Annelies Van Rie

Duration of immunity against pertussis after natural infection or vaccination.

Despite decades of high vaccination coverage, pertussis has remained endemic and reemerged as a public health problem in many countries in the past 2 decades. Waning of vaccine-induced immunity has been cited as one of the reasons for the observed epidemiologic trend. A review of the published data on duration of immunity reveals estimates that infection-acquired immunity against pertussis disease wanes after 4–20 years and protective immunity after vaccination wanes after 4–12 years. Further research into the rate of waning of vaccine-acquired immunity will help determine the optimal timing and frequency of booster immunizations and their role in pertussis control.

Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study

Objective:To determine the incidence, clinical manifestations, risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. Design:Prospective surveillance cohort and nested case–control study in a large, University hospital-based antiretroviral therapy (ART) clinic. Methods:A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case–control study with controls matched to IRIS cases on ART duration. Results:During the first 6 months of ART, 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44, 41%), abscess formation and suppurative folliculitis (8/44, 18.2%), varicella zoster (6/44, 13.6%), herpes simplex (4/44, 9.1%), cryptococcal meningitis (3/44, 6.8%), molluscum contagiosum (3/44, 6.8%), and Kaposis sarcoma (2/44, 4.5%). Median IRIS onset was 48 days (interquartile range, 29–99) from ART initiation. In comparison with controls, IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/μl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/μl; P = 0.05), but similar virological and immunological response to ART. In multivariable analyses, higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/μl increase). Most IRIS cases were mild, with ART discontinued in three (6.8%) patients, corticosteroids administered to four (9.1%) patients, and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. Conclusions:IRIS may affect 10% of patients initiating ART in Africa, particularly those with advanced immunosuppression, but severe, life-threatening IRIS is uncommon.

Immune reconstitution inflammatory syndrome (IRIS): Review of common infectious manifestations and treatment options

The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients initiating antiretroviral therapy (ART) results from restored immunity to specific infectious or non-infectious antigens. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden. The infectious pathogens most frequently implicated in the syndrome are mycobacteria, varicella zoster, herpesviruses, and cytomegalovirus (CMV). No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Prospective cohort studies addressing the optimal screening and treatment of opportunistic infections in patients eligible for ART are currently being conducted. These studies will provide evidence for the development of treatment guidelines in order to reduce the burden of IRIS. We review the available literature on the pathogenesis and epidemiology of IRIS, and present treatment options for the more common infectious manifestations of this diverse syndrome and for manifestations associated with a high morbidity.

Xpert(®) MTB/RIF for point-of-care diagnosis of TB in high-HIV burden, resource-limited countries: hype or hope?

Despite the identification of Mycobacterium tuberculosis as the cause of tuberculosis (TB) more than a century ago, diagnosing TB in resource-poor countries remains a challenge, especially in people living with HIV. In the past decade, important research investments have been made towards the development of new diagnostics for TB and the Xpert® MTB/RIF assay (Cepheid, CA, USA) has emerged as one of the most promising. In this article, we review the current knowledge on Xpert MTB/RIF, discuss the potential value of Xpert MTB/RIF as a point-of-care diagnostic for drug-sensitive and drug-resistant TB, and outline the potential indications for the assay in resource-limited, high-HIV burden settings. We also discuss key research questions that need to be addressed prior to possible large-scale implementation of the assay.

Is HIV Infection a Risk Factor for Multi-Drug Resistant Tuberculosis? A Systematic Review

Background Tuberculosis (TB) is an important cause of human suffering and death. Human immunodeficiency virus (HIV), multi-drug resistant TB (MDR-TB), and extensive drug resistant tuberculosis (XDR-TB) have emerged as threats to TB control. The association between MDR-TB and HIV infection has not yet been fully investigated. We conducted a systematic review and meta-analysis to summarize the evidence on the association between HIV infection and MDR-TB. Methods and Results Original studies providing Mycobacterium tuberculosis resistance data stratified by HIV status were identified using MEDLINE and ISI Web of Science. Crude MDR-TB prevalence ratios were calculated and analyzed by type of TB (primary or acquired), region and study period. Heterogeneity across studies was assessed, and pooled prevalence ratios were generated if appropriate. No clear association was found between MDR-TB and HIV infection across time and geographic locations. MDR-TB prevalence ratios in the 32 eligible studies, comparing MDR-TB prevalence by HIV status, ranged from 0.21 to 41.45. Assessment by geographical region or study period did not reveal noticeable patterns. The summary prevalence ratios for acquired and primary MDR-TB were 1.17 (95% CI 0.86, 1.6) and 2.72 (95% CI 2.03, 3.66), respectively. Studies eligible for review were few considering the size of the epidemics. Most studies were not adjusted for confounders and the heterogeneity across studies precluded the calculation of a meaningful overall summary measure. Conclusions We could not demonstrate an overall association between MDR-TB and HIV or acquired MDR-TB and HIV, but our results suggest that HIV infection is associated with primary MDR-TB. Future well-designed studies and surveillance in all regions of the world are needed to better clarify the relationship between HIV infection and MDR-TB.

Impact of the HIV/AIDS epidemic on the neurodevelopment of preschool-aged children in Kinshasa, democratic Republic of the Congo

OBJECTIVES. Pediatric HIV infection is a growing problem in most regions of the world. Data on the effects of HIV on the neurodevelopment of children in resource-poor settings are scarce but necessary to guide interventions. The purpose of this study was to compare the neurodevelopment of preschool-aged HIV-infected, HIV-affected (HIV-uninfected AIDS orphans and HIV-uninfected children whose mother had symptomatic AIDS), and healthy control children in Kinshasa, Democratic Republic of Congo. METHODS. Thirty-five HIV-infected, 35 HIV-affected, and 90 control children aged 18 to 72 months were assessed by using the Bayley Scales of Infant Development II, Peabody Developmental Motor Scales, Snijders-Oomen Nonverbal Intelligence Test, and Rossetti Infant-Toddler Language Scale, as appropriate for age. RESULTS. Overall, 60% of HIV-infected children had severe delay in cognitive function, 29% had severe delay in motor skills, 85% had delays in language expression, and 77% had delays in language comprehension, all significantly higher rates as compared with control children. Young HIV-infected children (aged 18–29 months) performed worse, with 91% and 82% demonstrating severe mental and motor delay, respectively, compared with 46% and 4% in older HIV-infected children (aged 30–72 months). HIV-affected children had significantly more motor and language expression delay than control children. CONCLUSIONS. The impact of the HIV pandemic on childrens neurodevelopment extends beyond the direct effect of the HIV virus on the central nervous system. AIDS orphans and HIV-negative children whose mothers had AIDS demonstrated significant delays in their neurodevelopment, although to a lesser degree and in fewer developmental domains than HIV-infected children. Young HIV-infected children were the most severely afflicted group, indicating the need for early interventions. Older children performed better as a result of a “survival effect,” with only those children with less aggressive disease surviving.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Neurodevelopment in perinatally HIV-infected children: a concern for adolescence

Globally, an estimated 3.4 million children are living with HIV, yet little is known about the effects of HIV and antiretroviral treatment (ART) on the developing brain, and the neurodevelopmental and behavioural outcomes of perinatally HIV‐infected (PHIV+) adolescents.

The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study

This observational cohort study by Andrew Edmonds and colleagues reports that treatment with highly active antiretroviral therapy (HAART) markedly improves the survival of HIV-infected children in Kinshasa, DRC, a resource-deprived setting.

Patient retention from HIV diagnosis through one year on antiretroviral therapy at a primary health care clinic in Johannesburg, South Africa.

Objective:To compare patient retention at 3 stages of pre-antiretroviral (ART) care and 2 stages of post-ART care to identify when greatest attrition occurs. Design:An observational cohort study. Methods:We reviewed files of all adult nonpregnant individuals testing HIV-positive January 1–June 30, 2010, at a primary health clinic in Johannesburg, South Africa (N = 842). We classified retention in pre-ART stage 1 (HIV diagnosis to CD4 results notification in ⩽3 months), pre-ART stage 2 (initially ineligible for ART with repeat CD4 test ⩽1 year of prior CD4), pre-ART stage 3 (initiating ART ⩽3 months after first eligible CD4 result), and at 0–6 and 6–12 months post-ART. Results:Retention among all patients during pre-ART stage 1 was 69.8% [95% confidence interval (CI): 66.7% to 72.9%]. For patients initially ART ineligible (n = 221), 57.4% (95% CI: 49.5% to 65.0%) returned for a repeat CD4 during pre-ART stage 2. Among those who were ART eligible (n = 589), 73.5% (95% CI: 69.0% to 77.6%) were retained during pre-ART stage 3. Retention increased with time on ART, from 80.2% (95% CI: 75.3% to 84.5%) at 6 months to 95.3% (95% CI: 91.7% to 97.6%) between 6 and 12 months. Cumulative retention from diagnosis to 12 months on ART was 36.9% (95% CI: 33.0% to 41.1%) for those ART eligible and 43.0% (95% CI: 36.4% to 49.8%) from diagnosis to repeat CD4 testing within one year among those ART ineligible. Conclusions:Patient attrition in the first year after HIV diagnosis was greatest before ART initiation: more than 25% at each of 3 pre-ART stages. As countries expand HIV testing and ART programs, success will depend on linkage to care, especially before ART eligibility and initiation.