Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial.

CONTEXT: While interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART). OBJECTIVE: To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone. DESIGN AND SETTING: Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States. PATIENTS: Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 10(6)/L to 500 x 10(6)/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study. INTERVENTIONS: Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone. MAIN OUTCOME MEASURES: Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels. RESULTS: The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log(10) copies for IL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving IL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received IL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed. CONCLUSIONS: Intermittent therapy with IL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end-point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with IL-2 therapy will translate into improved clinical outcomes. JAMA. 2000;284:183-189

Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial.

PURPOSE: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4 + T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and high-dose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL-2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). METHOD: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4 + T cell counts less than 300 cells/microL at screening and a stable HIV viral load received low-dose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). RESULTS: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/microL in the IL-2 group compared to 19.93 cells/microL in the control group (p <.001). Additionally, IL-2-treated patients experienced a statistically significant increase in the mean percentage of CD4 + T cells (3.52% increase) when compared to control patients (1.33% increase) (p <.001). The expanded CD4 + T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p <.001 for between-group difference). In addition, a higher proportion of IL-2-treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p =.08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. CONCLUSION: Daily, low-dose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells.

A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group.

BACKGROUND AND METHODS: Herpes simplex virus (HSV) infections are endemic, but the clinical characteristics of newly acquired HSV type 1 (HSV-1) and HSV type 2 (HSV-2) infections in adults have not been rigorously defined. We monitored 2393 sexually active HSV-2-seronegative persons for clinical and serologic evidence of new HSV infection. Of the participants, 1508 were seropositive for HSV-1 and 885 were seronegative. Charts were reviewed in a blinded manner for classification of those with genitourinary or oropharyngeal symptoms. Charts were also reviewed for all 174 persons with HSV seroconversion. RESULTS: The rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years, respectively. Of the 155 new HSV-2 infections, 57 (37 percent) were symptomatic, 47 of which (82 percent) were correctly diagnosed at presentation. Among the 74 patients given a clinical diagnosis of genital HSV-2 during the study, 60 were given a correct diagnosis and 14 were given an incorrect diagnosis of genital herpes, for a ratio of true positive results to false positive results of 4:1. Among the 98 persons with asymptomatic HSV-2 seroconversion, 15 percent had genital lesions at some time during follow-up. Women were more likely than men to acquire HSV-2 (P<0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion, as compared with symptomatic seroconversion, by a factor of 2.6 (P<0.001). Of the 19 new HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years). CONCLUSIONS: Nearly 40 percent of newly acquired HSV-2 infections and nearly two thirds of new HSV-1 infections are symptomatic. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.

Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group.

CONTEXT: In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. OBJECTIVE: To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. DESIGN: Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. SETTING AND PARTICIPANTS: We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. MAIN OUTCOME MEASURE: Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. RESULTS: Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. CONCLUSIONS: Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.

Menstrual bleeding patterns in Norplant-2 implant users.

The objective of the present study was to analyze the patterns of menstrual bleeding in Singaporean women using Norplant-2 contraceptive implants over a five-year period. Of the 100 women recruited for the study, 62 were still using the implant at the end of five years. Only 9 women discontinued for menstrual reasons and they did so within the first 21 months of implant use. Although a normal menstrual bleeding pattern was uncommon during the first three months of use, 69.4% had normal menstruation at the end of five years. Irregular bleeding was the most common form of menstrual abnormality throughout the study period. Infrequent periods and amenorrhoea were distinctly uncommon, especially after the first two years of use. The pattern of bleeding with Norplant-2 was not significantly different from that previously observed with Norplant.

PIP: To investigate the menstrual bleeding patterns among long-term users of Norplant-2 implants, 100 Singaporean women were followed for 5 years. All participants had delivered at least one child prior to implant insertion and had a history of regular menstrual periods. Monthly menstrual diaries indicating days of bleeding or spotting were collapsed into successive 90-day reference periods and analyzed for evidence of amenorrhea, prolonged bleeding (10 days or more), frequent bleeding (over four bleeding/spotting episodes per month), infrequent bleeding (less than two episodes), and irregular bleeding (bleeding-free interval exceeding 17 days). At the end of the 5-year study period, 62 women still had their implants, 9 had discontinued within 21 months after insertion for menstruation-related reasons, while 24 requested removal to achieve pregnancy. There were no pregnancies during Norplant use. Although only 9% of users experienced normal menstrual bleeding in the first three months of use, this statistic increased to 32.6%, 43.6%, 37.8%, 52.3%, and 69.4% after 1, 2, 3, 4, and 5 years of use, respectively. The most common menstrual irregularities were irregular bleeding and prolonged bleeding. Although more women had regular cycles with time, there was only minimal improvement in intraindividual variability in those who continued to have irregular bleeding. Overall, the bleeding disturbances recorded by Norplant-2 acceptors did not differ substantially from those found among users of the original Norplant delivery system.

Ethnicity and obstetric performance in Singapore.

The influence of ethnicity on obstetric performance in Singapore was assessed by retrospective analysis of all deliveries in the National University Hospital over a 7-year period. Malay mothers were younger, shorter, less educated, of higher parity, were more likely to have had no antenatal care, and had the highest incidence of premature labour. However, mothers of Indian origin had the smallest babies, the highest incidence of low birth weight and significantly higher perinatal mortality rates. Chinese mothers fared better than their Malay and Indian counterparts in all parameters assessed. The ethnic origin of the mother has an important bearing on perinatal performance. This emphasises the importance of designing appropriate strategies to improve perinatal health in the different ethnic groups.

Obstetrical outcome with increasing maternal age.

A retrospective study of 21,442 Singaporean women who gave birth at the National University Hospital, Singapore, between January 1986 and November 1991 is used to assess the effects of increasing age on obstetric performance. The results show that reproduction after the age of 35 years in Singapore is associated with a higher incidence of antenatal complications such as hypertension and diabetes and a higher rate of obstetric intervention. However, given the current level of obstetric and neonatal care in Singapore, these adverse features do not prejudice the obstetric and neonatal outcomes.

PIP: Physicians compared data on 2410 women, 35 years old and older, with 19,032 women younger than 35 years old, all of whom delivered at the National University Hospital in Singapore between January, 1986, and November, 1991, to examine the effects of advanced maternal age on pregnancy outcome. Older women were more likely to suffer from pregnancy-induced hypertension and diabetes mellitus than the younger women (odds ratio [OR] = 2.32 and 2.92 for primiparity; OR = 2.17 and 2.22 for multiparity, respectively; p .05 for all but diabetes among primiparae). Breech delivery occurred more frequently among the older mothers than younger, but it was significant only for primiparae (OR = 1.46; p .05). Intervention during delivery was more common among older mothers than younger mothers and among primiparae than multiparae. On the other hand, perinatal outcomes of neonatal death and stillbirths were essentially the same for primiparae and multiparae (OR = 0.76 and 0.78; respectively). When the researchers controlled for race and parity, the odds of pregnancy-induced hypertension and diabetes increased for every 5-year increase in age (OR = 1.46 and 1.81, respectively). The same was true for induced labor (OR = 1.22), elective cesarean section (OR = 1.96), and instrumental delivery (OR = 1.48). The odds did not increase, however, for premature birth and low birth weight. Since Singapore has quality obstetric and neonatal care facilities, and the older mothers tend to be of a higher socioeconomic class than younger mothers, the increased risk of pregnancy complications does not adversely affect obstetric outcome.

Premature childbirth: social and behavioural risks in Singapore.

The associations of social and behavioural factors on preterm birth in Singapore were studied using hospital maternity records of 20,723 consecutive singleton births between January 1986 and November 1991. The overall proportion of preterm births was 3.6%, the rates for the Chinese, Malay and Indian groups being 3.2%, 3.8% and 4.9% respectively. Teenage mothers were at a higher risk of preterm labour compared to women aged 20-29 years. The incidence of preterm labour decreased with increasing educational status. Preterm births were six times more likely in women who had no antenatal care. Women who had three or more previous births were at a higher risk, while those who had one or two previous births were at a lower risk compared to women who had none.

PIP: Maternity records for 19,772 singleton births from National University Hospital in Singapore between January 1986 and November 1991, provided data for chi=square analysis of the relationship between gestational age and sociodemographic factors. Multiple logistic regressions were generated to assess the joint effect of social and behavioral factors. The dependent variable was preterm or term labor. Preterm infants weighing less than 2500 gm constituted 3.6% of all births.

Relationships between cigarette smoking, blood pressure and serum lipids in the Singapore general population.

In a cross-sectional random survey of the whole of Singapore (2143 subjects aged 18-69 years), cardiovascular risk factors were measured by standardized techniques. For the analysis in the 18-69 year age group there was adjustment for ethnic group, age, body mass index, alcohol consumption and physical activity. Among serum lipids, high density lipoprotein (HDL-) cholesterol and fasting triglyceride were inversely related with partial correlation coefficients (r) of males -0.34 (P < 0.001) and females -0.26 (P < 0.001). There were no relationships between blood pressure and serum lipids except for direct ones with fasting triglyceride, being males (systolic r = 0.06, P = 0.066 and diastolic r = 0.12, P < 0.001) and females (systolic r = 0.11, P < 0.001 and diastolic r = 0.13, P < 0.001). Cigarette smoking, in males, was related to systolic blood pressure (inversely), with, compared to non-smokers, a reduction of 1.3 mm Hg (1.1%) in light smokers, 3.8 mm Hg (3.1%) in moderate smokers and 4.6 mm Hg (3.7%) in heavy smokers; there was no clear relation with diastolic blood pressure. Cigarette smoking, in males, was related to HDL-cholesterol (inversely), even after further adjustment for fasting triglyceride, with compared to non-smokers reductions of 0.03 mmol/l (3.4%) in light smokers, 0.09 mmol/l (10.3%) in moderate smokers and 0.12 mmol/l (13.8%) in heavy smokers. Cigarette smoking was related to fasting triglyceride (directly) but this was removed by further adjustment for HDL-cholesterol. Cigarette smoking was not related to low density lipoprotein cholesterol. These results are compared to those of other surveys.

Corneal arcus and cardiovascular risk factors in Asians in Singapore.

This study was a cross-sectional random survey of the whole of Singapore, based on 2143 subjects (aged 18-69 years, response rate 60.3%). The presence of corneal arcus was determined by a doctor using the naked eye in good light. Cardiovascular risk factors were measured by standardized techniques. The prevalence rates overall of corneal arcus were: 18-29 years (males 0.5%, females 0.3%), 30-49 years (males 18.1%, females 13.3%) and 50-69 years (males 70.7%, females 55.3%). In the 30-49 age group, people with arcus had higher serum low density lipoprotein (LDL) cholesterol concentrations than people without arcus, the mean differences being, males 0.31 mmol/l (P = 0.040) and females 0.62 mmol/l (P less than 0.001) with an increased likelihood of having values greater than 5.5.mmol/l of males 1.8 (95% confidence interval (95% CI): 1.0-3.4) and females 2.6 (95% CI: 1.4-4.8). There were no significant differences for LDL-cholesterol in the 50-69 age group. Arcus was weakly associated with fasting plasma glucose in the 30-49 age group. Arcus was not associated with serum high density lipoprotein (HDL) cholesterol, serum fasting triglyceride, blood pressure and cigarette smoking. It is concluded that while corneal arcus is primarily an age-related change, its formation is accelerated by high serum LDL-cholesterol so that in people under 50 years it is a marker for the condition.