HIV/AIDS preventive vaccine 'prime-boost' phase III trial: foundations and initial lessons learned from Thailand.
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AIDS Vaccines↗
Biomedical subjects
Arthur E Brown
Publications and source records attributed to Arthur E Brown.
Molecular epidemiology of HIV Type 1 in preparation for a Phase III prime-boost vaccine trial in Thailand and a new approach to HIV Type 1 genotyping.
To characterize HIV-1 genotypes in candidate populations for a prime-boost phase III vaccine trial in Thailand, specimens from prevalent and incident HIV-1 infections from a family planning clinic population in Rayong Province and a community cohort in Chon Buri Province, collected from 1998 to 2001, were genotyped. A new multiregion hybridization assay, MHAbce, capable of distinguishing HIV-1 CRF01_AE, subtype B, and subtype C and their recombinants, was developed and applied to prevalent infections. Most incident and selected prevalent infections were studied by complete genome sequencing. By MHAbce, 168 of 194 prevalent infections were genotyped. Of these, 90.5% were CRF01_AE, 2.4% were subtype B, and 7.2% showed discordant or dual probe reactivity, indicative of recombination or dual infection, respectively. Among 23 incident infections, 20 were sequenced. Eighteen CRF01_AE, one subtype B, and one CRF01/B recombinant strains were seen. Two CRF01/B and one CRF01/C recombinant were identified among selected prevalent infections. These results indicate that incident and prevalent HIV-1 infections in Rayong and Chon Buri during 1998-2001 were 90% CRF01_AE, 3% subtype B, and 7% either recombinant or dual. This study frames the genetic diversity of HIV-1 in these cohorts in their preparatory phase for the ongoing ALVACHIV (vCP1521) prime, AIDSVAX B/E boost, phase III vaccine trial and will provide a benchmark for interpretation and analysis.
AIDS Vaccines↗
Behavioral and social issues among volunteers in a preventive HIV vaccine trial in Thailand.
Behavioral and social issues were investigated in 363 phase I/II preventive HIV-1 vaccine trial volunteers in Thailand. These issues included risk behavior, HIV knowledge, distress, and social consequences of vaccine trial participation. Data were collected at baseline and at 4-, 8-, and 12-month follow-up visits. Volunteers reported relatively low levels of risk behaviors at baseline and at follow-up. Overtly negative reactions from family or friends were reported by 5.9%. No experiences of discrimination in employment, health care, or insurance were reported. Mean levels of distress were low throughout the trial, and HIV-related knowledge was high, although it was common to consider the possibility of HIV transmission through casual contact. Findings add to the evidence that preventive HIV vaccine trials are feasible in Thailand.
AIDS Vaccines↗
Antibody-dependent cell-mediated cytotoxic responses in participants enrolled in a phase I/II ALVAC-HIV/AIDSVAX B/E prime-boost HIV-1 vaccine trial in Thailand.
Antibody-dependent cell-mediated cytotoxicity (ADCC) was assessed in volunteers participating in an ALVAC-HIV (vCP1521)/AIDSVAX B/E gp120 prime-boost vaccine trial in Thailand. ADCC activity was measured using chromium release from gp120 subtype B- and CRF01_AE-coated targets in 95 vaccinees and 28 placebo recipients. There was a significant difference in the magnitude of the ADCC response to both targets between vaccinees and placebo recipients. The frequency of responders to subtype B and to CRF01_AE was 96% and 84% in the vaccine group versus 11% and 7% in the placebo group. The results demonstrate that this HIV vaccine is a potent inducer of ADCC activity and may be an additional protection of this prime-boost vaccine in preventing HIV disease.
AIDS Vaccines↗
A standardized regimen of antibiotics prevents infectious complications in skull base surgery.
OBJECTIVES/HYPOTHESIS: Craniofacial surgery has been associated with a significant improvement in disease outcome for patients with skull base neoplasms. Despite this improved survival, complications remain considerable. One major source of complications is infectious events. The current study was designed to evaluate a prospectively designed antibiotic regimen and its impact on the incidence and severity of infectious complications. This regimen was compared with a group of historic controls in which antibiotics were administered on an ad hoc basis. The specific objectives/hypothesis were to determine 1) the incidence and severity of infection in a group of patients treated with a nonstandardized antibiotic regimen undergoing craniofacial resection, and 2) whether the use of a prospectively designed, three-drug, broad spectrum antibiotic is associated with a reduced incidence and severity of infections. STUDY DESIGN: A single-arm, prospective antibiotic regimen consisting of ceftazidime, flagyl (metronidazole), and vancomycin (CMV) was compared with a historic control of patients treated with nonstandard antibiotic therapy (nonCMV), all of whom underwent craniofacial resection. Outcome measures focused on incidence of infection, severity of infection, and operative mortality. METHODS: In July 1990, a retrospective review (1973-1990) was performed of craniofacial resection. Beginning in July 1990, a prospective database (1990-2003) has been maintained. Demographics, prior therapy, anatomic site of origin and extent of disease, pathology, standard surgical data, and postoperative therapy were detailed. Antibiotic data were collected from chart review. Complications, focusing on infectious complications, were identified and categorized. Culture results and whether the inciting infection was sensitive or resistant to perioperative antibiotics were noted. Length of hospital stay was tabulated. Disease outcome, including incidence of postoperative mortality, was maintained for each patient. RESULTS: A total of 211 patients underwent craniofacial resection from 1973 to 2003. Major medical comorbidities were present in 53 (25%) patients, and 96 (46%) had prior therapy. The standardized antibiotic therapy (CMV) was used in 90 patients, and the nonstandardized antibiotics (nonCMV) were used in 107 patients. Free flap reconstruction was the sole surgical factor associated with a marked reduction in complications. Infectious wound complications were 11% within the CMV group versus 29% in the nonCMV regimen (P = .002). Moreover, the severity of infections was greatly diminished in the CMV group (P = .0001). With use of a multivariate analysis, the only factor which was predictive of infectious complications was the use of CMV. Patients who received nonCMV antibiotic therapy faced a risk of infection that was 2.5 times higher than those who received CMV. Hospital stay in days and operative mortality were both adversely affected by the use of nonCMV antibiotic therapy. CONCLUSIONS: The data supports the hypothesis that the use of a three-drug, broad spectrum antibiotic regimen in skull base surgery reduces the incidence of infectious complications and appears to reduce operative mortality. Broad spectrum coverage of Gram-positive, Gram-negative, and anaerobic pathogens leads to a marked reduction in infectious complications. Broad spectrum antibiotic coverage avoids many infectious complications and ultimately had a positive impact on patient outcome, quality of life, and, potentially, survival.
Adult↗
The development of HIV research laboratories in the Royal Thai Army Medical Department.
The development of HIV research laboratories at the Armed Forces Research Institute of Medical Sciences (AFRIMS), Royal Thai Army Medical Department in supporting of HIV-1 vaccine trials in Thailand was implemented in 1991. The collaboration between AFRIMS, Royal Thai Army Medical Department, and the US Military HIV Research Program with the ultimate goal to conduct the HIV-1 vaccine trial phase III. The HIV serology lab was set up for surveillance program in military recruits. Then, there was a need to strengthen more on the existing laboratories by training personnel to cope with the confidentiality of the lab results, specimen processing and data management which are critical. Later on, the necessary laboratory for measuring of vaccine immunogenicity was developed, such as lymphoproliferation assay. Additionally, a molecular biology lab was also developed. The HIV research laboratory management must include an ability to deal with some problems, such as late specimen receiving, fluctuating of power supply, technical staffs maintained. Good laboratory practices and safety must be strictly implemented. Communication network among facilities also played an important role in HIV laboratory strengthening at AFRIMS.
Academies and Institutes↗
Changes in HIV prevalence among young Thai men as defined by hepatitis C co-infection as a marker for mode of transmission.
To obtain a better understanding of the evolving HIV-1 epidemic in Thailand, we utilized antibody to hepatitis C virus (HCV) to indicate the mode of HIV-1 transmission. Although the proportion of men with HCV co-infection increased between 1995 and 2000, the prevalence was similar, whereas the prevalence of men not co- infected decreased (1.93-0.46%). This suggests that HIV-1 infection associated with parenteral transmission has been stable despite a dramatic reduction in the sexual transmission of HIV-1.
AIDS-Related Opportunistic Infections↗
Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults.
ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.
AIDS Vaccines↗
The natural history of HIV-1 infection in young Thai men after seroconversion.
The natural history and progression of HIV-1 infection in Thailand and other developing countries in Asia and Africa have not been well defined. Nevertheless, valid data are needed to evaluate the effects of interventions, which are designed to delay progression. We evaluated the progression to AIDS and death in 235 men who seroconverted during their 2 years of service in the Royal Thai Army. The men were conscripted at age 21 and seroconverted within a 6-month window during follow-up while in the military. The seroconverters were matched with men who were seronegative when discharged. Of the HIV-positive men, 156 (66.4%) were alive, 77 (32.8%) had died, and 2 (0.8%) could not be located 5-7 years after their seroconversion and discharge from the military. The 5-year survival rate was 82.3%; the median times to clinical AIDS and a CD4 cell count of <200/microL was 7.4 years and 6.9 years, respectively. The mortality rate was 56.3 deaths per 1000 patient-years for HIV-positive men and 6.1 deaths per 1000 patient-years for HIV-negative men. Our data suggest a more rapid progression to AIDS and death after HIV-1 infection in young men in Thailand than has been reported for similarly aged cohorts in developed countries.
Acquired Immunodeficiency Syndrome↗
Transmission of STLV in a closed colony of macaques.
A 3.3% seroprevalence of simian T-lymphotropic virus (STLV) was found in a closed breeding and research colony of rhesus and cynomolgus macaques in Thailand. Epidemiology of STLV within the colony was assessed by means of a retrospective analysis of banked and freshly collected serum samples, and a review of the animals' medical records. Evidence was found that the virus had been imported into the colony by some of the original animals, and was subsequently transmitted both vertically and horizontally. The cell-associated nature of STLV was demonstrated by iatrogenic transmission of the virus following a whole blood transfusion, but there was no transmission to animals that received only serum from the same infected donor. Transmission by all routes was infrequent, as indicated by the overall seroprevalence of 3.3% (14 of 420 samples) after the colony had been closed for 11 years. Maternal-infant transmission appeared to be < 12%.
Animals↗
Foundations for a Phase III human immunodeficiency virus vaccine trial: A decade of Thai-U.S. Army collaborative research.
As part of the response of the Royal Thai Army to the outbreak of human immunodeficiency virus (HIV) in Thailand, a collaboration was established with the U.S. Army to jointly work toward the development of vaccines for the prevention of HIV infection. During the first decade of this collaboration, studies have been carried out in the diverse disciplines that are crucial to providing the foundations for efficacy trials of candidate HIV vaccines. Studies of host, pathogen, and vaccine interventions included studies of viral diversity, epidemiology, disease course, potential vaccine cohorts, and Phase I/II clinical trials. Collaborations were expanded to other Thai institutions and to overseas partners, resulting in the Thai AIDS Vaccine Evaluation Group. The efforts of these collaborations resulted in the development of candidate vaccines specifically designed for use in Thailand, and sequential evaluations that have lead to the threshold of the world's next and largest efficacy trial of HIV vaccines.
AIDS Vaccines↗
In vitro susceptibility of Thai seronegative donor CD8+ T lymphocytes to human immunodeficiency virus-1 (HIV-1) infection.
To determine whether CD8+ T lymphocytes from Thai donor cells are susceptible to HIV-1 infection, undepleted peripheral blood mononuclear cells (PBMC) and CD8-enriched PBMC were infected with HIV-1 Thai subtype B and CRF01_AE (E) primary isolates. Virus kinetics in HIV-1 infection of CD4+ and CD8+ T lymphocytes peaked at day 7 or 10 post infection (pi); the TCID50 used for cell infection was proportional to the level of p24 production in the cultures. We also found that the level of p24 antigen in the supernatants of infected undepleted PBMC was significantly higher than that of infected CD8-enriched PBMC. Interestingly, both single positive T lymphocytes (CD4+ and CD8+ T lymphocytes) as well as double positive CD4+/CD8+ T lymphocytes were infected with HIV-1. The double positive T lymphocytes in PBMC were found only in the presence of both CD4+ and CD8+ T lymphocytes. The majority of p24+/CD4-/CD8- T lymphocytes were HIV-1 infected CD4 down-modulated PBMC. This report provides direct evidence that single positive CD8+ T lymphocytes and double positive CD4+/ CD8+ T lymphocytes from Thai donors can be infected with HIV-1 subtypes B and E in vitro.
CD4-Positive T-Lymphocytes↗
Subtype C/CRF01_AE recombinant HIV-1 found in Thailand.
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Adult↗
Safety and immunogenicity of combinations of recombinant subtype E and B human immunodeficiency virus type 1 envelope glycoprotein 120 vaccines in healthy Thai adults.
Safety and immunogenicity of 2 recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein (gp) 120 vaccines derived from SF2 (subtype B) and CM235 (CRF01_AE, Thai E) were evaluated in 370 Thai adults at low risk of HIV infection. Various doses of CM235 (25, 50, or 100 microg) and SF2 (0, 25, or 50 microg) gp120 were used. Eighty volunteers received placebo. There were no serious adverse events related to vaccination. Binding antibody developed in all vaccine recipients. There was no dose response to CM235 gp120, but a dose response to gp120 SF2 was present. Neutralizing antibodies to subtype E HIV-1 NPO3 and subtype B HIV-1 SF2 developed in 84% and 82% of vaccine recipients, respectively. Lymphoproliferative responses were detected in >95% of vaccine recipients. There was no evidence of antigenic interference in HIV-specific humoral or cellular responses. The gp120 Thai E and SF2 vaccines were safe and immunogenic in combination and could be advanced into phase 3 testing.
AIDS Vaccines↗
The association between hepatitis C virus and HIV-1 in preparatory cohorts for HIV vaccine trials in Thailand.
OBJECTIVES: To study the association between hepatitis C virus (HCV) and HIV-1, and HCV seropositivity as an indicator of HIV-1 risk behavior for HIV vaccine preparatory cohorts in Thailand. DESIGN: Cross-sectional study of HIV-1-infected persons identified at screening for potential HIV vaccine trial cohort studies. METHODS: Sera from HIV-1-infected and uninfected volunteers was matched by age, sex, and community, and tested for HCV reactivity. Logistic regression methods were used to measure associations between HIV-1, HCV and other risk factors for HIV infection. RESULTS: The prevalence of HCV among HIV-negative controls was 8.3% (6/72) for men and 4.2% (5/118) for women. Co-infection with HIV and occurred in 50.7% (37/73) of men and 3.4% (4/118) of women. Among men who reported injection drug use (IDU), 96.4% (27/28) were HCV seropositive. No women reported IDU. HCV was associated with HIV infection [odds ratio (OR), 11.3; 95% confidence interval (CI), 4.4-29.3] and IDU (OR, 12.0; 95% CI, 3.4-41.9) among men, but not women (OR, 0.8; 95% CI, 0.2-3.0). After adjustment for potential confounding, HCV, but not IDU, remained strongly associated with HIV-1 infection among men (OR, 9.4; 95% CI, 2.7-32.6). CONCLUSIONS: The strong associations between HCV seropositivity, HIV-1 infection, and IDU history suggest that IDU was reported accurately in this study. The surprisingly high prevalence of HCV among HIV-1-infected young men may assist health policy makers in the choice of behavioral interventions for this important subgroup of the population.
AIDS Vaccines↗
A new circulating recombinant form, CRF15_01B, reinforces the linkage between IDU and heterosexual epidemics in Thailand.
HIV-1 subtype B and CRF01_AE have been in circulation in Thailand and Southeast Asia for more than a decade. Initially separated by risk group, the two strains are increasingly intermixed, and two recombinant strains of essentially reciprocal structure have been recently reported. Here we identify additional CRF_01B recombinants and provide the evidence that HIV-1 strains now pass freely between the two high-risk populations. HIV isolates that showed discordance between CRF01_AE and subtype B in multi-region genotyping assays were selected for the study. They were drawn from 3 different cohorts in Thailand representing different risk behaviors and demographic characteristics: a drug user cohort in the north, a family planning clinic attendee cohort in the southeast, and a cohort study of the mucosal virology and immunology of HIV-1 infection in Thailand. The DNA from these isolates was PCR amplified to recover the full HIV-1 genome and subjected to sequencing and phylogenetic analysis. We establish that one particular CRF_01B recombinant, with the external envelope of subtype B and the rest of the genome from CRF01_AE, is circulating widely in Thailand. Termed CRF15_01B (also referred to as CRF15), the strain was primarily heterosexually transmitted, although injecting drug use (IDU) also played a role. In aggregate data from the studies, CRF15 constituted 1.7% of all HIV-1 infections (95% confidence interval 0.5-4.4%) and was dispersed widely in the country. The previously separate heterosexual and IDU epidemics have apparently been bridged by a new CRF. The entry of CRF15 into the mainstream of the epidemic signals new complexity in the long stable molecular picture in Thailand. These recombinants must be considered in ongoing or projected efficacy evaluations of HIV-1 vaccines and antiviral therapies.
Adult↗
Longitudinal study of humoral immune responses in HIV type 1 subtype CRF01_AE (E)-infected Thai patients with different rates of disease progression.
Identification of immune correlates associated with disease progression will provide information for HIV-1 vaccine design in countries such as Thailand, where the prevalent subtypes (B and CRF01_AE [E]) are characterized. In this study, plasma viral load and humoral immune responses were measured in 20 HIV-1 subtype E-infected Thai patients with different rates of disease progression, based on CD4(+) T cell decline and clinical symptoms. Nine progressors (PRs) and 11 slower progressors (SPs) were evaluated. CD4(+) T cell counts were inversely correlated with viral load (p = 0.004) and positively correlated with p24 Ab (p = 0.022). In progressors, p24 Ab showed a significant decrease (p < 0.001) over time. V3 and gp41 Ab did not change significantly in either group. Both CD4-binding site (CD4/gp120BS) and gp120 titers correlated positively with neutralizing antibody (NAb) against both a subtype E cell line-adapted virus (NP03) and a primary isolate (TH023). However, V3 Ab correlated only with NAb against NP03 (p < 0.001). Increased NAb over time was observed more frequently in SPs as compared with PRs, against both the TH023 (p = 0.004) and NPO3 (p = 0.004) viruses. Cross-clade antibody-dependent cellular cytotoxicity was demonstrated in both groups. These data suggest that in HIV-1 subtype E infection, declining p24 Ab titer is a predictive marker of disease progression, as described for subtype B. Furthermore, in subtype E-infected patients, slower progressors retain the immune competence to develop new antibody responses to Env over time; these evolving responses may contribute to prolonged survival during HIV-1 disease progression.
Antibody-Dependent Cell Cytotoxicity↗
Specific antibody responses to vaccination with bivalent CM235/SF2 gp120: detection of homologous and heterologous neutralizing antibody to subtype E (CRF01.AE) HIV type 1.
HIV-1 CRF.AE-01 (formerly subtype E) infection is highly prevalent in Southeast Asia. Despite success with public health measures, the development of an effective CRF01.AE vaccine is critical to the control of this epidemic. Sera from the open-label arms of the first clinical trial of a bivalent HIV gp120 SF2/CM235 (subtypes B and CRF.AE-01, respectively) vaccine were evaluated for the presence of gp120-specific binding (BAb) and neutralizing antibody (NAb). Twelve pre- and postvaccination sera pairs were tested for CM235 BAb; anti-gp120 CM235 BAb was found in all postvaccination samples. The 12 pre- and postvaccination (1 month after third vaccination) serum pairs were evaluated in several neutralization formats: heterologous T cell line adapted (TCLA) NP03/H9, homologous CM235/PBMC, CM235/dendritic cell, and CM235M4-C4.6/A3R5. A3R5 is a CCR5+ T cell line, and CM235M4-C4.6 is the homologous CM235 virus adapted to growth in A3R5 cells. All volunteers developed BAb, but meaningful NAb was not demonstrable against primary isolate CM235. Using the TCLA CRF01.AE virus NP03 in H9 cells, 9 of 12 persons had NAb with a geometric mean titer (GMT) of 46. The CM235M4-C4.6 virus in A3R5 cells also detected NAb in 9 of 12 persons, with a GMT of 41. CM235M4-C4.6/A3R5 detected NAb in two persons with negligible NAb to NP03/H9 and vice versa. Whether the NAb detected by the CM235M4-C4.6/A3R5 system is qualitatively different from those in more traditional NP03/H9 assays will require further study.
AIDS Vaccines↗