Articles tagged as "Preventing HIV infection in children"

Late maternal diagnosis results in mother-to-child transmission in Johannesburg, South Africa

Timing of maternal HIV testing and uptake of prevention of mother-to-child transmission interventions among women and their infected infants in Johannesburg, South Africa.

Technau KG, Kalk E, Coovadia A, Black V, Pickerill S, Mellins CA, Abrams EJ, Strehlau R, Kuhn L. P. J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):e170-8. doi: 10.1097/QAI.0000000000000068.

Background: By 2011, South African prevention of mother-to-child transmission (PMTCT) of HIV programs had reduced perinatal HIV transmission at 6 weeks of age to 2.7%. We investigated the profile of newly diagnosed vertically infected children and their mothers to identify shortfalls in the PMTCT program.

Methods: In this operational follow-up study, fieldworkers enrolled mothers of newly diagnosed HIV-infected children up to 2 years of age at 5 major health care facilities in Johannesburg. Structured questionnaires and clinical record reviews were conducted and analyzed to describe the population and assess factors associated with PMTCT uptake.

Results: Two hundred eighty-nine mother-child pairs were enrolled. Timing of maternal HIV diagnosis influenced PMTCT access and feeding choices and was associated with infants' age at HIV diagnosis (7 vs. 11 vs. 31 weeks where mothers tested before, during, or after the pregnancy, respectively; P < 0.0001). Women diagnosed before pregnancy (12%) were older (median, 31 years) than those diagnosed during the index pregnancy (53%; median, 27 years). Women diagnosed after delivery (35%) were younger (median, 25 years, P < 0.0001), of lower parity, and less likely to be South African citizens. In 81 cases (29%), late maternal diagnosis precluded any PMTCT access. Where women were diagnosed during or before pregnancy, the recommended PMTCT guidelines for mother and infant were followed in 86 (61%) pairs.

Conclusions: Failure to diagnose maternal HIV infection before delivery was the main reason for missing PMTCT prophylaxis and early infant testing. Timely maternal diagnosis enables PMTCT uptake, but implementation and follow-up gaps require attention to improve infant outcomes.

Abstract access

Editor’s notes: Significant numbers of infants continue to be HIV-positive despite high coverage of antiretroviral therapy for pregnant women in South Africa.  A combination of psychosocial, biological and health system factors were identified to have contributed to the failure of preventing infant infections in this operational study. Prevention of postnatal transmission requires retesting HIV negative women at delivery and at immunisation visits. This is to identify recently acquired HIV infection during late pregnancy and breastfeeding. Even when women are identified during pregnancy, health system and individual psychosocial factors result in suboptimal care, culminating in transmission.  Simplification of guidelines, increasing public awareness of benefits of early antenatal care, retesting HIV negative pregnant women and better patient support should improve effectiveness of programmes to prevent new infections in children.

Africa
South Africa
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Advocacy, sensitisation, and capacity building are key to integrating services

Development and pilot testing of HIV screening program integration within public/primary health centers providing antenatal care services in Maharashtra, India.

Bindoria SV, Devkar R, Gupta I, Ranebennur V, Saggurti N, Ramesh S, Deshmukh D, Gaikwad S. BMC Res Notes. 2014 Mar 26;7:177. doi: 10.1186/1756-0500-7-177.

Background: The objectives of this paper are: (1) to study the feasibility and relative benefits of integrating the prevention of parent-to-child transmission (PPTCT) component of the National AIDS Control Program with the maternal and child health component of the National Rural Health Mission (NRHM) by offering HIV screening at the primary healthcare level; and (2) to estimate the incremental cost-effectiveness ratio to understand whether the costs are commensurate with the benefits.

Methods: The intervention included advocacy with political, administrative/health heads, and capacity building of health staff in Satara district, Maharashtra, India. The intervention also conducted biannual outreach activities at primary health centers (PHCs)/sub-centers (SCs); initiated facility-based integrated counseling and testing centers (FICTCs) at all round-the-clock PHCs; made the existing FICTCs functional and trained PHC nurses in HIV screening. All "functional" FICTCs were equipped to screen for HIV and trained staff provided counseling and conducted HIV testing as per the national protocol. Data were collected pre- and post- integration on the number of pregnant women screened for HIV, the number of functional FICTCs and intervention costs. Trend analyses on various outcome measures were conducted. Further, the incremental cost-effectiveness ratio per pregnant woman screened was calculated.

Results: An additional 27% of HIV-infected women were detected during the intervention period as the annual HIV screening increased from pre- to post-intervention (55% to 79%, p < 0.001) among antenatal care (ANC) attendees under the NRHM. A greater increase in HIV screening was observed in PHCs/SCs. The proportions of functional FICTCs increased from 47% to 97% (p < 0.001). Additionally, 93% of HIV-infected pregnant women were linked to anti-retroviral therapy centers; 92% of mother-baby pairs received Nevirapine; and 89% of exposed babies were enrolled for early infant diagnosis. The incremental cost-effectiveness ratio was estimated at INR 44 (less than 1 US$) per pregnant woman tested.

Conclusions: Integrating HIV screening with the broader Rural Health Mission is a promising opportunity to scale up the PPTCT program. However, advocacy, sensitization, capacity building and the judicious utilization of available resources are key to widening the reach of the PPTCT program in India and elsewhere.

Abstract   Full-text [free] access 

Editor’s notes: This article evaluates the incremental unit cost of integrating rapid HIV testing into existing maternal and child health (MCH) and primary health care services. This approach is interesting in that it can be described as political as well as clinical.  These approaches included substantial advocacy with district political and administrative health heads, sensitisation and mobilization of health workers, and supply chain support to ensure that existing counselling and testing facilities were “functional” - equipped to provide the service.

The programme also included a number of activities intended to generate demand for HIV testing and counselling in antenatal care. These included integration of HIV screening with regular village health and nutrition days, and utilisation of community health workers (ASHAs) to mobilise people for testing. 

This article provides much-needed evidence on the cost-effectiveness of integrating HIV counselling and testing into primary and antenatal health care services in India. It also encourages us to think about integration more broadly as a health systems activity, rather than simply a clinical programme. It highlights the importance of demand creation and mobilization of political will through advocacy, sensitisation and capacity building as part of the integration process.

Asia
India
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Need for increased focus on mental health among HIV-positive pregnant women

Mental health of HIV-seropositive women during pregnancy and postpartum period: a comprehensive literature review.

Kapetanovic S, Dass-Brailsford P, Nora D, Talisman N. AIDS Behav. 2014 Mar 2. [Epub ahead of print]

With growing numbers of HIV-seropositive (HIV+) women of child-bearing age and increased access to effective clinical protocols for preventing mother-to-child transmission (MTCT) of HIV, mental health-related factors have become increasingly relevant due to their potential to affect the women's quality of life, obstetric outcomes and risk of MTCT. This review synthesizes evidence from 53 peer-reviewed publications examining mental health-related variables in pregnant and postpartum HIV+ women. The presentation of results is organized by the level of socioeconomic resources in the countries where studies were conducted (i.e., high-, middle-, and low-income countries). It is concluded that psychiatric symptoms, particularly depression, and mental health vulnerabilities (e.g., inadequate coping skills) are widespread among pregnant HIV+ women globally and have a potential to affect psychological well-being, quality of life and salient clinical outcomes. The current body of evidence provides rationale for developing and evaluating clinical and structural interventions aimed at improving mental health outcomes and their clinical correlates in pregnant HIV+ women.

Abstract access 

Editor’s notes: The comprehensive review summarises evidence from over fifty studies on a range of mental health variables in pregnant and post-partum HIV-positive women. The results highlight the need to screen for depression among pregnant HIV-positive women, and to provide appropriate referrals and programmes. Five randomised controlled trials were identified (all from low- and middle-income countries), with encouraging results of activities such as culturally-adapted psycho-educational programmes. Future randomised trials are needed to build on this evidence and assess the impact of such programmes not only on mental health outcomes, but also HIV-related factors such as antiretroviral therapy adherence and mother-to-child transmission of HIV. The absence of trials from high-income countries is noticeable, indicating the need for further focus on mental health needs of HIV-positive pregnant women in these settings.

Africa, Asia, Europe, Northern America
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Retention on antiretroviral therapy with “Option B+”: the Malawi experience

Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi.

Tenthani L, Haas AD, Tweya H, Jahn A, van Oosterhout JJ, Chimbwandira F, Chirwa Z, Ng'ambi W, Bakali A, Phiri S, Myer L, Valeri F, Zwahlen M, Wandeler G, Keiser O; Ministry of Health in Malawi and IeDEA Southern Africa. AIDS. 2014 Feb 20;28(4):589-98. doi: 10.1097/QAD.0000000000000143

Objective: To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women ('Option B+') in Malawi.

Design, setting, and participants: We examined retention in care, from the date of ART initiation up to 6 months, for women in the Option B+ program. We analysed nationwide facility-level data on women who started ART at 540 facilities (n = 21 939), as well as individual-level data on patients who started ART at 19 large facilities (n = 11 534).

Results: Of the women who started ART under Option B+ (n = 21 939), 17% appeared to be lost to follow-up 6 months after ART initiation. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4 cell count 350 cells/µl or less, to never return after their initial clinic visit [odds ratio (OR) 5.0, 95% confidence interval (CI) 4.2-6.1]. Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (OR 2.2, 95% CI 1.8-2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0 to 58%.

Conclusion: Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community or family-based models of care could improve its effectiveness.

 Abstract access 

 Editor’s notes: “Option B+” refers to the strategy of starting combination antiretroviral therapy (ART) for pregnant women who are HIV positive, and then continuing ART lifelong. This strategy has many advantages from a programmatic perspective, including maintaining the mother’s health and reducing the risk of transmission in future pregnancies and to HIV-negative partners. Implementation of option B+ has increased ART coverage among pregnant women in Malawi, an important positive outcome. However, the full benefits of this strategy will only be realised if women remain in care and sustain virologic suppression. These data on retention are therefore important for programme managers.

Some 17% of women who started antiretroviral therapy during pregnancy were lost to follow-up by six months. Women starting ART during pregnancy were almost five times more likely never to return after the first visit, compared to women starting ART for their own health (based on a CD4 count below 350 or WHO stage three or four). These women are of particular concern because their loss from programme likely reflects a missed opportunity to prevent HIV transmission to their children. Effective strategies to maximise retention in care need to be identified and implemented.

On a methodological note, in this analysis, loss to follow-up was defined as missing a visit by more than 60 days, whereas WHO recommends a cut-off of 90 days. This illustrates the need for ART programmes to report standardised outcomes in order to facilitate comparisons.  

Africa
Malawi
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Outcomes up to five years among children exposed to zidovudine or nevirapine at birth

Long-term follow-up of children in the HIVNET 012 perinatal HIV prevention trial: five-year growth and survival.

Owor M, Mwatha A, Donnell D, Musoke P, Mmiro F, Allen M, Jackson JB, Fowler MG, Guay LA. J Acquir Immune Defic Syndr. 2013 Dec 15;64(5):464-71. doi: 10.1097/QAI.0000000000000015.

Objectives: To describe 5-year growth, survival, and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012.

Methods: All study children who were alive at the age 18 months were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every 6 months from 24 to 60 months. At each visit, history, physical examination, and growth measures were taken. From these measurements, Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis.

Results: Five hundred twenty-eight study children were alive at the age 18 months and 491 (426 HIV uninfected and 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV-infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable with WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the 2 study arms were similar.

Conclusions: Both infected and uninfected children in the 5-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource-limited settings. Similarly, the low 5-year survival among HIV-infected children supports the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.

Abstract access 

Editor’s notes: There are limited studies on outcomes in HIV exposed/negative and positive children beyond infancy in the pre-ART era in Africa. As expected, HIV positive children were twice as likely to die as HIV negative children. The five-year survival was significantly higher among children infected postnatally (after eight weeks) than among those infected perinatally. Notably, more than 50% of deaths among HIV positive children occurred in the first two years of life; HIV negative children who managed to survive to two years had a greater than 70% probability of survival to five years, irrespective of the timing of infection. Overall, poor growth (stunting and underweight) was common, but growth failure rates remained significantly higher in HIV positive children throughout the period of follow-up. Importantly, use of peripartum zidovudine or nevirapine did not result in any longterm adverse outcomes.  

This study underscores the importance of early identification of HIV and timely institution of ART. However, a significant number of children do survive beyond infancy even without treatment, and therefore HIV testing strategies should also target older children who may have missed testing during infancy. Children in this setting remain highly vulnerable and growth monitoring and nutritional interventions are crucial. These should also be integrated within paediatric HIV care services.

Africa
Uganda
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Integrated paediatric services can improve uptake of HIV care but are still affected by stigma

Qualitative assessment of the integration of HIV services with infant routine immunization visits in Tanzania.

Wallace A, Kimambo S, Dafrossa L, Rusibamayila N, Rwebembera A, Songoro J, Arthur G, Luman E, Finkbeiner T, Goodson JL. J Acquir Immune Defic Syndr. 2013 Dec 8. [Epub ahead of print]

Background: In 2009, a project was implemented in 8 primary health clinics throughout Tanzania to explore the feasibility of integrating pediatric HIV prevention services with routine infant immunization visits.

Methods: We conducted interviews with 66 conveniently sampled mothers of infants who had received integrated HIV and immunization services and 16 providers who delivered the integrated services to qualitatively identify benefits and challenges of the intervention midway through project implementation.

Findings: Mothers' perceived benefits of the integrated services included time savings, opportunity to learn their child's HIV status and receive HIV treatment if necessary. Providers' perceived benefits included reaching mothers who usually would not come for only HIV testing. Mothers and providers reported similar challenges, including mothers' fear of HIV testing, poor spousal support, perceived mandatory HIV testing, poor patient flow affecting confidentiality of service delivery, heavier provider workloads, and community stigma against HIV-infected persons; the latter a more frequent theme in rural compared to urban locations.

Interpretation: Future scale-up should ensure privacy of these integrated services received at clinics and community outreach to address stigma and perceived mandatory testing. Increasing human resources for health to address higher workloads and longer waiting times for proper patient flow is necessary in the long term.

Abstract access 

Editor’s notes: In response to the poor uptake of antiretroviral therapy (ART) by children in Tanzania the Tanzanian Ministry of Health and Social Welfare and the US Centres for Disease Control and Prevention implemented a project to integrate early infant HIV diagnosis (EID) into routine immunisation visits in four urban and four rural clinics. The authors conducted a qualitative study to explore perceptions of this integrated service by mothers and health care providers. They conducted a large number of in depth interviews with mothers (66) and with health care providers (16). The majority of mothers and providers perceived the integrated services to be beneficial in relation to improving the uptake of HIV care and treatment. This is especially so as existing trust in immunisation services ensured that women were attending these services. However, they found a number of mixed messages about benefits for the mothers in terms of reduced costs and time in accessing both services together. Whilst most women reported cost and time savings, other women and providers reported that women spent a long time at the clinic, especially when queuing for both services. There were also issues in relation to confidentiality at the clinics concerning HIV status. Whilst many women trusted the staff to keep their information confidential, there were a number of ways in which the clinic processes were seen to compromise confidentiality. These included providing HIV services to groups of mothers together or providing care in designated HIV treatment rooms, which could be identified by other women at the clinic. This concern with confidentiality was important as women reported issues about stigma within their communities and fear of disclosure to partners or husbands who may be violent or leave them. There are concerns that this may impact on the uptake of immunization and the authors reported evidence of this in the rural clinics, from quantitative studies.

This paper highlights that future planning to provide more efficient services and increased uptake of HIV care and treatment needs to be highly sensitive to the ongoing issue of disclosure and stigma. Integrated services may provide a way to address this by providing all the services (such as immunisation and HIV care) in one session. In this way, other patients or mothers are not aware who is receiving HIV care. As the authors note though, this has implications for resource allocation.

Africa
United Republic of Tanzania
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The importance of continued infant prophylaxis against HIV-1 transmission throughout breastfeeding

Efficacy and safety of an extended nevirapine regimen in infants of breastfeeding mothers with HIV-1 infection for prevention of HIV-1 transmission (HPTN 046): 18-month results of a randomized, double-blind, placebo-controlled trial.

Fowler MG, Coovadia H, Herron CM, Maldonado Y, Chipato T, Moodley D, Musoke P, Aizire J, Manji K, Stranix-Chibanda L, Fawzi W, Chetty V, Msweli L, Kisenge R, Brown E, Mwatha A, Eshleman SH, Richardson P, Allen M, George K, Andrew P, Zwerski S, Mofenson LM, Jackson JB; for the HPTN 046 Protocol Team. J Acquir Immune Defic Syndr. 2013 Nov 1. [Epub ahead of print]

Background: HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to NVP or placebo to prevent postnatal infection: we report final 18 month outcomes.

Methods: Randomized, placebo-controlled trial in four African countries. Infant diagnostic HIV testing was done regularly from birth, through 18 months. Kaplan-Meier analysis was used to assess 18 month cumulative infant HIV infection, HIV infection/or death and mortality rates.

Results: Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower, among infants receiving daily NVP from 6 weeks to 6 months 1.1% (95% CI 0.2-1.8%), compared to placebo: 2.4% (95% CI 1.3-2.6%), p=0.049; but not significantly lower thereafter. Eighteen month postnatal infection rates were low: 2.2% [95% CI 1.1-3.3%] versus 3.1% [95% CI 1.9-4.4%], respectively, p=0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18 month postnatal infection rates (0.5%, 95% CI 0.0-1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI 1.9-5.5%); and infants of mothers with CD4 >350/mm not receiving ART (4.8%, 95% CI 2.7-6.8%), (p=0.46). There were no differences in adverse events between study arms.

Conclusion: This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age six weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.

Abstract access 

Editor’s notes: Despite increased coverage of antiretroviral treatment for pregnant women living with HIV, approximately 230 000 children are newly infected with HIV each year. The HPTN046 trial was designed to test the efficacy and safety of extended once daily infant nevirapine (NVP) prophylaxis to six months, among breastfed, HIV exposed infants who had received 6 weeks of NVP and were uninfected at age 6 weeks.  The trial was implemented at a time when breastfeeding was recommended to stop by 6 months for HIV exposed infants. This paper reports final HIV transmission, infant HIV-free survival and overall infant survival through to 18 months of age. Disappointingly, there was little evidence of a difference in postnatal HIV transmission rates between study arms (cumulative 18 month HIV-free survival rate of 94.5% in the NVP arm versus 93.3% in the placebo arm; p=0.32) and similar infant survival rates (95.3% versus 95.9%; p=0.72). The results of the 6 month follow-up, and the low transmission rate among infants whose mothers were on ART throughout 18 month follow-up emphasize the importance of ART provision to mothers who require it for their own health, and infant prophylaxis during the breastfeeding period (now recommended as 12 months). 

Africa
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Congenital CMV infection in Zambia – further population-based studies needed

High rates of congenital cytomegalovirus (CMV) infections linked with maternal HIV infection among neonatal admissions at a large referral centre in sub-Saharan Africa.

Mwaanza N, Chilukutu L, Tembo J, Kabwe M, Musonda K, Kapasa M, Chabala C, Sinyangwe S, Mwaba P, Zumla A, Bates M. Clin Infect Dis. 2013 Nov 21. [Epub ahead of print]

Congenital cytomegalovirus (CMV) infection is the major infectious cause of birth defects and hearing loss globally. There is a growing recognition of the potential clinical impact of congenital CMV infections in high seroprevalence settings.

Methods: A cross-sectional study of neonatal admissions at a large referral centre in sub-Saharan Africa to determine the prevalence of both symptomatic and asymptomatic congenital CMV infection. Real Time PCR was used to screen DNA-extracted from sera, urine and saliva, and an ELISA assay was used to screen sera for anti-CMV IgM. Multivariate binary logistic regression was used to identify risk factors associated with increased odds of congenital CMV infection.

Results: Congenital CMV was detected in 3.8% (15/395) of neonates. Among these cases 40% (6/15) presented with jaundice, one of which also had petechiae. Congenital CMV infection was detected in 11.4% (9/79) [6.1-20.3%] of neonates born to HIV-infected mothers and both maternal HIV (OR 6.661 [2.126-20.876], p=0.001) and jaundice (OR 5.701 [1.776-18.306], p=0.003) were independently linked with significantly increased odds of congenital CMV infection.

Conclusion: Congenital and early infant CMV infections may have important consequences for child health in sub-Saharan Africa and other high HIV and CMV seroprevalence populations globally.

Abstract access

Editor’s notes: Congenital cytomegalovirus (CMV) can lead to hearing impairment and neurodevelopmental delay, but few studies have estimated the prevalence of congenital CMV infection in Sub-Saharan Africa. This may be because it has been assumed that clinical impact of congenital CMV is likely to be low, resulting primarily from maternal re-infections or reactivations of CMV. This study recruited from an inpatient neonatal population in Lusaka, Zambia, and found a high prevalence of congenital CMV (3.8%) in this population and a strong association with maternal HIV infection.  The number of cases was small but a substantial minority (40%) were symptomatic. Limitations of the study include selection biases due to the recruitment process, and lack of information on antiretroviral status of the mother. Despite these, the study highlights the need for further, population-based studies in high HIV prevalence settings to assess the prevalence and risk factors for congenital CMV more widely, including the role of ART and maternal viral shedding on risk of transmission. 

Africa
Zambia
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Better outcomes with early time-limited versus deferred ART for infants in the CHER trial final results

Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial.

Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, Josipovic D, Liberty A, Lazarus E, Innes S, van Rensburg AJ, Pelser W, Truter H, Madhi SA,Handelsman E, Jean-Philippe P, McIntyre JA, Gibb DM, Babiker AG; CHER Study Team. Lancet. 2013 Nov 9;382(9904):1555-63. doi: 10.1016/S0140-6736(13)61409-9.

Background: Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART.

Methods: CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir-ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960.

Findings: 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35-109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART.

Interpretation: Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes.

Abstract access 

Editor’s notes: Early results of the CHER trial were published in 2008, showing that among infants aged 6-12 weeks, early vs. deferred antiretroviral therapy (ART) reduced mortality. These results were pivotal in prompting revisions to WHO guidelines. In 2010, WHO recommended universal ART for children under 2 years, irrespective of disease stage, and since 2013 have recommended universal ART for children under 5 years. These final results of the CHER trial confirm that early, time-limited ART is better than deferred ART in terms of the proportion of children who experienced failure of first-line ART or death. The trial was not powered to distinguish between the two early ART arms ---with ART interruption after 40 or 96 weeks and with re-initiation based on the CD4 percentage, although outcomes were slightly better for the 96-week arm. It also did not compare time-limited ART to continuous ART.

The strategy of interrupting ART for a period and restarting ART based on CD4 percentage is attractive but challenging to implement if CD4 monitoring is not available. These results add weight to WHO recommendations for early ART for infants. However, for children aged 1-5 years, the evidence concerning when to start ART is sparse, and further research is needed.

Africa
South Africa
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An integrated investment approach for women’s and children’s health

Advancing social and economic development by investing in women's and children's health: a new Global Investment Framework.

Stenberg K, Axelson H, Sheehan P, Anderson I, Gülmezoglu AM, Temmerman M, Mason E, Friedman HS, Bhutta ZA, Lawn JE, Sweeny K, Tulloch J, Hansen P, Chopra M, Gupta A, Vogel JP, Ostergren M, Rasmussen B, Levin C, Boyle C, Kuruvilla S, Koblinsky M, Walker N, de Francisco A, Novcic N, Presern C, Jamison D, Bustreo F; on behalf of the Study Group for the Global Investment Framework for Women's Children's Health. Lancet. 2013 Nov 18. doi: S0140-6736(13)62231-X. pii: 10.1016/S0140-6736(13)62231-X. [Epub ahead of print]

A new Global Investment Framework for Women's and Children's Health demonstrates how investment in women's and children's health will secure high health, social, and economic returns. We costed health systems strengthening and six investment packages for: maternal and newborn health, child health, immunisation, family planning, HIV/AIDS, and malaria. Nutrition is a cross-cutting theme. We then used simulation modelling to estimate the health and socioeconomic returns of these investments. Increasing health expenditure by just $5 per person per year up to 2035 in 74 high-burden countries could yield up to nine times that value in economic and social benefits. These returns include greater gross domestic product (GDP) growth through improved productivity, and prevention of the needless deaths of 147 million children, 32 million stillbirths, and 5 million women by 2035. These gains could be achieved by an additional investment of $30 billion per year, equivalent to a 2% increase above current spending.

Abstract access 

Editor’s notes: Over the past 20 years there have been substantial gains in maternal and child health (MCH). However, much still needs to be done – assuming a continuation of current rates of progress, there would nevertheless be shortfalls in the achievement of MDG 4 and 5 targets. Especially in sub-Saharan Africa, HIV is an important underlying cause of maternal and child ill health. This paper models the costs and benefits of an accelerated action on MCH, including for HIV, the prevention of mother to child HIV transmission; first line treatment for pregnant women; cotrimoxazole for children, and the provision of paediatric antiretroviral therapy (ART). These HIV services are complemented by health systems strengthening; increased family planning provision; and packages for malaria, immunisation, and child health. The paper is interesting for many reasons, including both the breadth of its intervention focus, and the detailed modelling of the likely health, social and economic benefits of such investments.

Although the direct HIV related benefits are not described in detail in the main paper, it is likely that these result both from increased contraceptive use (prong 2 for preventing vertical HIV transmission), as well as ART and cotrimoxazole provision. It also illustrates the potential value of developing a cross-disease investment approach, as a means to ensure that services effectively respond to the breadth of women’s and children’s health needs. This more ‘joined up’, integrated perspective on strategies for health investment can support core investments in health systems strengthening. It can also potentially achieve important cross-disease synergies, e.g., ensuring that a child who has not acquired HIV at birth does not then die from malaria. 

Africa, Asia, Latin America, Oceania
Afghanistan, Angola, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iraq, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Nepal, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, United Republic of Tanzania, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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