Fred T. Valentine, M.D.

Sex differences in the incidence of peripheral neuropathy among kenyans initiating antiretroviral therapy
Mehta, Sapna A; Ahmed, Aabid; Laverty, Maura; Holzman, Robert S; Valentine, Fred; Sivapalasingam, Sumathi
2011 Sep;53(5):490-496, Clinical infectious diseases
Background. Peripheral neuropathy (PN) is common among patients receiving antiretroviral therapy (ART) in resource-limited settings. We report the incidence of and risk factors for PN among human immunodeficiency virus (HIV)-infected Kenyan adults initiating ART. Methods. An inception cohort was formed of adults initiating ART. They were screened for PN at baseline and every 3 months for 1 year. We used the validated Brief Peripheral Neuropathy Screen (BPNS) that includes symptoms and signs (vibration perception and ankle reflexes) of PN. Results. Twenty-two (11%) of 199 patients had PN at baseline screening. One hundred fifty patients without evidence of PN at baseline were followed for a median of 366 days (interquartile range, 351-399). The incidence of PN was 11.9 per 100 person-years (95% confidence interval [CI], 6.9-19.1) and was higher in women than men (17.7 vs 1.9 per 100 person-years; rate ratio, 9.6; 95% CI, 1.27-72, P = .03). In stratified analyses, female sex remained statistically significant after adjustment for each of the following variables: age, CD4 cell count, body mass index, ART regimen, and tuberculosis treatment. Stratifying hemoglobin levels decreased the hazard ratio from 9.6 to 7.40 (P = .05), with higher levels corresponding to a lower risk of PN. Conclusions. HIV-infected Kenyan women were almost 10 times more likely than men to develop PN in the first year of ART. The risk decreased slightly at higher hemoglobin levels. Preventing or treating anemia in women before ART initiation and implementing BPNS during the first year of ART, the period of highest risk, could ameliorate the risk of PN
— id: 136612, year: 2011, vol: 53, page: 490, stat: Journal Article,

Susceptibility of Human Th17 Cells to Human Immunodeficiency Virus and Their Perturbation during Infection
El Hed, Aimee; Khaitan, Alka; Kozhaya, Lina; Manel, Nicolas; Daskalakis, Demetre; Borkowsky, William; Valentine, Fred; Littman, Dan R; Unutmaz, Derya
2010 Mar 15;201(6):843-854, Journal of infectious diseases
Background. Identification of the Th17 T cell subset as important mediators of host defense and pathology prompted us to determine their susceptibility to human immunodeficiency virus (HIV) infection. Methods and results. We found that a sizeable portion of Th17 cells express HIV coreceptor CCR5 and produce very low levels of CCR5 ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Accordingly, CCR5(+) Th17 cells were efficiently infected with CCR5-tropic HIV and were depleted during viral replication in vitro. Remarkably, HIV-infected individuals receiving treatment had significantly reduced Th17 cell counts, compared with HIV-uninfected subjects, regardless of viral load or CD4 cell count, whereas treatment-naive subjects had normal levels. However, there was a preferential reduction in CCR5(+) T cells that were also CCR6 positive, which is expressed on all Th17 cells, compared with CCR6(-)CCR5(+) cells, in both treated and untreated HIV-infected subjects. This observation suggests preferential targeting of CCR6(+)CCR5(+) Th17 cells by CCR5-tropic viruses in vivo. Th17 cell levels also inversely correlated with activated CD4(+) T cells in HIV-infected individuals who are receiving treatment. Conclusions. Our findings suggest a complex perturbation of Th17 subsets during the course of HIV disease potentially through both direct viral infection and virus indirect mechanisms, such as immune activation
— id: 107380, year: 2010, vol: 201, page: 843, stat: Journal Article,

A strategy for eliciting antibodies against cryptic, conserved, conformationally dependent epitopes of HIV envelope glycoprotein
Kelker, Hanna C; Itri, Vincenza R; Valentine, Fred T
2010 ;5(1):e8555-e8555, PLoS ONE
BACKGROUND: Novel strategies are needed for the elicitation of broadly neutralizing antibodies to the HIV envelope glycoprotein, gp120. Experimental evidence suggests that combinations of antibodies that are broadly neutralizing in vitro may protect against challenge with HIV in nonhuman primates, and a small number of these antibodies have been selected by repertoire sampling of B cells and by the fractionation of antiserum from some patients with prolonged disease. Yet no additional strategies for identifying conserved epitopes, eliciting antibodies to these epitopes, and determining whether these epitopes are accessible to antibodies have been successful to date. The defining of additional conserved, accessible epitopes against which one can elicit antibodies will increase the probability that some may be the targets of broadly neutralizing antibodies. METHODOLOGY/PRINCIPAL FINDINGS: We postulate that additional cryptic epitopes of gp120 are present, against which neutralizing antibodies might be elicited even though these antibodies are not elicited by gp120, and that many of these epitopes may be accessible to antibodies should they be formed. We demonstrate a strategy for eliciting antibodies in mice against selected cryptic, conformationally dependent conserved epitopes of gp120 by immunizing with multiple identical copies of covalently linked peptides (MCPs). This has been achieved with MCPs representing 3 different domains of gp120. We show that some cryptic epitopes on gp120 are accessible to the elicited antibodies, and some epitopes in the CD4 binding region are not accessible. The antibodies bind to gp120 with relatively high affinity, and bind to oligomeric gp120 on the surface of infected cells. CONCLUSIONS/SIGNIFICANCE: Immunization with MCPs comprised of selected peptides of HIV gp120 is able to elicit antibodies against conserved, conformationally dependent epitopes of gp120 that are not immunogenic when presented as gp120. Some of these cryptic epitopes are accessible to the elicited antibodies
— id: 106106, year: 2010, vol: 5, page: e8555, stat: Journal Article,

Implementation of a validated peripheral neuropathy screening tool in patients receiving antiretroviral therapy in mombasa, kenya
Mehta, Sapna A; Ahmed, Aabid; Kariuki, Beatrice W; Said, Swaleh; Omasete, Fanuel; Mendillo, Megan; Laverty, Maura; Holzman, Robert; Valentine, Fred; Sivapalasingam, Sumathi
2010 Sep;83(3):565-570, American journal of tropical medicine & hygiene
Limited objective data are available for the prevalence of peripheral neuropathy (PN) among antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected patients in resource-limited settings. A validated neuropathy-screening tool was integrated into routine ART visits at an HIV clinic in Mombasa, Kenya. Diagnosis of PN required at least one symptom and either abnormal vibratory sensation or deep tendon reflex bilaterally. Among 102 consecutively screened patients, 63% were women, 62% were receiving ART for </= 1 year, and 86% were receiving a stavudine (D4T)-based regimen. Thirty-seven (36%) had PN. Univariate analysis showed that current D4T use was protective against PN (P = 0.03) and older age was a marginal risk factor (P = 0.05). Multivariate analysis showed that older age was a risk factor for neuropathy (P = 0.04). Peripheral neuropathy was common, particularly among older HIV-infected adults in Kenya. The protective association with current D4T use likely represents survivor effect bias. Longitudinal studies using this screen will help further characterize PN in resource-limited settings
— id: 112054, year: 2010, vol: 83, page: 565, stat: Journal Article,

Evidence of dysregulation of dendritic cells in primary HIV infection
Sabado, Rachel Lubong; O'Brien, Meagan; Subedi, Abhignya; Qin, Li; Hu, Nan; Taylor, Elizabeth; Dibben, Oliver; Stacey, Andrea; Fellay, Jacques; Shianna, Kevin V; Siegal, Frederick; Shodell, Michael; Shah, Kokila; Larsson, Marie; Lifson, Jeffrey; Nadas, Arthur; Marmor, Michael; Hutt, Richard; Margolis, David; Garmon, Donald; Markowitz, Martin; Valentine, Fred; Borrow, Persephone; Bhardwaj, Nina
2010 Nov 11;116(19):3839-3852, Blood
Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV in-fection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation
— id: 114507, year: 2010, vol: 116, page: 3839, stat: Journal Article,

The Development and Implementation of an Outreach Program to Identify Acute and Recent HIV Infections in New York City
Silvera, Richard; Stein, Dylan; Hutt, Richard; Hagerty, Robert; Daskalakis, Demetre; Valentine, Fred; Marmor, Michael
2010 ;4:76-83, Open AIDS journal
INTRODUCTION: Since 2004, the authors have been operating First Call NYU, an outreach program to identify acute and recent HIV infections, also called primary HIV infections, among targeted at-risk communities in the New York City (NYC) metropolitan area. MATERIALS AND METHODOLOGY: First Call NYU employed mass media advertising campaigns, outreach to healthcare providers in NYC, and Internet-based efforts including search engine optimization (SEO) and Internet-based advertising to achieve these goals. RESULTS: Between October 2004 and October 2008, 571 individuals were screened through this program, leading to 446 unique, in-person screening visits. 47 primary HIV infections, including 14 acute and 33 recent HIV infections, were identified. DISCUSSION: Internet and traditional recruitment methods can be used to increase self-referrals for screening following possible exposure to HIV. CONCLUSION: Community education of at-risk groups, with the goal of increased self-diagnosis of possible acute HIV infection, may be a useful addition to traditional efforts to identify such individuals
— id: 109049, year: 2010, vol: 4, page: 76, stat: Journal Article,

Measurement of antiretroviral drugs in the lungs of HIV-infected patients
Twigg HL; Schnizlein-Bick CT; Weiden M; Valentine F; Wheat J; Day RB; Rominger H; Zheng L; Collman RG; Coombs RW; Bucy RP; Rezk NL; Kashuba AD
2010 Mar 1;4(2):247-251, HIV Therapy
AIMS: Prior studies have shown that HAART is associated with decreased HIV viral load in the lungs. The correlation between antiretroviral exposure in bronchoalveolar lavage (BAL) fluid and virologic response was evaluated in patients starting HAART and enrolled in The AIDS Clinical Trial Group Protocol 723. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 24 subjects underwent blood and BAL sampling prior to starting HAART, and after 4 and 24 weeks of HAART. Drug concentrations and HIV RNA were measured in paired plasma and BAL samples. RESULTS: Antiretroviral drugs, including efavirenz, were detectable in BAL fluid of HIV-infected subjects beginning HAART. Efavirenz was also associated with a higher likelihood of clearing HIV RNA from the lungs. CONCLUSION: These results suggest the excellent pulmonary virologic response to antiretroviral therapy may, in part, be due to penetration of antiretroviral drugs into the alveolar compartment
— id: 138270, year: 2010, vol: 4, page: 247, stat: Journal Article,

Implementation of HIV testing at 2 New York City bathhouses: from pilot to clinical service
Daskalakis, Demetre; Silvera, Richard; Bernstein, Kyle; Stein, Dylan; Hagerty, Robert; Hutt, Richard; Maillard, Alith; Borkowsky, William; Aberg, Judith; Valentine, Fred; Marmor, Michael
2009 Jun 1;48(11):1609-1616, Clinical infectious diseases
BACKGROUND: Commercial sex venues (e.g., bathhouses) that cater to men who have sex with men (MSM) continue to function in most urban areas. These venues present a challenge to developing strategies to prevent the spread of the human immunodeficiency virus (HIV), but they also provide opportunities for interventions to reduce the risk and rate of disease transmission. Several cities in the United States have developed programs that offer HIV testing in these venues. Similar programs have not existed before in New York City. METHODS: A pilot HIV testing program was implemented at 2 New York City bathhouses. Testing included rapid HIV testing, the use of the serologic testing algorithm for recent HIV seroconversion, and pooled plasma HIV viral load to detect and date incident and acute HIV infections. In addition to HIV tests, behavioral and demographic data were collected from 493 presumed HIV-negative participants. RESULTS: The pilot program recruited MSM who were at high risk for HIV infection. Of the 493 men tested, 20 (4%) were found to be positive for HIV, and 8 (40%) of these 20 men demonstrated evidence of acute or recent HIV infection. The program tested men often not tested in more traditional medical settings. Significant disparities were demonstrated in the testing habits of MSM who reported having sex with women and had not disclosed same-sex activities to their caregivers. CONCLUSIONS: Bathhouse-based testing for HIV infection can be implemented in New York City and would include a population of MSM who are at high risk for HIV infection. Because of the high rate of recent HIV infection, expanded testing in these venues may be a good strategy to reduce the forward transmission of HIV in this highly sexually active population
— id: 98009, year: 2009, vol: 48, page: 1609, stat: Journal Article,

Eliciting antibodies against cryptic, conserved, conformationally dependent epitopes of HIV envelope glycoprotein gp120: A strategy
Kelker, HC; Itri, V; Valentine, FT
2009 DEC ;6(2-3):115-115, Retrovirology
— id: 105704, year: 2009, vol: 6, page: 115, stat: Journal Article,

Monitoring virologic responses to antiretroviral therapy in HIV-infected adults in Kenya: evaluation of a low-cost viral load assay
Sivapalasingam, Sumathi; Wangechi, Beatrice; Marshed, Fatuma; Laverty, Maura; Essajee, Shaffiq; Holzman, Robert S; Valentine, Fred
2009 ;4(8):e6828-e6828, PLoS ONE
BACKGROUND: A key advantage of monitoring HIV viral load (VL) in persons receiving antiretroviral therapy (ART) is the ability to detect virologic failure before clinical deterioration or resistance occurs. Detection of virologic failure will help clarify the need for enhanced adherence counseling or a change to second- line therapy. Low-cost, locally performable alternates to expensive VL assays are needed where resources are limited. METHODOLOGY/PRINCIPAL FINDINGS: We monitored the response to 48-week ART in 100 treatment-naive Kenyan adults using a low-cost VL measurement, the Cavidi reverse transcriptase (RT) assay and gold-standard assays, Roche RNA PCR and Bayer Versant HIV-1 RNA (bDNA) assays. In Altman-Bland plots, the mean difference in viral loads between the three assays was small (<0.5 log(10) copies/mL). However, the limits of agreement between the methods exceeded the biologically relevant change of 0.5 log copies/ml. Therefore, the RT assay cannot be used interchangeably with the other assays to monitor individual patients. The RT assay was 100% sensitive in detecting viral loads of > or =400 copies/ml compared to gold-standard assays. After 24 weeks of treatment, viral load measured by the RT assay was undetectable in 95% of 65 patients with undetectable RNA PCR VL (<400 copies/ml), 90% of 67 patients with undetectable bDNA VL, and 96% of 57 patients with undetectable VL in both RNA PCR and bDNA assays. The negative predictive value of the RT assay was 100% compared to either assay; the positive predictive value was 86% compared to RNA PCR and 70% compared to bDNA. CONCLUSION: The RT assay compared well with gold standard assays. Our study highlights the importance of not interchanging viral load assays when monitoring an individual patient. Furthermore, the RT assay may be limited by low positive predictive values when used in populations with low prevalence of virologic failure
— id: 101963, year: 2009, vol: 4, page: e6828, stat: Journal Article,

Viral commensalism in humans?
Blaser, Martin J; Valentine, Fred T
2008 Jul 1;198(1):1-3, Journal of infectious diseases
— id: 79202, year: 2008, vol: 198, page: 1, stat: Journal Article,

Blood Dendritic Cell Subsets in Early HIV Infection
Sabado, RL; O'Brien, M; Subedi, A; Taylor, E; Hutt, R; Haggerty, R; Marmor, M; Margolis, D; Valentine, F; Borrow, P; Bhardwaj, N
2008 OCT ;24(1):84-85, AIDS research & human retroviruses
— id: 91419, year: 2008, vol: 24, page: 84, stat: Journal Article,

Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects
Twigg Iii, Homer L; Weiden, Michael; Valentine, Fred; Schnizlein-Bick, Carol T; Bassett, Roland; Zheng, Lu; Wheat, Joseph; Day, Richard B; Rominger, Helen; Collman, Ronald G; Fox, Lawrence; Brizz, Barbara; Dragavon, Joan; Coombs, Robert W; Bucy, R Pat
2008 Jan 1;197(1):109-116, Journal of infectious diseases
BACKGROUND: Human immunodeficiency virus (HIV) is readily detectable in the lungs of infected subjects and leads to an accumulation of CD8(+) lymphocytes in the alveolar space. Although highly active antiretroviral therapy (HAART) is effective in reducing viremia, less is known about its effect on tissue compartments. The AIDS Clinical Trials Group Protocol 723 Team evaluated the effect of HAART on lung viral load and cellular constituents. METHODS: Bronchoalveolar lavage (BAL) fluid and blood were collected before initiation of HAART and again at 4 and 24 weeks after initiation of therapy. The BAL cell differential was determined, lymphocyte phenotyping was performed, and acellular BAL fluid, plasma HIV RNA load, and BAL cell and peripheral blood mononuclear cell HIV RNA and DNA loads were measured. RESULTS: HAART induced a rapid decrease in HIV that was detectable in acellular BAL fluid and a slower decrease in the HIV RNA and DNA loads in BAL cells. HAART was associated with a significant decrease in the absolute number and percentage of CD8(+) alveolar lymphocytes. There was a significant correlation between residual BAL cell DNA at 24 weeks and the absolute number of CD4(+) lymphocytes in the alveolar space. CONCLUSION: HAART is associated with a significant decrease in the pulmonary HIV burden and a return of alveolar cellular constituents to normal
— id: 78802, year: 2008, vol: 197, page: 109, stat: Journal Article,

Immunological memory after exposure to variola virus, monkeypox virus, and vaccinia virus
Sivapalasingam, Sumathi; Kennedy, Jeffrey S; Borkowsky, William; Valentine, Fred; Zhan, Ming-Xia; Pazoles, Pamela; Paolino, Anna; Ennis, Francis A; Steigbigel, Neal H
2007 Apr 15;195(8):1151-1159, Journal of infectious diseases
We compared cellular and humoral immunity to vaccinia virus (VV) in individuals exposed to 3 different orthopoxviruses: 154 individuals previously vaccinated with VV, 7 individuals with a history of monkeypox virus infection, and 8 individuals with a history of variola virus infection. Among individuals vaccinated >20 years prior, 9 (14%) of 66 individuals demonstrated VV-specific interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) assay responses; 21 (50%) of 42 had lymphoproliferative (LP) responses, and 29 (97%) of 30 had VV-specific neutralizing antibodies. One year after monkeypox virus infection, 6 of 7 individuals had IFN- gamma ELISPOT responses, all had VV-specific LP responses, and 3 of 7 had VV-specific neutralizing antibodies. Of 8 individuals with a history of variola virus infection, 1 had a VV-specific IFN- gamma ELISPOT response, 4 had LP responses against whole VV, 7 had LP responses against heat-denatured vaccinia antigen, and 7 had VV-specific neutralizing antibodies. Survivors of variola virus infection demonstrated VV-specific CD4 memory cell responses and neutralizing antibodies >40 years after infection
— id: 71299, year: 2007, vol: 195, page: 1151, stat: Journal Article,

A Reverse Transcriptase Assay for Early Diagnosis of Infant HIV Infection in Resource-limited Settings
Sivapalasingam, Sumathi; Patel, Usha; Itri, Vincenza; Laverty, Maura; Mandaliya, Kishorchandra; Valentine, Fred; Essajee, Shaffiq
2007 Oct;53(5):355-358, Journal of tropical pediatrics
Early diagnosis of pediatric HIV infection is confounded by persistence of maternal antibodies until 18 months, necessitating the use of expensive assays such as HIV-1 DNA PCR, an untenable option in resource-limited settings. This is the first report of a low-cost, commercial, reverse transcriptase (RT) assay for the diagnosis of HIV-1 infection in infants. RT assays were performed on 42 samples from 30 HIV-exposed Kenyan infants under 15 months of age. When correlated with serologic testing conducted after 18 months, the sensitivity, specificity, positive and negative predictive values of the RT assay were 92%, 93%, 87% and 96%. A low-cost assay for infant HIV diagnosis is urgently needed, and these results merit further evaluation.
— id: 72999, year: 2007, vol: 53, page: 355, stat: Journal Article,

Low CD4+ T cell nadir is an independent predictor of lower HIV-specific immune responses in chronically HIV-1-infected subjects receiving highly active antiretroviral therapy
Siddique, M Atif; Hartman, Kelly E; Dragileva, Ella; Dondero, Marla; Gebretsadik, Tebeb; Shintani, Ayumi; Peiperl, Laurence; Valentine, Fred; Kalams, Spyros A
2006 Sep 1;194(5):661-665, Journal of infectious diseases
The influence of CD4(+) T cell nadirs on human immunodeficiency virus (HIV)-specific immune responses in subjects with apparently normal CD4(+) T cell counts is not known. We evaluated the frequency of HIV-1-specific immune responses in a cohort of patients with complete viral suppression (HIV-1 RNA load, <50 copies/mL) who were receiving highly active antiretroviral therapy and had a wide range of CD4(+) T cell nadirs. We found positive associations between CD4(+) T cell nadirs and the magnitude of HIV-specific CD8(+) T cell responses (P=.02) and of T cell helper responses (P=.04). These data show the CD4(+) T cell nadir to be an independent predictor of HIV-specific CD4(+) and CD8(+) T cell responses in HIV-1-infected subjects with optimal suppression of viremia
— id: 78899, year: 2006, vol: 194, page: 661, stat: Journal Article,

Human immunodeficiency virus (HIV) reverse transcriptase activity correlates with HIV RNA load: implications for resource-limited settings
Sivapalasingam, Sumathi; Essajee, Shaffiq; Nyambi, Phillipe N; Itri, Vincenza; Hanna, Bruce; Holzman, Robert; Valentine, Fred
2005 Aug;43(8):3793-3796, Journal of clinical microbiology
Measurement of human immunodeficiency virus type 1 (HIV-1) plasma RNA levels using Roche AMPLICOR version 1.5 (HIV RNA) is an integral part of monitoring HIV-infected patients in industrialized countries. These assays are currently unaffordable in resource-limited settings. We investigated a reverse transcriptase (RT) assay as a less expensive alternative for measuring viral burden that quantifies RT enzyme activity in clinical plasma samples. A comparison of RT and HIV RNA assays was performed on 29 paired plasma samples from patients living in the United States and 21 paired plasma samples from patients living in Cameroon. RT levels correlated significantly with plasma HIV RNA viral loads in plasma from U.S. patients (r = 0.898; P < 0.001) and Cameroonian patients, a majority of whom were infected with HIV-1 clade type CRF02_AG (r = 0.669; P < 0.01). Among 32 samples with HIV viral load of >2,000 copies/ml, 97% had detectable RT activity. One Cameroon sample had undetectable RNA viral load but detectable RT activity of 3 fg/ml. The RT assay is a simple and less expensive alternative to the HIV RNA assay. Field studies comparing these assays in resource-limited settings are warranted to assess the practicality and usefulness of this assay for monitoring HIV-infected patients on antiretroviral therapy
— id: 57865, year: 2005, vol: 43, page: 3793, stat: Journal Article,

Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307
Frank, Ian; Bosch, Ronald J; Fiscus, Susan; Valentine, Fred; Flexner, Charles; Segal, Yoninah; Ruan, Ping; Gulick, Roy; Wood, Kenneth; Estep, Scharla; Fox, Lawrence; Nevin, Thomas; Stevens, Michael; Eron, Joseph J Jr
2004 Sep;20(9):916-926, AIDS research & human retroviruses
We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy
— id: 78900, year: 2004, vol: 20, page: 916, stat: Journal Article,

Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248)
Vogler, Mary A; Teppler, Hedy; Gelman, Rebecca; Valentine, Fred; Lederman, Michael M; Pomerantz, Roger J; Pollard, Richard B; Cherng, Deborah Weng; Gonzalez, Charles J; Squires, Kathleen E; Frank, Ian; Mildvan, Donna; Mahon, Laura F; Schock, Barbara
2004 May 1;36(1):576-587, Journal of acquired immune deficiency syndromes. JAIDS
CONTEXT: Approaches to preserve or enhance immune function in HIV-1 infection are needed. OBJECTIVES: To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels. DESIGN: Twenty-four-week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997. PARTICIPANTS: A total of 115 HIV-infected persons with screening CD4+ T-cell counts between 300 and 700 cells/mm who were on stable single- or dual-nucleoside therapy for at least 2 months, 11% of whom were also on a protease inhibitor at study entry. INTERVENTIONS: Patients were randomly assigned to receive IL-2 at a dose of 1 million IU subcutaneously once daily plus continued anti-retroviral therapy (ART + IL-2, n = 57) vs. continued ART alone (ART alone, n = 58). IL-2 dose reductions were made for objective or subjective toxicities. All subjects randomly assigned to the IL-2 arm who interrupted ART were also required to discontinue IL-2 for the same period. MAIN OUTCOME MEASURES: The primary endpoint was a decrease in CD4 T-cell count from baseline; the safety analysis was based on change in plasma HIV RNA by bDNA; and clinical safety and tolerability were analyzed by standard clinical criteria. RESULTS: Of the patients with a baseline CD4 T-cell count recorded, 15 (27%) of 55 patients randomly assigned to ART alone had a drop of > or =25% in their CD4 T-cell count and 23 (41%) of 56 patients randomly assigned to ART + IL-2 had a drop of > or =25% in their CD4 T-cell count at some time over the 24 weeks of the study. This difference was not statistically significant. There was a statistically significant greater variance in CD4 T-cell counts in the IL-2-treated group. More patients in the IL-2 group had at least a 25% increase in CD4 T-cell counts over baseline (34 vs. 13%, P = 0.007). A comparison of grade 3 or worse toxicity showed no differences between the arms, but IL-2 was associated with significantly more grade 2 or worse general body symptoms, primarily discomfort and fatigue. There was no significant difference between the groups with regard to changes in plasma HIV RNA, lymphocyte proliferation, natural killer cell activity, skin test responses to recall antigens, or antibody responses to immunization. Plasma markers of immune activation all increased significantly in IL-2 recipients. CONCLUSIONS: In patients with baseline CD4 T-cell counts > or =300 cells/mm primarily treated with single- or dual-nucleoside ART, subcutaneously administered IL-2 at a dose of 1 million IU daily for up to 24 weeks had low toxicity but showed no consistent benefit in preventing decline in CD4 T-cell counts and minimal evidence of immunologic improvement vs. continued ART alone
— id: 57853, year: 2004, vol: 36, page: 576, stat: Journal Article,

A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults
Lalezari, Jacob P; DeJesus, Edwin; Northfelt, Donald W; Richmond, Gary; Wolfe, Peter; Haubrich, Richard; Henry, David; Powderly, William; Becker, Stephen; Thompson, Melanie; Valentine, Fred; Wright, David; Carlson, Margrit; Riddler, Sharon; Haas, Frances F; DeMasi, Ralph; Sista, Prokash R; Salgo, Miklos; Delehanty, John
2003 Aug;8(4):279-287, Antiviral therapy
Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens
— id: 42276, year: 2003, vol: 8, page: 279, stat: Journal Article,

A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy
Lalezari, Jacob P; Eron, Joseph J; Carlson, Margrit; Cohen, Calvin; DeJesus, Edwin; Arduino, Roberto C; Gallant, Joel E; Volberding, Paul; Murphy, Robert L; Valentine, Fred; Nelson, Emily L; Sista, Prakash R; Dusek, Alex; Kilby, J Michael
2003 Mar 28;17(5):691-698, AIDS
OBJECTIVES: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen. METHODS: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history. RESULTS: The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations. CONCLUSION: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts
— id: 42277, year: 2003, vol: 17, page: 691, stat: Journal Article,

Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion
Lederman, Howard M; Williams, Paige L; Wu, Julia W; Evans, Thomas G; Cohn, Susan E; McCutchan, J Allen; Koletar, Susan L; Hafner, Richard; Connick, Elizabeth; Valentine, Fred T; McElrath, M Juliana; Roberts, Norbert J Jr; Currier, Judith S
2003 Dec 15;188(12):1794-1803, Journal of infectious diseases
Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4+ cell counts of <50 cells/mm3, followed by a sustained increase to > or =100 cells/mm3 after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4+ cell count was 226 cells/mm3 at entry and 358 cells/mm3 at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4+ cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P=.009) and mumps skin test antigen (29% vs. 17%; P=.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk
— id: 42275, year: 2003, vol: 188, page: 1794, stat: Journal Article,

Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial
Hammer, Scott M; Vaida, Florin; Bennett, Kara K; Holohan, Mary K; Sheiner, Lewis; Eron, Joseph J; Wheat, Lawrence Joseph; Mitsuyasu, Ronald T; Gulick, Roy M; Valentine, Fred T; Aberg, Judith A; Rogers, Michael D; Karol, Cheryl N; Saah, Alfred J; Lewis, Ronald H; Bessen, Laura J; Brosgart, Carol; DeGruttola, Victor; Mellors, John W
2002 Jul 10;288(2):169-180, JAMA
CONTEXT: Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge. OBJECTIVE: To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen. DESIGN: Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks. SETTING: Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States. PARTICIPANTS: A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL. INTERVENTION: Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil. MAIN OUTCOME MEASURES: Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility. RESULTS: Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03). CONCLUSIONS: In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome
— id: 32249, year: 2002, vol: 288, page: 169, stat: Journal Article,

The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults
Kilby, J Michael; Lalezari, Jacob P; Eron, Joseph J; Carlson, Margrit; Cohen, Calvin; Arduino, Roberto C; Goodgame, Jeffrey C; Gallant, Joel E; Volberding, Paul; Murphy, Robert L; Valentine, Fred; Saag, Michael S; Nelson, Emily L; Sista, Prakash R; Dusek, Alex
2002 Jul 1;18(10):685-693, AIDS research & human retroviruses
Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment
— id: 78901, year: 2002, vol: 18, page: 685, stat: Journal Article,

Correlates of nontransmission in US women at high risk of human immunodeficiency virus type 1 infection through sexual exposure
Skurnick, Joan H; Palumbo, Paul; DeVico, Anthony; Shacklett, Barbara L; Valentine, Fred T; Merges, Michael; Kamin-Lewis, Roberta; Mestecky, Jiri; Denny, Thomas; Lewis, George K; Lloyd, Joan; Praschunus, Robert; Baker, Amanda; Nixon, Douglas F; Stranford, Sharon; Gallo, Robert; Vermund, Sten H; Louria, Donald B
2002 Feb 15;185(4):428-438, Journal of infectious diseases
Seventeen women who were persistently uninfected by human immunodeficiency virus type 1 (HIV-1), despite repeated sexual exposure, and 12 of their HIV-positive male partners were studied for antiviral correlates of non-transmission. Thirteen women had > or = 1 immune response in the form of CD8 cell noncytotoxic HIV-1 suppressive activity, proliferative CD4 cell response to HIV antigens, CD8 cell production of macrophage inflammatory protein-1 beta, or ELISPOT assay for HIV-1-specific interferon-gamma secretion. The male HIV-positive partners without AIDS had extremely high CD8 cell counts. All 8 male partners evaluated showed CD8 cell-related cytotoxic HIV suppressive activity. Reduced CD4 cell susceptibility to infection, neutralizing antibody, single-cell cytokine production, and local antibody in the women played no apparent protective role. These observations suggest that the primary protective factor is CD8 cell activity in both the HIV-positive donor and the HIV-negative partner. These findings have substantial implications for vaccine development
— id: 29358, year: 2002, vol: 185, page: 428, stat: Journal Article,

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years
Gunthard HF; Havlir DV; Fiscus S; Zhang ZQ; Eron J; Mellors J; Gulick R; Frost SD; Brown AJ; Schleif W; Valentine F; Jonas L; Meibohm A; Ignacio CC; Isaacs R; Gamagami R; Emini E; Haase A; Richman DD; Wong JK
2001 May 1;183(9):1318-1327, Journal of infectious diseases
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments
— id: 42278, year: 2001, vol: 183, page: 1318, stat: Journal Article,

Shipment impairs lymphocyte proliferative responses to microbial antigens
Betensky RA; Connick E; Devers J; Landay AL; Nokta M; Plaeger S; Rosenblatt H; Schmitz JL; Valentine F; Wara D; Weinberg A; Lederman HM
2000 Sep;7(5):759-763, Clinical & diagnostic laboratory immunology
Lymphocyte proliferation assays (LPAs) are widely used to assess T-lymphocyte function of patients with human immunodeficiency virus infection and other primary and secondary immunodeficiency disorders. Since these assays require expertise not readily available at all clinical sites, specimens may be shipped to central labs for testing. We conducted a large multicenter study to evaluate the effects of shipping on assay performance and found significant loss of LPA activity. This may lead to erroneous results for individual subjects and introduce bias into multicenter trials
— id: 42280, year: 2000, vol: 7, page: 759, stat: Journal Article,

3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine
Gulick RM; Mellors JW; Havlir D; Eron JJ; Meibohm A; Condra JH; Valentine FT; McMahon D; Gonzalez C; Jonas L; Emini EA; Chodakewitz JA; Isaacs R; Richman DD
2000 Jul 4;133(1):35-39, Annals of internal medicine
BACKGROUND: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. OBJECTIVE: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. DESIGN: Open-label extension of a randomized, double-blind study. SETTING: Four clinical research units. PATIENTS: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3. INTERVENTION: Indinavir, zidovudine, and lamivudine. MEASUREMENTS: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. RESULTS: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%). CONCLUSION: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years
— id: 15501, year: 2000, vol: 133, page: 35, stat: Journal Article,

Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214
Schooley RT; Spino C; Kuritzkes D; Walker BD; Valentine FA; Hirsch MS; Cooney E; Friedland G; Kundu S; Merigan TC Jr; McElrath MJ; Collier A; Plaeger S; Mitsuyasu R; Kahn J; Haslett P; Uherova P; deGruttola V; Chiu S; Zhang B; Jones G; Bell D; Ketter N; Twadell T; Chernoff D; Rosandich M
2000 Nov;182(5):1357-1364, Journal of infectious diseases
The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity
— id: 42279, year: 2000, vol: 182, page: 1357, stat: Journal Article,

Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258
Gulick RM; McAuliffe V; Holden-Wiltse J; Crumpacker C; Liebes L; Stein DS; Meehan P; Hussey S; Forcht J; Valentine FT
1999 Mar 16;130(6):510-514, Annals of internal medicine
BACKGROUND: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. OBJECTIVE: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. DESIGN: Phase I study. SETTING: Four clinical research units. PATIENTS: 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. INTERVENTION: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. MEASUREMENTS: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. RESULTS: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. CONCLUSIONS: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied
— id: 6055, year: 1999, vol: 130, page: 510, stat: Journal Article,

Delayed-type hypersensitivity to recombinant HIV envelope glycoprotein (rgp160) after immunization with homologous antigen
Katzenstein DA; Kundu S; Spritzler J; Smoller BR; Haszlett P; Valentine F; Merigan TC
1999 Dec 1;22(4):341-347, Journal of acquired immune deficiency syndromes. JAIDS
Delayed-type hypersensitivity (DTH) responses to intradermal recombinant HIV envelope glycoprotein (rgp160) may assess cell-mediated immune responses to HIV envelope. In three studies, DTH and lymphocyte proliferation responses to rgp160 were obtained in a total of 106 HIV-seropositive subjects with CD4+ counts >400 cells/mm3. Several subjects participated in more than one study. Before immunization, DTH responses were seen in 5 of 56 (9%) of HIV-infected study subjects. After immunization with an alum-adjuvanted experimental rgp160 vaccine, DTH responses were seen in 46 of 52 (89%). Using in vitro lymphocyte proliferation activity (LPA) to rgp160 as an indication of cellular immune response, skin testing has a sensitivity of 0.75 (95% confidence Interval [CI], 0.59-0.88) and a specificity of 0.84 (95% CI, 0.72-0.92). Biopsy samples of skin that had tested positive confirmed the presence of a DTH reaction with a predominance of CD4+ T cells in the perivascular, inflammatory infiltrate. Skin testing before and after immunization with candidate AIDS vaccines could provide a simple method in the field to assess new cell mediated immune responses
— id: 42281, year: 1999, vol: 22, page: 341, stat: Journal Article,

Peptide immunogens representing conserved epitopes of gp120 can induce immune responses recognizing gp120 that are not formed by immunization with whole rgp120
Kelker HC; Nardelli B; Itri V; Paolino A; Valentine FT
1998 Feb 1-5;5:94-94, Conference on Retroviruses & Opportunistic Infections
An octameric multiple chain peptide (MCP) derived from a conserved sequence of amino acids 419-439 of gp120, including amino acid residues that are part of the CD4 binding domain, induces antibodies against the domain that are not induced by rgp120. This MCP and not the monomeric peptide of the same sequence elicits antibodies recognizing conformational epitope(s) of gp120 (Kelker et al, 1994, J. Immunol, 152: 4139) in mice of different MHC type. Murine monoclonal antibodies (MAbs) to 419-439 MCP: 1) recognize rgp120 from several HIV isolates from Clade B as well as rgp120 from Clade E, 2) fail to recognize gp120 denatured by heating in the presence of SDS and DTT. One of these MAbs is able to 1) block up to 80% of the binding of rgp120 to the CD4+ cells, 2) recognize gp120 on the surface of HIV infected CEM-4 cells but not recognize rgp120 passively bound to the CD4+ cells and 3) neutralize low level of infectious units of primary isolate of HIV-1 in a PBMC assay. T helper cells induced by this MCP are stimulated the MCP immunogen, by monomeric peptide and by native rgp120 to release IL-2. 419-439 MCP also stimulates the formation of CTLs of CD8 phenotype in three murine strains of different MHC type. Furthermore, we compared the ability of 419-439 MCP and of rgp120 to elicit immune responses against this epitope and we determined that immunization of mice with 419-439 MCP elicits formation of both CTLs and of antibodies against 419-439 epitope that immunization with rgp120 can not induce. This is a strategy for inducing immune responses against conserved cryptic epitopes
— id: 6010, year: 1998, vol: 5, page: 94, stat: Journal Article,

Lymphocyte-proliferative responses to HIV antigens as a potential measure of immunological reconstitution in HIV disease
Valentine FT; Paolino A; Saito A; Holzman RS
1998 Jun;14 Suppl 2:S161-S166, AIDS research & human retroviruses
Lymphocyte-proliferative responses (LPRs) to HIV antigens are absent or of low magnitude in the majority of HIV-infected individuals, even early in the disease. However, lymphocytes from 2% to 3% of individuals proliferate very strongly to HIV Env or Gag antigens, and these individuals remain well clinically, without antiretroviral therapy. In established HIV infection, suppression of HIV-replication with potent antiretroviral therapy does not result in the development of strong LPRs to HIV antigens. Large LPRs to HIV antigens can be induced by HIV vaccines in patients with established infection, even though they were not formed in response to infection. Studies must be designed to determine whether large LPRs induced by vaccines administered in conjunction with potent antiretroviral therapy are associated with long-term control of HIV infection
— id: 7836, year: 1998, vol: 14 Suppl 2, page: S161, stat: Journal Article,

Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy [see comments]
Gulick RM; Mellors JW; Havlir D; Eron JJ; Gonzalez C; McMahon D; Richman DD; Valentine FT; Jonas L; Meibohm A; Emini EA; Chodakewitz JA
1997 Sep 11;337(11):734-739, New England journal of medicine
BACKGROUND: The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication. METHODS: In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts. RESULTS: The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of 31 patients in the three-drug group (90 percent), 12 of 28 patients in the indinavir group (43 percent), and none of 30 patients in the zidovudine-lamivudine group. The increase in CD4 cell counts over the first 24 weeks was greater in the two groups receiving indinavir than in the zidovudine-lamivudine group (P< or =0.01 for each comparison). The changes in the viral load and the CD4 cell count persisted for up to 52 weeks. All the regimens were generally well tolerated. CONCLUSIONS: In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year
— id: 12293, year: 1997, vol: 337, page: 734, stat: Journal Article,

Effect of therapeutic immunization with recombinant gp160 HIV-1 vaccine on HIV-1 proviral DNA and plasma RNA: relationship to cellular immune responses
Kundu SK; Katzenstein D; Valentine FT; Spino C; Efron B; Merigan TC
1997 Aug 1;15(4):269-274, Journal of acquired immune deficiency syndromes & human retrovirology
Therapeutic vaccination has been proposed as a strategy to augment immune mechanisms to control viral replication and slow clinical progression of HIV infection to disease. Following recombinant gp160 (r-gp160) immunization in three clinical trials, plasma HIV-1 RNA and cellular proviral DNA were assessed by quantitative polymerase chain reaction (PCR) in 76 HIV-seropositive subjects with CD4+ T cell counts > or = 300/mm3. Immunization increased HIV-specific cellular immune responses (e.g., cytotoxic T lymphocyte [CTL] activities, lymphocyte proliferative responses); however, there were no significant effects of immunization or cellular immune responses on measures of plasma RNA or cellular DNA viral load
— id: 15502, year: 1997, vol: 15, page: 269, stat: Journal Article,

Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection - A randomized, double-blind, placebo-controlled trial
DAquila, RT; Hughes, MD; Johnson, VA; Fischl, MA; Sommadossi, JP; Liou, SH; Timpone, J; Myers, M; Basgoz, N; Niu, M; Hirsch, MS; Costanzo, L; Ruben, S; Berzins, B; Martinez, A; Fishman, I; Kazial, K; Cort, SN; Robinson, P; Hall, D; Macy, H; McLaren, C; Rooney, J; Warwick, J; CavailleColl, M; Valentine, F; Booth, D; Soeiro, R; Stein, D; Zingman, B; Schliosberg, J; Polsky, B; Sepkowitz, K; Sharpe, V; Giordano, M; Wanke, C; Gulick, R; Craven, D; Grodman, C; Fife, K; Black, J; Todd, K; Nixon, H; Sperber, K; Gerits, P; Mildvan, D; Nicholas, P; Murphy, RL; Kessler, H; Pulvirenti, J; Squires, K; Saag, M; Weingarten, J; Gnann, J; Havlir, D; Fegan, C; Spector, S; Richman, D; Jacobson, M; Dybeck, K; Joseph, P; Clanon, K; McKenzie, S; Daniel, P; Dayton, D; Leonard, J; Schooley, R; Kuritzkes, D; Ray, G; Putnam, B; Jayaweera, D; PatroneReese, J; Tanner, T; Moebus, J; Reed, N; StJacque, R; Henry, K; Swindells, S; Eron, J; Ragan, D; Horton, J; Lane, T; Frank, I; Norris, A; Pomerantz, R; Hauptman, S; Geiseler, J; Leedom, J; Canchola, F; Olson, C; Deyton, L; Pettinelli, C
1996 JUN 15 ;124(12):1019-1030, Annals of internal medicine
Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. Patients: 398 adults who had HIV-1 infection, had 350 or fewer CD4(+) T lymphocytes/mm(3), and had had more than 6 months of previous nucleoside therapy. Intervention: 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing greater than or equal to 60 kg). Measurements: CD4(+) T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 log(10) lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 log(10) infectious units per million cells; P = 0.023), and a 0.25 log(10) lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 log(10) RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens
— id: 52887, year: 1996, vol: 124, page: 1019, stat: Journal Article,

Potent and sustained antiretroviral activity of indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC)
Gulick RM; Mellors J; Havlir D; Eron J; Gonzalez C; McMahon D; Richman D; Valentine F; Rooney J; Jonas L; Meibohm A; Emini E; Chodakewitz J
1996 Jul 7-12;11:19-19, International conference on AIDS
Objective: To determine the safety and duration of antiviral activity of IDV + ZDV + 3TC. Methods: Randomized, double-blind study comparing IDV 800mg q8h + ZDV 200mg q8h + 3TC 150mg q12h or IDV 800mg q8h or ZDV 200mg q8h + 3TC 150mg q12h in 97 adult patients with HIV infection, greater than or equal to 20,000 copies/ml of serum HIV RNA (Roche PCR kit assay), 50-400 CD4 cells/mm(3), greater than or equal to 6 months of prior ZDV therapy, and no previous use of 3TC or protease inhibitors. Results: At baseline, median HIV RNA was 41,130 copies/ml, median CD4 was 142 cells/mm(3), and median prior ZDV experience was 31 months. After up to 52 weeks of follow-up, 90 of 97 patients continue on study. One patient withdrew for an adverse event (grade 2 nausea). Nine patients had clinical nephrolithiasis, eight of whom were on indinavir containing study arms. All nine patients continued study medications; two underwent indinavir dose reduction. Nine patients had neutropenia, anemia, nausea, or headache requiring ZDV/3TC dose reduction. A summary of available viral load data is shown: (table: see text) Median HIV RNA log(10) decreases at 24 and 44 weeks; -2.2 and -2.2 (IDV+ZDV+3TC), -0.7 and -0.9 (IDV), and -0.6 and -0.2 (ZDV+3TC). Median CD4 changes from baseline (cells/mm(3)) at 24 and 44 weeks; +126 and +218 (IDV+ZDV+3TC), +105 and +158 (IDV) and +14 and +14 (ZDV+3TC). Conclusions: IDV + ZDV +3TC is a generally safe, well-tolerated regimen with potent antiretroviral activity and CD4 cell increases that are sustained for at least 44 weeks
— id: 6004, year: 1996, vol: 11, page: 19, stat: Journal Article,

A randomized, placebo-controlled study of the immunogenicity of human immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with > or = 400/mm3 CD4 T lymphocytes (AIDS Clinical Trials Group Protocol 137)
Valentine FT; Kundu S; Haslett PA; Katzenstein D; Beckett L; Spino C; Borucki B; Vasquez M; Smith G; Korvick J; Kagan J; Merigan TC
1996 Jun;173(6):1336-1346, Journal of infectious diseases
Immune responses provoked by human immunodeficiency virus (HIV) infection ultimately are insufficient to control the disease and do not include strong lymphocyte-proliferative responses to HIV antigens or antibodies to many viral epitopes. A randomized double-blind, placebo-controlled trial evaluated the immunogenicity of recombinant HIV envelope vaccine (rgp160) in HIV-infected subjects with > or = 400/mm3 CD4 T cells. Controls received hepatitis B vaccine. Of subjects receiving rgp160, 98% developed lymphocyte-proliferative responses to the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and p66, respectively. All doses of vaccine (20, 80, 320, 1280 microgram) induced new responses. New antibodies to epitopes on rgp160 developed only in recipients of higher doses of rgp160. CD4 T cell percentages declined less rapidly in recipients of rgp160 than in controls. Vaccination of HIV-infected subjects with rgp160 results in cellular and humoral immune responses to HIV that infection itself had not stimulated
— id: 8016, year: 1996, vol: 173, page: 1336, stat: Journal Article,

CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells
Nardelli B; Gonzalez CJ; Schechter M; Valentine FT
1995 Aug 1;92(16):7312-7316, Proceedings of the National Academy of Sciences of the United States of America
We have investigated the ability of human immunodeficiency virus (HIV)-infected cells to kill uninfected CD4+ lymphocytes. Infected peripheral blood mononuclear cells were cocultured with autologous 51Cr-labeled uninfected cells. Rapid death of the normal CD4-expressing target population was observed following a brief incubation. Death of blood CD4+ lymphocytes occurred before syncytium formation could be detected or productive viral infection established in the normal target cells. Cytolysis could not be induced by free virus, was dependent on gp120-CD4 binding, and occurred in resting, as well as activated, lymphocytes. CD8+ cells were not involved in this phenomenon, since HIV-infected CEMT4 cells (CD4+, CD8- cells) mediated the cytolysis of uninfected targets. Reciprocal isotope-labeling experiments demonstrated that infected CEMT4 cells did not die in parallel with their targets. The uninfected target cells manifested DNA fragmentation, followed by the release of the 51Cr label. Thus, in HIV patients, infected lymphocytes may cause the depletion of the much larger population of uninfected CD4+ cells without actually infecting them, by triggering an apoptotic death
— id: 6850, year: 1995, vol: 92, page: 7312, stat: Journal Article,

The ability of CD8 cells to suppress HIV replication is affected by their stat of activation
Schnoll S; Hennesey NP; Valentine F
1995 Jan 29-Feb 2;2:86-86, National Conference on Human Retroviruses & Related Infections
Objective: To investigate the effect of lymphocyte activation on CD8-mediated suppression of HIV replication. Methods: CD4 and CD8 cells from HIV+ and HIV- donors were positively selected. The CD4 cells were stimulated and superinfected with HIV and the two cell populations were cocultured at various CD8:CD4 ratios. In addition to determining the concentration of p24 in the resultant supernatants, a fixed volume of each coculture was analyzed by three-color flow cytometry. Results: CD8 cells from healthy, infected donors are capable of powerfully suppressing vital replication regardless of whether they had been PHA stimulated. This suppression, however, was more powerful and less reversible using stimulated CD8 cells. In some cases CD8-mediated HIV suppression was more effective than 2 micromolar AZT, but often required both AZT and CD8 cells to completely shut off viral production. The CD8 cells from HIV negative donors also demonstrated antiviral activity but only when the CD8 cells were used at high CD8:CD4 ratios and were stimulated. The method of activation of the CD4 cells (PHA vs. anti-CD3) did not appear to play a role. Unstimulated CD8 cells from HIV negative donors in some cases could suppress viral replication in HIV negative allogeneic CD4 cell donors, but this was associated with CD4 cell death within the culture. Conclusion: The CD8 cells from HIV positive individuals possess the ability to powerfully suppress viral replication. This property can also be demonstrated using the CD8 cells from HIV negative donors, however it requires in vitro conditions that are probably not pertinent to the in vivo situation
— id: 5996, year: 1995, vol: 2, page: 86, stat: Journal Article,

Analysis of potential risk factors associated with the development of pancreatitis in phase I patients with AIDS or AIDS-related complex receiving didanosine [see comments]
Grasela TH; Walawander CA; Beltangady M; Knupp CA; Martin RR; Dunkle LM; Barbhaiya RH; Pittman KA; Dolin R; Valentine FT; et al
1994 Jun;169(6):1250-1255, Journal of infectious diseases
Phase I dose-escalating trials of didanosine revealed dose-limiting toxicities, including pancreatitis, and established a total daily dose of 12.5 mg/kg/day as the maximum tolerated dose. Clinical and pharmacokinetic data of 61 patients from two trials were analyzed to further evaluate the risk of pancreatitis: 1 (6.3%) of 16 patients who received < 500 mg/day didanosine, 2 (13.3%) of 15 who received 500-750 mg/day, and 15 (50%) of 30 who received > 750 mg/day developed pancreatitis (P < .001). A relationship between risk of pancreatitis and steady-state plasma concentrations of didanosine and age was also observed, suggesting that knowledge of didanosine pharmacokinetics provided additional information regarding risk of toxicity. Further confirmation of these findings will be necessary to determine if the risk factors for pancreatitis remain the same at lower doses currently used
— id: 15503, year: 1994, vol: 169, page: 1250, stat: Journal Article,

Within-subject variation in CD4 lymphocyte count in asymptomatic human immunodeficiency virus infection: implications for patient monitoring
Hughes MD; Stein DS; Gundacker HM; Valentine FT; Phair JP; Volberding PA
1994 Jan;169(1):28-36, Journal of infectious diseases
Changes in CD4 lymphocyte counts are widely used in monitoring human immunodeficiency virus (HIV)-infected patients for disease progression. However, random fluctuations may obscure clinically significant changes. CD4 cell counts from 1020 untreated subjects with asymptomatic HIV infection monitored by standardized methods for up to 2 years were assessed. The within-subject coefficient of variation averaged 25% but was higher in subjects with lower counts; in 6% of subjects the count was half or double the one obtained 8 weeks before. Proportionate rates of decline, which had negligible correlation with the baseline count, averaged 14.3%/year but varied considerably between subjects: An estimated 29% had increasing trends. Declines were greater in HIV p24-positive subjects and those with higher lymphocyte percentages or lower platelet counts or hemoglobin levels. With such high variation, changes between single counts should be interpreted cautiously. Using multiple counts and other markers may provide more precise assessment of immune status
— id: 15504, year: 1994, vol: 169, page: 28, stat: Journal Article,

PHASE-II DOSE-RANGING TRIAL OF FOSCARNET SALVAGE THERAPY FOR CYTOMEGALOVIRUS RETINITIS IN AIDS PATIENTS INTOLERANT OF OR RESISTANT TO GANCICLOVIR (ACTG PROTOCOL 093)
JACOBSON, MA; WULFSOHN, M; FEINBERG, JE; DAVIS, R; POWER, M; OWENS, S; CAUSEY, D; HEATHCHIOZZI, ME; MURPHY, RL; CHEUNG, TW; DIETERICH, DT; SPECTOR, SA; MCKINLEY, GF; PARENTI, DM; CRUMPACKER, C; NISHIMOTO, B; LEEDOM, JM; KRAMER, F; COHEN, C; LOFTUS, J; KESSLER, HA; POTTAGE, JC; BENSON, CA; PHAIR, JP; GERITS, P; CHUSID, E; SACKS, HS; FRIEDBERG, D; CURRANKRIKORIAN, K; VALENTINE, FT; MENG, TC; FREEMAN, WR; MEIXNER, L; RICHMAN, D; ODONNELL, JJ; KIMBRELL, C; BOGGIO, K; LARSON, J; WHITMORE, PV; SIMON, GL; LELACHEUR, S; FIFE, K; ZWICKL, B; RELUE, J; STEIGBIGEL, RT; FUHRER, J; DONLON, W; BURK, RA; PORTMORE, AC; WEISSBACH, NE; HOOTON, TM; HOLZWORTH, P; DAVISON, S; COLLIER, AC; POWDERLY, WG; KLEBERT, M; ROYAL, M; SEYFRIED, W; SQUIRES, KC; WEISS, W; BARBACCI, M; BECKER, RL; JABS, D; BARTLETT, JG; PARA, MF; JONES, M; NEIDIG, JL; FASS, RJ; VANDERHORST, C; KYLSTRA, J; RAASCH, R; BLOODGOOD, K; WOLITZ, R; KIRK, S; ROLFE, L; PATRONEREESE, J; BARTLETT, JA; WASKIN, HA; WILLIAMS, DK; SHIP, KW; KAHL, P; ASSAYKEEN, T; KAROL, C; MARTINMUNLEY, S; SUMNER, P
1994 APR ;8(4):451-459, AIDS
Objective: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. Methods: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. Results: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occuring at less-than-or-equal-to 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. Conclusion: in patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied
— id: 52528, year: 1994, vol: 8, page: 451, stat: Journal Article,

Immunogenic and antigenic properties of an HIV-1 gp120-derived multiple chain peptide
Kelker HC; Schlesinger D; Valentine FT
1994 Apr 15;152(8):4139-4148, Journal of immunology
An HIV-1 envelope protein gp120-derived monomeric peptide (amino acid residues 419-439) and its homologous multiple chain peptide (MCP) construct were compared for immunogenicity in mice. The Abs stimulated by the MCP recognized epitopes on the MCP that were not present on the homologous monomer. The anti-419-439 MCP sera recognized a conformational determinant on the native envelope glycoprotein, as indicated by: 1) detection of native but not denatured recombinant envelope glycoprotein by ELISA and dot blot and 2) reaction with infected cell lines expressing gp120 on their surface as detected by flow cytometry. In contrast, the anti-monomer sera were highly specific for the monomer and recognized the envelope glycoprotein at lower titers. The low reactivity of the anti-monomer sera with the envelope glycoprotein was not decreased by denaturation. Reciprocally, murine antiserum to HIV-1 envelope glycoprotein gp160 recognized the MCP construct but not the homologous monomeric peptide. The data indicate that the MCP construct forms additional antigenic determinants not present on the homologous monomer, and that the anti-419-439 MCP Abs recognize a conformational determinant on the envelope glycoprotein not recognized by Abs against the homologous monomer. Furthermore, antisera against another envelope-derived MCP (amino acid residues 105-117) also recognize conformational determinants on the envelope glycoprotein, whereas antisera against the homologous monomeric peptide do not
— id: 6419, year: 1994, vol: 152, page: 4139, stat: Journal Article,

Didanosine: long-term follow-up of patients in a phase 1 study
Lambert JS; Seidlin M; Valentine FT; Reichman RC; Dolin R
1993 Feb;16 Suppl 1:S40-S45, Clinical infectious diseases
Long-term follow-up of 44 patients with AIDS or AIDS-related complex (ARC) in a phase 1 trial of didanosine is reported. These patients were monitored for as long as 72 weeks (mean, 34 weeks) for toxicity and activity of didanosine. Pancreatitis and neuropathy, the major clinical toxicities, developed infrequently at the doses of didanosine (250-750 mg/d) employed during the latter part of the study. Consistent hematologic toxicity was not encountered; moreover, mean values for hematologic parameters such as hemoglobin concentration, white blood cell count, neutrophil count, lymphocyte count, and platelet count improved for up to 20-60 weeks. CD4 counts increased significantly through 10 weeks of therapy and in some patients remained at or above counts at enrollment for as long as 60 weeks. Serum concentrations of p24 antigen decreased significantly and remained at the decreased level for up to 48 weeks. An initial diagnosis of ARC (as opposed to AIDS), an initial CD4 count of > 100/mm3, and an increase in CD4 counts during the first 10 weeks of therapy were associated with a higher rate of survival and with lower rates of development of opportunistic infections and of other clinical manifestations of disease progression
— id: 15505, year: 1993, vol: 16 Suppl 1, page: S40, stat: Journal Article,

Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial
Drusano GL; Yuen GJ; Lambert JS; Seidlin M; Dolin R; Valentine FT
1992 Apr 1;116(7):562-566, Annals of internal medicine
OBJECTIVE: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, phase I study. SETTING: Two university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. INTERVENTION: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. MEASUREMENTS: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. RESULTS: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant. CONCLUSIONS: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less
— id: 15507, year: 1992, vol: 116, page: 562, stat: Journal Article,

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials
Drusano GL; Yuen GJ; Morse G; Cooley TP; Seidlin M; Lambert JS; Liebman HA; Valentine FT; Dolin R
1992 Jun;36(6):1280-1283, Antimicrobial agents & chemotherapy
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.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 15506, year: 1992, vol: 36, page: 1280, stat: Journal Article,

Lymphocytes from some long-term seronegative heterosexual partners of HIV-infected individuals proliferate in response to HIV antigens
Kelker HC; Seidlin M; Vogler M; Valentine FT
1992 Aug;8(8):1355-1359, AIDS research & human retroviruses
A comparison of the proliferative responses of lymphocytes to human immunodeficiency virus (HIV) antigens from long-term, seronegative heterosexual partners of HIV-infected subjects, from normal unexposed controls and from healthy seropositive heterosexual partners or seropositive, asymptomatic men, reveals that lymphocytes from healthy seropositive individuals with strong proliferative responses to recall, microbial antigens respond only minimally to HIV proteins or envelope peptides, and that even these low responses do not occur in all individuals. If the frequency of responses to several HIV antigens are analyzed, lymphocytes from both HIV-exposed seropositive and seronegative partners of infected individuals proliferate to HIV antigens to a greater degree than lymphocytes from unexposed, normal control individuals. Although lymphocytes from seropositive partners proliferate to a greater degree than those from seronegative partners, the latter are more similar to seropositive partners than they are to normal controls. This observation suggests that these seronegative partners may have become sensitized to HIV antigens through sexual exposure but without infection, and/or that the presence or development of these small immune responses in some individuals might be associated with a failure to become infected
— id: 13495, year: 1992, vol: 8, page: 1355, stat: Journal Article,

Extended follow-up of peripheral neuropathy in patients with AIDS and AIDS-related complex treated with dideoxyinosine
Kieburtz KD; Seidlin M; Lambert JS; Dolin R; Reichman R; Valentine F
1992 ;5(1):60-64, Journal of acquired immune deficiency syndrome
Neuropathic complaints were frequently observed in a Phase I study of dideoxyinosine (ddI) in 44 patients with AIDS and AIDS-related complex. Ten patients (23%) were thought to have a ddI-related peripheral neuropathy. The symptoms were primarily sensory, and there was limited motor involvement. The sensory symptoms improved in all patients with discontinuation of ddI. Some patients tolerated reintroduction of ddI at lower doses without significant recurrence of the neuropathic symptoms. Although the neuropathy was usually seen in patients taking higher doses of ddI than used in current treatment protocols, clinicians must be aware of this potential toxicity as more human immunodeficiency virus-infected patients are being treated with ddI
— id: 42282, year: 1992, vol: 5, page: 60, stat: Journal Article,

ADRENALECTOMY FAILS TO ABOLISH CORTICOTROPIN-RELEASING FACTOR (CRF)-INDUCED IMMUNOSUPPRESSION IN HUMANS AS WELL AS RATS
NABRISKI, D; SHAPIRO, M; SAPERSTEIN, A; SHENKMAN, L; VALENTINE, FT; YAO, JS; ROSENZWEIG, S; HUTCHINSON, B; AUDYHA, T; HOLLANDER, CS
1992 APR ;40(2):A373-A373, Clinical research
— id: 52005, year: 1992, vol: 40, page: A373, stat: Journal Article,

Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex
Pai SM; Shukla UA; Grasela TH; Knupp CA; Dolin R; Valentine FT; McLaren C; Liebman HA; Martin RR; Pittman KA; et al
1992 Mar;32(3):242-247, Journal of clinical pharmacology
Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach
— id: 15508, year: 1992, vol: 32, page: 242, stat: Journal Article,

Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease
Schacter LP; Rozencweig M; Beltangady M; Allan JD; Canetta R; Cooley TP; Dolin R; Kelley S; Lambert J; Liebman HA; Messina M; Nicaise C; Seidlin M; Valentine FT; Yarchoan R; Smaldone LF
1992 Dec 15;80(12):2969-2976, Blood
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
— id: 42283, year: 1992, vol: 80, page: 2969, stat: Journal Article,

Pancreatitis and pancreatic dysfunction in patients taking dideoxyinosine
Seidlin M; Lambert JS; Dolin R; Valentine FT
1992 Aug;6(8):831-835, AIDS
OBJECTIVE: To describe the incidence, clinical characteristics and dose relationship of dideoxyinosine (ddI)-associated pancreatitis. DESIGN: Patients enrolled in a Phase I dose escalation trial of ddI [AIDS Clinical Trials Group (ACTG) 064] were evaluated for signs and symptoms of pancreatic dysfunction. SETTING: Two ACTG sites. PATIENTS: Forty-four patients with AIDS or AIDS-related complex (ARC) and a CD4 cell count less than or equal to 400 x 10(6)/l. MAIN OUTCOME MEASURES: Seven patients developed pancreatitis that lasted from 1 to 7 weeks and varied in severity from mild to life-threatening. Seven other patients had evidence of hyperamylasemia or hypertriglyceridemia. Six patients who developed pancreatitis were able to tolerate rechallenge with lower doses of ddI. RESULTS: Development of pancreatitis correlated with cumulative dose of ddI but not with stage of disease or concomitant medications. Cumulative dose was not significantly associated with development of hyperamylasemia or hypertriglyceridemia in patients without clinical pancreatitis. CONCLUSIONS: The development of pancreatitis in AIDS or ARC patients receiving ddI varies in severity and time course and is associated with cumulative dose. Patients who develop pancreatitis may be able to tolerate therapy with a lower dose after resolution of their symptoms. Patients receiving ddI require careful monitoring for the development of this complication
— id: 13502, year: 1992, vol: 6, page: 831, stat: Journal Article,

Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex
Knupp CA; Shyu WC; Dolin R; Valentine FT; McLaren C; Martin RR; Pittman KA; Barbhaiya RH
1991 May;49(5):523-535, Clinical pharmacology & therapeutics
The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials
— id: 15509, year: 1991, vol: 49, page: 523, stat: Journal Article,

HYPERICIN - A HEXAHYDROXYL, DIMETHYL-NAPHTHODIANTHRONE WITH ACTIVITY AGAINST HIV INVITRO AND AGAINST MURINE RETROVIRUSES INVIVO
VALENTINE, FT
1991 FEB 14 ;4(3):317-317, Journal of acquired immune deficiency syndromes & human retrovirology
— id: 51726, year: 1991, vol: 4, page: 317, stat: Journal Article,

Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study
Hochster, H; Dieterich, D; Bozzette, S; Reichman, R C; Connor, J D; Liebes, L; Sonke, R L; Spector, S A; Valentine, F; Pettinelli, C
1990 Jul 15;113(2):111-117, Annals of internal medicine
OBJECTIVE: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease. DESIGN: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. SETTING: Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). PATIENTS: Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed. INTERVENTIONS: Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. MEASUREMENTS AND MAIN RESULTS: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. CONCLUSION: The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion
— id: 101812, year: 1990, vol: 113, page: 111, stat: Journal Article,

2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial [see comments]
Lambert JS; Seidlin M; Reichman RC; Plank CS; Laverty M; Morse GD; Knupp C; McLaren C; Pettinelli C; Valentine FT; et al
1990 May 10;322(19):1333-1340, New England journal of medicine
2',3'-Dideoxyinosine (ddI) is a purine analogue that after intracellular metabolic conversion suppresses the replication of the human immunodeficiency virus (HIV). We conducted a Phase I dose-escalation study of ddI in 17 patients with the acquired immunodeficiency syndrome (AIDS) and 20 patients with AIDS-related complex. The drug was administered twice daily over a dose range of 0.4 to 66 mg per kilogram of body weight per day for 2 to 44 weeks. The maximal tolerated oral dose of ddI was estimated to be 12 mg per kilogram per day. The major dose-limiting toxic effects were a painful peripheral neuropathy (in eight patients) and pancreatitis (in five). Asymptomatic elevations of the serum aminotransferase levels (in 13 patients) and the serum urate level (in 10) were also noted, but there was no dose-related hematologic toxicity. At the maximal tolerated dose, the peak plasma levels of ddI were 6.3 to 9.6 mumol per liter 0.6 to 1 hour after oral administration; the mean plasma half-life was 1.5 hours. The administration of ddI was associated with statistically significant decreases in serum level of p24 antigen and increases in the numbers of CD4 cells at 2, 6, 10, and 20 weeks. These changes were seen at all dose levels studied. Either a clinical improvement or a weight gain of greater than or equal to 2 kg was observed in 25 of 34 patients at six weeks. We conclude that ddI is a promising therapeutic agent in patients with AIDS or AIDS-related complex. Its efficacy is currently being evaluated in large-scale, controlled clinical trials
— id: 15511, year: 1990, vol: 322, page: 1333, stat: Journal Article,

Pathogenesis of the immunological deficiencies caused by infection with the human immunodeficiency virus
Valentine FT
1990 Jun;17(3):321-334, Seminars in oncology
— id: 8240, year: 1990, vol: 17, page: 321, stat: Journal Article,

Immunological and virological surrogate markers in the evaluation of therapies for HIV infection
Valentine FT; Jacobson MA
1990 ;4 Suppl 1:S201-S206, AIDS
— id: 15512, year: 1990, vol: 4 Suppl 1, page: S201, stat: Journal Article,

Phase I study of 2',3'-dideoxyinosine: experience with 19 patients at New York University Medical Center
Valentine FT; Seidlin M; Hochster H; Laverty M
1990 Jul-Aug;12 Suppl 5:S534-S539, Reviews of infectious diseases
We performed a phase I study of escalating dosages of 2',3'-dideoxyinosine (didanosine; ddI) in 19 patients with AIDS or AIDS-related complex in order (1) to establish the maximal tolerated dosage, (2) to determine the nature of toxic adverse effects, (3) to measure changes in levels of circulating human immunodeficiency virus p24 antigen and in CD4+ cell counts, and (4) to evaluate the pharmacokinetics of ddI. Almost all patients had received zidovudine therapy previously. The maximal tolerated dosage of ddI was found to be approximately 12 mg/(kg.d) when it was administered orally for 28 weeks. The major dosage-limiting adverse effects encountered were neuropathy, pancreatitis, and hepatitis. These occurred at dosages higher than those associated with decreases in levels of p24 antigen. The major toxic effects of ddI are different from those associated with zidovudine. At the proper dosage, ddI may prove to be an effective agent for the chronic treatment of infection with human immunodeficiency virus and should be especially useful in the treatment of patients who cannot tolerate zidovudine
— id: 15510, year: 1990, vol: 12 Suppl 5, page: S534, stat: Journal Article,

Phase I/II trial of thymostimulin in opportunistic infections of the acquired immune deficiency syndrome
Chachoua A; Green MD; Valentine F; Muggia FM
1989 ;7(3):225-229, Cancer investigation
Fifteen patients with acquired immune deficiency syndrome (AIDS) and opportunistic infection, were randomized to receive treatment with either thymostimulin (TP-1) at 1 mg/kg for 14 days then weekly for 12 weeks or placebo. The objectives of this study were to evaluate the toxicity of TP-1 in this patient population and to make observations on clinical response as measured by time to second opportunistic infection (OI) and changes in laboratory parameters of immune function. The study demonstrates that TP-1 can be administered safely. There were no differences, however, in time to second OI or overall survival between patient groups. In addition, no change in the immune function could be detected in patients receiving thymostimulin
— id: 10760, year: 1989, vol: 7, page: 225, stat: Journal Article,

Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin
Lavie G; Valentine F; Levin B; Mazur Y; Gallo G; Lavie D; Weiner D; Meruelo D
1989 Aug;86(15):5963-5967, Proceedings of the National Academy of Sciences of the United States of America
Administration of the aromatic polycyclic dione compounds hypericin or pseudohypericin to experimental animals provides protection from disease induced by retroviruses that give rise to acute, as well as slowly progressive, diseases. For example, survival from Friend virus-induced leukemia is significantly prolonged by both compounds, with hypericin showing the greater potency. Viremia induced by LP-BM5 murine immunodeficiency virus is markedly suppressed after infrequent dosage of either substance. These compounds affect the retroviral infection and replication cycle at least at two different points: (i) Assembly or processing of intact virions from infected cells was shown to be affected by hypericin. Electron microscopy of hypericin-treated, virus-producing cells revealed the production of particles containing immature or abnormally assembled cores, suggesting the compounds may interfere with processing of gag-encoded precursor polyproteins. The released virions contain no detectable activity of reverse transcriptase. (ii) Hypericin and pseudohypericin also directly inactivate mature and properly assembled retroviruses as determined by assays for reverse transcriptase and infectivity. Accumulating data from our laboratories suggest that these compounds inhibit retroviruses by unconventional mechanisms and that the potential therapeutic value of hypericin and pseudohypericin should be explored in diseases such as AIDS
— id: 10542, year: 1989, vol: 86, page: 5963, stat: Journal Article,

Results of the flow cytometry ACTG quality control program: analysis and findings
Paxton, H; Kidd, P; Landay, A; Giorgi, J; Flomenberg, N; Walker, E; Valentine, F; Fahey, J; Gelman, R
1989 Jul;52(1):68-84, Clinical immunology & immunopathology
The AIDS Clinical Trial Group's (ACTG) Immunology Committee was charged with initiating a quality control program for all laboratories participating in the ACTG program reporting flow cytometry data. Forty-one laboratories were evaluated. This report defines the goals of this program and the subsequent findings after 19 send-outs were made. Both HIV positive volunteer donors and normal age-matched donors were used. Sample sets included both heparin and EDTA anticoagulated bloods. Laboratories were asked to report hematologic parameters as well as flow cytometry data both in percentages and absolute numbers. Results were evaluated using nonparametric statistical analysis. Robust CVs and interquartile ranges were used to define the performance of individual laboratories for each CD subset analyzed. Intralaboratory reproducibility was analyzed by paired sample sets. All laboratories were found to be able to define normal samples as normal. Seventy-five percent of the laboratories were able to define abnormal samples as abnormal. Twenty-five percent could not identify two abnormal samples as abnormal. Forty percent of the labs were found unable to reproduce paired samples within an absolute of +/- 5%. EDTA was found slightly superior to heparin in bloods evaluated by flow cytometry within 30 hr of collection. The analysis of specific histograms, questionnaires, and data analysis led to a specific set of recommendations for performance of flow cytometry studies
— id: 135032, year: 1989, vol: 52, page: 68, stat: Journal Article,

Prevalence of HIV infection in New York call girls
Seidlin M; Krasinski K; Bebenroth D; Itri V; Paolino AM; Valentine F
1988 ;1(2):150-154, Journal of acquired immune deficiency syndrome
In order to evaluate the frequency of sexual transmission of human immunodeficiency virus (HIV) among promiscuous heterosexuals, we studied the prevalence of HIV infection among a group of predominantly Caucasian call girls and women working for escort services and massage parlors in New York City. In the 78 subjects studied, the mean age was 31.6 years and the mean duration of prostitution was 5.1 years. Study participants each had a median of 200 different sexual partners in the preceding year. Six women had a history of intravenous drug abuse and none had a history of any other recognized risk factor for HIV infection. Ninety percent of the women studied used condoms during intercourse with at least some of their partners. One of the six women with a history of drug abuse and none of the 72 non-drug-abusers were seropositive for HIV. This study indicates that despite their promiscuity, HIV infection is still uncommon in call girls in New York City
— id: 11246, year: 1988, vol: 1, page: 150, stat: Journal Article,

Detection of HIV antigen and specific antibodies to HIV core and envelope proteins in sera of patients with HIV infection
Cao YZ; Valentine F; Hojvat S; Allain JP; Rubinstein P; Mirabile M; Czelusniak S; Leuther M; Baker L; Friedman-Kien AE
1987 Aug;70(2):575-578, Blood
The sera of well-characterized populations were examined for three markers of human immunodeficiency virus (HIV) infection; HIV antigen (HIV Ag), and antibodies to HIV envelope (gp41) and core (p24) proteins. Of 563 serum samples tested, 251 were from HIV-infected patients diagnosed as having AIDS manifested by opportunistic infections (AIDS-OI), AIDS-associated Kaposi's sarcoma (AIDS-KS), or AIDS-related complex (ARC). One hundred seventy-six specimens tested were from asymptomatic high-risk individuals, and 136 were from heterosexual control subjects or patients with non-AIDS-related disease. None of the 136 control individuals tested had HIV Ag or HIV antibodies to either p24 or gp41. Of the 427 HIV-seropositive individuals, 99% to 100% were positive for gp41 antibodies to HIV. In contrast, the seroprevalence of p24 antibodies to HIV varied from 23% to 83% and appeared to be inversely associated with the severity of the patients' clinical symptoms. When specimens were analyzed for the presence of HIV Ag, in seropositive individuals the prevalence rate for this marker was lowest (1.4%) in asymptomatic individuals and highest (50%) in the AIDS-OI diagnosed group. Also, 240 cases with AIDS-KS, AIDS-OI, and ARC and the group of asymptomatic high-risk individuals were analyzed for T helper/T lymphocytes (T4) cell number and T4/T8 ratio; only one (2.0%) HIV Ag-positive case showed a T4 cell number greater than 400 and a normal T4/T8 ratio. These studies appear to demonstrate a direct correlation between the presence of HIV Ag and the severity of clinical complications of HIV infection
— id: 14776, year: 1987, vol: 70, page: 575, stat: Journal Article,

Immunophenotype of human melanoma cells in different metastases
Bystryn JC; Bernstein P; Liu P; Valentine F
1985 Nov;45(11 Pt 2):5603-5607, Cancer research
The pattern of melanoma-associated antigens (MAAs) expressed on the surface of melanoma cells in 23 metastases, 15 obtained from different patients and 8 from different metastases in two patients, was studied by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis using monoclonal and polyclonal melanoma antisera. Though there were differences in the MAAs expressed by each melanoma, there were marked similarities as well. No more than two melanomas had a similar pattern of MAAs. However, all melanomas expressed some MAAs, and most MAAs were commonly expressed by several melanomas. Two of the MAAs studied, with molecular weights of approximately 75,000 and 95,000 to 97,000, were particularly well represented, and at least one of these two antigens was expressed by all melanoma cells. These results suggest that complete absence of tumor-associated antigens on metastatic melanoma cells is a rare phenomenon. All melanoma lines we studied expressed at least one of a restricted number of antigens. Thus despite antigenic heterogeneity, sufficient similarity remains between different melanomas to permit specific immunotherapy to be targeted to a limited number of tumor antigens
— id: 16255, year: 1985, vol: 45, page: 5603, stat: Journal Article,

Cryptococcal pericarditis in an intravenous drug abuser
Schuster M; Valentine F; Holzman R
1985 Oct;152(4):842-842, Journal of infectious diseases
— id: 63235, year: 1985, vol: 152, page: 842, stat: Journal Article,

METASTATIC MELANOMA-CELLS BEAR ANTIGENS THAT MAY BE RECOGNIZED INVIVO BY THE PATIENTS LYMPHOCYTES
Valentine, FT
1985 ;11(8):821-821, Journal of dermatologic surgery & oncology
— id: 30863, year: 1985, vol: 11, page: 821, stat: Journal Article,

Reduced Langerhans' cell Ia antigen and ATPase activity in patients with the acquired immunodeficiency syndrome
Belsito DV; Sanchez MR; Baer RL; Valentine F; Thorbecke GJ
1984 May 17;310(20):1279-1282, New England journal of medicine
We investigated the possible role of a defect in antigen-presenting cells in the acquired immunodeficiency syndrome (AIDS), by enumeration of Langerhans' cells, the epidermal antigen-presenting cells. These cells were stained for the characteristic markers, surface Ia antigen and surface ATPase activity. A significant reduction was observed in the number of stained cells per square millimeter of body-surface area in 24 patients with AIDS and either opportunistic infections (Ia, 258 +/- 34, and ATPase, 274 +/- 46) or Kaposi's sarcoma (Ia, 378 +/- 100, and ATPase, 530 +/- 26), as compared with 38 appropriate controls (Ia, 721 +/- 13, and ATPase, 693 +/- 12). Examination of six patients with an 'AIDS-related complex' revealed significantly reduced numbers of Langerhans' cells per square millimeter; this reduction was more pronounced in staining for Ia antigen (306 +/- 69) than in staining for ATPase activity (517 +/- 101). Given the known role of Ia expression in antigen presentation, we suggest that functional alterations in Langerhans' cells, and perhaps also in antigen-presenting cells in tissues other than skin, may be involved in the pathogenesis of AIDS.
— id: 8829, year: 1984, vol: 310, page: 1279, stat: Journal Article,

REDUCED LANGERHANS CELL IA-ANTIGEN AND ATPASE ACTIVITY IN THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
BELSITO, D; SANCHEZ, M; BAER, R; VALENTINE, F; THORBECKE, GJ
1984 ;82(4):398-398, Journal of investigative dermatology
— id: 40815, year: 1984, vol: 82, page: 398, stat: Journal Article,

REDUCED LANGERHANS CELL IA-ANTIGEN AND ATPASE ACTIVITY IN THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
BELSITO, D; SANCHEZ, M; BAER, R; VALENTINE, F; THORBECKE, GJ
1984 ;32(2):A570-A570, Clinical research
— id: 40835, year: 1984, vol: 32, page: A570, stat: Journal Article,

STRATEGIES TO CIRCUMVENT ANTIGENETIC HETEROGENEITY RESTRICTING THE SPECIFIC IMMUNOTHERAPY OF MELANOMA
BYSTRYN, JC; BERNSTEIN, P; VALENTINE, F
1984 ;32(2):A481-A481, Clinical research
— id: 40828, year: 1984, vol: 32, page: A481, stat: Journal Article,

MAPPING OF CELL-SURFACE MELANOMA-ASSOCIATED ANTIGENS IN DIFFERENT INDIVIDUALS AND IN DIFFERENT METASTASES IN THE SAME INDIVIDUAL
BYSTRYN, JC; LIU, P; VALENTINE, F; BERNSTEIN, P
1984 ;57(3):344-344, Yale journal of biology & medicine
— id: 40771, year: 1984, vol: 57, page: 344, stat: Journal Article,

Acquired immune deficiency syndrome possibly related to transfusion in an adult without known disease-risk factors
Gordon SM; Valentine FT; Holzman RS; Holliday RA; Baggott B; Chinitz LA; Brick PD
1984 Jun;149(6):1030-1032, Journal of infectious diseases
— id: 15513, year: 1984, vol: 149, page: 1030, stat: Journal Article,

HUMAN-TUMOR CLONOGENIC-ASSAY - CHEMOSENSITIVITY TESTING IN SOFT AGAR AND CLINICAL CORRELATION IN MALIGNANT-MELANOMA
CUMPS, E; BOWEN, J; HARRIS, M; ROSES, D; GOLOMB, F; VALENTINE, F; MUGGIA, F; LEVIN, M
1983 ;31(2):A405-A405, Clinical research
— id: 40682, year: 1983, vol: 31, page: A405, stat: Journal Article,

SURFACE-PROPERTIES OF MELANOMA-CELLS IN DIFFERENT METASTASES IN THE SAME INDIVIDUAL
LIU, P; VALENTINE, F; BYSTRYN, JC
1983 ;31(2):A265-A265, Clinical research
— id: 40543, year: 1983, vol: 31, page: A265, stat: Journal Article,

Cytotoxicity of natural killer cells: correlation with emperipolesis and surface enzymes
Burns ER; Zucker-Franklin D; Valentine F
1982 Jul;47(1):99-107, Laboratory investigation
Cell-mediated cytotoxicity involving natural killer cells requires contact between effector and target cells for effective cytolysis. Ultrastructural studies of biopsies of primary human malignant melanoma showed mononuclear leukocytes to be located in close proximity to tumor cells and, on occasion, within the confines of the melanoma cell itself. This phenomenon, called emperipolesis, was examined in vitro to determine whether the same population of cells that exhibits emperipolesis is responsible for cytotoxicity. Since natural killer cells have been identified morphologically and functionally as large granular lymphocytes with surface receptors for the Fc portion of immunoglobulin (FcR+ cells), lymphocytes were depleted of FcR+ cells, and their cytotoxicity and ability to emperipolese were measured. Both of these properties were markedly diminished (88 and 85 per cent, respectively). Systematic comparison of emperipolesis and cytotoxicity from donors known to exhibit either high or low lymphocyte cytotoxicity showed perfect concordance. Ultrastructural analysis of in vitro emperipolesis revealed the emperipolesing lymphocytes to be FcR+ cells establishing identity with the large granular cells known to mediate cytotoxicity. The morphologic marker found in both FcR+ cells, purified by rosetting techniques, and in emperipolesed lymphocytes consisted of cytoplasmic parallel tubular arrays. Further studies designed to elucidate a mechanism for cytotoxicity and emperipolesis implicated cell surface proteases as mediators of these activities. Competitive inhibition of surface proteases with artificial and natural inhibitors markedly reduced both cytotoxicity and emperipolesis. Therefore, it is likely that lymphocytes that are FcR+ participate in cell-medicated cytotoxicity through mechanisms involving cell contact and enzyme-initiated damage of target cells. Emperipolesis represents one type of effector-target cell contact leading to cytotoxicity
— id: 61762, year: 1982, vol: 47, page: 99, stat: Journal Article,

EFFECTS INVIVO OF AUTOLOGOUS LYMPHOKINES(LK) ON INJECTED AND ON NON-INJECTED METASTATIC NODULES OF HUMAN-MALIGNANT MELANOMA
Valentine, F; Golomb, F; Fazzini, E
1982 ;4(4):375-375, International journal of immunopharmacology
— id: 30533, year: 1982, vol: 4, page: 375, stat: Journal Article,

Characterization of the cell population mediating cytotoxicity and emperipolesis in human malignant melanomas
Burns ER; Zucker-Franklin D; Valentine F
1981 ;94:366-371, Transactions of the Association of American Physicians
— id: 61770, year: 1981, vol: 94, page: 366, stat: Journal Article,

CHARACTERIZATION OF THE CELL-POPULATION MEDIATING CYTO-TOXICITY AND EMPERIPOLESIS IN HUMAN-MALIGNANT MELANOMA
BURNS, ER; ZUCKERFRANKLIN, D; VALENTINE, F
1981 ;29(2):A580-A580, Clinical research
— id: 40228, year: 1981, vol: 29, page: A580, stat: Journal Article,

Interaction of mononuclear leukocytes with malignant melanoma
Fujinami N; Zucker-Franklin D; Valentine F
1981 Jul;45(1):28-37, Laboratory investigation
Since it is well established that cellular immunity plays a role in the defense against melanoma, the morphologic aspects of this reaction warranted investigation. Accordingly, peripheral blood mononuclear cells obtained from healthy donors were incubated with human melanoma cells for 1 to 24 hours to examine, on the ultrastructural level, the cellular interaction that eventuates in cytolysis of the tumor cells. Within 1 hour of incubation, monocytes and lymphocytes were seen attached to approximately 40 per cent of the melanoma cells with marked interdigitation of cellular processes. After 4 hours of incubation, the percentage of tumor cells with attached leukocytes remained the same, but 2 to 9 per cent of the melanoma cells showed interiorized lymphocytes when kept in suspension, 10 to 25 per cent when maintained in culture dishes. Erythrocytes or fixed lymphocytes were not taken up by the melanoma cells nor were living lymphocytes seen in fibroblasts or endothelial cells which served as controls for the neoplastic cell lines. Thus, melanoma cells did not prove to be randomly phagocytic, and the interiorization displayed by lymphocytes--a process called emperipolesis--appears to be selective. It is postulated that emperipolesis may enhance the tumoricidal effect exerted by cytotoxic lymphocytes on melanoma cells
— id: 61768, year: 1981, vol: 45, page: 28, stat: Journal Article,

The proliferative response of human lymphocytes to antigen is suppressed preferentially by lymphocytes precultured with the same antigen
Borkowsky W; Valentine FT
1979 May;122(5):1867-1873, Journal of immunology
Human blood lymphocytes activated in vitro with antigen to which the donor is reactive are capable of suppressing the secondary proliferative response of autochthonous fresh cells to antigen. Both antigen-specific and antigen-nonspecific suppression can be detected in each experiment. These suppressor cells act by decreasing the number of lymphocytes entering the proliferative response rather than by slowing or otherwise inhibiting ongoing proliferation. The suppressor cells must be added soon after fresh cells are stimulated with antigen to be effective, but the suppressor cells themselves need not proliferate to exert their effect. Suppressor cells are optimally effective when added in numbers equal to those of the responding population, but still exert a significant effect at one-eighth that number
— id: 14599, year: 1979, vol: 122, page: 1867, stat: Journal Article,

Activated lymphocytes depress phagocytosis of latex particles by human monocyte-macrophages
Al-Ibrahim MS; Valentine FT; Lawrence HS
1978 Dec;41(2):217-230, Cellular immunology
— id: 15514, year: 1978, vol: 41, page: 217, stat: Journal Article,

A micromethod for evaluating the phagocytic activity of human macrophages by ingestion of radio-labelled polystyrene particles
Al-Ibrahim MS; Chandra R; Kishore R; Valentine FT; Lawrence HS
1976 Mar;10(2-3):207-218, Journal of immunological methods
Studies in vitro of human macrophage function in health and disease have been impeded by the difficulty of obtaining such cells in sufficient number. Unlike animal species, the only readily available source of human macrophages are circulating monocytes. Herein, a method is described whereby the phagocytic rate of small numbers of glass-adherent mononuclear cells can be accurately measured. The method utilizes the ingestion by macrophages of technetium labelled polystyrene particles; both the radiolabel and ingestible substrate are readily available and the labelling process simple and efficient. The phagocytic rate can be expressed as radioactive counts per microgram of cell protein; data is also presented showing that the number of particles ingested per cell can be accurately derived
— id: 15516, year: 1976, vol: 10, page: 207, stat: Journal Article,

MICRO-ASSAY FOR MACROPHAGE ACTIVATION IN MAN
Alibrahim, MS; Valentine, FT; Lawrence, HS
1976 ;24(3):A444-A444, Clinical research
— id: 28758, year: 1976, vol: 24, page: A444, stat: Journal Article,

Leucocyte dialysates require precommitted, antigen-reactive cells to augment lymphocyte proliferation
Cohen L; Holzman RS; Valentine FT; Lawrence HS
Transfer factor: basic properties and clinical applications New York, Academic Press, 1976,
— id: 2535, year: 1976, vol: , page: 61, stat: Chapter,

Requirement of precommitted cells as targets for the augmentation of lymphocyte proliferation by leukocyte dialysates
Cohen L; Holzman RS; Valentine FT; Lawrence HS
1976 Apr 1;143(4):791-804, Journal of experimental medicine
After our initial report tha leukocyte dialysates containing transfer factor augment the thymidine incorporation of antigen-stimulated lymphocytes, we have adapted the system to microleukocyte cultures. This modification permits both (a) the simultaneous assay of a single dialysate on the cells of multiple individuals, and (b) the assay of multiple dialysates on the cells of a single individual. The data thus secured, demonstrate that dialysates from both skin-test-positive and -negative donors produced similar degrees of augmentation whether the data are expressed as an arithmetic difference or as a ratio. When expressed as an arithmetic difference, the amount of augmentation is increased in proportion to the level of thymidine incorporation of the assay cells when they were stimulated by antigen alone. When expressed as a ratio, however, the degree of augmentation is independent of the response of the assay cells. An analysis of the ability of dialysates to engage previously uncommitted lymphocytes and thus to augment thymidine incorporation, revealed that precommitted cells were required. In these experiments, antigen-reactive cells were deleted from populations of peripheral blood lymphocytes by incubation with purified protein derivative of tuberculin, diphtheria toxoid, or streptokinase-streptodornase in the presence of [3H]thymidine of high specific activity. This deletion depressed or abolished the effect of dialysate on the residual population when it was recultured with the same antigen, but the effect on the response of the remaining lymphocytes to other antigens was unaltered. In this study, leukocyte dialysate appeared to augment nonspecifically the thymidine incorporation of an antigen-specific precommitted clone of lymphocytes. The relationship of these adjuvant effects on peripheral blood lymphocytes in vitro to the specific and nonspecific activities of transfer factor in vivo remains to be elucidated
— id: 15515, year: 1976, vol: 143, page: 791, stat: Journal Article,

PRECOMMITTED ANTIGEN RESPONSIVE CELLS ARE REQUIRED FOR AUGMENTATION OF LYMPHOCYTE-PROLIFERATION BY LEUKOCYTE DIALYSATES
Cohen, L; Holzman, RS; Valentine, FT; Lawrence, HS
1976 ;24(4):A604-A604, Clinical research
— id: 28729, year: 1976, vol: 24, page: A604, stat: Journal Article,

Transfer factor: is it related to immune RNA
Valentine FT
Immune RNA in neoplasia New York, Academic Press, 1976,
— id: 2534, year: 1976, vol: , page: 75, stat: Chapter,

LYMPHOCYTE STIMULATION BY HERPES-SIMPLEX ANTIGENS IN RECURRENT HERPES INFECTIONS
Valentine, FT
1975 ;51(10):1193-1193, Bulletin of the New York Academy of Medicine
— id: 28636, year: 1975, vol: 51, page: 1193, stat: Journal Article,

In vitro properties of leukocyte dialysates containing transfer factor
Ascher MS; Schneider WJ; Valentine FT; Lawrence HS
1974 Apr;71(4):1178-1182, Proceedings of the National Academy of Sciences of the United States of America
— id: 15518, year: 1974, vol: 71, page: 1178, stat: Journal Article,

Effects of dialyzable transfer factor in patients with breast cancer
Oettgen HF; Old LJ; Farrow JH; Valentine FT; Lawrence HS; Thomas L
1974 Jun;71(6):2319-2323, Proceedings of the National Academy of Sciences of the United States of America
— id: 15517, year: 1974, vol: 71, page: 2319, stat: Journal Article,

Soluble factors produced by lymphocytes
Valentine FT
1974 ;221:317-323, Annals of the New York Academy of Sciences
— id: 15519, year: 1974, vol: 221, page: 317, stat: Journal Article,

Preparation and properties of cloning inhibitory factor. I. Inhibition of HeLa cell cloning by stimulated lymphocytes and their culture supernatants
Holzman RS; Lebowitz AS; Valentine FT; Lawrence HS
1973 Aug;8(2):249-258, Cellular immunology
— id: 15521, year: 1973, vol: 8, page: 249, stat: Journal Article,

Preparation and properties of cloning inhibitory factor. II. Factors affecting its production and assay
Holzman RS; Valentine FT; Lawrence HS
1973 Aug;8(2):259-269, Cellular immunology
— id: 15520, year: 1973, vol: 8, page: 259, stat: Journal Article,

Cell-mediated immunity
Valentine, F T; Lawrence, H S
1971 ;17:51-93, Advances in internal medicine
— id: 15522, year: 1971, vol: 17, page: 51, stat: Journal Article,

Transfer factor and other mediators of cellular immunity
Lawrence HS; Valentine FT
1970 Sep;60(3):437-452, American journal of pathology
— id: 15523, year: 1970, vol: 60, page: 437, stat: Journal Article,

Transfer factor in delayed hypersensitivity
Lawrence HS; Valentine FT
1970 Feb 13;169(1):269-287, Annals of the New York Academy of Sciences
— id: 15524, year: 1970, vol: 169, page: 269, stat: Journal Article,

Cellular immunity in vitro. Clonal proliferation of antigen-stimulated lymphocytes
Marshall WH; Valentine FT; Lawrence HS
1969 Aug 1;130(2):327-343, Journal of experimental medicine
— id: 15526, year: 1969, vol: 130, page: 327, stat: Journal Article,

Lymphocyte stimulation: transfer of cellular hypersensitivity to antigen in vitro
Valentine FT; Lawrence HS
1969 Sep 5;165(897):1014-1016, Science
— id: 15525, year: 1969, vol: 165, page: 1014, stat: Journal Article,