Jeffrey Edwards

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries in both the healthy and the HIV-infected populations. This correlates with the fact that hardly any AIDS-related Kaposi’s sarcoma has been reported in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres show that only 3/82 (3.7%) have antibody to HHV-8, demonstrating that there is little, if any, cross-reactivity between antibodies to these two gamma viruses.

The international epidemiology of disseminated Mycobacterium avium complex infection in AIDS

Objective:To determine rates of disseminated Mycobacterium avium complex (MAC) infection among AIDS patients in developed and developing countries, and to determine whether different rates reflect differences in exposure or immunity, or both. Design:Prospective cohort study. Setting:University hospitals and outpatient AIDS programs. Methods:HIV-infected subjects with CD4 counts < 200×106/l were interviewed and had CD4 lymphocyte counts, blood cultures for mycobacteria (baseline and at 6 months), and skin tests with purified protein derivative (PPD) and M. avium sensitin. Results:Among 566 study patients rates of disseminated MAC were 10.5–21.6% in New Hampshire, Boston and Finland compared to 2.4–2.6% in Trinidad and Kenya (P < 0.001). PPD skin test reactions ≥ 5 mm were present in 20% of patients from Kenya compared to 1% at other sites (P < 0.001). Among patients from the United States and Finland, multiple logistic regression indicated that occupational exposure to soil and water was associated with a decreased risk of disseminated MAC, whereas the following were associated with an increased risk of disseminated MAC: low CD4 count, swimming in an indoor pool, history of bronchoscopy, regular consumption of raw or partially cooked fish/shellfish and treatment with granulocyte colony-stimulating factor. Conclusions:Rates of disseminated MAC in AIDS are higher in developed than developing countries and are due to both differences in exposure and differences in immunity. These data provide a rationale for prevention of MAC through both active immunization and reduction in exposure to the organism.

Improved classification of recent HIV-1 infection by employing a two-stage sensitive/less-sensitive test strategy.

Current serologic techniques for the classification of recent HIV-1 infection produce some misclassifications, and, together with the loss to follow-up of individuals, results in decreased enrollment of HIV-infected persons into appropriate intervention programs. We report on the development of a sensitive/less sensitive (S/LS) test strategy that includes a rapid assay to quickly identify persons most likely to have recent infection, followed by an enzyme immunoassay (EIA) with exquisite specificity. The Uni-Gold Recombigen HIV rapid assay (UG; Trinity Biotech, Dublin, Ireland) was procedurally-modified and calibrated as an LS test to differentiate recent (<133 days) from established HIV infections using 178 samples from persons with known dates of infection. This method correctly classified 83.0% of recent infections, but with a high misclassification rate of persons with established infection. By performing the rapid test followed by a modified S/LS EIA, the positive predictive value of the combined results for recent infections was increased to 100%. This two-stage testing algorithm can result in an increased efficiency for the enrollment of recent infection cases over a standard EIA S/LS method alone due to provisional enrollment during an initial testing visit, and because of an increased accuracy for identifying truly recent infections. We conclude that the rapid S/LS assay provides a tool for capturing recent infection cases quickly and is particularly valuable in resource-limited settings, and that the two-stage strategy provides a more accurate identification of persons with recent HIV infection.

Rapid Clearance of Virus after Acute HIV-1 Infection: Correlates of Risk of AIDS

OBJECTIVE Our objective was to define early virologic and immunologic determinants of human immunodeficiency virus (HIV) type 1 disease progression among 22 case subjects with acute infection from the Trinidad Seroconvertor Cohort. METHODS A linear segmented regression model was fitted to sequential quantitative virus load measurements. Parameters of virus kinetics during different phases of primary infection were correlated with clinical and immunologic end points, by use of Kaplan-Meier estimates and Cox regression. RESULTS Ten individuals developed acquired immunodeficiency syndrome (AIDS)-defining events. In univariate analysis, progression to AIDS was associated with rate of initial HIV clearance (P=.002), virus load during set point (P=.008), and CD4(+) cell count during steady state (P=.04). In the multivariate analysis, a rapid rate of initial clearance was the sole independent predictor of subsequent progression to AIDS and was associated with a 92% reduction in the risk of AIDS. The rate of initial clearance is inversely correlated with the number of early symptoms (r=-0.66; P=.0008). However, symptoms did not predict subsequent risk of AIDS. CONCLUSION Among a subset of patients, rapid clearance of plasma HIV-1 after peak viremia is associated with lower viral set point, prolonged virus suppression before loss of virologic control, and decreased risk of AIDS. These findings are consistent with the hypothesis that effective immune responses during the earliest phase of infection are important determinants of the subsequent natural history.

HIV-1 prevalence and risk factors among sexually transmitted disease clinic attenders in Trinidad:

Objectives: To study trends in prevalence and to ascertain risk factors for HIV‐1 among sexually transmitted disease (STD) clinic attenders in Trinidad. Design and methods: Serial cross‐sectional studies were conducted in 1987‐1988 and 1990‐1991 at a centralized STD clinic in Port of Spain. A case‐control study was carried out to examine in greater detail the demographic and behavioral risk factors for HIV‐1 among self‐declared heterosexuals in this population. Results: HIV‐1 prevalence increased from 3.0% [95% confidence interval (Cl), 2.3‐3.9] in 1987‐1988 to 13.6% (95% Cl, 11.8‐15.6) in 1990‐1991. Age ≥40 years [odds ratio (OR), 2.0; 95% Cl, 1.4‐2.8], urban residence (OR, 2.2; 95% Cl, 1.6‐3.0), and human T‐lymphotropic virus‐I seropositivity (OR, 3.1; 95% Cl, 1.6‐6.0) were significant risk factors for HIV‐1 in 1990‐1991. In the case‐control analysis, significant independent risk factors for men included current genital ulcer disease (OR, 5.2; 95% Cl, 2.2‐12.5), current genital warts (OR, 3.9; 95% Cl, 1.2‐12.0), having ever had syphilis (OR, 3.2; 95% Cl, 1.6‐6.1), and use of crack cocaine in the preceding 6 months (OR, 6.2; 95% Cl, 2.7‐14.2). Corresponding risk factors for women were commercial sex work (OR, 5.7; 95% Cl, 1.3‐25.7), initiation of sexual activity before age 14 years (OR, 4.8; 95% Cl, 1.5‐16.0), and past non‐gonococcal cervicitis (OR, 4.1; 95% Cl, 1.3‐13.1). Conclusions: HIV‐1 in this setting is primarily heterosexually transmitted in a milieu of unprotected sexual activity fuelled by a crack cocaine epidemic. Targeted interventions to prevent, detect and treat STD and crack cocaine addiction, as well as disrupt their adverse synergism, may substantially reduce HIV‐1 transmission in this population. AIDS 1995, 9:389‐394

The risks and benefits of childhood bacille Calmette-Guerin immunization among adults with AIDS

Objective:To define the risks of disseminated bacille Calmette-Guérin (BCG) or disseminated Mycobacterium tuberculosis in adults with AIDS who were immunized with BCG in childhood. Design:HIV-infected patients with CD4 < 200 × 106/l were enrolled from five study sites (New Hampshire, Boston, Finland, Trinidad and Kenya). Prior BCG immunization was determined and blood cultures for mycobacteria were obtained at study entry and at 6 months. Acid-fast bacilli were identified as Mycobacterium tuberculosis complex (MTBC) using DNA probes. MTBC isolates were then typed by both IS6110 restriction fragment length polymorphism and polymerase chain reaction/restriction enzyme analysis. Setting:Most patients in New Hampshire and Finland were outpatients; most patients in Trinidad were inpatients with terminal illness; and most patients in Kenya were outpatients, although 44 were inpatients with terminal illness. Participants:A total of 566 patients were enrolled, including 155 with childhood BCG immunization; 318 patients had a single study visit and culture, and 248 patients had two study visits and cultures. Main outcome measures:Isolation and identification of mycobacteria from blood cultures. Results:Blood cultures were positive for MTBC in 21 patients; none were positive for M. bovis BCG, and 21 were M. tuberculosis-positive. In Trinidad, seven (87%) out of eight isolates of M. tuberculosis were indistinguishable by IS6110 typing; BCG immunization was associated with a decreased risk of bacteremic infection with M. tuberculosis (P = 0.05). Conclusions:The risk of disseminated BCG among adult AIDS patients with childhood BCG immunization is very low. Childhood BCG immunization is associated with protection against bacteremia with M. tuberculosis among adults with advanced AIDS in Trinidad.

Immunologic and virologic analyses of an acutely HIV type 1-infected patient with extremely rapid disease progression

The immunologic and virologic factors that impact on the rate of disease progression after acute infection with human immunodeficiency virus (HIV) type 1 are poorly understood. A patient with an extraordinarily rapid disease course leading to AIDS-associated death within 6 months of infection was studied intensively for the presence of anti-HIV immune reactivities as well as changes in the genetic and biologic properties of virus isolates. Although altered humoral responses were evident, the most distinctive immunologic feature was a nearly complete absence of detectable HIV-specific CTL responses. In addition to a rapid decline in CD3+CD4+ cells, elevated percentages of CD8+CD45RA+ and CD8+CD57+ cells and diminished CD8+CD45R0+ and CD8+CD28+ cells were evident. Primary viral isolates recovered throughout the course of infection exhibited limited sequence diversity. Cloned viral envelopes were found to have unusually broad patterns of coreceptor usage for cell-cell fusion, although infectivity studies yielded no evidence of infection via these alternative receptors. The infectivity studies demonstrated that these isolates and their envelopes maintained an R5 phenotype throughout the course of disease. The absence of demonstrable anti-HIV CTL reactivities, coupled with a protracted course of seroconversion, highlights the importance of robust HIV-specific immune responses in the control of disease progression.

A study of HTLV-I infection and breast cancers in Trinidad and Tobago.

The human T-cell lymphoma/leukaemia virus (HTLV-I), the first human retrovirus to be discovered, causes lymphoma/ leukaemia. Viruses may also be associated with a number of cancers, including liver, cervical and nasopharyngeal tumours. One viral model for breast cancer is the mouse mammary tumour virus (MMTV), a retrovirus which gives rise to a significant incidence of mammary cancer even in mice fosternursed on virus-free strains to eliminate maternal transmissions (Coffın, 1982). Several lines of research support the participation of MMTV in human breast cancer, but such evidence has been contradicted by further research. Clark et al. (1985), in a study to determine the prevalence of HTLV-I antibodies in individuals with various malignancies in Jamaica, observed HTLV-I seropositivity in 6 (27.3%) of 22 patients with breast cancer. This was higher but not statistically significant when compared with the age-matched population without malignancies in Jamaica. Our present study was conducted to determine whether there is any association between HTLV-I infection and the development of breast cancer in Trinidad and Tobago. Between June 1995 and September 1996, surveillance for cases of breast cancer was conducted by research nurses through visits to the National Oncology and Radiotherapy Centre in Port of Spain, and the wards and the pathology departments of the Port of Spain and San Fernando General Hospitals; 112 cases were recalled and enrolled. Cases of breast cancer were confirmed by histology. Thirty-two percent were infiltrating duct carcinoma, 29% invasive duct carcinoma, 12% adenocarcinoma and the remaining 27% lobular and papillary carcinoma. At enrollment, following written informed consent, a short questionnaire collecting demographic data was administered. Of the 112 cases enrolled, 111 were female and 1 was male. Age at diagnosis ranged from 25 to 89 years (mean 55 years). There were 78 (69.6%) individuals of African and mixed African descent, 30 (26.8%) of East Indian descent and 4 (3.6%) of other ethnic groups. Three (2.7%) of the 112 patients were HTLV-I ELISA– and Western blot–positive. Seropositive patients were females of African descent over 40 years of age (47, 69 and 75 years) at the time of diagnosis of the breast cancer. Since HTLV-I infection in Trinidad and Tobago occurs predominantly in Trinidadians of African origin (Blattner et al., 1990; Miller et al., 1986) and increases with age (Mueller et al., 1990), the HTLV-I prevalence by age of the breast cancer patients was compared with that of females of African descent in a 1986 general population HTLV-1 sero-survey in Trinidad. As shown in Table I, the overall HTLV-I seroprevalence of the women with breast cancer (3/78 or 3.8%) was not different from that of women in the general population sero-survey: 16/388 or 4.1% (p 5 0.8). There was also no significant difference in HTLV-I seropositivity between women older than 40 years among the general population and the breast cancer groups: 8.1% compared with 4.6% (p 5 0.6). In our study of 112 subjects in Trinidad and Tobago, there was no association of the retrovirus HTLV-I with breast cancer. Yours sincerely, Noreen JACK1, Jeffrey EDWARDS1, William DHANESSAR2, Hess BENJAMIN2 and Courtenay BARTHOLOMEW1*