Expert Review of Anti-infective Therapy

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Efavirenz-based antiretroviral therapy versus nevirapine-including regimens for prevention of mother-to-child transmission of HIV option B plus in resource-limited settings: is there anything missing? Pasquale De Nardo, Elisa Gentilotti, Boniface Nguhuni, Francesco Vairo, Zainab Chaula, Emanuele Nicastri & Giuseppe Ippolito To cite this article: Pasquale De Nardo, Elisa Gentilotti, Boniface Nguhuni, Francesco Vairo, Zainab Chaula, Emanuele Nicastri & Giuseppe Ippolito (2016) Efavirenz-based antiretroviral therapy versus nevirapine-including regimens for prevention of mother-to-child transmission of HIV option B plus in resource-limited settings: is there anything missing?, Expert Review of Anti-infective Therapy, 14:1, 19-27, DOI: 10.1586/14787210.2016.1116383 To link to this article: http://dx.doi.org/10.1586/14787210.2016.1116383

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Efavirenz-based antiretroviral therapy versus nevirapineincluding regimens for prevention of mother-to-child transmission of HIV option B plus in resource-limited settings: is there anything missing? Expert Rev. Anti Infect. Ther. 14(1), 19–27 (2016)

Pasquale De Nardo*1,2, Elisa Gentilotti1,3, Boniface Nguhuni1,2, Francesco Vairo2, Zainab Chaula1, Emanuele Nicastri2 and Giuseppe Ippolito2 1

Resource Centre for Infectious Diseases, Clinical Department, Dodoma Regional Referral Hospital, Dodoma, Tanzania 2 National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy 3 Department of Infectious Diseases, University Hospital Tor Vergata, Rome, Italy *Author for correspondence: Tel.: +39 065 51701 [email protected]

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In 2013, an estimated 1.5 million HIV-positive pregnant women gave birth, with 240,000 children worldwide acquiring HIV. More than 90% of new pediatric infections occurred in Sub-Saharan Africa. The latest WHO guidelines recommended efavirenz (EFV)-based antiretroviral therapy as the first-line regimen for prevention of mother-to-child transmission of HIV (PMTCT). On the other hand, some data suggest that nevirapine (NVP), a well-known antiretroviral, could still play a relevant role in PMTCT, especially in resource-limited settings (RLSs) where the fertility rate is dramatically high compared to developed countries. Given the lack of an unanimous consensus and definitive opinions, this paper goes through the reasons for WHO decisions and aims at refreshing the debate about NVP and EFV pros and cons for PMTCT in RLSs. ● PMTCT ● HIV-positive pregnant women ● nevirapine ● efavirenz ● resource-limited settings ● SubSaharan Africa ● option B plus

KEYWORDS: HIV

Background

Surveillance data from the UNAIDS on the burden and impact of HIV on mothers and infants living in resource-limited settings (RLSs) over the past two decades showed that Sub-Saharan Africa carries the greatest burden of the epidemic. In the year 2012, among the 260,000 new pediatric infections worldwide, 90% occurred in Sub-Saharan Africa.[1] In 2013, 240,000 children worldwide acquired HIV: one new infection every 2 min.[2] Mother-to-child transmission (MTCT) consists in vertical HIV transmission during

10.1586/14787210.2016.1116383

pregnancy, labor and delivery or through breastfeeding. In the absence of preventive interventions, the risk of transmission is about 25% at delivery, with increased rate of transmission after 36 weeks and intrapartum.[3,4] Maternal plasma viral load directly correlates with the risk of MTCT, as known since the original trial on the efficacy of zidovudine (AZT; also known as ZDV) in preventing HIV-1 vertical transmission (PACTG 076).[5] However, other maternal risk factors, such as immunologic status, more advanced WHO clinical disease stage, mastitis, acute

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seroconversion during pregnancy, have been associated with increased risk of transmission.[6] Cultural factors and socioeconomic barriers may also play a relevant role in delaying mother access to treatment and/or in limiting retention in care, thus enhancing the risk of MTCT.[7,8] Approximately the 40% of the pediatric HIV infections in Sub-Saharian Africa occurs during the postnatal period through breastfeeding.[3] Evidence of MTCT through breastfeeding includes detection of viral load in breast milk, demonstration of a higher risk of postnatal HIV transmission in countries where breastfeeding is a norm even among HIV-positive pregnant women (HPWs) and randomized clinical trials (RCTs) reporting an increased risk of infections in breastfed infants compared with non-breastfed children.[9] Prolonged breastfeeding is a common practice in RLS, resulting in a difficult-to-avoid burden of infections.[10] On the other hand, non-breastfed infants in RLS have an increased risk of diarrheal disease, respiratory illness, malnutrition and increased mortality.[11] In the absence of any interventions, plasma HIV load has been shown to be the dominant risk factor. Therefore, prevention of mother-to-child transmission (PMTCT) has been mostly driven by the use of antiretroviral (ARVs; drug) which reduced plasma viral load. According to 2013 UNAIDS report, an estimated 50% of HIV-infected postpartum women and their infants did not receive antiretroviral therapy (ART) or prophylaxis.[1] Accelerating global and national scale-up of effective and comprehensive PMTCT services is among the main objectives of WHO.[12] Prevention of mother-to-child transmission: current guidelines

The 2010 WHO PMTCT guidelines recommended lifelong ART for women eligible for treatment (CD4 ≤ 350 cells/mm3 or WHO stage 3 and 4) and ARV prophylaxis for those not eligible for treatment, with: “Option A”, AZT during pregnancy, single-dose nevirapine (sd-NVP) plus AZT and 3TC at delivery and continued for a week postpartum; and “Option B”, triple ARV drugs during pregnancy and throughout breastfeeding. NVP-based regimens were not recommended in Option B because of the risk of its adverse events. Prophylaxis was recommended to start as early as 14 weeks of gestation and both options included 4–6 weeks of peripartum NVP or AZT for the infant. Countries were advised to choose a national approach for their ARV option for PMTCT based on operational considerations.[13] Available data show similar efficacy of Option A and B in clinical trial settings. Nonetheless, the complexities of Option A render it difficult to apply for scaling up PMTCT in clinical settings. For this reason, the Guidelines Development Group proposed a revision of the previous recommendations. Revised 2013 WHO guidelines for PMTCT no longer recommend Option A, suggesting that countries should transition, with appropriate planning, to initiating ART for all pregnant and breastfeeding HPWs regardless of CD4 count and WHO clinical stage. According to WHO 2013 guidelines, countries should consider the advantages and disadvantages of 20

implementing lifelong ART for all pregnant and breastfeeding women in their setting (Option B+). The advantages of Option B+ are not yet completely assessed. In generalized epidemic settings with limited access to CD4 testing, long duration of breastfeeding and high fertility rate, this approach would assure a maximum ART coverage for women eligible for treatment, reduce MTCT and provide early protection for future pregnancies, avoid stopping and restarting ART during repeated pregnancies and limit transmission to HIV-seronegative partners. On the other hand, the affordability of this approach in RLS, still needs to be addressed.[12] According to WHO, a once-daily fixed-dose combination of tenofovir disoproxil fumarate (TDF) + 3TC [or emtricitabine (FTC)] + efavirenz (EFV) is recommended as first-line ART in pregnant and breastfeeding women, including the first trimester of pregnancy, even if the potential teratogenity of EFV still needs to be fully understood.[12] ART regimens during pregnancy and breastfeeding PMTCT efficacy data, toxicity and teratogenicity

Alternative first-line regimens are AZT + 3TC plus either EFV or NVP and TDF + 3TC (or FTC) + NVP. Nonetheless, WHO 2013 guidelines advise to use NVP with caution in pregnant women and even in women who might be pregnant (who represent the majority of HIV-positive women in RLS), due to concerns about the increased risk of toxicity of NVP among HPWs with higher CD4 counts.[12] Indeed, several references [14–18] cited by WHO 2013 guidelines describe an increased risk of hepatotoxicity and/or skin rash induced by NVP-including regimens. Among them, two studies dated 2007 reported a severe hepatotoxicity (grade III/IV or AST/ALT ≥ 5 times the upper limit of normal) in 4 out of 146 HPWs (all of them with baseline CD4 count > 250 cell/mm3) [14] and 5 out of 244 HPWs (with no association with baseline CD4 count),[15] respectively. However, these two observational studies with no comparative arms were conducted on a small number of patients and it is not clear whether possible obstetrical causes (i.e., pre-eclampsia) of LEE were differentiated from drug-induced hepatotoxicity. Furthermore, Phanuphak et al. concluded by considering NVP to be safe even when used as a component of ART in pregnant women.[15] WHO guidelines also cited a retrospective study conducted by Aaron et al. [16] assessing adverse events in NVP versus nonNVP ART on a multi-site cohort of 612 HIV-positive women, of whom 153 were pregnant. Among these, 86 started a NVPbased regimen and 67 a non-NVP regimen. The authors concluded that there were no significant differences in the overall percentage of patients developing LEE between regimen groups. Furthermore, no statistically significant association between baseline CD4 > 250 cells/mm3 and the risk of hepatotoxicity in patients taking NVP were found, as also documented previously.[19] A large study conducted on 1809 HIV-infected naïve adults initiating NVP-based ART also found no association between early hepatotoxicity and several variables, including CD4 baseline count, in RLSs.[20] Similarly, data from Expert Rev. Anti Infect. Ther. 14(1), (2016)

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Zambia, Thailand and Kenya show that in 820 women initiating a NVP-based regimen hepatotoxicity was not predicted by CD4 > 250 cell/mm3, and the only three participants who died with symptoms suggestive of hepatotoxicity had a baseline CD4 < 100 cell/mm3 and were receiving anti-TB treatment.[21] Another report in the subset of HPWs receiving ART regimens as PMTCT in Côte d’Ivoire, showed that among women receiving NVP-based ART, neither baseline CD4 > 250 cell/mm3 nor initiation of a NVP-based regimen during pregnancy were associated with higher risk of severe hepatotoxicity and/or rash.[22] WHO 2013 guidelines also reported a meta-analysis on the risk of NVP-associated toxicity in HPWs, suggesting that the frequency of adverse events is elevated but no higher than that observed in the general adult population and that the association of high CD4 counts and risk of adverse events in HPWs compared with the general population with HIV is weak.[17] Another reference cited, a meta-analysis from 8 RCT and 26 prospective cohorts [18] reported a lower incidence of severe adverse events, in particular treatment discontinuation, among patients receiving EFV-based regimens compared with those under NVP-including ART. This meta-analysis provided a strong evidence on the differences in the tolerability of this two non-nucleoside reverse-transcriptase inhibitors (NNRTIs), however it did not include the subset of pregnant women in the research strategy, which may be of interest considering the higher compliance to treatment usually reported among HPWs and breastfeeding women. Furthermore, in 14 out of 34 studies reviewed, the comorbidities were not described, while in nine studies a co-existing HBV and/or HCV infection was reported. Hence, in 23 of the reviewed studies it is not clear if a possible hepatic disease could have influenced the outcome both in terms of drug discontinuation and hepatotoxicity. Ten months later, a new systematic review and meta-analysis was published, reporting data from 12 RCTs comparing the safety and effectiveness of NVP-based regimens with EFV or boosted protease inhibitors (bPIs) including ones in HIV-infected ARVs naïve patients.[23] The authors concluded that the efficacy in terms of reaching undetectable plasma HIV-RNA level, disease progression and death was comparable. Discontinuation of treatment due to adverse events did not statistically differ between EFV including ART and NVP-based regimens. Concerning safety, although the risk of hepatotoxicity and rash after NVP treatment initiation should be taken into account, NVP seems to be a safe therapeutic option in special groups of patient, that is in those at risk of cardiovascular disease or depression, while EFV has several important limitations to be considered especially during and after pregnancy. First, it is recognized that the most important clinical issue with EFV is that it frequently causes CNS side effects, including depression. [24] Depression is common among HPWs (especially in newly diagnosed patients), it predicts treatment non-adherence and consequently it may compromise clinical, maternal and child health outcomes.[25] To the best of our knowledge, no data resulting from large trials are available on the effects of EFV on perinatal pregnancy depression. Second, concerns have been www.tandfonline.com

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raised on the potential teratogenity of EFV,[26] as several cases of birth defects (anencephaly, microphthalmia, cleft palate) and neural tube defects have been described following in utero exposure.[27,28] Although recent evidences on the use of EFV during pregnancy are reassuring on the risk of teratogenity,[29] most of the data came from retrospective, prospective and casereport studies carried out in developed countries and could not be sufficiently representative of pregnant women living in RLS. [30] A retrospective survey conducted in Abidjan, Côte d’Ivoire, within four adult HIV clinical centers participating in the IeDEA (International epidemiological Databases to Evaluate AIDS) West Africa collaboration, found no external and visible congenital malformation among newborns either exposed to EFV or to NVP during pregnancy. On the other hand, abortion was more frequent for EFV exposure compared with NVP exposure.[31] Similarly, a retrospective multicenter cohort study conducted in the Republic of Congo between 2005 and 2012 observed an increased incidence of adverse pregnancy outcomes among women receiving EFV-based regimens compared with NVP regimens (p = 0.019).[32] Indeed, an international agreement on whether EFV exposure may be considered completely safe or not during pregnancy has not been achieved, yet. US FDA and European Medicines Agency (EMA) advise against using EFV in the first trimester and in women of childbearing potential, while the British HIV Association recently changed its recommendation to allow EFV to be used in the first trimester. Hence, a prospective trial assessing the risk of birth defects among EFV exposed newborns especially during the first trimester of pregnancy, is urgent and particularly needed in RLSs (Table 1). Adherence and socio-economic issues

According to WHO 2013 guidelines, the ideal first-line regimen for HPWs and breastfeeding women should be available at low cost and fixed-dose combination, should have low monitoring requirement and low drug resistance profile, should be compatible with other drugs used in clinical care and should be safe and well tolerated.[12] The economic aspect is certainly one of the main issues to take into account while suggesting a lifelong HAART for all pregnant and breastfeeding women in RLSs. The cost of EFV has declined significantly since 2010,[33] so that today EFV and NVP compare favorably cost-wise. As per the pill burden, EFV-based regimens are available in once-a-day fixed-dose combination. Once-a-day administration has been observed to be associated with higher adherence to treatment, however no advantages have been reported in taking a fixed dose combination compared with > 1 pill regimen,[34] so pill burden among once-a-day regimens has not been proven to predict adherence. A recent meta-analysis found that depressive symptoms, among others, were significantly associated with their effect sizes being small to medium, while daily frequency was also significantly associated with its effect size being small. The pill burden also showed significant association, but with its effect size being very small.[35] NVP 400 mg extended release tablets with once daily administration is now available, showing 21

22 Prospective

Prospective

Retrospective, multicenter Prospective Prospective

Prospective

AITRP6, University of Washington (US)



IMPAACT P1025³, WITS*

Boehringer Ingelheim Pharmaceuticals



PMTC-Plus Initiative, Columbia University (US)



Institute of Pharmacology of Polish Academy of Sciences (Poland)

Jamisse et al., 2007 [14]

Phanuphak et al., 2007 [15]

Ouyang et al., 2010 [19]

Aaron et al., 2010 [16]

Chu et al., 2010 [20]

Coffie et al., 2010 [22]

Peters et al., 2012 [21]

Kawalec et al., 2013 [23]

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Argentina, Brazil, Canada, Côte d’Ivoire, Ireland, Italy, Kenya, Mozambique, Netherlands, South Africa, Tanzania, Thailand, UK, US

Asia, Australia, Botswana, England, Germany, India, Iran, Côte d’Ivoire, Italy, Malawi, Mexico, Nigeria, Spain, South Africa, Switzerland, Thailand, Uganda, US, Uzbekistan

South Africa, Switzerland, Thailand, Uganda, UK, US Zambia, Zimbabwe

Argentina, Australia, Botswana, Canada, France, Germany, Italy, Kenya, Malawi, Mexico, Netherlands, Poland, Romania, Spain,

Kenya

Côte d’Ivoire

South Africa

US

US

Thailand

Mozambique

Setting

3582 HPWs

3975 children

26446 adults

3856 naïve adults

522 HPWs

290 women

1809 naïve adults

612 women including 153 HPWs

1129 HPWs

409 total patients including 244 HPWs

146 HPWs

Population

NVP use in pregnant women, although high, is no higher than reported for NVP in the general adult population. Pregnant women with a high CD4 cell count may be at increased risk of adverse events, but evidence supporting this association is weak.

The frequency of adverse events associated with

Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations.

NVP, EFV, and RTV boosted PIs, added to the background regimens, were equally effective in terms of reaching undetectable plasma HIV RNA level as well as risk of disease progression or death.

Among women who initiated NVP, a baseline CD4 count ≥250 cells/ μL was not associated with severe hepatotoxicity or rash-associated hepatotoxicity.

Neither CD4 cell count > 250 cells/ μL at treatment initiation nor initiation NVP-based regimen initiated during pregnancy were associated with the occurrence of severe adverse events

The cumulative proportion of early hepatotoxicity in nevirapine based antiretroviral therapy was low

CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women

LEE was not significantly associated with CD4+ count > 250 cells/μL or NVP use

While larger studies are needed, data support continued use of NVP-containing regimens as first-line treatment in developing countries for HIV-infected patients, including pregnant women.

HAART was more common at higher CD4+ counts

Severe hepatotoxicity from NVP-containing

Outcome

AIDS International Training and Research Program. 3International Maternal Pediatric Adolescent AIDS Clinical Trials. *Women and Infants Transmission Study

Systematic review and methanalysis



Ford N et al. 2013 [17]

6

Systematic review and methanalysis, 8 RCTs and 27 prospective cohorts

WHO fundings

Shubber Z et al. 2013 [18]

Systematic review and methanalysis, 12 RCTs

Prospective, multicenter

Type of study

Affiliation/ study/support/ funding

Study author, year of publication

Table 1. Systematic reviews and meta-analysis and most important studies cited.

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comparable virologic outcomes and similar tolerability.[36] On this base, we may hypothesizes that, as the frequency of administration seems to be a better compliance indicator compared with pill burden, EFV and NVP could be considered equally effective in terms of adherence. In most of RLSs, close CD4 count and biochemical blood monitoring is often not feasible. HIV-RNA measurement is usually not possible due to the costs and the lack of PCR capability in the laboratories. For these reasons, low monitoring and low drug resistance profile are required to the first-line regimen for HPWs. Most of the reports available show a trend towards higher virologic failure with resistances for NVP-regimens compared with EFV-based ones.[37] Furthermore, in patients receiving NVP, a routine safety monitoring is usually mandatory. These aspects raise concerns on the use of NVP in RLSs, being this drug more demanding in terms of efficacy and safety monitoring. However, several reports from RLSs led to a reconsideration of the effective risk of NVP-associated severe hepatotoxicity, suggesting that focused monitoring of liver enzymes in the first month of therapy with further exams only in case of symptoms occurrence, may be a cost-effective and pragmatic option in settings with limited resources.[20] Drug interactions

WHO 2013 guidelines also stressed the importance of ART compatibility with other treatments. This is widely agreeable, especially in tropical and sub-tropical countries where a large number of tropical and neglected diseases are often life-threatening in the absence of an appropriate treatment. Malaria and tuberculosis (TB) incidence in tropical and sub-tropical settings is still high, thus representing an issue to be taken into account while choosing a lifelong ART regimen. In areas of malaria endemicity, WHO recommends the use of ACT as first line treatment for uncomplicated Plasmodium falciparum malaria. Artemether-lumefantrine is the WHO recommended first choice option in case of P. falciparum malaria.[38] Artemether, lumefantrine, EFV and NVP are all metabolized by CYP450 enzyme systems, therefore drug-drug interaction is a possible risk in case of co-administration. Recently, a prospective pharmacokinetic study was performed in Tanzania on HIV-patients with uncomplicated P. falciparum malaria, receiving NVP or EFV-based regimens or not yet on ART. The results from this study showed that co-administration of artemether-lumefantrine with EFV-based ART but not NVP regimens, significantly reduces lumefantrine bioavailability and consequently total exposure. The authors concluded that in malaria and HIV endemic countries, NVP may still be an appropriate alternative among NNRTIs when ART initiation is needed.[39] Latest WHO guidelines for the treatment of malaria reported the risk of hepatotoxicity for EFV co-administration with artesunate plus amodiaquine and a two- to fourfold decrease in exposure to lumefantrine when given together with EFV in healthy volunteers and malaria-infected adults and children, with increased rates of recurrent malaria after treatment.[38] Suboptimal exposure to antimalarials can result in drug-resistant parasites www.tandfonline.com

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emergence, thus increasing treatment failure and mortality.[40] According to WHO guidelines, exposure to lumefantrine and other NNRTIs, such as NVP, did not show consistent changes that would require dose adjustment.[38] Regarding TB, latest WHO guidelines recommends EFV as the preferred NNRTI in patients starting ART while on rifampin-based anti-TB treatment, due to a lower risk of sub-therapeutic concentration compared with NVP.[12] Indeed, a recent systematic review comparing the efficacy and safety of standard doses of NVP and EFV in patients co-infected with HIV and TB showed better virologic outcomes in EFV regimens compared with NVP, while anti-TB treatment outcome was comparable between the two groups. This meta-analysis suggests to choose EFV-based ART while co-administered along with rifampinbased anti-TB therapy. However, the authors also concluded that NVP-based ART could be considered an acceptable alternative in situation in which EFV cannot be administered.[41] Pharmacological features

NVP is the NNRTI that has been most studied in pregnancy. Average cord to maternal plasma concentration ratios were dispersed from 0.6 to 1.0 in patients on chronic NVP, showing a reliable maternal-to-fetal transfer.[42] Effective NVP concentrations (≥100 ng/ml) after perinatal single dose have been demonstrated in maternal plasma and breast milk during the early postpartum period (1 week after delivery), accompanied by suppressed HIV-RNA in plasma and breast milk. This finding suggest a similar NVP potency in decreasing HIV viral load in both systemic and mucosal compartments.[43,44] A report on 66 HPWs receiving ART prophylaxis with NVP or LPV/r based regimens from gestational week 25 until 6 months postdelivery, showed that the regimens were effective and safe for both mothers and infants, but NVP was the only drug to reach significant levels in the breastfed ‘newborns’ blood.[45] MTCT during breastfeeding has been reported to be lower among newborns receiving extended NVP once-a-day up for 6 months compared to 6 weeks.[46] No adverse events to 6 months NVP once-a-day administration in infants were observed.[47] Less is known about EFV transfer from mother to infant in utero or through breast milk.[48,49] Large trials aimed at assessing the extent of ARVs delivery from mother to child during breastfeeding could contribute to current guidelines on ARV prophylaxis for breastfed newborns. Conclusion

To conclude with, this paper raises doubts about the decision of considering EFV as the best candidate for a first-line regimen in HPWs starting lifelong ART during pregnancy in RLSs. Even WHO, while suggesting EFV as first-line ART in pregnant and breastfeeding women, including HPWs in the first trimester of pregnancy and women of childbearing age, reported a low-quality evidence for the specific population of pregnant and breastfeeding women and infants. Furthermore, WHO Guidelines Development Group highlighted the need of more research to support the new recommendations, with particular focus on 23

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those referred to as “key research gaps”: ARV toxicity surveillance, maternal and child health outcome, adherence and retention. This paper emphasize the need to provide more evidences on the safety of EFV during the first trimester of pregnancy, especially in RLSs where fetal ultrasound facilities are often lacking; to plan large trials aimed at assessing the effect of this drug on perinatal pregnancy depression and to address the concern on suggesting EFV-based regimens as lifelong treatment even in malaria endemic countries where lumefantrine-containing antimalarials are often prescribed. In addition, more efforts should be invested in carrying out the research on NVP pharmacokinetic and pharmacodynamic in breast milk and newborn’s blood, as this drug could still represent an useful option, especially in RLS. Several reports documented a substantial success of Option B+ in terms of reduction of maternal mortality and efficacy of PMTCT in RLS.[50,51] Nonetheless, concerns have been raised on how to guarantee long-term adherence and sustainability of service delivery in fragile primary care settings.[52,53] For many years, NVP has been among the most important and most commonly used component of firstline regimens. In addition, it has been one of the preferred drug for PMTCT for a long time. Its potential in preventing vertical transmission and in reaching effective concentration in the breast milk, may lead to consider NVP as a still appealing and useful solution.

maternal-to-fetal transfer). Furthermore, a low-quality evidence for the specific population of pregnant and breastfeeding women and infants was reported by WHO while suggesting EFV as the firstline regimen in this subset of the population. Based on our experience, NVP could still play a role in prevention of MTCT, especially in RLSs. Large RCTs are needed to better define the optimal PMTCT strategy in terms of ARV toxicity, maternal and child health outcome, adherence and retention. Five-year view

WHO Guidelines Development Group highlighted the need of more research to support the new recommendations. New evidences are emerging from literature data and newer ones will be provided in the years to come. On the bases of the upcoming data and guided by clinical settings’ experiences, a deeper knowledge of ARVs’ efficacy in PMTCT, its adverse events during pregnancy and breastfeeding and on the newborns will be available in the future. This could have a relevant impact on clinicians’ behavior regarding PMTCT and could help in reaching the goal of elimination of pediatric infections worldwide. Acknowledgments

This manuscript was supported by grants from Italian Development Cooperation-Ministry of Foreign Affairs AID 9562 and “Ricerca Corrente” of Italian Ministry of Health. All authors approved the final manuscript.

Expert commentary

Few authors provide strong evidences supporting latest WHO guidelines that recommend EFV-based ART as the first-line regimen for PMTCT and limit the use of NVP due to its adverse events and its inferiority in terms of effectiveness compared with EFV. On the other hand, several papers provide evidences on NVP’s virological non-inferiority, good tolerability even during pregnancy and well documented pharmacological features (reliable

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues ●

In the year 2013, an estimated 1.5 million HPWs gave birth, with 240,000 children worldwide acquiring HIV. More than 90% of new pediatric infections occurred in Sub-Saharan Africa.



EFV-based ART is currently the first choice regimen for the treatment of HIV-infected patients.



The latest WHO guidelines recommend EFV-based ART as the first-line regimen also for PMTCT, limiting the use of NVP due to its adverse events and its inferiority in terms of effectiveness compared with EFV.



Low-quality evidence on the use of EFV for the specific population of pregnant and breastfeeding women and infants is reported by WHO.



Several studies and meta-analysis provide evidences on NVP’s virological non-inferiority, good tolerability even during pregnancy and well documented pharmacological features (reliable maternal-to-fetal transfer).



In malaria endemic countries, NVP may still be an appropriate alternative among NNRTIs when ART initiation is needed, due to its few drug interactions with artemether-lumefantrine.



EFV has several important limitations to be considered especially during and after pregnancy, such as CNS side effects including depression and the potential teratogenity.



Large RCTs are needed to better define the optimal PMTCT strategy in terms of ARV toxicity, maternal and child health outcome, adherence and retention.

24

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References • of interest

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UNAIDS report on the global AIDS epidemic. 2013. [cited 2015 Oct 23]. Available from: http://www.unaids.org/ sites/default/files/en/media/unaids/conten tassets/documents/epidemiology/2013/ gr2013/UNAIDS_Global_Report_2013_ en.pdf. UNAIDS The Gap Report 2014 Children and pregnant women living with HIV. Available from: http://www.unaids.org/ sites/default/files/media_asset/09_ ChildrenandpregnantwomenlivingwithHI V.pdf [cited 2015 Oct 23].



This review published on Lancet in 2014 is a recent and exhaustive overview of HIV pathogenesis, treatment and prevention, deepening the topic of MTCT expecially in RLSs.

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Kourtis AP, Lee FK, Abrams EJ, et al. Mother-to-child transmission of HIV-1: timing and implications for prevention. Lancet Infect Dis. 2006;6:726–732.

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This report from UNAIDS provides detailed information on the current situation of children and pregnant women living with HIV. Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet. 2014;384:258–271.

Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331 (18):1173–1180. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-tochild transmission of HIV-1 despite a maternal viral load

Efavirenz-based antiretroviral therapy versus nevirapine-including regimens for prevention of mother-to-child transmission of HIV option B plus in resource-limited settings: is there anything missing?

In 2013, an estimated 1.5 million HIV-positive pregnant women gave birth, with 240,000 children worldwide acquiring HIV. More than 90% of new pediatri...
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