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.

A survey of occupational blood contact and HIV infection among traditional birth attendants in Rwanda.

OBJECTIVE: To investigate the risk of occupationally acquired HIV infection among traditional birth attendants (TBA) in Rwanda, Africa. DESIGN AND METHODS: A serosurvey was conducted among 219 TBA practicing in a rural but densely populated area in southern Rwanda. Each TBA was interviewed about sociodemographic information, work-related habits and practices, and presence of nonoccupational risk factors for HIV infection. The frequency of skin exposure to HIV-infected blood was estimated for each TBA from HIV seroprevalence data collected previously from pregnant women stratified by the geographic zones in which the TBA practiced. RESULTS: Four TBA (1.8%) tested HIV-1-antibody-positive; all four had reported nonoccupational risk factors for HIV infection. We estimated that the 215 HIV-negative TBA had 2234 potentially infectious blood-skin contacts out of a total of approximately 35,000 deliveries assisted in the past 5 years. However, we found no evidence of HIV infection caused by occupational blood contact (none out of 2234; upper limit of the 95% confidence interval because of one potentially infectious blood-skin contact = 0.2%). CONCLUSION: Although these findings may not be universal to all TBA in Africa, the risk of occupationally acquired HIV infection among TBA appears small. The high frequency of blood-skin contact among TBA in Rwanda highlights the need to include infection control precautions in the training of TBA.

PIP: Samples of blood from 219 traditional birth attendants (TBA) practicing in a rural, densely populated area in southern Rwanda were tested for the presence of antibody against HIV-1 in an investigation of the risk for acquiring HIV infection occupationally. The TBAs were interviewed for sociodemographic data, on work-related habits and practices, and about nonoccupational risk factors for HIV infection. The researchers also estimated the frequency of skin exposure to HIV-infected blood for each TBA from HIV seroprevalence data collected previously from pregnant women stratified by the geographic zones in which each TBA practiced. Four TBAs tested seropositive for HIV-1 antibody; all had reported nonoccupational risk factors for infection. It was also estimated that the 215 HIV-negative TBAs had 2234 potentially infectious blood-skin contacts out of a total of approximately 35,000 deliveries assisted over the previous past five years. No evidence was therefore found of HIV infection caused by occupational blood contact and the risk of occupationally acquired HIV infection among TBAs seems small. The high frequency of blood-skin contact among TBAs in Rwanda, however, highlights the need to include infection control precautions in the training of TBAs.

Incident HIV-1 infection in a cohort of young women in Butare, Rwanda.

OBJECTIVE: To determine the incidence of HIV-1 infection and associated risk factors among young, seronegative, and sexually active women in a mixed rural and urban population in southern Rwanda. DESIGN: A prospective cohort study. METHODS: Between October 1991 and April 1993, we completed a 2-year follow-up survey among HIV-1-seronegative women aged < or = 30 years at the time of their initial HIV-1 screening during pregnancy. All women aged < or = 25 years and a randomly selected sample of 26-30-year olds were invited to participate from five prenatal clinics in the Butare region. The interview focused on potential risk factors for HIV-1 acquisition during the 2-year interval between blood collection. RESULTS: Out of 1524 women selected, 1150 (75%) participated in the follow-up survey. The 2-year incidence of HIV-1 infection was 2.7% [95% confidence interval (CI), 1.8-3.9]. Teenage women were at the highest risk (incidence, 10.5%; 95% CI, 5.2-19.4), with incidence leveling off with increasing age (P < 0.001). Women who began sexual activity recently were also at higher risk; the lowest risk category consisted of women aged 26-30 years with 5 or more years of sexual experience. The more urban the geographic residence of the woman, the more likely she was to have acquired HIV-1 infection (P < 0.001). In the urban and peri-urban zones, the poorest women were at significantly higher risk of incident HIV-1 infection than women reporting higher household income. In a multivariate analysis, young maternal age, marital status (being single, divorced or widowed), multiple sexual partners, and a history of sexually transmitted diseases remained strongly associated with incident HIV-1 infection. Geographic residence, hormonal contraception, and receipt of injections were no longer significantly associated with incident HIV-1 infection when these other factors were accounted for simultaneously. CONCLUSION: Among young Rwandan women, the early years of sexual activity are particularly dangerous for acquisition of HIV-1 infection. Interventions should focus on young teenagers before they become sexually active.

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.

Multiple sexual partners and mother-to-child transmission of HIV-1.

OBJECTIVE: To investigate risk factors for mother-to-child transmission of HIV-1, particularly sexual behavior before and during pregnancy. DESIGN AND METHODS: This study is part of a prospective cohort study in Butare, Rwanda, of 318 HIV-1-seropositive and 309 HIV-1-seronegative women enrolled during pregnancy and followed for a mean duration of 21 months (range, 8-34 months). Clinical follow-up of the mother-infant pairs was performed at 6-week intervals during the first year of life and at 4-month intervals thereafter. Detailed sexual history interviews were conducted during pregnancy and at the first postnatal visit. RESULTS: Of 184 singleton infants born to HIV-1-infected mothers who survived the neonatal period, 32 (17%) children were classified as HIV-1-infected, 130 (71%) as not infected, and 22 (12%) died with indeterminate HIV-1 infection status. The vertical transmission rate was estimated to be between 20 and 29%. Unprotected sexual intercourse with increased number of partners during the past 5 years was strongly associated with mother-to-child transmission (P < 0.001), even after adjustment for maternal CD4/CD8 ratio, parity, history of sexually transmitted diseases, and evidence of genital infection during pregnancy. In a multivariate analysis, excluding children with indeterminate HIV-1 status, odds ratios for vertical transmission were 2.6 [95% confidence interval (CI), 1.0-6.9] for maternal CD4/CD8 ratio < 0.5 and 3.6 (95% CI, 1.1-11.8) for more than three sexual partners versus a single partner. Women with more than one sexual partner during the first trimester of pregnancy were at particularly high risk of transmitting the virus. CONCLUSION: Unprotected sexual intercourse with multiple partners before and during pregnancy in a population with high HIV-1 seroprevalence may well increase the likelihood of HIV-1 transmission from an infected mother to her child.

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.

Chronic fetal hypoxia and sudden infant death syndrome: interaction between maternal smoking and low hematocrit during pregnancy.

To investigate the hypothesis that chronic fetal hypoxia contributes to the etiology of sudden infant death syndrome (SIDS), a possible interaction between the effect of maternal cigarette smoking and low hematocrit during pregnancy on the risk of SIDS was studied using the US Collaborative Perinatal Project cohort. The 193 SIDS cases identified in the cohort were analyzed with 1930 controls randomly selected from infants who survived the first year of life. After adjustment for maternal age, infants born to mothers who smoked 10 or more cigarettes per day and who were anemic (hematocrit less than 30%) during pregnancy were at a much higher risk of SIDS than infants born to mothers who did not smoke and were not anemic (odds ratio = 4.0; 95% confidence limits, 2.1 and 7.4). Smoking 10 or more cigarettes per day vs none increased the risk of SIDS by 70% among women with hematocrit at or above 30% but increased risk threefold among women with hematocrit below 30%. After adjustment for more potential confounders in a logistic regression model, the effect of smoking on SIDS continued to increase with lower levels of hematocrit during pregnancy. Birth weight accounted for very little of these associations. Low hematocrit was not a risk factor for SIDS among nonsmokers but became an important predictor among heavy smokers. These findings are in agreement with the hypothesis that chronic fetal hypoxia may predispose to SIDS, possibly by impairing the normal development of the fetal central nervous system.

HIV-1 sequence variation between isolates from mother-infant transmission pairs.

To examine the sequence diversity of human immunodeficiency virus type 1 (HIV-1) between known transmission sets, sequences from the V3 and V4-V5 region of the envelope gene from four mother-infant pairs were analyzed. The mean interpatient sequence variation between isolates from linked mother-infant pairs was comparable to the sequence diversity found between isolates from other close contacts. The mean intrapatient variation was significantly less in the infants' isolates then the isolates from both their mothers and other characterized intrapatient sequence sets. In addition, a distinct and characteristic difference in the glycosylation pattern preceding the V3 loop was found between each linked transmission pair. These findings indicate that selection of specific genotypic variants, which may play a role in some direct transmission sets, and the duration of infection are important factors in the degree of diversity seen between the sequence sets.

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.

Maternal human immunodeficiency virus 1 infection and intrauterine growth: a prospective cohort study in Butare, Rwanda.

A prospective cohort study of 318 human immunodeficiency virus 1 (HIV-1)-infected and 309 seronegative pregnant women was carried out in Butare, Rwanda. Birth weight was significantly lower among singleton infants born alive to HIV-1-infected mothers compared with those born alive to seronegative mothers (2706 g vs. 2825 g; P = 0.002). Crown-to-heel length, head circumference, chest circumference and placental weight were also reduced. Maternal HIV-1 infection was significantly associated with intrauterine growth retardation but not with preterm birth. Differences in the body mass index and weight/head ratio suggest that the adverse impact on live born infants may have been most severe towards the end of pregnancy, resulting in a lean infant with a relatively large head. The higher frequency of intrauterine growth retardation could not be explained by potential confounding factors such as maternal cigarette smoking, history of sexually transmitted diseases or sociodemographic characteristics. The neonatal physical examination did not reveal any differences in clinical signs or symptoms within 48 hours of birth except for the presence of conjunctivitis which was more common among infants of HIV-1-infected mothers. The perinatal and neonatal mortality rates were not significantly affected by maternal HIV-1 status.

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.

Risk factors for sudden infant death syndrome in the US Collaborative Perinatal Project.

Risk factors for sudden infant death syndrome (SIDS) were studied among infants born to the nearly 56,000 women enrolled in the US Collaborative Perinatal Project from 1959 through 1966. The 193 SIDS cases identified in the cohort were compared with 1930 controls randomly selected from infants who survived the first year of life. The previously documented excess risk associated with black race disappeared after adjusting for maternal education and family income. Maternal smoking, maternal anaemia during pregnancy, and lack of early prenatal care were all positively associated with SIDS. After adjustment for gestational age, infants with low weight and length at birth were still at increased SIDS risk, suggesting that intrauterine growth retardation may be a risk factor. Neurological abnormalities diagnosed before death were associated with SIDS, but much of the association was removed by adjusting for birthweight. The negative association of breastfeeding with SIDS was much reduced upon adjustment by maternal education and birthweight. These findings may have important implications in our understanding of the epidemiology of SIDS.

Risk factors associated with prevalent HIV-1 infection among pregnant women in Rwanda. National University of Rwanda-Johns Hopkins University AIDS Research Team.

This study evaluated risk factors associated with prevalent HIV-1 infection among pregnant women in a semi-rural but densely populated area surrounding the town of Butare in Rwanda. Overall seroprevalence was 9.3% in 5690 pregnant women who sought antenatal care at one of five health centres. Factors associated with higher seroprevalence of HIV-1 included history of multiple sexual partners, history of at least one sexually transmitted disease (STD), relatively high socioeconomic status (SES), being unmarried, young age at first pregnancy, and low gravidity. Women who had used oral contraceptives, smoked more than one cigarette per day, whose partners were circumcised, and had had sex to support themselves were also at higher risk of being infected. A history of blood transfusion in the past 5 years was not associated with HIV-1 infection. History of multiple sexual partners, history of STD, high household income, partner circumcision, and past oral contraceptive use remained strongly associated with HIV-1 infection even when simultaneously controlling for other covariates. Among legally married women who lacked sexual behaviour risk factors, history of STD, high SES, young age at first pregnancy, and low gravidity were significantly associated with HIV-1 seroprevalence.

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.

The expected impact of a smoking cessation program for pregnant women on infant mortality among Native Americans.

To quantify the expected impact of a smoking cessation program for pregnant women on infant mortality among Native Americans, we estimated the proportional reduction (impact fraction) and the absolute reduction (impact risk) in neonatal and postneonatal mortality as a result of the intervention program. The estimated attributable fraction due to maternal smoking was 16.6% of infant deaths in the Aberdeen Indian Health Service (IHS) Area, 16.2% in the Alaska IHS Area, and 5.2% in the Navajo IHS Area. Under the assumptions that 14% of the smokers participating in a smoking cessation program would quit and that the intervention would have 60% relative efficacy in preventing infant deaths attributable to smoking, the impact fraction was estimated to be 0.9% of all infant deaths in the Aberdeen Area, 1.0% in the Alaska Area, and 0.3% in the Navajo Area. Under the "best" model assumptions (28% cessation rate and 90% relative efficacy), 2.6% of all infant deaths, 3.7% of postneonatal deaths, and 1.2% of neonatal deaths would be prevented by a smoking cessation program in the Aberdeen Area. When applied to 1984-1986 infant mortality data, the impact risk per 100,000 live births under the "best" model assumptions was 10 neonatal deaths and 41 postneonatal deaths in the Aberdeen Area, 10 neonatal and 34 postneonatal deaths in Alaska, and 2 neonatal and 8 postneonatal deaths in the Navajo Area. This report points to the need to develop effective smoking cessation programs for Native Americans, targeted in particular to women of reproductive age.

Prevention of HIV infection in children.

The threshold of a new century is an opportune time to review advances in the prevention of HIV infection in children. In the United States, progress in the ability to virtually eliminate perinatal HIV transmission that was unthinkable just a few years ago has been achieved. Clinicians providing care to pregnant women should educate and counsel women about HIV and strongly recommend that they be tested. They should also counsel HIV-infected women about the means available to substantially decrease the risk for HIV transmission to their infants (e.g., antiretroviral drug use, avoidance of breast-feeding, elective C-section, encouraging pregnant women to use barrier methods during sexual intercourse, and to discontinue injection drug use). This article has highlighted some of the remaining challenges that constitute barriers to achieving maximal decrease of HIV infection in children. Studies conducted in resource-poor countries have added greatly to the understanding of vertical transmission of HIV, and they are now leading to practical and affordable approaches to reduce vertical HIV transmission world-wide. The results of this research must lead to coordinated public health action and a global political commitment to extend the benefits of antiretroviral drug prophylaxis that now exist widely in the United States to more resource-poor countries.

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.