Craig W. Hendrix
Johns Hopkins University
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Featured researches published by Craig W. Hendrix.
The New England Journal of Medicine | 2012
Jared M. Baeten; Deborah Donnell; Patrick Ndase; Nelly Mugo; James D. Campbell; Jonathan Wangisi; Jordan W. Tappero; Elizabeth A. Bukusi; Craig R. Cohen; Elly Katabira; Allan R. Ronald; Elioda Tumwesigye; Edwin Were; Kenneth H. Fife; James Kiarie; Carey Farquhar; Grace John-Stewart; Aloysious Kakia; Josephine Odoyo; Akasiima Mucunguzi; Edith Nakku-Joloba; Rogers Twesigye; Kenneth Ngure; Cosmas Apaka; Harrison Tamooh; Fridah Gabona; Andrew Mujugira; Dana Panteleeff; Katherine K. Thomas; Lara Kidoguchi
BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).
The New England Journal of Medicine | 2012
Michael C. Thigpen; Poloko Kebaabetswe; Lynn A. Paxton; Dawn K. Smith; Charles E. Rose; Tebogo M. Segolodi; Faith L. Henderson; Sonal Pathak; Fatma Soud; Kata Chillag; Rodreck Mutanhaurwa; Lovemore Ian Chirwa; Michael Kasonde; Daniel Abebe; Evans Buliva; Roman Gvetadze; Sandra H. Johnson; Thom Sukalac; Vasavi Thomas; Clyde E. Hart; Jeffrey A. Johnson; C. Kevin Malotte; Craig W. Hendrix; John T. Brooks
BACKGROUND Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain. METHODS We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants. RESULTS A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03). CONCLUSIONS Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669.).
The Lancet | 2013
Kachit Choopanya; Michael Martin; Pravan Suntharasamai; Udomsak Sangkum; Philip A. Mock; Manoj Leethochawalit; Sithisat Chiamwongpaet; Praphan Kitisin; Pitinan Natrujirote; Somyot Kittimunkong; Rutt Chuachoowong; Roman Gvetadze; Janet M. McNicholl; Lynn A. Paxton; Marcel E. Curlin; Craig W. Hendrix; Suphak Vanichseni
BACKGROUND Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users. METHODS In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20-60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00119106. FINDINGS Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6-72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002). INTERPRETATION In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs. FUNDING US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.
The New England Journal of Medicine | 2015
Jeanne M. Marrazzo; Gita Ramjee; Barbra A. Richardson; Kailazarid Gomez; Nyaradzo Mgodi; Gonasagrie Nair; Thesla Palanee; Clemensia Nakabiito; Ariane van der Straten; Lisa Noguchi; Craig W. Hendrix; James Y. Dai; Shayhana Ganesh; Baningi Mkhize; Marthinette Taljaard; Urvi M. Parikh; Jeanna M. Piper; Benoît Mâsse; Cynthia I. Grossman; James F. Rooney; Jill L. Schwartz; Heather Watts; Mark A. Marzinke; Sharon L. Hillier; Ian McGowan; Z. Mike Chirenje
BACKGROUND Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. METHODS We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. RESULTS Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events. CONCLUSIONS None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).
Journal of Clinical Investigation | 1993
Mario Clerici; Frances T. Hakim; David Venzon; Stephen P. Blatt; Craig W. Hendrix; Thomas A. Wynn; Gene M. Shearer
Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.
Antimicrobial Agents and Chemotherapy | 2000
Craig W. Hendrix; Charles Flexner; Ronald Trevor Macfarland; Christen Giandomenico; Edward J. Fuchs; Ella Redpath; Gary Bridger; Geoffrey W. Henson
ABSTRACT AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4+ T cells via selective blockade of the chemokine CXCR-4 receptor. Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 μg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 μg/kg). Three subjects received two escalating oral doses each (80 and 160 μg/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing. AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (Cmax) and the area under the concentration-time curve from 0 h to ∞ (AUC0–∞) over the entire dose range. At the highest intravenous dose (80 μg/kg), the medianCmax was 515 (range, 470 to 521) ng/ml and the AUC0–∞ was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0.27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenous dose of AMD-3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.
Journal of Clinical Investigation | 1994
Mario Clerici; Thomas A. Wynn; Jay A. Berzofsky; Stephen P. Blatt; Craig W. Hendrix; Alan Sher; Robert L. Coffman; Gene M. Shearer
The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.
Journal of Acquired Immune Deficiency Syndromes | 2004
Craig W. Hendrix; Ann C. Collier; Michael M. Lederman; Dominique Schols; Richard B. Pollard; Stephen Brown; J. Brooks Jackson; Robert W. Coombs; Marshall J. Glesby; Charles Flexner; Gary Bridger; Karin Badel; Ronald Trevor Macfarland; Geoffrey W. Henson; Gary Calandra
AMD3100 is a CXCR4 receptor inhibitor with anti–HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 μg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non–SI (45%), or not tested (25%). One patient (5 μg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 μg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-μg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1–11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9–3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 μg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.
Circulation | 2000
Alan D. Michelson; Mark I. Furman; Pascal J. Goldschmidt-Clermont; Mary Ann Mascelli; Craig W. Hendrix; Lindsay D. Coleman; Jeanette Hamlington; Marc R. Barnard; Thomas S. Kickler; Douglas J. Christie; Sourav Kundu; Paul F. Bray
BACKGROUND Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity. METHODS AND RESULTS In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab. CONCLUSIONS Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.
Annals of Surgery | 2001
Robert K. Pelz; Craig W. Hendrix; Sandra M. Swoboda; Marie Diener-West; William G. Merz; Janet M. Hammond; Pamela A. Lipsett
ObjectiveTo evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. Summary Background DataInvasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. MethodsThe authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. ResultsThe primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients “on-therapy” and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. ConclusionsEnteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.