Ahmed, Saeed; Kim, Maria H.; Abrams, Elaine J.
In 2011, UNAIDS announced a call to eliminate new HIV infections among children by 2015 . This was a bold pronouncement, considering that almost 400 000 children were infected in that same year. How would the global community progress from 400 000 infections per year to elimination of mother-to-child-transmission (E-MTCT) in 4 short years? Much of the optimism surrounding the E-MTCT campaign followed recent advances in prevention of mother-to-child transmission (PMTCT) research, with several studies demonstrating that HIV transmission through breastfeeding could be prevented either by providing the mother with triple drug antiretroviral therapy (ART) or the infant with extended prophylaxis throughout breastfeeding [2–8]. With these new strategies, overall transmission could be reduced to less than 2% even in breastfeeding populations , finally allowing for the contemplation of not just PMTCT, but E-MTCT.
2010 WHO GUIDANCE FOR PREVENTION OF MOTHER-TO-CHILD HIV TRANSMISSION: OPTION A OR B?
In 2010, the WHO released new PMTCT guidelines , which emphasized initiation of lifelong ART for eligible women and offered two prophylaxis options for women with CD4 cell count (CD4) at least 350 cells/μl, who did not yet require ART for their own health, Options A and B (Table 1). Both required CD4 measurement to distinguish women who required ART for their own health from those requiring prophylaxis. Of 22 high-burden countries, the majority chose Option A, citing lower costs and similarity to the 2006 PMTCT guidelines, with only four countries choosing Option B (Table 1) . The Republic of Malawi, however, announced they would pursue a modified strategy.
THE EMERGENCE OF THE OPTION B+ APPROACH
In Malawi, release of the new guidelines was viewed as an opportunity to reboot the PMTCT program and align it with the more successful ART program. Malawi had not fully implemented 2006 WHO recommendations, with most sites still only offering single-dose nevirapine (sdNVP). The PMTCT program was viewed as overly complex, requiring special training, monitoring, and procurement. To address these issues, Malawi proposed Option B+ (B+)  (Table 2), a novel approach in which all HIV-infected pregnant and breastfeeding women, regardless of CD4 cell count, would be started on lifelong ART with a once daily, fixed-dose combination (FDC) regimen of tenofovir (TDF) with lamivudine (3TC) or emtricitabine (FTC) with efavirenz (EFV; Table 1).
DECONSTRUCTING THE EVIDENCE SURROUNDING THE OPTION B+ APPROACH
B+ has generated excitement and conjecture that it is the most promising approach to achieving E-MTCT. In 2012, WHO released a PMTCT update stating that ‘Options B and specifically B+ are likely to prove preferable to Option A for operational, programmatic and strategic reasons’ [13▪▪]. Though not officially a guideline, many viewed this update as an endorsement of B+ [14▪▪]. As of January 2013, 11 countries had endorsed B+ for their national PMTCT programs with an additional six actively costing and developing operational plans to switch over. What is the evidence for this rapidly developing consensus?
In this article, we review the current evidence informing the proposed benefits as well as potential risks of the B+ approach. Our analysis distinguishes individual health concerns for mother and child from programmatic and public health issues. We also summarize research priorities wherein data and experience with B+ are limited.
THE B+ APPROACH: RISKS AND BENEFITS FOR MOTHER AND CHILD
Discussed below and in Table 3 are five major issues of concern for individual patients impacted by B+.
Table 3-a Benefits a...Image Tools
Prevention of mother-to-child transmission efficacy and effectiveness
Table 3-b Benefits a...Image Tools
Table 3-c Benefits a...Image Tools
Options A and B have to date not been directly compared in a trial, though indirect evidence suggests similar efficacy [2–8,59▪]. The only studies to make direct comparisons, Kesho Bora  comparing in utero transmission and BAN  comparing postnatal transmission, both suggested similar MTCT rates at birth and at 7 months, respectively. The Promoting Maternal and Infant Survival Everywhere (PROMISE)-IMPAACT 1077 (NCT01061151) trial aims to further differentiate the impact of Options A and B on MTCT, infant HIV-free survival, and maternal health outcomes .
Although efficacy is believed to be similar, there are limited data on effectiveness outside clinical trials. Low early (4–8 weeks) MTCT rates have been reported for the South Africa national program under Option A conditions suggesting good overall effectiveness in a relatively well resourced health system [60▪▪]. However, several observational studies under Option A have reported paradoxically lower early MTCT rates among ART-eligible pregnant women receiving ART compared with noneligible women receiving short-course zidovudine (AZT) prophylaxis [15,16▪,17,61▪]. Women on ART had lower CD4 cell counts, a factor associated with MTCT, but were still less likely to transmit HIV. At the same time, no data are available to assess late MTCT through the end of breastfeeding in any programmatic settings.
Several studies have demonstrated that the lowest rates of transmission occur among women on ART at the time of conception [18–20,61▪]. Therefore, particularly in settings with high rates of unplanned pregnancies and poor penetration of family planning, B+ is likely to be superior to A and B for PMTCT in subsequent pregnancies.
The debate around the impact of B+ on maternal health has centered on women with CD4 cell count more than 350: whether ART will yield individual health benefits and; whether discontinuing ART, the Option B approach, will jeopardize long-term health outcomes. Mounting evidence suggests that women treated under B+ will benefit from early treatment [22–24] and avoid possible negative consequences associated with treatment interruptions [27–29]. Several modeling studies [62▪▪,63▪▪] predict improved maternal health outcomes with B+, with Ciaranello predicting an increased undiscounted maternal life expectancy of 1.16 and 1.12 years as compared to A and B, respectively. However, there have been no randomized clinical trials to determine whether starting lifelong ART at higher CD4 results in measurable health benefits compared with delaying initiation until CD4 declines to 350 or less . INSIGHT's strategic timing of anti-retroviral treatment (START) (NCT00867048) trial, is addressing this question among nonpregnant adults . Further, for pregnant women, cessation of ART has not been compared to continuous treatment in women with CD4 more than 350 [30▪▪]. The PROMISE trial will examine the impact of early ART and treatment interruption on maternal health and survival .
With increased use of ART via B+, more fetuses and infants will be exposed to multiple antiretrovirals (ARVs) from conception through breastfeeding. ART has been associated in several studies with increased risk of poor outcomes, including stillbirth delivery, preterm delivery, and small-for-gestational-age babies as compared to AZT monotherapy [47▪▪,50▪▪,51▪▪,52]. Risks may also extend beyond the neonatal period. Although several studies have demonstrated no association between in utero ARV exposure and neurodevelopmental outcomes [44▪,48,64–67], data on the effects of ART exposure during pregnancy and breastfeeding on postnatal development and growth are limited. At the same time, several studies have drawn an association between in utero AZT exposure and pediatric mitochondrial disorders [45,46], underscoring that any ARV use during pregnancy is not without risk to the fetus.
Specific concerns have been raised about the safety of EFV and TDF, two of the drugs in the recommended B+ regimen. Although TDF has been associated with renal damage and bone density loss, studies to date suggest no increase in poor pregnancy outcomes [41▪▪,42▪▪] or birth defects in infants with TDF exposure as compared with non-TDF ART [41▪▪,43▪]. However, uncertainty about effects on long-term growth emphasizes the need for follow-up studies [41▪▪]. EFV has been more controversial due to the association with significant central nervous system defects in animal studies and retrospective case reports [68–70]. A recently updated meta-analysis reported 39 birth defects among live-births in 1437 women receiving first trimester EFV [2.0%, 95% confidence interval, CI (0.82–3.18)]. The relative risk of birth defects when comparing women on EFV-based (1290 live-births) and non-EFV-based regimens (8122 live-births) was 0.85 (CI 0.61–1.20). Only one neural tube defect was observed, giving an incidence of 0.07% (CI 0.002–0.39), lower than what is reported in the general population [39,40]. However, a much larger sample size is needed to definitively rule out a two-fold increase in low-incidence birth defects [71▪▪]. Indeed, a recent observational study in the USA reported increased birth defects with first trimester EFV use . Although it appears that the potential risks with EFV exposure is low, given the large numbers of women likely to become pregnant on EFV with B+ , surveillance for birth defects and adverse outcomes is warranted.
Proper adherence to treatment is a challenge worldwide, in both resource-rich and resource-limited settings. Women may be particularly vulnerable to disruptions in adherence during pregnancy and breastfeeding. In a systematic review and meta-analysis [54▪▪], including 53 studies from over 20 countries, adequate adherence (>80%) was shown to drop from 75.7% (CI 71.5–79.7) during pregnancy to 53% (CI 32.8–72.7) postpartum among women on ART. Most women included in these studies, however, did not receive a once-daily FDC, which has been associated with improved adherence when compared with a twice-daily regimen .
For patients in resource-limited settings, the B+ approach represents a radical departure in messaging wherein until now patients have been advised they should wait until they get sick or their CD4 cell counts are low before starting medication. Massive public education and sensitization will be needed for the population to understand this shift in strategy. Indeed, a recent report of focus group discussions held in Uganda and Malawi concerning B+ with communities of people living with HIV, highlighted varied and limited understanding of what B+ entails, and particular concerns about side-effects and adherence when initiating ART with a high CD4 [37▪▪]. Without concerted efforts to address these concerns, the B+ approach may contribute to the risk of inadequate adherence despite the advantages of the simplified approach.
Resistance in infected infants
Resistance in HIV-infected infants exposed to PMTCT will likely be a major challenge regardless of PMTCT regimen. Infants infected while receiving extended nevirapine (NVP) under Option A are at high risk for NNRTI resistance [55,56]. Under Options B/B+, due to frequent breastfeeding and reduced clearance of ARVs in infants, infants will be exposed to biologically significant ARV concentrations leading to potential development of multidrug resistance. In the Kisumu Breastfeeding Study (KIBS) of maternal prophylaxis with AZT/3TC/NVP or nelfinavir, drug-resistant virus was identified in 67% of infected infants including M184V (3TC) and K103N (NVP) mutations . The pattern of acquisition of mutations suggests that drug resistance developed due to exposure of the infant to subtherapeutic ARV levels present in breast milk, rather than through transmission of drug-resistant virus. Although effective PMTCT is expected to substantially decrease the number of new pediatric infections, those children who fail PMTCT will likely harbor nonnucleoside reverse transcriptase inhibitor (NNRTI) and possibly NRTI-resistant virus. Availability of potent ART regimens will be critical to ensure successful treatment of these infants [73,74].
THE B+ APPROACH: RISKS AND BENEFITS FOR PROGRAM DELIVERY AND PUBLIC HEALTH
Discussed below and in Table 4 are five major issues for program delivery and public health impacted by B+.
Table 4-a Benefits a...Image Tools
Reduced transmission to partners
Table 4-b Benefits a...Image Tools
Several clinical and modeling studies have shown that ART can reduce incidence of HIV and is strongly protective of HIV-uninfected partners in serodiscordant couples. In the HPTN 052 study, starting ART for the infected partner in a serodiscordant couple resulted in a 96% reduction in HIV transmission to the uninfected partner [75–79]. This may be of particular importance during pregnancy as risk of transmission may be higher: the Partners in Prevention Study demonstrated that HIV-1 incidence in male partners of infected women was 3.46 vs. 1.58 per 100 person-years when their partners were pregnant vs. not pregnant (hazard ratio 2.31, CI 1.22–4.39) .
B+ harmonizes with efforts for universal treatment access [1,25▪,26] and will be the first large-scale intervention to utilize a ‘test and treat’ approach [35,36,92]. The benefit of treatment as prevention will likely vary between countries due to differences in population size, HIV prevalence, and proportion of couples that are discordant . El-Sadr et al.  modeled the epidemic impact of treating all HIV-serodiscordant couples and demonstrated a large reduction in HIV incidence in Malawi, but only a small reduction in Ghana. As the B+ approach only provides universal treatment to a subset of the population, pregnant and breastfeeding women, the prevention benefits may be restricted to their individual partners with limited impact on population level incidence.
From a programmatic standpoint, B+ simplifies many aspects of PMTCT implementation. All HIV-infected pregnant and breastfeeding women, on identification, are started on lifelong ART. There is no need for immunologic or clinical staging, eliminating a critical hurdle for treatment initiation . B+ allows for rapid scale-up with full integration of PMTCT and ART, getting pregnant women onto treatment quickly and efficiently. Utilizing one FDC pill for all adults, harmonizing regimens for ART and PMTCT, B+ facilitates forecasting and procurement and is in line with international efforts toward ARV simplification [93,94]. With B+, there is potential for fewer medication errors with one drug throughout pregnancy, delivery, and breastfeeding rather than the switches that occur with Option A. As compared with Option B, there is no need for CD4 to stop medication after breastfeeding cessation and restart with subsequent pregnancies.
Despite these benefits, logistical concerns persist. B+ harmonizes regimens, but institutes different initiation criteria for a subset of adults (pregnant and breastfeeding women), potentially creating confusion and conflict. Two parallel clinical tracks are created, with most adults still requiring staging before initiating treatment. A recent evaluation among individuals living with HIV in Malawi and Uganda suggests communities may not understand or accept this differential access to ART [37▪▪]. Furthermore, how best to monitor failure among women started on treatment under B+, those without CD4 as well as those with high CD4, is yet to be determined.
Access to care and uptake of services
By making program delivery simpler as described above, B+ facilitates decentralization of services, improving access and uptake of services. A recent report from Malawi using aggregate country-level data demonstrated that implementation of B+ resulted in an eight-fold increase in maternal ART initiations, with the number receiving ART jumping from 1257/quarter to 10 663/quarter after B+ implementation [84▪▪]. This significant increase in coverage included all pregnant and breastfeeding women. Due to limited CD4 coverage in Malawi, it is unknown whether B+ has improved ART initiation rates for eligible women, but based on the absolute numbers, this seems likely. In addition, 2689 (25.2%) of these women initiated ART while breastfeeding. Why these women were not started on ART during pregnancy is unknown.
These data contrast with reports from countries implementing Option A type regimens demonstrating that ART-eligible pregnant women are not adequately being linked to HIV care services [86,87▪,88,89]. A systematic review [85▪▪] with 16 studies from sub-Saharan Africa found a failure to initiate ART in 38–88% of eligible women. On the contrary, findings from the South African PMTCT Effectiveness (SAPMTCTE) nationally representative PMTCT survey demonstrated encouraging results with 98.8% of women receiving an HIV test during pregnancy, 78.3% having CD4 testing, and 91.8% receiving either ART or ARV prophylaxis [60▪▪]. Better-resourced health services likely contributed to the more robust performance of Option A in South Africa compared to other countries.
In terms of access, ethical concerns have been raised that initiating lifelong ART among healthy pregnant women, a lower risk group for transmission and disease progression, may divert resources from sicker patients. This is a critical concern, considering that fewer than 50% of eligible adults worldwide are receiving treatment .
Retention and linkages in care
Retention in care is a major challenge facing all PMTCT programs, with numerous reports consistently demonstrating high rates of loss-to-follow-up along the PMTCT cascade [88,89,96–101]. In one representative study from Tanzania [87▪], of 240 women, 123 (51.3%) were referred to HIV clinic, 71 (57.7%) attended, 30 (24.3%) received CD4 testing, five (16.7%) were ART-eligible, and three initiated ART. PMTCT efficacy is limited if women and infants do not access all available services, remain in care and on therapy throughout the duration of MTCT risk . By simplifying service delivery and reducing the number of steps that mothers need to negotiate, B+ should improve retention and transmission outcomes. Preliminary data from Malawi demonstrate B+ not only increased maternal ART initiations, but also that 77% continued to receive ART at 12 months [84▪▪]. Although this rate is comparable to nonpregnant adults, retention will need to improve if E-MTCT is to be achieved.
Retention and linkage into care of HIV-exposed and infected infants are of particular concern, with a mere 6–15% of HIV-exposed infants receiving an HIV test [13▪▪,102]. This challenge is common across all PMTCT approaches. In the SAPMTCTE study, only 35.1% of HIV-infected mothers intended to access early infant diagnosis services [60▪▪]. In Malawi's recent HIV program report, of 8700 HIV-exposed infants discharged from maternity, only 3778 (43%) were enrolled in follow-up before age 2 months . Further, no programs outside of clinical trials have reported on long-term outcomes and final infection status of exposed infants, speaking to the difficulty in retaining infants in follow-up care. Improving infant retention is not only critical for preventing new pediatric infections, but also for reducing mortality in those infants who become infected through rapid ART initiation .
A number of studies have demonstrated that extended combination prophylaxis whether with Option A, B, or B+ is cost effective compared with no intervention, sdNVP, or short-course prophylaxis [104–108,109▪,110,111▪▪]. Ciaranello et al.[62▪▪] using a Zimbabwe-based model, concluded that Option B would improve outcomes and decrease costs compared to Option A. B+ further improves outcomes over Option B, increasing maternal life expectancy by 1.12 years, with an incremental cost–effectiveness ratio of US$1370 per year life saved. Fasawe et al.[63▪▪], using a Malawi-based model, concluded that Option A was the most cost-effective regimen for preventing infant infections and improving maternal outcomes. However, maternal outcomes overall were far superior with B+. Of 66 500 women entering PMTCT, 42 137 would still be alive after 10 years with B+, as compared to only 30 057 with B and 28 567 with A.
Some experts have expressed concern that starting all pregnant women on lifelong ART will lead to a massive expansion of the overall ART program, perhaps to a degree greater than current health systems can absorb [14▪▪]. The short-term costs of B/B+ for women who do not qualify for ART are roughly four to five times the cost of Option A prophylaxis. This does not account for the added B+ ART costs between pregnancies for women who do not require it for their own health. Over a 10-year period in Malawi, B+ is estimated to cost 2–2.5 times more than Options A or B [63▪▪]. Consequently, despite better long-term outcomes and associated healthcare cost savings predicted with B+, Option A may be more cost effective, especially in scenarios in which poor adherence with consequent early virologic failure or high rates of lost-to-follow-up is common [62▪▪]. This is a particularly important consideration for resource-constrained nations that are balancing ART costs with other critical health expenditures.
Considerable debate has emerged on whether Option B+ is the best approach to achieving elimination of mother-to-child transmission. As detailed above, and in Tables 3 and 4, there are both considerable benefits and risks entailed with B+, for individual patients, for health systems, and for society at large. B+ represents a profound paradigm shift, in which treatment initiation is based not solely on the health needs of the individual patient, but also on the transmission risk that the patient represents.
Analysis in this paper was based on current ART guidelines at CD4 less than 350. If global treatment guidelines endorse a higher CD4 criteria of 500 for ART initiation, the risks and benefits analysis changes. With a higher CD4 cut-off, the majority of pregnant women would qualify for treatment with proportionately fewer needing prophylaxis . The purported individual health benefits of B+ over A and B would largely be blunted, as the only women not eligible for lifelong treatment would be those with CD4 more than 500, a low risk group both for progression and transmission. However, if the majority of women now qualify for treatment based on their own health, the programmatic advantages of B+ in terms of simplicity and feasibility may be even stronger. Why should the health system expend effort to find that minority of patients who would qualify for prophylaxis as opposed to treatment?
The debate over regimen has obscured the larger operational issues facing all PMTCT programs regardless of approach – identification of HIV-infected pregnant women, continuity of care, and follow-up of infants. Indeed, the major challenge facing national PMTCT programs is more fundamental and system-based than regimen. Broadly speaking, HIV-infected women are not adequately identified, when identified are not referred properly for HIV care, are frequently lost to follow-up, and are not adequately linked to their infants. Even the most efficacious regimen is useless if women and infants do not receive them.
A majority of high-burden countries are actively implementing or making plans to implement B+. Included within those plans should be measures to address the many outstanding issues we have highlighted, including implementing rigorous monitoring and evaluation systems to document maternal and child outcomes with surveillance systems for birth defects and toxicities from ART exposure, ensuring availability of potent ART regimens for treatment of infected infants, and instituting programs to address uptake, adherence, and retention. Furthermore, it will be critical to actively engage communities, particularly women of childbearing age living with HIV, to ensure optimal health outcomes for mothers and their children. However, we should be cautiously optimistic that this long-awaited global attention to PMTCT will propel substantial progress toward E-MTCT in the coming years.
The authors would like to thank Andrea Ciaranello for critical review of the costing sections of this review.
Conflicts of interest
The authors have no conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 518).
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Study using early infant diagnosis data from 2007 to 2010 in Zambia to evaluate risk factors for HIV transmission. Demonstrates increased MTCT when mothers received AZT/sd-NVP (885/9197 = 9.6%) vs. HAART (511/8698 = 5.9%).
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41▪▪. Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med 2012; 9:e1001217Epub 2012/05/23.
Reassuring information from a subanalysis of the Development of Antiretroviral Therapy (DART) trial that found no evidence that TDF (compared with non-TDF ART) had adverse effects on pregnancy outcomes or on congenital, renal, bone, or growth abnormalities up to age 4 years among children born to women with severe HIV immunodeficiency at ART initiation and exposed throughout the intrauterine period. Small sample size (226 live births, 182 enrolled) was a limitation.
42▪▪. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26:1151–1159.Epub 2012/03/03.
US-based prospective cohort study of HIV-exposed uninfected children found no differences in birth outcomes [SGA, LBW, or newborn length-for-age z-scores (LAZ), and head circumference-for-age (HCAZ) z-scores] between children exposed vs. not exposed to TDF during pregnancy. However, at age 1 year, TDF-exposed infants had significantly lower adjusted mean LAZ and HCAZ. Findings provide reassurance about TDF safety in pregnancy, but the significance of the findings 1 year is unclear, suggesting need for more study.
43▪. Colbers A, Hawkins D, Gingelmaier A, et al. The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1 infected pregnant women. AIDS 2012; 27:739–748.
Pharmacokinetics study among 34 women demonstrating that though TDF and FTC exposure is approximately 25% lower during the third trimester of pregnancy compared with the postpartum period, there was no evidence that lower drug levels impacted viral suppression or MTCT outcomes.
44▪. Sirois PA, Huo Y, Williams PL, et al. Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants. Pediatr Infect Dis J 2013; Epub 2013/01/24.
Study of 374 HIV-exposed, uninfected infants (age 9–15 months) enrolled in the SMARTT study (multisite prospective study of HIV and ARV-exposed children) evaluating neurodevelopmental outcomes using the Bayley Scales of Infant and Toddler Development (Bayley-III). No Bayley-III outcome was significantly associated with overall perinatal exposure to ARVs.
45. Heidari S, Mofenson L, Cotton MF, et al. Antiretroviral drugs for preventing mother-to-child transmission of HIV: a review of potential effects on HIV-exposed but uninfected children. J Acquir Immune Defic Syndr 2011; 57:290–296.Epub 2011/05/24.
46. Barret B, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17:1769–1785.Epub 2003/08/02.
47▪▪. Watts DH, Mofenson LM. Antiretrovirals in pregnancy: a note of caution. J Infect Dis 2012; 206:1639–1641.Epub 2012/10/16.
Commentary on findings by Chen et al. highlighting findings of an increased risk of preterm birth among women receiving HAART, compared with ZDV and dual nucleoside regimens. The authors suggest that the increased risk of adverse birth outcomes associated with ART exposure makes ZDV prophylaxis an important option among women not eligible for treatment.
48. Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J 2010; 29:721–727.Epub 2010/06/12.
49. Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J 2012; 31:164–170.Epub 2011/10/11.
50▪▪. Watts DH, Williams PL, Kacanek D, et al. Combination antiretroviral use and preterm birth. J Infect Dis 2013; 207:612–621.Epub 2012/12/04.
In a study including 1869 live-births of infants born to mothers receiving PMTCT in the United States, only combination regimens including a protease inhibitor started in the first trimester were associated with increased risk of preterm birth or spontaneous preterm birth. There was no increased risk with NNRTI-based regimens, triple nucleoside regimens, or ARV exposure starting later in pregnancy.
51▪▪. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206:1695–1705.Epub 2012/10/16.
Study evaluating data abstracted from obstetric medical records to compare rates of adverse pregnancy outcomes among HIV-infected women in Botswana, demonstrating that initiating HAART during pregnancy compared to AZT was associated with a significantly increased risk of stillbirth delivery, preterm delivery, small-for-gestational-age infants, and neonatal death. When analyses were limited to the 49% of women with available CD4+, no differences were observed in the findings, suggesting ART exposure, not maternal health was the cause of the association.
52. Townsend CL, Tookey PA, Newell ML, Cortina-Borja M. Antiretroviral therapy in pregnancy: balancing the risk of preterm delivery with prevention of mother-to-child HIV transmission. Antivir Ther 2010; 15:775–783.Epub 2010/08/17.
53. Buscher A, Hartman C, Kallen MA, Giordano TP. Impact of antiretroviral dosing frequency and pill burden on adherence among newly diagnosed, antiretroviral-naive HIV patients. Int J STD AIDS 2012; 23:351–355.Epub 2012/06/01.
54▪▪. Nachega JB, Uthman OA, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. AIDS 2012; 26:2039–2052.Epub 2012/09/07.
Important systematic review and meta-analysis examines adherence during pregnancy reviewing 51 studies, from over 20 high-resource and low-resource countries involving 20 153 HIV-infected pregnant women, suggesting that good adherence (>80%) was higher during pregnancy (75.7%) compared to the postpartum period (53.0%). Highlights that adherence is a major concern, regardless of PMTCT regimen, especially in the postpartum period.
55. Moorthy A, Gupta A, Bhosale R, et al. Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants. PloS One 2009; 4:e4096Epub 2009/01/03.
56. Persaud D, Bedri A, Ziemniak C, et al. Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission. AIDS Res Hum Retroviruses 2011; 27:823–829.Epub 2011/01/19.
57. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother 2009; 53:1170–1176.Epub 2008/12/31.
58. Zeh C, Weidle PJ, Nafisa L, et al. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med 2011; 8:e1000430Epub 2011/04/07.
59▪. Hudgens MG, Taha TE, Omer SB, et al. Pooled individual data analysis of 5 randomized trials of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Clin Infect Dis 2013; 56:131–139.Epub 2012/09/22.
Pooled analysis from five randomized clinical trials further demonstrating that extended prophylaxis with NVP significantly reduces postnatal HIV-1 infection in breastfeeding infants. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
60▪▪. SAPMTCTE study group. Evaluation of the Effectiveness of the National Prevention of Mother-to-Child Transmission (PMTCT) Programme Measured at Six Weeks Postpartum in South Africa, 2010. South African Medical Research Council, National Department of Health of South Africa and PEPFAR/US Centers for Disease Control and Prevention; 2012.
Nationally representative PMTCT survey from South Africa demonstrating low rates of early MTCT under Option A conditions: 98.8% of pregnant women received an HIV test, 78.3% had a CD4 cell count done, and 91.8% received either HAART or ARV prophylaxis. The national weighted infant HIV-exposure prevalence was 32.0% (95% CI 30.7–33.3%) and the national weighted MTCT rate measured at 4–8 weeks of infant age was 3.5% (95% CI 2.9–4.1%.).
61▪. Kim MH, Ahmed S, Buck WC, et al. The Tingathe programme: a pilot intervention using community health workers to create a continuum of care in the prevention of mother to child transmission of HIV (PMTCT) cascade of services in Malawi. J Int AIDS Soc 2012; 15 (4 Suppl 2):1–11.
Descriptive study of a community health worker intervention demonstrates improvement in uptake, retention, and outcomes within the Malawi PMTCT program at three high-burden health centers implementing the full combination prophylaxis regimen prior to B+ roll-out.
62▪▪. Ciaranello AL, Perez F, Engelsmann B, et al. Cost–effectiveness of World Health Organization 2010 Guidelines for prevention of mother-to-child HIV transmission in Zimbabwe. Clin Infect Dis 2013; 56:430–446.Epub 2012/12/04.
Comprehensive modeling with extensive sensitivity analyses comparing cost-effectiveness of implementing four PMTCT regimens in Zimbabwe: sd-NVP, Options A, B, and B+. Modeling demonstrates the following: Option A improves outcomes and reduces costs as compared to sd-NVP; Option B further improves outcomes compared to Option A and is cost saving within 4 years after delivery; Option B+ further improves maternal and infant health, with an ICER of US$1370 per Year Life Saved compared with Option B.
63▪▪. Fasawe O, Avila C, Shaffer N, et al. Cost–effectiveness analysis of Option B+ for HIV prevention and treatment of mothers and children in Malawi. PloS One 2013; 8:e57778.
Important modeling analysis assessing cost–effectiveness of B+ in Malawi. Authors found that Option A is the most cost-effective PMTCT approach for prevention of new pediatric infections, but that maternal outcomes would be substantially better with B+. Of 66 500 women entering PMTCT, 42 137 would still be alive after 10 years with B+, as compared to 30 057 with B and 28 567 with A.
64. European Collaborative StudyExposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003; 32:380–387.Epub 2003/03/18.
65. Alimenti A, Forbes JC, Oberlander TF, et al. A prospective controlled study of neurodevelopment in HIV-uninfected children exposed to combination antiretroviral drugs in pregnancy. Pediatrics 2006; 118:e1139–e1145.Epub 2006/08/31.
66. Williams PL, Marino M, Malee K, et al. Neurodevelopment and in utero antiretroviral exposure of HIV-exposed uninfected infants. Pediatrics 2010; 125:e250–e260.Epub 2010/01/20.
67. Lindsey JC, Malee KM, Brouwers P, Hughes MD. Neurodevelopmental functioning in HIV-infected infants and young children before and after the introduction of protease inhibitor-based highly active antiretroviral therapy. Pediatrics 2007; 119:e681–e693.Epub 2007/02/14.
68. Fundaro C, Genovese O, Rendeli C, et al. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS 2002; 16:299–300.Epub 2002/01/25.
69. De Santis M, Carducci B, De Santis L, et al. Periconceptional exposure to efavirenz and neural tube defects. Arch Internal Med 2002; 162:355Epub 2002/02/28.
70. Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol 2005; 25:555–556.Epub 2005/07/28.
71▪▪. World Health OrganizationUse of efavirenz during pregnancy: a public health perspective. 2012; Geneva, Switzerland:World Health Organization
Technical update reviewing the evidence on safety, tolerability, and efficacy of EFV. Argues that review of recent clinical and programmatic data provides reassurance that exposure to EFV in early pregnancy has not increased the rate of birth defects of other significant toxicities, and that EFV provides superior viral suppression, better side-effect profile, and lower risk of resistance as compared to NVP. Supports the use of EFV in pregnant women and those of reproductive age.
72. Myer L, Carter RJ, Katyal M, et al. Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub-Saharan Africa: a cohort study. PLoS Med 2010; 7:e1000229Epub 2010/02/18.
73. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med 2010; 363:1510–1520.Epub 2010/10/15.
74. Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 2012; 366:2380–2389.Epub 2012/06/22.
75. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493–505.Epub 2011/07/20.
76. El-Sadr WM, Coburn BJ, Blower S. Modeling the impact on the HIV epidemic of treating discordant couples with antiretrovirals to prevent transmission. AIDS 2011; 25:2295–2299.Epub 2011/10/14.
77. Bunnell R, Ekwaru JP, Solberg P, et al. Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. AIDS 2006; 20:85–92.Epub 2005/12/06.
78. Mugo NR, Heffron R, Donnell D, et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. AIDS 2011; 25:1887–1895.Epub 2011/07/26.
79. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 2010; 375:2092–2098.Epub 2010/06/12.
80. Barker PM, Mphatswe W, Rollins N. Antiretroviral drugs in the cupboard are not enough: the impact of health systems’ performance on mother-to-child transmission of HIV. J Acquir Immune Defic Syndr 2011; 56:e45–e48.Epub 2010/11/19.
81. Hosseinipour MC, van Oosterhout JJ, Weigel R, et al. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS 2009; 23:1127–1134.Epub 2009/05/07.
82. Mugyenyi P, Walker AS, Hakim J, et al. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised noninferiority trial. Lancet 2010; 375:123–131.Epub 2009/12/17.
83. Laurent C, Kouanfack C, Laborde-Balen G, et al. Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised noninferiority trial. Lancet Infect Dis 2011; 11:825–833.Epub 2011/08/13.
84▪▪. CDCImpact of an innovative approach to prevent mother-to-child transmission of HIV – Malawi, July 2011-September 2012. MMWR Morbid Mortal Wkly Rep 2013; 62:148–151.Epub 2013/03/01.
First programmatic report from Malawi after implementation of B+. Over 1 year, service delivery was decentralized from 303 ART sites to 641 integrated PMTCT/ART sites with a eight-fold increase in maternal ART initiations (during pregnancy and breast feeding), from 1257/quarter to 10 663/quarter after B+ implementation.
85▪▪. Ferguson L, Grant AD, Watson-Jones D, et al. Linking women who test HIV-positive in pregnancy-related services to long-term HIV care and treatment services: a systematic review. Trop Med Int Health 2012; 17:564–580.Epub 2012/03/08.
Systematic review demonstrating that pregnant women needing ART for their own health are not adequately linked to HIV services. Included 16 studies from sub-Saharan Africa and found a failure to initiate treatment in 38–88% of eligible women.
86. Braun M, Kabue MM, McCollum ED, et al. Inadequate coordination of maternal and infant HIV services detrimentally affects early infant diagnosis outcomes in Lilongwe, Malawi. J Acquir Immune Defic Syndr 2011; 56:e122–e128.Epub 2011/01/13.
87▪. Watson-Jones D, Balira R, Ross DA, et al. Missed opportunities: poor linkage into ongoing care for HIV-positive pregnant women in Mwanza, Tanzania. PloS One 2012; 7:e40091Epub 2012/07/19.
Excellent study documenting poor retention within the PMTCT cascade with short-course AZT prophylaxis (WHO 2006 guidelines) in Tanzania. Of 240 women diagnosed HIV-positive, 123 (51.3%) were referred to HIV clinic, 71 (57.7%) attended, 30 (24.3%) received CD4 testing, five (16.7%) were found eligible, and three initiated HAART.
88. Killam WP, Tambatamba BC, Chintu N, et al. Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation. AIDS 2010; 24:85–91.Epub 2009/10/08.
89. Hussain A, Moodley D, Naidoo S, Esterhuizen TM. Pregnant women's access to PMTCT and ART services in South Africa and implications for universal antiretroviral treatment. PloS One 2011; 6:e27907Epub 2011/12/14.
90▪▪. Horwood C, Vermaak K, Butler L, et al. Elimination of paediatric HIV in KwaZulu-Natal, South Africa: large-scale assessment of interventions for the prevention of mother-to-child transmission. Bull World Health Organ 2012; 90:168–175.Epub 2012/03/31.
Evaluation of PMTCT in six districts in KwaZulu-Natal, South Africa utilizing early infant diagnosis among 4–8-week-old infants attending immunization clinics combined with a maternal survey. Found encouraging results with short-course AZT (WHO 2006 guidelines). Overall 89.9% of mothers received HIV testing and of those reporting HIV-positive, 79.9% received CD4 testing and 80.9% received either ART or prophylaxis. Early MTCT rate was 7.1%.
91. Malawi Ministry of Health. Integrated HIV program Report, July–September 2012, Lilongwe, Malawi.
92. Zachariah R, Harries AD, Philips M, et al. Antiretroviral therapy for HIV prevention: many concerns and challenges, but are there ways forward in sub-Saharan Africa? Trans R Soc Trop Med Hyg 2010; 104:387–391.Epub 2010/02/02.
93. World Health OrganizationThe treatment 2.0 framework for action: catalysing the next phase of treatment, care and support. Geneva, Switzerland:World Health Organization; 2011.
94. World Health OrganizationThe strategic use of antiretrovirals to help end the HIV epidemic. Geneva, Switzerland:World Health Organization; 2012.
95. Scanlon ML, Vreeman RC. Current strategies for improving access and adherence to antiretroviral therapies in resource-limited settings. HIV AIDS (Auckl) 2013; 5:1–17.Epub 2013/01/18.
96. Ahoua L, Ayikoru H, Gnauck K, et al. Evaluation of a 5-year programme to prevent mother-to-child transmission of HIV infection in Northern Uganda. J Trop Pediatr 2010; 56:43–52.Epub 2009/07/16.
97. Stringer EM, Ekouevi DK, Coetzee D, et al. Coverage of nevirapine-based services to prevent mother-to-child HIV transmission in 4 African countries. JAMA 2010; 304:293–302.Epub 2010/07/20.
98. Mirkuzie AH, Hinderaker SG, Sisay MM, et al. Current status of medication adherence and infant follow up in the prevention of mother to child HIV transmission programme in Addis Ababa: a cohort study. J Int AIDS Soc 2011; 14:50Epub 2011/10/25.
99. Manzi M, Zachariah R, Teck R, et al. High acceptability of voluntary counselling and HIV-testing but unacceptable loss to follow up in a prevention of mother-to-child HIV transmission programme in rural Malawi: scaling-up requires a different way of acting. Trop Med Int Health 2005; 10:1242–1250.Epub 2005/12/20.
100. Wettstein C, Mugglin C, Egger M, et al. Missed opportunities to prevent mother-to-child-transmission: systematic review and meta-analysis. AIDS 2012; 26:2361–2373.Epub 2012/09/06.
101. Tudor Car L, Brusamento S, Elmoniry H, et al. The uptake of integrated perinatal prevention of mother-to-child HIV transmission programs in low- and middle-income countries: a systematic review. PloS One 2013; 8:e56550Epub 2013/03/14.
102. Kellerman S, Essajee S. HIV testing for children in resource-limited settings: what are we waiting for? PLoS Med 2010; 7:e1000285Epub 2010/07/24.
103. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359:2233–2244.Epub 2008/11/21.
104. Johri M, Ako-Arrey D. The cost-effectiveness of preventing mother-to-child transmission of HIV in low- and middle-income countries: systematic review. Cost Eff Resour Alloc 2011; 9:3Epub 2011/02/11.
105. Orlando S, Marazzi MC, Mancinelli S, et al. Cost-effectiveness of using HAART in prevention of mother-to-child transmission in the DREAM-Project Malawi. J Acquir Immune Defic Syndr 2010; 55:631–634.Epub 2011/09/22.
106. Robberstad B, Evjen-Olsen B. Preventing mother to child transmission of HIV with highly active antiretroviral treatment in Tanzania: a prospective cost-effectiveness study. J Acquir Immune Defic Syndr 2010; 55:397–403.Epub 2010/08/27.
107. Shah M, Johns B, Abimiku A, Walker DG. Cost-effectiveness of new WHO recommendations for prevention of mother-to-child transmission of HIV in a resource-limited setting. AIDS 2011; 25:1093–1102.Epub 2011/04/21.
108. Kuznik A, Lamorde M, Hermans S, et al. Evaluating the cost-effectiveness of combination antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Uganda. Bull World Health Organ 2012; 90:595–603.Epub 2012/08/16.
109▪. Ciaranello AL, Perez F, Keatinge J, et al. What will it take to eliminate pediatric HIV? Reaching WHO target rates of mother-to-child HIV transmission in Zimbabwe: a model-based analysis. PLoS Med 2012; 9:e1001156Epub 2012/01/19.
Comprehensive modeling examining the hypothetical impact of sd-NVP, and Options A and B on PMTCT outcomes in Zimbabwe. Authors found that at current uptake levels, even with the more efficacious regimens, MTCT risk is estimated at 14.4% (Option A) or 13.4% (Option B). Only with 95% uptake of Option A or Option B, would projected transmission risks (6.1–7.7%) approach the WHO goal of less than 5%. These findings support the importance of PMTCT access and retention in addition to ARV regimen to achieve elimination goals.
110. Ciaranello AL, Perez F, Maruva M, et al. WHO 2010 guidelines for prevention of mother-to-child HIV transmission in Zimbabwe: modeling clinical outcomes in infants and mothers. PloS One 2011; 6:e20224Epub 2011/06/10.
111▪▪. Sawe F, Lockman S. Editorial commentary: To B or Not to B? That Is the Question, for Global Mother-to-Child HIV-1 Transmission Prevention Programs. Clin Infect Dis 2013; 56:447–449.Epub 2012/12/04.
Commentary in response to Ciaranello et al. PMTCT cost–effectiveness modeling proposing that both Options B and B+ will improve maternal and infant outcomes compared to Option A. Option B+ has several programmatic and epidemiologic advantages over Option B including reduced transmission to partners and lower likelihood of emerging resistance with treatment interruption.
112. Carter RJ, Dugan K, El-Sadr WM, et al. CD4+ cell count testing more effective than HIV disease clinical staging in identifying pregnant and postpartum women eligible for antiretroviral therapy in resource-limited settings. J Acquir Immune Defic Syndr 2010; 55:404–410.Epub 2010/07/03.
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