Edward L. Murphy

Global epidemiology of HTLV-I infection and associated diseases.

Epidemiologic aspects of human T-lymphotropic virus type I (HTLV-I) infection have been thoroughly studied over the course of approximately 25 years since its first description. The geographic distribution of the virus has been defined, with Japan, Africa, Caribbean islands and South America emerging as the areas of highest prevalence. The reasons for HTLV-I clustering, such as the high ubiquity in southwestern Japan but low prevalence in neighboring regions of Korea, China and eastern Russia are still unknown. The major modes of transmission are well understood, although better quantitative data on the incidence of transmission, and on promoting/inhibiting factors, are needed. Epidemiologic proof has been obtained for HTLV-Is causative role in major disease associations: adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-associated uveitis and infective dermatitis. However, more and better studies are needed for other apparent disease outcomes such as rheumatologic, psychiatric and infectious diseases. Since curative treatment of ATL and HAM/TSP is lacking and a vaccine is unavailable, the social and financial cost for the individual, his/her family and the health system is immense. For this reason, public health interventions aimed at counseling and educating high-risk individuals and populations are of paramount importance.

Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease

The introduction of combination antiretroviral therapy for HIV infection revolutionized treatment of AIDS and HIV disease. Such treatment, which usually includes two nucleoside analogue inhibitors of HIV reverse transcriptase and at least one HIV protease inhibitor or non-nucleoside inhibitor of HIV reverse transcriptase, is called highly active antiretroviral therapy (HAART). Early cohort and registry-based studies showed a lower incidence of AIDS and decreased rates of AIDS-related mortality after the introduction of HAART in late 1995 in the United States (1-3), France (4), Australia (5), Germany (6), and Switzerland (7). However, ecologic studiesthose that measured use of HAART and mortality in groups rather than in individual patientsmay be subject to confounding by calendar period changes in other unmeasured variables. In addition, many studies that directly measured the effects of HAART on survival of patients with AIDS did not provide specific evidence of such effects in the patients with the most advanced cases (8-10), with the exception of small cohorts of patients with cytomegalovirus (CMV) retinitis (11) and progressive multifocal leukoencephalopathy (12). We therefore studied the effect of HAART in a large multicenter trial of blood transfusion in patients with advanced HIV disease who were also anemic, an indicator of poor prognosis (13, 14). Because the study spanned the period before and after the introduction of HAART, we could directly assess the effect of HAART status on subsequent death or opportunistic events. In addition, because our person-year analysis was controlled for calendar time, our estimates of the magnitude of the effect of HAART on mortality and morbidity are less likely to be confounded by changes in patient mix or medical practice compared with previously published studies. Methods Patients and Study Design The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus nonleukoreduced red blood cell transfusion in HIV-infected patients who required a first transfusion for anemia. Details of the study design have been published elsewhere (15, 16). In brief, we enrolled patients who were HIV seropositive, were CMV seropositive or had a history of documented CMV disease, had an expected survival of at least 1 month, and required red blood cell transfusion for anemia. Data on clinical end points and prescribed medications were obtained by interview and medical record review at baseline and every 3 months thereafter. Ophthalmologic examinations to detect CMV retinitis were done at baseline and every 6 months thereafter. In patients who did not return for follow-up visits, vital status was ascertained by review of the medical record, a search for a death certificate, and tracing by using public databases. Of 528 patients, 58 were excluded before death or end of the study, including 29 for whom no follow-up information on opportunistic events was available and 3 for whom follow-up for death but not for opportunistic events was complete. The CD4+ lymphocyte count and plasma HIV RNA level were measured by using frozen blood specimens at the central study laboratory, as described elsewhere (15). The study protocol was approved by the institutional review boards of the 11 participating medical centers, and informed consent was obtained from all participants. Definitions of HAART and End Points The VATS did not dictate the choice of antiretroviral therapy for enrolled patients, except that prescription of new antiretroviral drugs was discouraged during the 2 weeks after the first two transfusion episodes. Highly active antiretroviral therapy was defined as prescription of at least three antiretroviral medications with activity against HIV, at least one of which was an HIV protease inhibitor or a non-nucleoside HIV reverse transcriptase inhibitor. Medication history collected at each quarterly visit included the names and start and stop dates of any HIV antiretroviral medications taken since the previous visit or in the 30 days before entry into the study. Patients taking no HIV antiretroviral medications and those taking HIV antiretroviral medications that did not fulfill our definition of HAART were classified as before HAART until the day that they began HAART. Once a patient initiated HAART, all of his or her subsequent follow-up time remained designated as after HAART even if they discontinued HAART, to approximate an intention-to-treat analysis. We made this conservative decision to avoid overestimating the effect of HAART, which would occur if patients who stopped HAART because of intolerance subsequently contributed outcomes to the before HAART person-years. Adherence to prescribed medications was not measured. End points of the current study were death, opportunistic events, and recurrent transfusions. Opportunistic events were defined a priori and confirmed by expert reviewers; they included clinical diagnoses corresponding to the Centers for Disease Control and Preventions AIDS-defining conditions (17), with some modifications. Presumptive diagnoses of central nervous system toxoplasmosis were allowed according to the Centers for Disease Control and Preventions definition. For CMV retinitis, progression of disease requiring initiation of or a change in anti-CMV medication counted as a clinical event. For analysis, end points were grouped as follows: CMV opportunistic events; non-CMV opportunistic events; all opportunistic events; death; and any end point, including death and all opportunistic events. We analyzed recurrent red blood cell transfusion (that is, occurring after the enrollment transfusion event) as a separate end point. Statistical Analysis We used a person-years approach to analyze event rates. The denominator for these rates was not the individual patient but was person-years of observation time, defined as study follow-up time for each patient classified as before or after initiation of HAART and summed over all patients. For example, patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively. Observation time for a patient extended from the date of study entry to death or the end of follow-up. Because some patients had no follow-up information for opportunistic events and a few had less follow-up for opportunistic events than for mortality, the total observation time for opportunistic events was shorter than that for overall survival. Events were assigned to the time period during which they occurred, and incidence was reported as the number of events per person-year of observation time. A single patient could contribute multiple events (except for the mortality analysis) to the same or to different time periods. The association between HAART use and incidence rates was expressed as a rate ratio. Confidence intervals and P values were calculated from a Poisson regression model using generalized estimating equations with exchangeable correlation structure to adjust for correlated observations across time within the same patient (18, 19). All P values are two sided. Because the use of HAART increased dramatically over the 4 years of the study, the comparison of post-HAART and pre-HAART data is confounded with calendar time. In addition, the mixture of HIV risk groups, prevalence of prophylaxis against opportunistic infections, diagnostic testing accuracy, and physician experience may have changed over time. To evaluate and control for these and other calendar time effects, each patients observation time was further categorized as four 1-year calendar time periods, starting in July 1995. Similarly, a patients time since entering the study was divided into five study time periods (0 to 6, 7 to 12, 13 to 18, 19 to 24, or >24 months from randomization). The Poisson regression generalized estimating equations method was then used to calculate the rate ratios associated with CD4 T-cell count, plasma HIV RNA level, calendar time, and time on study and to adjust the comparisons of post-HAART and pre-HAART data for these covariates, both in pairs and combined with patient characteristics. Results Participants The VATS enrolled patients with anemia and HIV infection who received a first red blood cell transfusion between August 1995 and July 1998. Patients were followed until death or their last scheduled quarterly visit before 30 June 1999. Of 531 patients enrolled in VATS, we excluded 3 patients for whom no data on medication were available; thus, the sample for analysis in this study was 528 patients. Table 1 shows the baseline characteristics of the study sample. Most patients were 30 to 49 years of age and male, and equal proportions of patients were of white and nonwhite ethnicity. Half of the patients were men who reported sex with other men as their only HIV risk factor; 19% each were injection drug users or sexually active heterosexuals without other risk factors for HIV; and 12% had multiple or other risk factors. At baseline, the median CD4+ lymphocyte count was 0.015 109 cells/L, and 69% of patients had a CD4+ lymphocyte count less than 0.050 109 cells/L. The median HIV RNA level was 4.8 log10 copies/mL, and only 8% of patients had plasma levels of HIV RNA levels less than 200 copies/mL. Table 1. Baseline Characteristics of 528 Patients in the Viral Activation Transfusion Study At baseline, most patients had previously taken antiretroviral medication; more than half had taken such medication for 12 months or longer. The proportion of patients taking prophylaxis or treatment of Pneumocystis carinii pneumonia and Mycobacterium avium complex infection decreased from 95% and 49%, respectively, in 19951996 to 82% and 44% in 19

Transfusion related acute lung injury: incidence and risk factors

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

Natural history of "high-risk" bundle-branch block: final report of a prospective study.

We conducted a prospective study in which 554 patients with chronic bifascicular and trifascicular conduction abnormalities were followed for an average of 42.4 +/- 8.5 months. Heart block occurred in 19 patients, and 17 were successfully treated. The actuarial five-year mortality from an event that could conceivably have been a bradyarrhythmia was 6 per cent (35 per cent from all causes). Of the 160 deaths 67 (42 per cent) were sudden; most of these were not ascribable to bradyarrhythmia but to tachyarrhythmia and myocardial infarction. Mortality was higher in patients with coronary-artery disease (P less than 0.01) and congestive heart failure (P less than 0.05). Patients in whom syncope developed before or after entry into the study had a 17 per cent incidence of heart block (2 per cent in those without syncope)(P less than 0.05); however, no single variable was predictive of which patients were at high risk of death from a bradyarrhythmia. The predictors of death were increasing age, congestive heart failure, and coronary-artery disease; the predictors of sudden death were coronary-artery disease and increasing age. The risks of heart block and of death from a bradyarrhythmia are low; in most patients, heart block can be recognized and successfully treated with a pacemaker.

The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy

BACKGROUND: Antibodies to human leukocyte antigens (HLA) in donated blood have been implicated as a cause of transfusion‐related acute lung injury (TRALI). A potential measure to reduce the risk of TRALI includes screening plateletpheresis donors for HLA antibodies. The prevalence of HLA antibodies and their relationship to previous transfusion or pregnancy in blood donors was determined.

Sexual Transmission of Human T-Lymphotropic Virus Type I (HTLV-I)

STUDY OBJECTIVE To study the seroprevalence of human T-lymphotropic virus type I (HTLV-I) in a sexually active population and to determine sexual behavior risk factors for infection. DESIGN Cross-sectional seroprevalence study using enzyme-linked immunosorbent assay (ELISA) and Western blot. Risk-factor data were gathered by administered questionnaire and chart review. SETTING Two urban, primary care clinics for persons with sexually transmitted diseases run by the Jamaican Ministry of Health. PATIENTS Of the 2050 consecutive patients presenting with new episodes of sexually transmitted disease, 1977 patients were eligible for analysis. MEASUREMENTS AND RESULTS Overall HTLV-I seroprevalence was 5.7%; prevalence increased with age from 1.6% (age, 14 to 19 years) to 5.1% (age, 30 years and older) in men and from 5.3% (age, 14 to 19 years) to 14.1% (age, 30 years and older) in women. Compared with a reference cohort of food service employees, age-adjusted HTLV-I seroprevalence was increased in female patients with sexually transmitted disease (odds ratio = 1.83; CI, 1.41 to 2.83) but not in male patients with sexually transmitted disease. Independent risk factors for HTLV-I infection in women included having had more than ten lifetime sexual partners (odds ratio = 3.52, CI, 1.28 to 9.69) and a current diagnosis of syphilis (odds ratio = 2.12; CI, 1.12 to 3.99). In men, a history of penile sores or ulcers (odds ratio = 2.13; CI, 1.05 to 4.33) and a current diagnosis of syphilis (odds ratio = 3.56; CI, 1.24 to 10.22) were independent risk factors for HTLV-I infection. Of 1977 patients, 5 (0.3%) had antibodies to human immunodeficiency virus type 1 (HIV-1), including 2 with HTLV-I and HIV-1 coinfection. CONCLUSIONS We conclude that HTLV-I is transmitted from infected men to women during sexual intercourse. Our data are consistent with the lower efficiency of female-to-male sexual transmission of HTLV-I, but penile ulcers or concurrent syphilis may increase a mans risk of infection.

EVALUATION OF SCREENED BLOOD DONATIONS FOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 INFECTION BY CULTURE AND DNA AMPLIFICATION OF POOLED CELLS

BACKGROUND Reports of transmission of the human immunodeficiency virus type 1 (HIV-1) from transfusions of screened blood and reports of silent, antibody-negative HIV-1 infections in persons at high risk continue to foster concern about the safety of the blood supply. Previous estimates of the risk of HIV-1 range from 1 in 38,000 to 1 in 300,000 per unit of blood but are based on either epidemiologic models or the demonstration of seroconversion in recipients. METHODS We isolated peripheral-blood mononuclear cells from blood that was fully screened and found to be seronegative, combined them into pools of cells from 50 donors, and tested them for HIV-1 by viral culture and the polymerase chain reaction, using protocols specifically adapted for this analysis. RESULTS The 1530 pools of mononuclear cells were prepared from 76,500 blood donations made in San Francisco between November 1987 and December 1989. Of these pools, 1436 (representing 71,800 donations) were cultured successfully; 873 (43,650 donations) were evaluated by the polymerase chain reaction. Only one pool was confirmed as HIV-1--infected by both methods. After adjustment for sample-based estimates of the sensitivity of the detection systems using culture and the polymerase chain reaction, the probability that a screened donor will be positive for HIV-1 was estimated as 1 in 61,171 (95 percent upper confidence bound, 1 in 10,695). CONCLUSIONS Silent HIV-1 infections are exceedingly rare among screened blood donors, so the current risk of HIV-1 transmission from blood transfusions, even in high-prevalence metropolitan areas, is extremely low.

Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study.

The efficiency of hepatitis C virus (HCV) transmission by sexual activity remains controversial. We conducted a cross‐sectional study of HCV‐positive subjects and their partners to estimate the risk for HCV infection among monogamous heterosexual couples. A total of 500 anti–HCV‐positive, human immunodeficiency virus–negative index subjects and their long‐term heterosexual partners were studied. Couples were interviewed separately for lifetime risk factors for HCV infection, within‐couple sexual practices, and sharing of personal grooming items. Blood samples were tested for anti‐HCV, HCV RNA, and HCV genotype and serotype. Sequencing and phylogenetic analysis determined the relatedness of virus isolates among genotype‐concordant couples. The majority of HCV‐positive index subjects were non‐Hispanic white, with a median age of 49 years (range, 26‐79 years) and median of 15 years (range, 2‐52 years) of sexual activity with their partners. Overall, HCV prevalence among partners was 4% (n = 20), and nine couples had concordant genotype/serotype. Viral isolates in three couples (0.6%) were highly related, consistent with transmission of virus within the couple. Based on 8,377 person‐years of follow‐up, the maximum incidence rate of HCV transmission by sex was 0.07% per year (95% confidence interval, 0.01‐0.13) or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples. Conclusion: The results of this study provide quantifiable risk information for counseling long‐term monogamous heterosexual couples in which one partner has chronic HCV infection. In addition to the extremely low estimated risk for HCV infection in sexual partners, the lack of association with specific sexual practices provides unambiguous and reassuring counseling messages. (HEPATOLOGY 2013)

Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study

Background: Almost 20 years after its discovery, the prevalence and clinical course of human T-lymphotropic virus type I (HTLV-I)–associated myelopathy (HAM, also known as tropical spastic paraparesis [TSP]) remain poorly defined. Whereas the causative association of HTLV-I and HAM/TSP is generally recognized, controversy still surrounds the relationship between HTLV-II and HAM/TSP. Methods: The HTLV Outcomes Study (HOST—formerly Retrovirus Epidemiology Donor Study [REDS]) is a prospective cohort study including 160 patients with HTLV-I, 405 patients with HTLV-II, and 799 uninfected controls who have been followed every 2 years since 1990–1992. Clinical outcomes are measured by health interviews and examinations, and blood samples are obtained. Results: Six cases of HTLV-I–associated myelopathy (3.7%, 95% CI 1.4 to 8.0) and four cases of HTLV-II myelopathy (1.0%, 95% CI 0.3 to 2.5) have been diagnosed since the formation of the cohort. There have been no cases of HAM/TSP diagnosed among HTLV-negative subjects (0.0%, 95% CI 0.0 to 0.5). Clinical features of the cases include lower extremity hyperreflexia, variably associated with weakness, spasticity, and bladder dysfunction. Conclusions: Systematic screening of HTLV-infected blood donors reveals a high prevalence of HAM/TSP. The clinical course of HAM/TSP appears highly variable. HTLV-II–associated myelopathy generally presents with milder and more slowly progressive signs and symptoms.

Mother‐to‐child transmission of human T‐cell‐leukemia/lymphoma virus type I: Implication of high antiviral antibody titer and high proviral load in carrier mothers

In order to gain new insights into the risk factors influencing human‐T‐cell‐leukemia/lymphoma‐virus‐type‐I (HTLV‐I) mother‐to‐child transmission, a retrospective study of HTLV‐I infection among children born to HTLV‐I‐seropositive women was carried out in a highly HTLV‐I‐endemic population of African origin living in French Guyana. The study covered 81 HTLV‐I‐seropositive mothers and their 216 children aged between 18 months old and 12 years old. All plasma samples were tested for the presence of HTLV‐I antibodies by ELISA, immunofluorescence assay and Western blot. HTLV‐I provirus was detected, in the DNA extracted from peripheral‐blood mononuclear cells, by polymerase chain reaction (PCR) using primers specific for 3 different HTLV‐I genomic regions (LTR, gag and pX) and quantified by a competitive PCR assay. Out of the 216 children, 21 were found to be HTLV‐I‐seropositive, giving a crude HTLV‐I transmission rate of 9.7%, while among the 180 breast‐fed children 10.6% were HTLV‐I‐seropositive. Perfect concordance between serological and PCR results was observed, and none of the 195 HTLV‐I‐negative children was found HTLV‐I‐positive by PCR. In conditional (by family) logistic‐regression models, HTLV‐I seropositivity in children was associated with an elevated maternal anti‐HTLV‐I‐antibody titer (OR 2.2, p = 0.0013), a high maternal HTLV‐I proviral load (OR 2.6, p = 0.033) and childs gender, girls being more frequently HTLV‐I‐infected than boys: OR 3.6, p = 0.0077 in the model including maternal anti‐HTLV‐I‐antibody titer and OR 4.1, p = 0.002 in the model including the maternal HTLV‐I proviral load. Int. J. Cancer 82:832–836, 1999.