Articles tagged as "Preventing HIV infection in children"

AZT monotherapy vs. combination ART for prevention of vertical transmission in Ukraine

Impact of expanded access to combination antiretroviral therapy in pregnancy: results from a cohort study in Ukraine.

Bailey H, Townsend CL, Semenenko I, Malyuta R, Cortina-Borja M, Thorne C; Ukraine European Collaborative Study Group in EuroCoord., Bull World Health Organ. 2013;91(7):491-500. doi: 10.2471/BLT.12.114405

Objectives: To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV).

Methods: Data on 3 535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008-2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) - rather than cART - and rates of mother-to-child transmission (MTCT) of HIV were investigated.

Findings: cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm - rather than cART - was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02-1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11-1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03-1.20). The overall MTCT rate was 4.1% (95% CI: 3.4-4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16-0.56).

Conclusion: Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization's Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed.

Abstract Full-text [free] access

Editor’s notes:  Elimination of infant infections by 2015 is a global target. The guideline for PMTCT has moved from using Option A (AZT monotherapy or AZTm) and Option B (combination ART in pregnancy or cART) to the most recent recommendation in 2013 of Option B+ (initiation of life-long ART for all HIV-infected pregnant women).  

Coverage of cART in Ukraine increased significantly over the study period.  The majority of women who did not receive any ART were either diagnosed before conception and lost to care or were diagnosed before delivery.  cART was associated with a significantly lower risk of MTCT than AZTm even after adjusting for duration of ART and despite women with advanced disease more likely to be given cART . Women were diagnosed during pregnancy were however, more likely to get AZTm probably because there was less opportunity to counsel them about cART.  Notably, those who were co-habiting or had had two or more previous pregnancies were also less likely to receive cART.  This group had a lower educational status, a factor associated with AZTm receipt.  Underlying contextual factors such as practical and financial barriers to attending for care in this group may explain why they may have received AZTm, as clinicians are less likely to prescribe cART to infrequent attenders. 

This study demonstrates that engagement with and retention in care of women is a pre-requisite for successful scale-up of cART. This is going to be an even more important consideration if Option B+ is to be successfully implemented.

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Missed opportunities for vaginal delivery among women with HIV in Europe

Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery.

 Aebi-Popp K, Mulcahy F, Glass TR, Rudin C, Martinez de Tejada B, Bertisch B, Fehr J, Grawe C, Scheibner K, Rickenbach M, Hoesli I, Thorne C; for the European Collaborative Study in EuroCoord and the Swiss Mother & Child HIV Cohort Study., J Acquir Immune Defic Syndr. 2013 Jul 9. [Epub ahead of print]

Introduction:  Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe.

Methods: In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre-or post-publication of national guidelines recommending vaginal delivery.

Results: Overall, 2 663 women with 3 013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2 020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2 377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2 354) before to 7% (42/599) after the change in guidelines (P < 0.001).

Conclusion: There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.

Abstract access

Editor’s notes: In 1999, following a randomised controlled trial showing a lower risk of vertical HIV transmission among babies delivered by elective Caesarean section, pregnant women with HIV were advised to deliver by elective Caesarean section where this option was available to them. In the last decade, accumulating observational data suggested that women taking combination ART with suppressed viral load who delivered vaginally were at very low risk of vertical transmission. This led to revised guidelines allowing vaginal delivery for women with suppressed viral load on combination ART.

This analysis of European data (with largest numbers contributed by Italy, Belgium and Switzerland) shows the increasing number of women having vaginal deliveries over the last decade. However, a substantial proportion of women had unsuppressed viral load at the time of delivery, and some received no ART prior to delivery, suggesting the need to engage pregnant women with HIV in care earlier.  In addition, the data suggest that more women who have suppressed viral load could safely undergo vaginal delivery.  The proportion of infants acquiring HIV infection in the period after introduction of guidelines allowing vaginal delivery was 0.6%, which is lower than 1.6% prior to the guideline change but suggests that further efforts are required to ensure that all children in Europe are born HIV-free.

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Health system barriers to achieving the potential of integrated service delivery

Integrated maternal and child health services in Mozambique: structural health system limitations overshadow its effect on follow-up of HIV-exposed infants.

Geelhoed D, Lafort Y, Chissale E, Candrinho B, Degomme O. BMC Health Serv Res. 2013 Jun 7;13:207. doi: 10.1186/1472-6963-13-207.

Background: The follow-up of HIV-exposed infants remains a public health challenge in many Sub-Saharan countries. Just as integrated antenatal and maternity services have contributed to improved care for HIV-positive pregnant women, so too could integrated care for mother and infant after birth improve follow-up of HIV-exposed infants. We present results of a study testing the viability of such integrated care, and its effects on follow-up of HIV-exposed infants, in Tete Province, Mozambique.

Methods: Between April 2009 and September 2010, we conducted a mixed-method, intervention-control study in six rural public primary healthcare facilities, selected purposively for size and accessibility, with random allocation of three facilities each for intervention and control groups. The intervention consisted of a reorganization of services to provide one-stop, integrated care for mothers and their children under five years of age. We collected monthly routine facility statistics on prevention of mother-to-child HIV transmission (PMTCT), follow-up of HIV-exposed infants, and other mother and child health (MCH) activities for the six months before (January-June 2009) and 13 months after starting the intervention (July 2009-July 2010). Staff were interviewed at the start, after six months, and at the end of the study. Quantitative data were analysed using quasi-Poisson models for significant differences between the periods before and after intervention, between healthcare facilities in intervention and control groups, and for time trends. The coefficients for the effect of the period and the interaction effect of the intervention were calculated with their p-values. Thematic analysis of qualitative data was done manually.

Results: One-stop, integrated care for mother and child was feasible in all participating healthcare facilities, and staff evaluated this service organisation positively. We observed in both study groups an improvement in follow-up of HIV-exposed infants (registration, follow-up visits, serological testing), but frequent absenteeism of staff and irregular supply of consumables interfered with healthcare facility performance for both intervention and control groups.

Conclusions: Despite improvement in various aspects of the follow-up of HIV-exposed infants, we observed no improvement attributable to one-stop, integrated MCH care. Structural healthcare system limitations, such as staff absences and irregular supply of essential commodities, appear to overshadow its potential effects. Regular technical support and adequate basic working conditions are essential for improved performance in the follow-up of HIV-exposed infants in peripheral public healthcare facilities in Mozambique.

Abstract   Full-text [free] access 

Editor’s notes: Despite rapid advances in the delivery of PMTCT services in many sub-Saharan African countries, the follow-up of HIV-exposed infants until the age of 18 months remains a critical challenge.  This mixed methods, quasi-experimental evaluation study evaluated the viability of providing one-stop, integrated care, its acceptability to healthcare providers, and its effect upon the follow-up of HIV-exposed infants and other MCH services, in the public health system. The intervention consisted of a reorganization of MCH services, to deliver integrated, one-stop consultations for mothers and their children up to 5 years of age. Absence of MCH staff occurred in 16% of months, and stock-outs of HIV testing commodities and MCH drugs occurred in almost half of all months. The improvements in both arms suggests that improving some of the basic working conditions of peripheral MCH staff and ensuring an adequate supply of commodities might be effective ways to improve the follow-up of HIV-exposed infants in peripheral public healthcare facilities in Mozambique. 

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Children: higher rates of virological failure on nevirapine-, as compared to efavirenz-based ART

Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children.

Lowenthal ED, Ellenberg JH, Machine E, Sagdeo A, Boiditswe S, Steenhoff AP, Rutstein R, Anabwani G, Gross R. JAMA. 2013 May 1;309(17):1803-9.

Worldwide, the non-nucleoside 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), 57/421 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101/383 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.

Abstract access 

Editor’s notes: Out of 3.4 million children infected with HIV world-wide, 90% live in sub-Saharan Africa. The majority of children initiating ART receive nevirapine-based regimens, a regimen in-line with WHO recommendations (children > 3 years old should receive nevirapine or efavirenz together with two drugs from the NRTI class). However, data regarding the relative effectiveness of nevirapine and efavirenz in children are limited. In this large retrospective clinic-based cohort study in Botswana rates of virological failure were found to be higher in patients initiating nevirapine as compared to those initiating efavIrenz (HR 2.0 [95% CI: 1.4-2.7; p<0.001). Whilst differences in effectiveness may be one explanation, the authors also discuss alternative explanations: drug interactions and resistance were thought to be unlikely as few patients were on anti-tuberculosis therapy, and only 2.2% of the cohort was known to have been exposed to single-dose nevirapine at birth. The role of sub-optimal adherence could not be assessed as, in common with many programme cohorts, data on adherence were limited. As highlighted by the authors, treatment decisions are rarely made randomly and are often influenced by the characteristics of the patients. Recognizing this limitation the authors explored whether female adolescents were more likely to be prescribed nevirapine (due to concerns about efavirenz in women of child-bearing age), with the underlying assumption that adolescents were more likely to exhibit sub-optimal adherence; however this did not explain the differences in virological outcomes. In summary, this study highlights the need for further research regarding the optimal first-line regimens in children.

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Integration of ANC and ART services increases PMTCT uptake but provision remains sub-optimal

Integration of Antiretroviral Therapy Services into Antenatal Care Increases Treatment Initiation during Pregnancy: A Cohort Study.

Stinson K, Jennings K, Myer L. PLoS One. 2013 May 16;8(5):e63328. Print 2013

Objectives: Initiation of antiretroviral therapy (ART) during pregnancy is critical to promote maternal health and prevent mother-to-child HIV transmission (PMTCT). The separation of services for antenatal care (ANC) and ART may hinder antenatal ART initiation. We evaluated ART initiation during pregnancy under different service delivery models in Cape Town, South Africa.

Methods: A retrospective cohort study was conducted using routinely collected clinic data. Three models for ART initiation in pregnancy were evaluated ART 'integrated' into ANC, ART located 'proximal' to ANC, and ART located some distance away from ANC ('distal'). Kaplan-Meier methods and Poisson regression were used to examine the association between service delivery model and antenatal ART initiation.

Results: Among 14 617 women seeking antenatal care in the three services, 30% were HIV-infected and 17% were eligible for ART based on CD4 cell count <200 cells/µL. A higher proportion of women started ART antenatally in the integrated model compared to the proximal or distal models (55% vs 38% vs 45%, respectively, global p = 0.003). After adjusting for age and gestation at first ANC visit, women who at the integrated service were significantly more likely to initiate ART antenatally (rate ratio 1.33; 95% confidence interval: 1.09-1.64) compared to women attending the distal model; there was no difference between the proximal and distal models in antenatal ART initiation however (p = 0.704).

Conclusions: Integration of ART initiation into ANC is associated with higher levels of ART initiation in pregnancy. This and other forms of service integration may represent a valuable intervention to enhance PMTCT and maternal health. .

Abstract Full-text [free] access

Editor’s notes: This study highlights the challenges of successful delivery of effective PMTCT. The authors compare 3 PMTCT delivery sites with differing modes of care, principally with respect to distance between ANC and ART provision services. It must be noted that other baseline differences between study participants and site services also existed (such as algorithms of care and support from international agencies etc), however this is often seen in observational (and operational research) studies and the pertinence of the findings remain. An important result of this study is that even with integration of ANC and ART services, initiation of treatment was only achieved in just over half of eligible women. There was a notable trend in ART initiation by gestational age at presentation for ANC – the more advanced the gestational age at presentation, the less likely women were to start ART antenatally, reflecting delays in ART initiation even after a woman is in care. Many of the women proceeded to eventually start treatment postnatally. This is an important reminder of the missed opportunities that exist both for preventing HIV in infants and for earlier initiation of treatment in women for their own health.

South Africa
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Almost a quarter of deaths in pregnant and post-partum women may be attributable to HIV

Effect of HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses of pooled community-based data from the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA).

Zaba B, Calvert C, Marston M, Isingo R, Nakiyingi-Miiro J, Lutalo T, Crampin A, Robertson L, Herbst K, Newell ML, Todd J, Byass P, Boerma T, Ronsmans C. Lancet. 2013 May 18;381(9879):1763-71.

Background: Model-based estimates of the global proportions of maternal deaths that are in HIV-infected women range from 7% to 21%, and the effects of HIV on the risk of maternal death is highly uncertain. We used longitudinal data from the Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA) network to estimate the excess mortality associated with HIV during pregnancy and the post-partum period in sub-Saharan Africa.

Methods: The ALPHA network pooled data gathered between June, 1989 and April, 2012 in six community-based studies in eastern and southern Africa with HIV serological surveillance and verbal-autopsy reporting. Deaths occurring during pregnancy and up to 42 days post partum were defined as pregnancy related. Pregnant or post-partum person-years were calculated for HIV-infected and HIV-uninfected women, and HIV-infected to HIV-uninfected mortality rate ratios and HIV-attributable rates were compared between pregnant or post-partum women and women who were not pregnant or post partum.

FINDINGS: 138,074 women aged 15-49 years contributed 636,213 person-years of observation. 49,568 women had 86,963 pregnancies. 6760 of these women died, 235 of them during pregnancy or the post-partum period. Mean prevalence of HIV infection across all person-years in the pooled data was 17.2% (95% CI 17.0-17.3), but 60 of 118 (50.8%) of the women of known HIV status who died during pregnancy or post partum were HIV infected. The mortality rate ratio of HIV-infected to HIV-uninfected women was 20.5 (18.9-22.4) in women who were not pregnant or post partum and 8.2 (5.7-11.8) in pregnant or post-partum women. Excess mortality attributable to HIV was 51.8 (47.8-53.8) per 1000 person-years in women who were not pregnant or post partum and 11.8 (8.4-15.3) per 1000 person-years in pregnant or post-partum women.

Interpretation: HIV-infected pregnant or post-partum women had around eight times higher mortality than did their HIV-uninfected counterparts. On the basis of this estimate, we predict that roughly 24% of deaths in pregnant or post-partum women are attributable to HIV in sub-Saharan Africa, suggesting that safe motherhood programmes should pay special attention to the needs of HIV-infected pregnant or post-partum women.

Abstract access 

Editor’s notes: This study is the first to estimate the contribution of HIV to mortality in pregnant and post-partum women using HIV sero-surveillance and verbal autopsy data from a network of studies in eastern and southern Africa. While there is variation by country, excess mortality due to HIV was considerably higher in non-pregnant women compared with pregnant/post-partum women. This is not entirely surprising as fertility falls with advancing HIV, so only healthier women with HIV conceive – the so-called ‘healthy pregnant woman effect’. They are therefore less likely to die while pregnant/post-partum. However, the study estimates that almost a quarter of deaths in pregnant/post-partum women are attributable to HIV. This highlights the importance of integrating HIV into safe motherhood programmes. It is noteworthy that the majority of women at the time of this study would not have had access to antiretroviral treatment to benefit their own health (as opposed to single dose treatment to reduce mother-to-child transmission alone). While pointing to the potential benefits of the WHO PMTCT B option, the study emphasizes the potential further advantage of PMTCT B+ to reduce HIV related morbidity and mortality, both for women’s own health and their unborn infants, with implications for current and future pregnancies.

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Integrating HIV testing into routine infant immunization programmes

Evaluation of Using Routine Infant Immunization Visits to Identify and Follow-Up HIV-Exposed Infants and Their Mothers in Tanzania.

Goodson JL, Finkbeiner T, Davis NL, Lyimo D, Rwebembera A, Swartzendruber AL, Wallace AS, Kimambo S, Kimario CJ, Wiktor SZ, Luman ET. J Acquir Immune Defic Syndr. 2013 May 1;63(1):e9-e15

Background: Without treatment, approximately half of HIV-infected infants die by age 2 years, and 80% die before age 5 years. Early identification of HIV-infected and HIV-exposed infants provides opportunities for life-saving interventions. We evaluated integration of HIV-related services with routine infant immunization in Tanzania. METHODS: During April 2009 to March 2010, at 4 urban and 4 rural sites, mothers' HIV status was determined at first-month immunization using antenatal cards. HIV-exposed infants were offered HIV testing and follow-up care. Impact of integrated service delivery was assessed by comparing average monthly vaccine doses administered during the study period and a 2-year baseline period; acceptance was assessed by interviewing mothers and service providers. FINDINGS: During 7569 visits, 308 HIV-exposed infants were identified and registered; of these, 290 (94%) were tested, 15 (5%) were HIV infected. At urban sites, first-month vaccine doses remained stable (+2% for pentavalent vaccine and -4% for polio vaccine), and vaccine doses given later in life (pentavalent, polio, and measles) increased 12%, 8%, and 11%, respectively. At rural sites, first-month vaccine doses decreased 33% and 35% and vaccine doses given later in life decreased 23%, 28%, and 28%. Mothers and service providers generally favored integrated services; however, HIV-related stigma and inadequate confidentiality controls of HIV testing were identified, particularly at rural sites. INTERPRETATION: Integration of HIV-related services at immunization visits identified HIV-exposed infants, HIV-infected infants, and HIV-infected mothers; however, decreases in vaccine doses administered at rural sites were concerning. HIV-related service integration with immunization visits needs careful monitoring to ensure optimum vaccine delivery.

Abstract access 

Editor’s notes: One of the targets set in the Global Plan in 2009 was that there should be a 90% reduction in the number of children newly infected with HIV by 2015. Although progress has been made towards achieving this target, with a 24% reduction in HIV infections between 2009 and 2011, it is estimated that in 2011 alone 300 000 children in sub-Saharan Africa were newly infected with HIV. Despite the knowledge that antiretroviral therapy (ART) substantially reduces morbidity and mortality in children, only 23% of children eligible for treatment are estimated to be receiving ART; without access to ART these children will die. One of the major barriers to initiating ART, which urgently needs to be addressed, is access to HIV testing for children. This paper demonstrates the feasibility and acceptability of integrating routine HIV testing of mothers and infants into national immunization programmes. However, the implementation of such a strategy would have be to done with care, as the integration of HIV testing into immunization programmes may have a negative impact on vaccination uptake.

United Republic of Tanzania
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Feasibility and acceptability of routine HIV testing into a general paediatric out-patient clinic

The Acceptability and Feasibility of Routine Pediatric HIV Testing in an Outpatient Clinic in Durban, South Africa.

Ramirez-Avila L, Noubary F, Pansegrouw D, Sithole S, Giddy J, Losina E, Walensky RP, Bassett IV Pediatr Infect Dis J. 2013

Background: Limited access to HIV testing for children impedes early diagnosis and access to ART. Our objective was to evaluate the feasibility and acceptability of routine pediatric HIV testing in an urban, fee-for-service, outpatient clinic in Durban, South Africa. METHODS: We assessed the number of patients (0-15yrs) who underwent HIV testing upon physician referral during a baseline period. We then established a routine, voluntary HIV testing study for pediatric patients, regardless of symptoms. Parents/caretakers were offered free rapid fingerstick HIV testing for their child. For patients <18mo, the biological mother was offered HIV testing and HIV DNA PCR was used to confirm the infant's status. The primary outcome was the HIV testing yield, defined as the average number of positive tests per month during the routine compared to the baseline period. RESULTS: Over a 5-month baseline testing period, 931pediatric patients registered for outpatient care. Of the 124 (13%) patients who underwent testing upon physician referral, 21 (17%, 95% CI 11-25%) were HIV-infected. During a 13-month routine testing period, 2,790 patients registered for care and 2,106 (75%) were approached for participation. Of these, 1,234 were eligible and 771(62%) enrolled. Among those eligible, 637 (52%, 95% CI 49-54%) accepted testing for their child or themselves (biological mothers of infants <18 months).There was an increase in the average number of HIV tests during the routine compared to the baseline HIV testing periods (49 vs. 25 tests per month, p=0.001) but no difference in the HIV testing yield during the testing periods (3 vs. 4 positive HIV tests/month, p=0.06). However, during the routine testing period HIV prevalence remains extraordinarily high with 39 (6%, 95% CI 4-8%) newly-diagnosed HIV-infected children (median 7 years, 56% female). CONCLUSIONS: Targeted and symptom-based testing referral identifies an equivalent number of HIV-infected children as routine HIV testing. Routine HIV testing identifies a high burden of HIV and is a feasible and moderately acceptable strategy in an outpatient clinic in a high prevalence area.

Abstract access 

Editor’s notes: ART coverage of children in resource-limited settings is very low, in part because HIV positive children are being diagnosed late, or not at all. This has significant implications in terms of morbidity and mortality, as without access to treatment these children will die. Additionally late initiation of ART may result in irreversible conditions e.g. chronic lung disease. Routine HIV testing of children in an out-patient setting is one potential strategy which could be used to identify HIV positive children and link them into care. In this study the introduction of routine, voluntary HIV testing of children (0-15 years) into a general out-patient clinic in a high HIV prevalence setting, resulted in more children being tested than previously seen with provider-initiated testing. Despite this, no more HIV positive children were identified. One potential reason, as discussed in the paper, was selection bias; a significant proportion of children registering at the clinic did not have an HIV test. It is possible that children who were considered ineligible for testing, or whose caretakers either declined participation in the study or HIV testing, were at higher risk of being HIV positive. HIV positive children have the right to access life-saving ART; however as shown in this study routine voluntary testing was only moderately acceptable and as a result we may be failing to test those children who are at highest risk. Innovative solutions, such as opt-out testing need to be considered and debated at a national level.

South Africa
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The scale up of PMTCT in China

An integrated city-driven perinatal HIV prevention program covering 1.8 
million pregnant women in Shenzhen, China, 2000 to 2010.

Song J, Feng T, Bulterys M, Zhang D, Korhonen C, Shi X, Wang X, Cheng J, Chen L, Ma H. Sex Transm Dis. 2013
Apr;40(4):329-34. doi: 10.1097/OLQ.0b013e3182805186.

Background: Despite the scale-up of prevention of mother-to-child transmission (PMTCT) programs worldwide, the translation from research studies into public health policy has been slow. This report details the experiences of a city-driven PMTCT program in China using existing health resources.

Methods: The PMTCT program was devised to hospital based and city-wide. It achieves full use of available resources: the local Centers for Disease Control and Prevention, the Infectious Disease Hospital, Maternal and Child Health Hospitals, and all qualified comprehensive hospitals.

Results: From 2000 to 2010, 1 843 122 pregnant women attended prenatal care or labor and delivery services. Overall, 97.4% received pretest HIV counseling, and 96.2% were tested for HIV. Among the 81.1% (1 495 122) of women who attended prenatal clinics, 97.2% (1 452 753) received pretest counseling and 95.7% (1 430 799) were tested for HIV. Among the 18.9% (348 000) of women with an undocumented HIV status at labor and delivery, 98.6% (343 038) received pretest counseling, and 98.1% (341 371) were tested for HIV. In total, 229 women were determined HIV positive for a prevalence of 1.3 per 10 000 pregnant women. Among the 107 HIV-infected women who carried to delivery, 87.9% received antiretroviral prophylaxis for themselves and their infants. Among the 58 women who were identified HIV positive at labor, 10.3% of mothers and 72.4% of infants received antiretroviral prophylaxis. The estimated mother-to-child transmission rate was 5.3% (95% confidence interval, 2.2%, 10.7%).

Conclusions: With appropriate integration, existing health care resources are adequate for a comprehensive city-driven PMTCT program in an area with a low HIV prevalence.

Abstract access

Editor’s notes: The elimination of new HIV infections among children is an important UNAIDS goal. There is the potential for substantial numbers of vertical infections in countries such as China, that have a relatively low population prevalence of HIV infection, but large numbers of people that could be infected with HIV. This paper describes the findings from 10 years of implementing a city driven, large scale PMTCT programme that tested almost 1.5 million women over 10 years. The HIV infection rate detected was low (1.3/10 000 pregnant women), identifying 229 pregnant women living with HIV. Interestingly, less than a half (109) continued the pregnancy to delivery, with four-fifths of these women receiving ART drugs, resulting in a mother to child HIV transmission rate of 5.3%. This scale of programming and achievements is impressive, and illustrate the potential to deliver PMTCT programmes at scale. Questions remain regarding why so many women did not continue with their pregnancy, and the cost and cost-effectiveness of such a broad approach to PMTCT, compared to the potential use of a more targeted approach to PMTCT delivery.

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ARROW: monitoring strategies for management of ART in children

Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial

ARROW Trial team, Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P et al. Lancet. 2013 Apr 20;381(9875):1391-403. doi: 10.1016/S0140-6736(12)62198-9. Epub 2013 Mar 7.

No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. 1 206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1·13, 95% CI 0·73-1·73, p=0·59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1·3 vs 0·4 per 100 child-years, difference 0·99, 0·37-1·60, p=0·002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0·98, 0·83-1·16, p=0·83). Mean CD4 percentage change did not differ between ART groups at week 72 (16·5% [SD 8·6] vs 17·1% [8·5] vs 17·3% [8·0], p=0·33) or week 144 (p=0·69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12·4% [7·2] vs 14·1% [7·1] vs 14·6% [7·3], p<0·0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B:A] 1·32, 1·07-1·63) and C (218 [54%] children in C; HR [C:A] 1·58, 1·29-1·94; global p=0·0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively. NNRTI plus NRTI-based three-drug or four-drug ART can be given across childhood without routine toxicity monitoring; CD4monitoring provided clinical benefit after the first year on ART, but event rates were very low and long-term survival high, suggesting ART rollout should take priority. CD4 benefits from four-drug induction were not durable, but three-NRTI long-term maintenance was immunologically and clinically similar to NNRTI-based ART and could be valuable during tuberculosis co-treatment.

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Editor’s notes: With an estimated 2 million children in need of ART in 2011 but only 28% accessing treatment, there is clearly an urgent need to scale-up access to ART. ARROW, a landmark randomised controlled trial comparing clinical to 3-monthly laboratory monitoring (CD4 count, haematology and biochemistry) has greatly added to the knowledge base about how to monitor children on ART in resource-limited settings. Firstly, ARROW demonstrates that with high-quality clinical care, excellent clinical outcomes are possible, regardless of the monitoring strategy used: with a continuous supply of ART, 1-monthly review by a nurse and 3-monthly review by a doctor, 5-year survival was remarkably high (96%) with reasonable levels of viral suppression seen in both monitoring arms (77-78% had a VL<400 copies/ml). Secondly, although rates of clinical progression were higher in the clinical monitoring arm after the second year of treatment, overall there was no morbidity / mortality benefit with routine versus clinically driven laboratory monitoring. Thirdly, as was seen in a similar trial in adults (DART), this study shows that WHO-recommended regimens can be provided safely without the need for routine monitoring for toxicity. As these excellent outcomes are unlikely to be replicated in programmatic settings, there remain uncertainties about the optimal strategy for monitoring children on ART, particularly with respect to viral load monitoring. However, the results from ARROW are very encouraging and these uncertainties should not undermine efforts to dramatically increase children’s access to ART in resource-limited settings. A commentary on the same article by Kuhn and Coovadia in the same issue of the Lancet is found here.

Uganda, Zimbabwe
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