Andrew P. Steenhoff

Emergence of Vaccine-Related Pneumococcal Serotypes as a Cause of Bacteremia

BACKGROUND The heptavalent pneumococcal conjugate vaccine (PCV7) has decreased the incidence of invasive pneumococcal disease among children in the United States. In the postlicensure period, the impact of non-PCV7 serotypes against pediatric pneumococcal bacteremia is unknown. METHODS Episodes of bacteremia due to Streptococcus pneumoniae and other respiratory pathogens (ORP), namely Neisseria meningitidis, Haemophilus influenzae, and Moraxella catarrhalis, were identified in children <18 years old at the Childrens Hospital of Philadelphia from January 1999 to May 2005. For pneumococci, serotype distribution and antibiotic resistance were compared. RESULTS A total of 188 episodes of pneumococcal bacteremia and 55 episodes of ORP bacteremia were identified. By comparing data from 1999-2000 with data from 2001 to May 2005, we found that the incidence of pneumococcal bacteremia decreased by 57%. The incidence of bacteremia caused by ORPs was unchanged; 1.43 episodes (95% confidence interval [CI], 0.84-2.29 episodes) to 1.25 (95% CI, 0.88-1.71) per 10,000 emergency department visits. Vaccine serotypes caused 85% of episodes of bacteremia in 1999-2000, compared with 34% of episodes of bacteremia in 2001 to May 2005 (P<.01). The percentage of isolates nonsusceptible to penicillin increased from 25% to 39% (P<.05). The percentage of episodes of pneumococcal bacteremia caused by vaccine-related serotypes--those of the same serogroup but not of the same serotype as PCV7--increased from 6% of episodes in the prelicensure period to 35% of episodes in the postlicensure period (P<.01). Rates of serotype pneumococcal bacteremia caused by nonvaccine serotypes were not statistically different between the 2 periods. CONCLUSIONS The overall incidence of pneumococcal bacteremia decreased by 57% after the introduction of PCV7. During the postlicensure period, there were significant decreases in the incidence of pneumococcal bacteremia caused by vaccine serotypes; however, rates of penicillin resistance and bacteremia due to vaccine-related serotypes increased.

The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally acquired HIV.

Objective:To explore the association between previous severe HIV disease, defined as past Centers for Disease Control and Prevention class C diagnosis, and neurocognitive and psychiatric outcomes in long-term survivors of perinatally acquired HIV. Design:A retrospective cohort study of perinatally HIV-infected adolescents receiving outpatient care at a single site. Methods:Comparisons were made between those with and without class C diagnoses. Results:Eighty-one patients formed the study group, 47% were females and 72% were African–American. Median patient age was 15 years (interquartile range 13–17). Of the study group, 47% had a past class C diagnosis. The median age at class C diagnosis was 3.1 years (interquartile range 0.9–8.1). There were no significant differences between the groups with respect to most recent CD4+ cell percentage or plasma viral RNA level. Class C patients were more likely to have a history of psychiatric diagnosis [odds ratio 2.6; 95% confidence interval (CI) 1.1–6.3], psychiatric hospitalization (odds ratio 4.8; 95% CI 1.2–17.4), or learning disability (odds ratio 4.5; 95% CI 1.7–11.4). There was a significant difference in full-scale intelligence quotient between the groups (adjusted linear regression coefficient −11.7; 95% CI −17.9 to 5.5). After adjusting for age at antiretroviral therapy initiation, the associations between class C diagnosis and lower full-scale intelligence quotient, learning disorders, and psychiatric diagnoses remained significant. Conclusion:A distant history of AIDS diagnosis was associated with an increased risk of neurocognitive and psychiatric impairment in adolescents with perinatally acquired HIV. Further research should help delineate if early treatment, possibly soon after birth and definitely prior to AIDS diagnosis, might lead to improved outcomes.

Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study

BackgroundThe primary objective of this study was to determine the prevalence of neurocognitive impairment among HIV-positive individuals in Botswana, using the International HIV Dementia Scale (IHDS). We also compared performance on the IHDS with performance on tests of verbal learning/memory and processing speed, and investigated the association between performance on the IHDS and such variables as depression, age, level of education and CD4 count.MethodsWe conducted a cross-sectional study of 120 HIV-positive individuals randomly selected from an outpatient HIV clinic in Gaborone, Botswana. Patients provided a detailed clinical history and underwent neuropsychological testing; measures of depression, daily activities and subjective cognitive complaints were recorded.ResultsDespite the fact that 97.5% of subjects were receiving highly active antiretroviral therapy (HAART), 38% met criteria for dementia on the IHDS, and 24% were diagnosed with major depressive disorder. There was a significant association between neurocognitive impairment as measured by the IHDS and performance on the other two cognitive measures of verbal learning/memory and processing speed. Level of education significantly affected performance on all three cognitive measures, and age affected processing speed and performance on the IHDS. Depression and current CD4 count did not affect performance on any of the cognitive measures.ConclusionsThe prevalence of neurocognitive impairment in HIV-positive individuals in Botswana is higher than expected, especially since almost all of the subjects in this study were prescribed HAART. This suggests the need to reconsider the timing of introduction of antiretroviral therapy in developing countries where HAART is generally not administered until the CD4 cell count has dropped to 200/mm3 or below. The contribution of other factors should also be considered, such as poor central nervous system penetration of some antiretrovirals, drug resistance, potential neurotoxicity, and co-morbidities. Memory impairment and poor judgment may be underlying causes for behaviours that contribute to the spread of HIV and to poor adherence. It is important to identify these neurobehavioural complications of HIV so that effective treatments can be developed.

Early Versus Delayed Antiretroviral Therapy and Cerebrospinal Fluid Fungal Clearance in Adults With HIV and Cryptococcal Meningitis

BACKGROUND The burden of Cryptococcus neoformans in cerebrospinal fluid (CSF) predicts clinical outcomes in human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) and is lower in patients on antiretroviral therapy (ART). This study tested the hypothesis that initiation of ART during initial treatment of HIV/CM would improve CSF clearance of C. neoformans. METHODS A randomized treatment-strategy trial was conducted in Botswana. HIV-infected, ART-naive adults aged≥21 years initiating amphotericin B treatment for CM were randomized to ART initiation within 7 (intervention) vs after 28 days (control) of randomization, and the primary outcome of the rate of CSF clearance of C. neoformans over the subsequent 4 weeks was compared. Adverse events, including CM immune reconstitution inflammatory syndrome (CM-IRIS), and immunologic and virologic responses were compared over 24 weeks. RESULTS Among 27 subjects enrolled (13 intervention and 14 control), [corrected] the median times to ART initiation were 7 (interquartile range [IQR], 5–10) and 32days (IQR, 28–36), respectively. The estimated rate of CSF clearance did not differ significantly by treatment strategy (-0.32 log10 colony-forming units [CFU]/mL/day±0.20 intervention and -0.52 log10 CFUs/mL/day (±0.48) control, P=.4). Two of 13 (15%) and 5 of 14 (36%) subjects died in the intervention and control arms, respectively (P=0.39). Seven of 13 subjects (54%) in the intervention arm vs 0 of 14 in the control arm experienced CM-IRIS (P=.002). CONCLUSIONS Early ART was not associated with improved CSF fungal clearance, but resulted in a high risk of CM-IRIS. Further research on optimal incorporation of ART into CM care is needed. CLINICAL TRIALS REGISTRATION NCT00976040.

A Cross-Sectional Study of HPV Vaccine Acceptability in Gaborone, Botswana

Background Cervical cancer is the most common cancer among women in Botswana and elsewhere in Sub-Saharan Africa. We sought to examine whether HPV vaccine is acceptable among parents in Botswana, which recently licensed the vaccine to prevent cervical cancer. Methods and Findings We conducted a cross-sectional survey in 2009, around the time the vaccine was first licensed, with adults recruited in general medicine and HIV clinics in Gaborone, the capital of Botswana. Although only 9% (32/376) of respondents had heard of HPV vaccine prior to the survey, 88% (329/376) said they definitely will have their adolescent daughters receive HPV vaccine. Most respondents would get the vaccine for their daughters at a public or community clinic (42%) or a gynecology or obstetricians office (39%), and 74% would get it for a daughter if it were available at her school. Respondents were more likely to say that they definitely will get HPV vaccine for their daughters if they had less education (OR = 0.20, 95% CI = 0.07–0.58) or lived more than 30 kilometers from the capital, Gaborone (OR = 2.29, 95% CI = 1.06–4.93). Other correlates of acceptability were expecting to be involved in the decision to get HPV vaccine, thinking the vaccine would be hard to obtain, and perceiving greater severity of HPV-related diseases. Conclusions HPV vaccination of adolescent girls would be highly acceptable if the vaccine became widely available to the daughters of healthcare seeking parents in Gaborone, Botswana. Potential HPV vaccination campaigns should provide more information about HPV and the vaccine as well as work to minimize barriers.

Primary Varicella and Herpes Zoster Among HIV-Infected Children From 1989 to 2006

OBJECTIVES. The primary objective of this study was to determine the incidence of herpes zoster in perinatally HIV-infected children. Secondary objectives included assessing the impact of highly active antiretroviral therapy and varicella zoster virus immunization on primary varicella and herpes zoster incidence and identifying risk factors for herpes zoster. We hypothesized that the incidence of herpes zoster has decreased in this population as a result of highly active antiretroviral therapy and routine varicella zoster virus immunization. PATIENTS AND METHODS. This retrospective cohort study included HIV-infected children at a pediatric HIV clinic from 1989 to 2006. Incidence rates for 3 intervals (1989–1996, 1997–1999, and 2000–2006) were compared on the basis of introduction of highly active antiretroviral therapy (1996) and varicella zoster virus vaccination (1999). A Cox proportional-hazards regression model was developed for the time to herpes zoster among the subset of patients with primary varicella infection. RESULTS. In 356 patients followed for 1721 person-years, the incidence of herpes zoster according to period was 30.0 per 1000 person-years in 1989–1996, 31.9 per 1000 person-years in 1997–1999, and 6.5 per 1000 person-years in 2000–2006. There was no difference in incidence-rate ratio between 1989–1996 and 1997–1999. However, there was a significant difference in herpes zoster incidence when comparing 1989–1999 with 2000–2006. The incidence of primary varicella zoster virus infection and herpes zoster in the 57 patients who received the varicella zoster virus vaccine was 22.3 per 1000 and 4.5 per 1000 person-years, respectively. Highly active antiretroviral therapy at the time of primary varicella zoster virus infection was protective against herpes zoster and increased herpes zoster-free survival. CONCLUSIONS. The incidence of herpes zoster has decreased since 1989. The decline occurred after 2000, likely representing the combined effect of immunization and highly active antiretroviral therapy. The use of highly active antiretroviral therapy at the time of primary varicella zoster virus infection decreased the risk of herpes zoster and increased herpes zoster-free survival. Varicella zoster virus immunization was effective in preventing both primary varicella zoster virus and herpes zoster in this cohort.

Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study

BACKGROUND Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation. METHODS We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls. FINDINGS Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNFα (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006). INTERPRETATION Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis. FUNDING National Institutes of Health and the Penn Center for AIDS Research.

Depression among HIV-positive individuals in Botswana: a behavioral surveillance.

This study examined incidence of depression in HIV-positive individuals in Botswana. One hundred and twenty HIV-positive individuals were administered a measure of daily activities and two measures of depression. Twenty four to 38% were diagnosed with depression, suicidal ideation ranged from 9 to 12%, with a positive correlation between scores on the two depression measures. Depression was associated with greater impairment in activities of daily living, especially the ability to take medication. These instruments can diagnose depression in persons living with HIV in developing countries, which will help to target those at risk for poor adherence, and will enable better allocation of limited resources.

In-hospital mortality of HIV-infected cryptococcal meningitis patients with C. gattii and C. neoformans infection in Gaborone, Botswana

The clinical presentations and outcomes of cryptococcal meningitis (CM) may be associated with the cryptococcal species causing the infections. To evaluate clinical differences between CM caused by C. neoformans and Cryptococcus gattii, we examined outcomes in HIV-infected adults with CM admitted to Princess Marina Hospital in Gaborone, Botswana. Among HIV-infected adults with CM, we found that 29 of 96 (30%) patients were infected with C. gattii, but species type was not associated with in-hospital mortality [mortality for C. gattii: 5 of 29 (17%) vs C. neoformans: 13 of 67 (19%); OR = 0.87 (95% CI 0.28 to 2.70)]. The proportion of C. gattii infection among this HIV-infected cohort in Botswana is the highest reported to date, but we found no difference between C. gattii and C. neoformans in clinical presentation or in-hospital mortality.

Association Between Efavirenz-Based Compared With Nevirapine-Based Antiretroviral Regimens and Virological Failure in HIV-Infected Children

IMPORTANCE Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited. OBJECTIVE To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. MAIN OUTCOMES AND MEASURES The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis. RESULTS With a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses. CONCLUSIONS AND RELEVANCE Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.