reverse transcriptase genotype. Despite a transient rash, DLV therapy was well tolerated. Combination therapy with DLV and nucleoside analogs appears promising, with the three-drug combination appearing to be more potent that either two-drug combinations or monotherapy.

Didanosine

Stavudine

Reverse-transcriptase inhibitor

Zalcitabine

10.1128/aac.40.7.1657

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Citations (68)

Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection

Blood (2004)

Claire E Farel Doreen Chaitt Barbara Hahn Jorge A. Tavel Joseph A. Kovacs

Subcutaneous injection

10.1182/blood-2003-09-3283

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Citations (40)

Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection

JAMA (2015)

Anu Osinusi Kerry Townsend Anita Kohli Amy Nelson Cassie Seamon

There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV).

Ledipasvir

Sofosbuvir

Hepatitis C

10.1001/jama.2015.1373

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Citations (199)

Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystis pneumonia

Antimicrobial Agents and Chemotherapy (1994)

Judith Falloon James P. Lavelle Debra Ogata-Arakaki Adam J. Byrne Amy L. Graziani

The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found to be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg plus pyrimethamine at 25 mg once weekly. Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.

Dapsone

Pneumocystis pneumonia

10.1128/aac.38.7.1580

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Citations (18)

Ongoing HIV dissemination during HAART

Nature Medicine (1999)

Zvi Grossman Michael A. Polis Mark B. Feinberg Zehava Grossman I Levi

10.1038/13410

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Citations (146)

Idiopathic CD4+ Lymphocytopenia: Natural History and Prognostic Factors.

International Journal of Infectious Diseases (2008)

Dimitrios Zonios Judith Falloon John E. Bennett Pamela A. Shaw Doreen Chaitt

Lymphocytopenia

10.1016/s1201-9712(08)60017-x

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Citations (4)

Effects of Intermittent Interleukin‐2 Therapy on Plasma and Tissue Human Immunodeficiency Virus Levels and Quasi‐Species Expression

The Journal of Infectious Diseases (2000)

Joseph A. Kovacs Hiromi Imamichi Susan Vogel Julia A. Metcalf Robin Dewar

To characterize the effects of intermittent interleukin (IL)—2 therapy on human immunodeficiency virus (HIV), 11 patients underwent detailed virological evaluation during a year of IL-2 therapy. Six patients showed a 10.5 log increase in plasma HIV during at least 1 IL-2 cycle, with 2 experiencing an increase in >50% of cycles. Three of the remaining 5 patients had a >0.5 log decrease during at least 1 IL-2 cycle, and the remaining patients exhibited <0.5 log changes. No changes in lymphoid (tonsil) levels of HIV were seen during the year. Quasispecies analysis in a separate cohort demonstrated that the virus induced by IL-2 most commonly resembled pre—IL-2 plasma quasi species. Thus, intermittent IL-2 does not result in sustained increases in either plasma or tissue levels of HIV and does not result in sustained expression of a previously silent quasi species.

Tonsil

10.1086/315821

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Citations (31)

Early assessment of anti-HIV drug efficacy

The Lancet (2002)

Michael A. Polis Igor A. Sidorov Dimiter S. Dimitrov

Efavirenz

Viremia

Resistance mutation

Regimen

10.1016/s0140-6736(02)08572-0

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Citations (0)

Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661.

Proceedings of the National Academy of Sciences (1993)

Richard T. Davey Robin Dewar G. F. Reed M. B. Vasudevachari Michael A. Polis

L-697,661 is a non-nucleoside analogue with potent, selective inhibitory activity against the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1). The present study evaluated the potential role of this compound in the treatment of HIV-1-infected patients in a double-blinded, placebo- and zidovudine-controlled trial using plasma viremia as a marker of antiviral activity and real-time phenotypic evaluation of viral isolates for the emergence of resistance. Participants received 12 weeks of either placebo, 25 mg twice a day, 100 mg three times a day, or 500 mg twice a day of L-697,661, or zidovudine, 100 mg five times a day. Mean logarithmic reciprocal titers of plasma virus in patients taking either L-697,661 or zidovudine decreased by week 4 of therapy; for L-697,661 recipients these changes were dose-dependent and, at the highest dose tested, were comparable in magnitude to those seen with zidovudine. Viral suppression induced by L-697,661 persisted through 8 weeks of treatment but decreased by week 12. This rebound paralleled emergence of viral isolates showing resistance to L-697,661. We conclude that although L-697,661 has potent antiretroviral activity in vivo, its utility may be compromised by rapid emergence of L-697,661-resistant virus. Plasma viremia is a highly sensitive technique affording considerable utility in the early testing of such agents.

Viremia

Reverse-transcriptase inhibitor

10.1073/pnas.90.12.5608

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Citations (48)

The use of flare photometry in the detection of cytomegalic virus retinitis in AIDS patients

Robert B. Nussenblatt M. D. S. et Marvin J. Podgor C. Lane Michael A. Polis

Flare

Source

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Citations (3)