Robert P. Nugent

The Relationship between Serum Human Immunodeficiency Virus Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in HIV-1—Infected Children

Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was >100,000 copies/mL (95% confidence interval [CI], 1.4-3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2-4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3-2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6-4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log 10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1-3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% Cl, 1.2-1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.

Efficacy of Zidovudine and Human Immunodeficiency Virus (HIV) Hyperimmune Immunoglobulin for Reducing Perinatal HIV Transmission from HIV-Infected Women with Advanced Disease: Results of Pediatric AIDS Clinical Trials Group Protocol 185

Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether zidovudine combined with human immunodeficiency virus (HIV) hyperimmune immunoglobulin (HIVIG) infusions administered monthly during pregnancy and to the neonate at birth would significantly lower perinatal HIV transmission compared with treatment with zidovudine and intravenous immunoglobulin (IVIG) without HIV antibody. Subjects had baseline CD4 cell counts </=500/microL (22% had counts <200/microL) and required zidovudine for maternal health (24% received zidovudine before pregnancy). Transmission was associated with lower maternal baseline CD4 cell count (odds ratio, 1.58 per 100-cell decrement; P=.005; 10.0% vs. 3.6% transmission for count <200 vs. >/=200/microL) but not with time of zidovudine initiation (5.6% vs. 4.8% if started before vs. during pregnancy; P=. 75). The Kaplan-Meier transmission rate for HIVIG recipients was 4. 1% (95% confidence interval, 1.5%-6.7%) and for IVIG recipients was 6.0% (2.8%-9.1%) (P=.36). The unexpectedly low transmission confirmed that zidovudine prophylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine therapy, although it limited the studys ability to address whether passive immunization diminishes perinatal transmission.

Encephalopathy and progression of human immunodeficiency virus disease in a cohort of children with perinatally acquired human immunodeficiency virus infection

OBJECTIVE To describe the incidence, predictors, and survival of children with human immunodeficiency virus (HIV) encephalopathy followed in the Women and Infants Transmission Study cohort. STUDY DESIGN Retrospective review of clinical and immunologic staging of perinatally HIV-infected infants, based on the 1994 Centers for Disease Control and Prevention Classification System. RESULTS Data were available for 128 HIV-infected children, with a median follow-up of 24 months. HIV encephalopathy was diagnosed in 27 (21%) of children. Median survival after diagnosis was 14 months. Of children with encephalopathy, 74% had at least moderate immunosuppression by the time of diagnosis. Encephalopathy represented the first acquired immunodeficiency syndrome-defining condition in 67%, and the only one in 26% of children. Hepatosplenomegaly or lymphadenopathy during the first 3 months of life was diagnosed in 63%, in contrast to 29% of those without encephalopathy (p value = 0.001). Cardiomyopathy was present in 30% of the children with encephalopathy versus 2% of those without encephalopathy. High viral load in infancy was associated with increased risk of encephalopathy but was not predictive of age at onset. CONCLUSIONS Encephalopathy in children with HIV is common and is associated with high viral load, immunodeficiency, and shortened survival. Encephalopathy was more likely to develop in infants with early signs and symptoms of HIV, although age at onset could not be predicted.

Outcome of the vaginal infections and prematurity study: Results of a clinical trial of erythromycin among pregnant women colonized with group B streptococci☆

OBJECTIVE Our purpose was to determine whether erythromycin treatment of pregnant women colonized with group B streptococci would reduce the occurrence of low birth weight (< 2500 gm) and preterm (< 37 completed weeks) birth. STUDY DESIGN In a double-blind clinical trial, 938 carriers of group B streptococci were randomized to receive erythromycin base (333 mg three times a day) or matching placebo beginning during the third trimester and before 30 weeks and continuing for 10 weeks or until 35 weeks 6 days of pregnancy. RESULTS Pregnancy outcomes were available for 97% of randomized women; 14% of subjects withdrew from the trial. Birth weight < 2500 gm occurred in 8.6% of the erythromycin and 6.1% of the placebo recipients (relative risk 1.4, 0.9 to 2.2, p = 0.16). Preterm delivery occurred in 11.4% of women randomized to erythromycin and in 12.3% randomized to placebo (relative risk 0.9, 95% confidence limits 0.6 to 1.3, p = 0.65). Greater benefit of erythromycin in reducing these outcomes was not observed among women reporting the best compliance. CONCLUSIONS In this study of pregnant women colonized with group B streptococci treatment with erythromycin was not shown to be effective at prolonging gestation or reducing low birth weight. Greater than anticipated complicating factors, including spontaneous clearance of the organism, use of nontrial antibiotics, and density of colonization, may have resulted in population sizes too small to detect a benefit of treatment. Future studies should take these factors into account in determining sample sizes.

Changes in CD4+ and CD8+ cell levels during pregnancy and post partum in women seropositive and seronegative for human immunodeficiency virus-1 ☆ ☆☆ ★ ★★

OBJECTIVE Our objective was to examine changes in CD4+ and CD8+ cell levels during pregnancy and post partum and to determine whether they differ for human immunodeficiency virus-1-seropositive and seronegative women. STUDY DESIGN A total of 192 human immunodeficiency virus-1-seropositive and 148 seronegative women enrolled in a study of mother-to-child transmission of human immunodeficiency virus-1 who had at least two lymphocyte subset measurements performed during pregnancy or post partum were included in this analysis. Mixed effects repeated-measures models were developed to examine changes in CD4+ and CD8+ cell levels during this period. RESULTS Consistent with prior reports that CD4+ cell levels decline during pregnancy and return to normal post partum, percent levels increased between the third trimester and 12 months post partum among human immunodeficiency virus-seronegative women (1.98%, p = 0.04). However, CD4+ levels declined steadily during pregnancy and post partum among seropositive women (-1.57%, p = 0.02 between the third trimester and 12 months post partum; =2.65%, p = 0.0004 between 2 and 24 months post partum). The percent CD8+ cell levels increased at or near delivery and declined to baseline between 2 and 6 months post partum in both seronegative and seropositive women, although only the declines were statistically significant in both groups (-2.66%, p = 0.004; and -2.02%, p = 0.02, respectively). CONCLUSIONS The percent CD4+ cell levels declined steadily during pregnancy and post partum among human immunodeficiency virus-seropositive women, indicating that human immunodeficiency virus disease continues to progress during this period. The percent CD8+ cell levels increased at or near delivery and declined to baseline post partum in both seronegative and seropositive women. These findings may have important clinical implications for both human immunodeficiency virus-infected and uninfected pregnant women.

Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20 x 10(9)/L or more. Effect on viral, opportunistic, and bacterial infections. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group

OBJECTIVE To evaluate the efficacy of intravenous immunoglobulin (IVIG) for prevention of viral, opportunistic, and minor bacterial infections in children infected with human immunodeficiency virus (HIV). DESIGN Randomized, double-blind, placebo-controlled, outpatient clinical trial comparing subjects treated with 400 mg of IVIG per kilogram of body weight every 28 days with those given albumin placebo. SETTING Twenty-eight clinical centers in mainland United States and Puerto Rico. PATIENTS Three hundred seventy-six children infected with human immunodeficiency virus with clinical or immunologic evidence of HIV disease, 313 of whom had entry CD4+ counts of at least 0.20 x 10(9)/L (greater than or equal to 200/mm3). MAIN OUTCOME MEASURES The incidence of laboratory-proven and clinically diagnosed viral, opportunistic, and bacterial infections. MAIN RESULTS Viral infections and minor bacterial infections contributed more frequently to morbidity in children with entry CD4+ counts of at least 0.20 x 10(9)/L (together over five times as frequent) than did serious bacterial infection, the primary outcome measure of the trial. Opportunistic infections occurred at a similar rate as laboratory-proven serious bacterial infections. In this group of children, IVIG was significantly associated with a decrease in the rate of viral infections and minor bacterial infections per 100 patient-years (36.0 vs 54.0 episodes of viral infection per 100 patient-years, IVIG vs placebo, P = .01; and 115.1 vs 159.7 episodes of minor bacterial infection per 100 patient-years, IVIG vs placebo, P = .02), as well as a decrease in the rate of serious bacterial infections per 100 patient-years (26.4 vs 48.2 episodes per 100 patient-years; P = .002). There was no apparent difference in the rate of opportunistic infections between treatment arms. CONCLUSIONS Beneficial effect of IVIG was seen across multiple infectious outcome measures, with reductions in serious and minor viral and bacterial infections observed in children with entry CD4+ counts of at least 0.20 x 10(9)/L.

Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings

Cheaper, simpler alternatives to CD4 lymphocyte count and HIV-1 RNA detection for assessing the prognosis of HIV-1 infection are needed for resource-poor settings. However, little is known about the predictive value of alternative assays, in particular in children. We assessed the prognostic value of total lymphocyte count, immune complex-dissociated p24 antigen, white blood cell count, packed-cell volume (haematocrit), and serum albumin for mortality in 376 HIV-1-infected, mainly African-American or Hispanic children enrolled during March, 1988 to January, 1991. In a Cox proportional hazards model, including all assay-alternatives to CD4 and RNA, total lymphocyte count (p<0.0001) and serum albumin (p=0.0107) independently predicted mortality. Further assessment of these markers is warranted in resource-poor settings.

Serum HIV-1 p24 antibody, HIV-1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1-infected children

OBJECTIVE The role of HIV-1 antibody in modulating disease progression must be assessed in the context of other immune and viral load markers. We evaluated the association between HIV-1 p24 antibody, HIV-1 RNA, immune complex-dissociated (ICD) p24 antigen, CD4 cell percentage, and mortality in a cohort of 218 HIV-infected children enrolled in a trial of intravenous immunoglobulin prophylaxis of bacterial infections. METHODS CD4 cell percentage was measured and sera collected and stored at baseline and every 3 months on study (1988-1991). Stored sera were assayed for HIV-1 p24 antibody, HIV-1 RNA, and ICD p24 antigen. Mortality was recorded during the trial and updated through 1996 (mean total follow-up, 6.3 years). RESULTS Eighty-one (37%) children died; probability of mortality for children with baseline HIV-1 p24 antibody concentrations of undetectable (< 1), 1-4, 5-124, and > or = 125 reciprocal titer units (RTU) was 61, 50, 24, and 10%, respectively. A 3.5-fold increase in the relative risk (RR) of death [95% confidence interval (CI), 2.2-5.5] was observed among children with baseline HIV-1 p24 antibody concentration < 5 RTU compared with > or = 5 RTU. In multivariate analyses, p24 antibody, HIV-1 RNA, and CD4 cell percentage but not ICD p24 antigen were independently associated with mortality; the RR of death increased by 1.7 (95% CI, 1.3-2.1) for each log10 decrement in baseline HIV-1 p24 antibody. CONCLUSIONS HIV-1 p24 antibody, HIV-1 RNA and CD4 cell percentage independently predict mortality amongst infected children. Whereas CD4 cell percentage provides an estimate of the general degree of immune suppression, HIV-1 p24 antibody could provide an easily obtained, inexpensive assessment of CD4 cell function and could augment prognostic information provided by CD4 cell count and viral load for clinical management of infected children.

Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virus-infected children

&NA; After completion of a placebo‐controlled trial of intravenous immunoglobulin (IVIG) infection prophylaxis, patients were offered open label IVIG and optional participation in a follow‐up study. The purpose of the follow‐up study was to evaluate the IVIG effect in original placebo recipients and longevity of IVIG benefit in original IVIG recipients. Of 212 human immunodeficiency virus‐infected children on study at trial closure, 148 (67 of 98 (68%) placebo and 81 of 114 (71%) IVIG patients) received open label IVIG for a mean of 16 months. When open label IVIG was begun, 45% were receiving trimethoprim‐sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia (43% of placebo and 47% of IVIG patients) and 54% were receiving zidovudine (55% of placebo and 53% of IVIG patients). In patients who received placebo during the original study, the rate of serious bacterial infections was significantly lower after change to open label IVIG (estimated 15.8 fewer episodes/100 patient years; 95% confidence interval, 3.2 to 28.5; P = 0.014). Similar findings were observed for minor bacterial infections (estimated 61.2 fewer/100 patient years; 95% confidence interval, 29.2 to 93.3; P < 0.001) and hospitalizations (estimated 43.7 fewer/100 patient years; 95% confidence interval, 27.7 to 59.6; P < 0.001). Decreases were observed whether or not trimethoprim‐sulfamethoxazole prophylaxis was being given at the time open label IVIG was begun. In patients who received IVIG during the original study, no significant difference was seen in infections or hospitalizations after change to open label IVIG. These results confirm IVIG effectiveness for reduction of bacterial infections and hospitalizations in human immunodeficiency virus‐infected children and indicate that benefit is maintained for at least 3 years. In this patient cohort decrease in infections and hospitalizations with IVIG was independent of trimethoprim‐sulfamethoxazole P. carinii pneumonia prophylaxis.

Double-Blind Placebo-Controlled Treatment Trial of Chlamydia trachomatis Endocervical Infections in Pregnant Women.

Objective: The purpose of this study was to determine if treatment of pregnant women with Chlamydia trachomatis infection would lower the incidence of preterm delivery and/or low birth weight. Methods: Pregnant women between the 23rd and 29th weeks of gestation were randomized in double-blind fashion to receive either erythromycin 333 mg three times daily or an identical placebo. The trial continued until the end of the 35th week of gestation. Results: When the results were examined without regard to study site, erythromycin had little impact on reducing low birth weight (8% vs. 11%, P = 0.4) or preterm delivery (13% vs. 15%, P = 0.7). At the sites with high persistence of C. trachomatis in the placebo-treated women, low birth weight infants occurred in 9 (8%) of 114 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.04) and delivery <37 weeks occurred in 15 (13%) of 115 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.4). Conclusions: The results of this trial suggest that the risk of low birth weight can be decreased by giving erythromycin to some women with C. trachomatis. Due to the high clearance rate of C. trachomatis in the placebo group, these data do not provide unequivocal evidence that erythromycin use in all C. trachomatis-infected women prevents low birth weight.