Courtenay Bartholomew

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.

Incidence of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica and Trinidad

HTLV-I is sexually transmitted more efficiently from men to women than vice versa, and the majority of HTLV-I endemic areas report a female preponderance of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases. The objective of this study was to estimate the gender- and age-specific incidence rates of HAM/TSP in the general population as well as in the HTLV-I-infected population in Jamaica and in Trinidad and Tobago. Incidence rates for HAM/TSP were computed based on all reported incident cases in both countries between 1990 and 1994. Population census reports for 1990 were used to calculate the population at risk. The age-standardized HAM/TSP incidence rate (mean +/- standard error of the mean) in Jamaica was 1.8 +/- 0.2/100,000 person years (PY). Among individuals of African descent in Trinidad and Tobago, the rate was 1.7 +/- 0.4/100,000 PY. As in HTLV-I seroprevalence, the incidence rate of HAM/TSP increased with age through the fifth decade of life and was three times as high in women than in men. The HAM/TSP incidence rate, calculated as a function of the number of HTLV-I-infected persons in each age stratum, is higher in women (24.7/100,000 PY) than in men (17.3/100,000 PY). With HTLV-I infection, the lifetime risk of developing HAM/TSP was estimated to be 1.9% overall and is slightly higher in women (1.8%) than in men (1.3%). Thus, the higher prevalence of HTLV-I in women in endemic areas does not fully explain the preponderance of female HAM/TSP, suggesting that other cofactors must be present. The higher incidence rate in women between the ages of 40 and 59 years, as well as the increase in HAM/TSP incidence rates with age, are indicative of the importance of adult-acquired HTLV-I infection, presumably through sexual transmission.

HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.

In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (TCR) in T lymphocytes of HIV-infected individuals. Total amounts of protein tyrosine kinases (PTKs) Lck, Fyn, and ZAP-70 and the zeta chain of the TCR were found significantly decreased in T cells of symptomatic/AIDS patients as well as in T cells of individuals in acute and early asymptomatic stages of HIV infection. Unexpectedly, the detection of Lck, Fyn, and ZAP-70 was reversed after the treatment of cell lysates with dithiothreitol. This suggests that PTKs Lck, Fyn, and ZAP-70 were modified by a mechanism altering the status of sulfhydryl groups. Moreover, this mechanism seems to affect selectively T cells of HIV infected patients since B cell PTKs Syk and Lyn were detected structurally and functionally intact. Interestingly, similar alterations of signaling molecules were not detected in T cells of HIV-infected long-term asymptomatic individuals. Modification of T cell PTKs may thus underlie the HIV-induced impairment of lymphocyte function and may potentially predict disease progression.

HTLV-I AND TROPICAL SPASTIC PARAPARESIS

Furthermore, we have shown that platelets prepared from patients admitted with the provisional diagnosis of acute myocardial infarction (AMI) tend to aggregate after heparin challenge in vitro. This was observed whether AMI was confirmed or not, provided patients had a history of, for example, myocardial infarction or peripheral vascular disease. The figures for samples producing more than 50% aggregation after the addition of heparin in vitro

Role of HTLV-I in development of non-Hodgkin lymphoma in Jamaica and Trinidad and Tobago

Human T-cell lymphotropic virus type I (HTLV-I) has been implicated in the aetiology of adult T-cell leukaemia/lymphoma in Japan and elsewhere, particularly the Caribbean. We have carried out parallel case-control studies in Jamaica and in Trinidad and Tobago to quantify the role of HTLV-I in the development of non-Hodgkin lymphoma (NHL). 135 cases of NHL were enrolled in Jamaica and 104 in Trinidad and Tobago. Controls were selected from patients treated in the same wards or clinics at the same time as the cases. Overall, patients with NHL were 10 times more likely than were controls to be seropositive for HTLV-I (Jamaica odds ratio 10.3 [95% CI 6.0-18.0], Trinidad and Tobago 14.4 [7.6-27.2]). In both countries the association between NHL and HTLV-I was greatest for T-cell lymphomas (18.3 [9.5-35.6] and 63.3 [25-167]). Among T-cell lymphomas especially, there was no significant difference between men and women in the association between NHL and HTLV-I, but there was a significant inverse relation between age and likelihood of HTLV-I seropositivity. B-cell lymphomas were predominant in the older age groups and were not associated with HTLV-I seropositivity. These findings are consistent with the hypothesis that early life exposure to HTLV-I is important for risk of subsequent ATL. Prevention of vertical transmission of HTLV-I could reduce by 70-80% cases of NHL in people under 60 years in this region.

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.

Lessons from a multisite international trial in the Caribbean and South America of an HIV-1 Canarypox vaccine (ALVAC-HIV vCP1452) with or without boosting with MN rgp120.

Background:The first multicenter, international National Institutes of Allergy and Infectious Diseases (NIAID)-sponsored HIV vaccine trial took place in Brazil, Haiti, Peru and Trinidad. This randomized, double-blind, placebo-controlled, phase 2 trial evaluated the safety and immunogenicity of a clade B-derived, live canarypox HIV vaccine, vCP1452. vCP1452 was administered alone or with a heterologous boost of MN rgp120 glycoprotein. The trial was pivotal in deciding whether these vaccines advanced to phase 3 efficacy trials. Methods:Forty seronegative volunteers per site were randomized to ALVAC alone, ALVAC plus MN rgp120, or placebo in a 0, 1, 3, and 6 month schedule. Immunogenicity was assayed by chromium-release cytotoxic T lymphocyte (CTL) responses; interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot assays (ELISpot); lymphocyte proliferation assays (LPA); neutralization; and enzyme-linked immunosorbent assays (ELISA). Results:Enrollment and follow-up were excellent. Both vaccines were well tolerated. Neutralizing antibody to the laboratory-adapted MN strain was detected. Cellular immune responses, as measured by CTL, ELISpot, and LPA, did not differ between vaccines and placebos. Conclusions:The observation of disappointing immunogenicity in this and a parallel domestic study has informed future vaccine development. Equally important, challenges to doing an integrated trial across countries, cultures, languages, and differing at-risk populations were overcome. The identification of specific safety, ethical, logistic, and immunological issues in this trial established the foundation for current larger international studies.

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.