Missed opportunities for diagnosis and treatment in patients with TB symptoms: a systematic review.

BACKGROUND: The identification of patients with symptoms is the foundation of facility-based TB screening and diagnosis, but underdiagnosis is common. We conducted this systematic review with the hypothesis that underdiagnosis is largely secondary to patient drop out along the diagnostic and care pathway. METHODS: We searched (up to 22 January 2019) MEDLINE, Embase, and Cinahl for studies investigating patient pathway to TB diagnosis and care at health facilities. We used Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias. We reported proportions of patients with symptoms at each stage of the pathway from symptom screening to treatment initiation. RESULTS: After screening 3,558 abstracts, we identified 16 eligible studies. None provided data addressing the full cascade of care from clinical presentation to treatment initiation in the same patient population. Symptom screening, the critical entry point for diagnosis of TB, was not done for 33-96% of participants with symptoms in the three studies that reported this outcome. The proportion of attendees with symptoms offered a diagnostic investigation (data available for 15 studies) was very low with a study level median of 38% (IQR 14-44, range 4-84). CONCLUSIONS: Inefficiencies of the TB symptom screen-based patient pathway are a major contributor to underdiagnosis of TB, reflecting inconsistent implementation of guidelines to ask all patients attending health facilities about respiratory symptoms and to offer diagnostic tests to all patients promptly once TB symptoms are identified. Better screening tools and interventions to improve the efficiency of TB screening and diagnosis pathways in health facilities are urgently needed.

CONTEXTE: L'identification des patients symptomatiques est à la base du dépistage et du diagnostic de la TB en centres de soins, mais les sous-diagnostics sont fréquents. Nous avons réalisé cette revue systématique en émettant l'hypothèse que le sous-diagnostic était bien moins important que la perte de vue des patients tout au long du parcours diagnostique et thérapeutique. MÉTHODES: Nous avons interrogé les bases de données MEDLINE, Embase et Cinahl (jusqu'au 22 janvier 2019) pour identifier les études ayant évalué le parcours diagnostique et thérapeutique des patients atteints de TB en centres de soins. Nous avons utilisé le QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) afin d'évaluer le risque de biais. Nous avons rapporté les proportions de patients présentant des symptômes à chaque stade du parcours, du dépistage symptomatique à l'instauration du traitement. RÉSULTATS: Après avoir passé en revue 3 558 résumés, nous avons identifié 16 études éligibles. Aucune ne fournissait, dans une même population de patients, de données sur l'ensemble de la cascade de soins, de la présentation clinique à l'instauration du traitement. Le dépistage symptomatique (point de départ essentiel du diagnostic de la TB) n'avait pas été réalisé pour 33­96% des participants symptomatiques dans les trois études ayant rapporté ce résultat. La proportion de personnes symptomatiques consultant à qui un examen diagnostique a été proposé (données disponibles pour 15 études) était très faible, avec une médiane de 38% (IQR 14­44 ; écart 4­84). CONCLUSIONS: Le manque d'efficacité du parcours patient fondé sur le dépistage symptomatique de la TB est un facteur contributif majeur du sous-diagnostic de la maladie. Cette inefficacité reflète une mise en œuvre incohérente des recommandations qui stipulent de demander à tous les patients consultant en centres de soins s'ils présentent des symptômes respiratoires et de proposer rapidement des tests diagnostiques à tous les patients une fois les symptômes de TB identifiés. De meilleurs outils et interventions de dépistage permettant d'améliorer l'efficacité du parcours de dépistage et de diagnostic de la TB en centres de soins sont urgemment nécessaires.

Evaluation of recorded video-observed therapy for anti-tuberculosis treatment.

BACKGROUND: Asynchronous video directly observed therapy (VDOT) may reduce tuberculosis (TB) program costs and the burden on patients. We compared VDOT performance across three cities in the United States, each of which have TB incidence rates above the national average.METHODS: Patients aged ≥18 years who are currently receiving directly observed anti-TB treatment were invited to use VDOT for monitoring treatment. Pre- and post-treatment interviews and medical records were used to assess site differences in treatment adherence and patient characteristics and perceptions.RESULTS: Participants were enrolled in New York City, NY (n = 48), San Diego, CA (n = 52) and San Francisco, CA, USA (n = 49). Overall, the mean age was 41 years (range 18-87); 59% were male; most were Asian (45%) or Hispanic/Latino (30%); and 77% were foreign-born. The median fraction of expected doses observed (FEDO) was 88% (IQR 76-96). At follow-up, 97% thought VDOT was "very or somewhat easy to use" and 95% would recommend VDOT to other TB patients. Age, race/ethnicity, annual income, and country of birth differed by city (P < 0.05), but FEDO and VDOT perceptions did not.CONCLUSIONS: TB programs in three large US cities observed a high FEDO using VDOT while minimizing staff time and travel. Similar findings across sites support VDOT adoption by other large, urban TB programs.

Mycobacterium tuberculosis infection among persons who inject drugs in San Diego, California.

BACKGROUND: Persons who inject drugs (PWID) might be at increased risk for Mycobacterium tuberculosis infection and reactivation of latent tuberculous infection (LTBI) due to their injection drug use. OBJECTIVES: To determine prevalence and correlates of M. tuberculosis infection among PWID in San Diego, California, USA. METHODS: PWID aged 18 years underwent standardized interviews and serologic testing using an interferon-gamma release assay (IGRA) for LTBI and rapid point-of-care assays for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Independent correlates of M. tuberculosis infection were identified using multivariable log-binomial regression. RESULTS: A total of 500 participants met the eligibility criteria. The mean age was 43.2 years (standard deviation 11.6); most subjects were White (52%) or Hispanic (30.8%), and male (75%). Overall, 86.7% reported having ever traveled to Mexico. Prevalence of M. tuberculosis infection was 23.6%; 0.8% were co-infected with HIV and 81.7% were co-infected with HCV. Almost all participants (95%) had been previously tested for M. tuberculosis; 7.6% had been previously told they were infected. M. tuberculosis infection was independently associated with being Hispanic, having longer injection histories, testing HCV-positive, and correctly reporting that people with 'sleeping' TB cannot infect others. CONCLUSIONS: Strategies are needed to increase awareness about and treatment for M. tuberculosis infection among PWID in the US/Mexico border region.

Discordance between CD4 cell count and CD4 cell percentage: implications for when to start antiretroviral therapy in HIV-1 infected children.

OBJECTIVE: Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. DESIGN: Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. METHODS: Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. RESULTS: Among 3345 children, with a total of 21,815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. CONCLUSIONS: More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children.

Role of the laboratory in ensuring global access to ARV treatment for HIV-infected children: consensus statement on the performance of laboratory assays for early infant diagnosis.

A two day meeting hosted by the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) was held in May 2006 in Entebbe, Uganda to review the laboratory performance of virologic molecular methods, particularly the Roche Amplicor DNA PCR version 1.5 assay, in the diagnosis of HIV-1 infection in infants. The meeting was attended by approximately 60 participants from 17 countries. Data on the performance and limitations of the HIV-1 DNA PCR assay from 9 African countries with high-burdens of HIV/AIDS were shared with respect to different settings and HIV- subtypes. A consensus statement on the use of the assay for early infant diagnosis was developed and areas of needed operational research were identified. In addition, consensus was reached on the usefulness of dried blood spot (DBS) specimens in childhood as a means for ensuring greater accessibility to serologic and virologic HIV testing for the paediatric population.

Comparison of human herpesvirus 8 and Epstein-Barr virus seropositivity among children in areas endemic and non-endemic for Kaposi's sarcoma.

Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS). Several studies indicate horizontal HHV-8 transmission among children in areas where KS is endemic, but few studies have assessed acquisition of HHV-8 by children in low seroprevalence areas. Antibody screening was carried out for HHV-8 and Epstein-Barr virus (EBV) on 787 serum specimens from children living in two areas where HHV-8 is not endemic, the United States (US) and Germany, and on 184 specimens from children living in a KS-endemic area (Nigeria). For children in the US and Germany, the results showed low HHV-8 seroprevalence rates (3-4%). However, US children aged 6 months to 5 years had higher HHV-8 antibody titers than did 6-17-year-old children (P < 0.01), a finding consistent with more recent infections being detected in the younger children. Compared with seroprevalence rates and antibody titers in US and German children, those in Nigerian children were significantly higher, and seroprevalence increased with age. There was no evidence of cross-reactivity between assays for HHV-8 and EBV, despite the genetic similarity of these two herpesviruses. The data indicate that HHV-8 transmission among children where HHV-8 is not endemic occurs, but is uncommon. The findings also suggest that HHV-8 antibodies, as measured by current tests, may not persist for long periods in populations at low risk for KS and that vertical transmission is rare, although longitudinal studies are necessary to address directly these issues.

Experience with routine voluntary perinatal human immunodeficiency virus testing in an inner city hospital.

Women enrolled in prenatal care at Grady Health System, Atlanta, GA, have routinely been offered HIV counseling and voluntary testing since 1987. Consistently >90% have accepted testing. With implementation of US Public Health Service guidelines for perinatal zidovudine prophylaxis in 1994, the mother-to-child HIV transmission rate rapidly decreased from 18% to 8% during the subsequent 2 years.

Efficacy of a less-sensitive enzyme immunoassay (3A11-LS) for early diagnosis of human immunodeficiency virus Type 1 infection in infants.

We evaluated a less-sensitive enzyme immunoassay (3A11-LS) for its possible use for early diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in infants. The results were compared with those from the immunoglobulin G-capture enzyme immunoassay. A total of 239 sera from 77 infants were tested. All 25 sera from the 10 infants born to seronegative mothers were found to be negative by both assays. Forty-one seroreverting infants showed a complete decay of maternal antibodies by 4 months by the 3A11-LS assay. However, the assay detected HIV antibodies in only 9 (36%) of 25 sera collected from infected infants between 4 and 6 months and in 27 (63%) of 43 sera collected after 6 months of age. Further analysis with alternative cutoff values indicated that the 3A11-LS had a sensitivity of 12 to 44% and a specificity of 90 to 100% for infants between 4-6 months of age. This data suggest that a diagnosis of HIV infection in some of the infants could be made after 4 months of age by the 3A11-LS assay, although a negative 3A11-LS test result may not rule out infection and may require a further followup.

Antiretroviral resistance mutations among pregnant human immunodeficiency virus type 1-infected women and their newborns in the United States: vertical transmission and clades.

To assess the impact of antiretroviral resistance on perinatal transmission prevention efforts, human immunodeficiency virus type 1 (HIV-1) genotypic resistance testing was done for 220 HIV-1-infected, zidovudine (AZT)-exposed pregnant women and 24 of their infected infants. The women were prospectively enrolled in 4 US cities in 1991-1997. Phylogenetic and sequencing analyses revealed 5 women with non-clade B infections traced to western African origins. AZT-associated mutations were detected in 17.3% of pregnant women, whereas genotypic resistance to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors was infrequent. No significant association was detected between perinatal transmission and the presence of either AZT or nucleoside reverse-transcriptase inhibitor resistance-associated mutations. AZT resistance mutations were detected in 2 (8.3%) neonatal samples, but the mutation pattern was not identical to the mother's. Although no effect of viral resistance on mother-infant transmission was demonstrated, the advent of more-potent drug classes and the potential for the rapid emergence of resistance warrant prospective surveillance.

Mother-to-child discordance in HLA-G exon 2 is associated with a reduced risk of perinatal HIV-1 transmission.

Definitive genetic parameters correlating with mother-to-child transmission (MCT) of HIV have not been fully established. We screened for the potential correlation between HLA-G variants and MCT, in a cohort of mother-child pairs. Discordance in exon 2 of HLA-G was significantly more common among non-transmitting (93%) than transmitting mother-child pairs (40%). Our results suggest that mother-child pairs both carrying the identical mutation in HLA-G exon 2 may be at higher risk of MCT of HIV-1.

Maternal characteristics associated with antenatal, intrapartum, and neonatal zidovudine use in four US cities, 1994-1998.

OBJECTIVES: To evaluate implementation of 1994 United States Public Health Service guidelines for zidovudine (ZDV) use in HIV-infected women and their newborns by describing the prevalence of use of perinatal ZDV and other antiretrovirals and by investigating determinants of not receiving perinatal ZDV. DESIGN/METHODS: The Perinatal AIDS Collaborative Transmission Study is a prospective cohort study designed to collect information related to mother-to-child HIV transmission that was conducted in New York City (NY), Newark (NJ), Baltimore (MD), and Atlanta (GA), U.S.A. The current analysis was restricted to infants born between July 1994 and June 1998. RESULTS: Utilization rates for antenatal, intrapartum, and neonatal ZDV increased from 41% to 70% during the 4-year period. Use of combination antiretrovirals increased from fewer than 2% of women in 1994 to 1995 to 35% in 1997 to 1998. Antenatal and neonatal ZDV use increased each year, but intrapartum ZDV use reached a plateau after 1996. Mother-infant pairs with the following characteristics were less likely to have received a complete 3-part ZDV regimen: older maternal age, CD4 count >500 cells/microl, preterm birth, cocaine or heroin use during pregnancy, positive newborn drug screen test result, and smoking or alcohol use during pregnancy. By multivariate logistic regression adjusted for hospital and year of birth, cocaine or heroin use during pregnancy (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.3), maternal CD4 count (OR, 0.4; 95% CI, 0.2-0.8; comparing <200 with >500 cells/microl), and preterm birth (OR, 1.6; 95% CI, 1.1-2.5) remained independently associated with not receiving the complete ZDV regimen. CONCLUSIONS: ZDV use by pregnant HIV-infected women and their infants has increased dramatically since publication of the 1994 guidelines. Nevertheless, women who abuse substances, give birth preterm, or have less advanced immunosuppression, were at substantial risk of not receiving the complete ZDV regimen.

Preventing vertical HIV transmission in the year 2000: progress and prospects--a review.

In the USA, progress in the ability to eliminate vertical HIV-1 transmission that was unthinkable just a few years ago has been virtually achieved with fewer than 200 new cases of infant HIV infection reported in 1999. Nevertheless, critical research questions as well as public health challenges remain. New infant HIV infections continue to occur among women who did not obtain prenatal care or who were not offered HIV testing during pregnancy and innovative approaches are needed to address these barriers. The CDC-funded Mother-Infant Rapid Intervention At Delivery (MIRIAD) Study in five US metropolitan areas is one such approach that will test the feasibility of offering rapid testing to women presenting late in pregnancy or at delivery with undocumented HIV status. In addition, further research addressing the role of the placenta in preventing or enhancing in utero HIV transmission is needed. Internationally, new clinical trial findings provide hope that a short course of antiretrovirals can substantially reduce vertical HIV-1 transmission in resource-poor settings in the developing world where most paediatric HIV infections occur. Future research will focus on the role of post-perinatal exposure prophylaxis with antiretrovirals administered to the infant and on the prevention of postnatal transmission of HIV-1 through breast milk while maintaining adequate nutrition. A major challenge is to translate trial results into a coordinated public health implementation plan in order to maximally reduce mother-to-child HIV-1 transmission worldwide.

Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml.

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Association between heroin use, needle sharing and tattoos received in prison with hepatitis B and C positivity among street-recruited injecting drug users in New Mexico, USA.

This study aimed to assess the seroprevalence and risk factors for hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV-1 infections among injecting drug users (IDU) in New Mexico. Serological and behavioural surveys were conducted in conjunction with street-based outreach, education and HIV counselling and testing. High rates of antibody positivity for HCV (82.2%) and HBV (61.1%), and a low rate for HIV (0.5%) were found. In multivariate analyses, both HBV and HCV infection were positively associated with increasing age, increasing years of injection and heroin use. Receipt of a tattoo in prison/jail was associated with HBV (odds ratio = 2.3, 95% confidence interval 1.4, 3.8) and HCV (OR = 3.4, 95% CI = 1.6, 7.5) infections. Prevention of bloodborne pathogens among IDUs should focus on young users, early in their drug use experience. Studies examining the relationship between tattooing and HBV and HCV infection are needed as are efforts to promote sterile tattooing, in prisons and elsewhere.

Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study.

A recent report suggesting mitochondrial dysfunction among eight HIV-exposed but uninfected children exposed perinatally to nucleoside reverse transcriptase inhibitors (NRTIs) prompted a review within the Perinatal AIDS Collaborative Transmission Study (PACTS). A standardized retrospective review was conducted of 118 deaths at < 5 years. Deaths were classified as unrelated to mitochondrial dysfunction (Class 1), unlikely related (Class 2), possibly related (Class 3), or likely related or proven (Class 4). Among 35 deaths recorded in HIV-uninfected or indeterminate children, none were classified in either Class 2, 3, or 4. We also reviewed signs or symptoms consistent with possible mitochondrial dysfunction among 1,954 living uninfected children. Only one child was in Class 3 and two siblings were in Class 2; none had perinatal antiretroviral drug exposure. We found no evidence indicating that uninfected infants exposed to perinatal NRTIs died of mitochondrial disorders or that living exposed children had symptoms of mitochondrial dysfunction.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

OBJECTIVE: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. METHODS: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. RESULTS: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. CONCLUSIONS: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Disease progression and early viral dynamics in human immunodeficiency virus-infected children exposed to zidovudine during prenatal and perinatal periods.

Zidovudine (Zdv) is widely used to reduce maternal-infant human immunodeficiency virus transmission (HIV), but its consequences for disease progression among children infected despite Zdv exposure remain unknown. In a multicenter observational cohort study of 325 HIV-infected children born during 1986-1997, clinical progression was compared among infected children exposed or unexposed to Zdv during prenatal and perinatal periods. Zdv exposure was associated with 1.8-fold (95% confidence interval, 1.02-3.11) increased risk of progressing to AIDS or death after adjusting for year of birth, maternal CD4 cell count, maternal AIDS diagnosis, and subsequent antiretroviral therapy of the child. Mean log(10) viral copies at 7-12 weeks were higher among Zdv-exposed children (P=.004). No infected child treated early with multidrug therapy progressed to AIDS or died by 1 year, regardless of early Zdv exposure. More rapid disease progression was observed among infected children exposed during pregnancy or birth to Zdv if effective multidrug therapy was not initiated.