Introduction of a DTG-based regimen for children older than six years appears to be feasible, especially given the possibility of using a simplified dosing approach with a 50-mg generic DTG formulation from at least 25 kg.
Treating neonates requires early infant diagnosis and linkage to care in the first four weeks of life. In settings where this is possible, using RAL granules is expected to be feasible, as demonstrated in a rapid assessment undertaken in KwaZulu-Natal, South Africa (67).
Difficulties in introducing 25-mg chewable RAL tablets for first-line treatment for children four weeks to six years of age has raised concerns about procurement and supply. The Antiretroviral Procurement Working Group acknowledges challenges with countries introducing RAL for a timelimited period until DTG becomes available and has flagged potential high risk of overstock or stock-out situations.

# Clinical and implementation considerations
Despite a lower risk of drug-drug interactions compared with NNRTIs and boosted PIs, DTG cannot be used with some anticonvulsants (such as carbamazepine) and should not be simultaneously administered with cation-containing antacids, laxatives and multivitamin supplements because of the risk of chelation. If combined, DTG should be administered two hours before or six hours after taking medicines containing polyvalent cations (68). This guidance applies equally to all populations and is particularly relevant for pregnant women and children, who frequently receive vitamin supplementation (Annex 4). For adolescent girls and women taking DTG in combination with hormonal contraception, there are no reported or expected drug-drug interactions, although data is limited. Web Annex E provides details of contraceptive options for women and adolescent girls with HIV, including those taking an integrase inhibitors. Annex B shows contraceptive options for women and adolescent girls taking raltegarvir. This can be applied to dolutegravir.
People coinfected with HIV and TB treated with rifampicin-containing regimens should receive an additional 50 mg of DTG 12 hours after taking their main ARV drug regimen.
Given the suboptimal viral suppression on NNRTI-based regimens as demonstrated by increasing evidence from programmatic and observational data, use of NNRTI-based regimens is discouraged if alternatives are available. LPV/r-based regimens can provide a more robust option that overcomes potential resistance to NNRTIs and provides the opportunity to harmonize regimens across paediatric age groups until DTG dosing information becomes available for children younger than six years. EFV-based regimens can be used as a first-line regimen for children 3-6 years old in special circumstances.
When RAL granules are used to start treatment among neonates diagnosed with HIV, careful consideration should be given to making the appropriate dose change after the first week of life and then again after four weeks (Annex 3) for ARV dosing for children and ensuring adequate training of health-care workers to instruct caregivers because of the challenges of correctly reconstituting and administering the granule formulation.
For infants older than four weeks, because of the administration challenges presented by the RAL granule formulation, the Paediatric Antiretroviral Working Group has recommended use of the 25-mg chewable tablets as dispersible tablets after reviewing in vitro data on solubility and bioequivalence between tablets and granules (67) and taking into account the lack of adequate alternatives for this age group.
HIV programmes should plan carefully to ensure that DTG supply is available to meet the anticipated demand; a phased approach to implementation is highly recommended. Several countries have adopted approaches to start transitioning to DTG among people initiating firstline ART and/or those already receiving first-line NNRTI-based ART and who have intolerance of or contraindication to NNRTIs. To ensure supply security during the transition of DTGcontaining regimens, country programmes should plan orders 6-12 months in advance and stagger large orders into smaller deliveries to avoid overburdening the procurement system. Ensuring sufficient buffer stocks of existing and new regimens throughout the transition period is also important. Implementing partners have developed specific toolkits and checklists to guide countries (44).
Not all countries can transition at the same time or speed. Some countries have limited capacity to develop and manage multiple implementation polices. Several clinical, operational and programmatic factors need to be considered. For example, the availability of country-level information on pretreatment HIV drug resistance to EFV or NVP can accelerate the transition to DTG (Box 5), and the lack of access to generic fixed-dose combinations and large stocks of EFVcontaining regimens can be a barrier to rapidly scaling up DTG in some countries (4). Given the above-mentioned safety signal for women and adolescent girls of childbearing potential, ensuring that EFV continues to be widely available as countries introduce DTG is critical.
Additional factors to be considered during transition include training of health-care workers, appropriate messaging to communities and revision of monitoring tools.

# Box 5. Considerations for countries with national estimates of pretreatment HIV drug resistance to EFV or NVP 10%
Increasing pretreatment HIV drug resistance among people initiating or reinitiating first-line ART has been documented in many low-and middle-income countries (69).
Pretreatment HIV drug resistance to EFV or NVP ranges from 4% to 19% and exceeds 10% in six of the 11 countries in Africa, Asia and Central and South America reporting nationally representative estimates (70).
A systematic review of 26 studies showed that adults and children with pretreatment HIV drug resistance to EFV or NVP initiating NNRTI-based regimens are more likely to experience failure of viral suppression, more likely to discontinue treatment and more likely to acquire new resistance mutations. This evidence informed WHO to recommend that NNRTIs not be used for first-line ART in countries with a national prevalence of pretreatment HIV drug resistance to EFV or NVP exceeding 10% (71).
Women represent a population at high risk for pretreatment resistance to EFV or NVP, about twice as high as men, probably because of previous use of ARV drugs for preventing mother-to-child transmission (70). Although TDF + 3TC + DTG is generally the preferred regimen, DTG should be offered to adolescents and women of childbearing potential only when consistent and reliable contraception can be assured. Atazanavir/ritonavir (ATV/r) appears to be a suitable alternative based on considerations around cost, availability, toxicity profile, pill burden and genetic barriers to resistance. However, the higher comparative cost and potential increased risk for low birth weight and prematurity with using PIs in pregnancy should be considered. Other PI/r may have similar risks among pregnant women; LPV/r may also be associated with potential higher risk of early infant death when given at higher dosing in association with TDF in the third trimester (71).
The choice of alternative options to EFV in this context therefore needs to be made by weighing drug availability and toxicity profile. In countries with high levels of pretreatment HIV drug resistance, the risk and benefit balance should be carefully evaluated, and DTG (with consistent and reliable contraception for adolescent girls and women of childbearing potential) or ATV/r are the drug options to be considered.
Among people starting NNRTI-based ART with reported previous use of ARV drugs (such as women exposed because of preventing mother-to-child transmission and people restarting ART after treatment interruption), pretreatment HIV drug resistance to EFV or NVP ranges from 10% to 33% and is significantly higher than in the treatment-naive populations in all WHO regions (3). WHO recommends that people starting ART with reported previous ARV drug exposure use a non-NNRTI-containing regimen, regardless of the country's prevalence of pretreatment HIV drug resistance to NNRTIs (4).
If the use of a non-NNRTI-containing regimen cannot be implemented, countries may consider using HIV drug resistance testing to guide the selection of first-line ART regimens, provided that capacity and resources are available (4).  (73,74). This would also apply to children for whom an approved DTG dose is available and who are stable on NNRTI-based or PI-based regimens (18). However, this approach may not be optimal for people with evidence of failure of suppression of viral loads given the high levels of resistance to NRTIs and the unknown efficacy of DTG in combination with an inactive NRTI backbone (see Box 7).
Many low-and middle-income countries have limited access to routine viral load monitoring and would not be able to identify individuals for whom ART is failing and who could be at potential risk of receiving suboptimal therapy if this strategy is adopted.
Programmatic advantages associated with large-scale substitution of TDF + 3TC (or FTC) + NNRTI with TDF + 3TC + DTG have led to consideration of using the latter regimen for everyone receiving NNRTI-based ART who is clinically stable, regardless of viral suppression. Among children, consolidating ARV drug regimens is particularly important to reduce market fragmentation, facilitate the procurement and supply of formulations for children, lower the risk of stock-outs and increase the availability of formulations for children. However, the potential programmatic benefits need to be weighed against the potential increased risks of adverse events for people who tolerate their existing treatments when substituting with a new regimen (75).
WHO conducted structured online surveys with people living with HIV, healthcare workers and HIV country programme managers to assess the acceptability, feasibility, values and preferences regarding the large-scale implementation of DTG-containing regimens (Web Annex 4). The survey sought the views of participants on the option of switching people who are stable on an EFV 600-containing regimen to a DTG-containing regimen. Almost 60% of the people living with HIV surveyed preferred to have the choice to remain on an EFV 600-containing regimen, while 25% would be happy to change to DTG; 43% of programme managers and 44% of health-care workers would prefer that people stable on EFV 600-containing regimens remain on their current regimen, and 45% of programme managers and 52% of health-care workers stated that they would want to switch to DTG even if people were stable on EFV.
An important consideration is the issue of changing to a DTG-based regimen for people who are stable on a first-line NNRTI-containing regimen (Box 6).
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# Research gaps
Active research and surveillance are urgently needed to assess the risk of neural tube defects among neonates born to mothers with exposure to DTG during the periconception period.
Further research is also required to determine the long-term safety of DTG in various subpopulations, including breastfeeding infants born to women receiving DTG. These studies should reflect the characteristics of the people in treatment programmes, such as pregnant women and women and adolescent girls of childbearing potential, children and adolescents and people with TB coinfection and other comorbidities.
Similarly, the association of DTG with central nervous system and cardiovascular events, immune reconstitution inflammatory syndrome and other adverse reactions, including fatigue and headache, requires further long-term investigation to ensure safe harmonization across populations. Toxicity surveillance systems implemented alongside ART can provide data to better understand the frequency and clinical relevance of various types of toxicity.
A better understanding of the pharmacokinetics and appropriate dosing of DTG in neonates and children younger than six years old -including those coinfected with TB -is also needed. More evidence is also required to assess the risk of selecting resistance to integrase inhibitors by using RAL in first-line therapy and how that will affect the subsequent use of DTG.
Switching clinically stable people with viral suppression from TDF + 3TC (or FTC) + EFV to TDF + 3TC + DTG can maintain viral suppression, but more data are needed on the benefits in reducing adverse events (75). Evidence on the benefits and risks of this approach requires urgent investigation.
Resistance to both TDF and 3TC is common and is estimated to be present in about 60% of the people for whom NNRTI-based regimens are failing and about 10% among all people receiving ART regardless of whether treatment is failing or not (76,77). Since the efficacy of DTG in the presence of an inactive NRTI backbone is unknown, substituting NVP or EFV with DTG without viral load testing may be associated with increased risk for selection of DTG resistance and transmission in the population. This may affect future DTG efficacy and preclude the future use of DTG in salvage therapy (78).
Although viral load monitoring before substituting from TDF + 3TC (or FTC) + NNRTI to TDF + 3TC + DTG is encouraged and considered good practice, if countries adopt this substitution in the absence of viral load testing, closely monitoring outcomes and assessing viral load levels and drug resistance using standardized prospective studies and cross-sectional national HIV drug resistance surveys are encouraged to generate data that can be more easily interpreted and compared across settings (15,68).

# SECOND-LINE ARV DRUG REGIMENS
The scaling up of ART has substantially reduced HIV-related morbidity and mortality worldwide (79). With more people living with HIV receiving ART and improved early detection of failure to suppress viral loads through monitoring in low-and middle-income countries, many people are anticipated to need to switch to second-line and subsequent ART regimens (80).
Estimates suggest that, by 2020, 2-3 million people living with HIV will be receiving secondline ART (58). However, estimates indicate that fewer than 1 million adults and 100 000 children living with HIV are currently receiving second-line treatment in low-and middleincome countries. Limited access to viral load monitoring and lack of simplified regimens and formulations -especially for children -are important challenges to improving timely switching to second-line regimens (81).
The 2016 WHO consolidated guidelines (2) recommended two NRTIs plus LPV/r or ATV/r as the preferred second-line regimen for individuals for whom EFV-based or DTG-based regimens are failing; two NRTIs + DRV/r and LPV/r + RAL were recommended as alternatives because of cost constraints and the fact that DRV/r is not yet available in a heat-stable co-formulation (5). The choice of NRTI backbone for second-line ART continued to depend on which NRTI was used in first-line ART (if ABC + 3TC or TDF + 3TC (or FTC) were used, AZT + 3TC should be used in second-line ART and vice versa) with the goal of optimizing sequencing in the context of lack of access to genotyping.
Since the WHO consolidated ARV guidelines were published in 2016, several studies exploring various strategies for second-line therapy have been conducted, including those focusing on using ART classes other than PIs and NRTIs, NRTI-sparing regimens and strategies for optimizing PI doses (19,82).
More robust second-line options are needed for children among whom rates of viral suppression on ART have been consistently lower than among adults, as recently reported by the Population-based HIV Impact Assessments undertaken in several African countries. These studies suggest that suppression of viral loads is lowest among children younger than five years (18,83), who are at high risk of treatment failure and likely to need second-line treatment. a See Box 1 on women and adolescent girls of childbearing potential using DTG.

# N E W N E W
Second-line ARV drug regimens Despite major advances in ARV drug development for adults, treatment for children often relies on suboptimal drug regimens and formulations. Except for LPV/r, co-formulated boosted PIs are still unavailable.
The 2016 WHO consolidated guidelines reviewed preferred regimens for second-line ART for children, and RAL was introduced as a preferred option for second-line regimens for infants and children for whom LPV/r-based regimens are failing. ATV/r was also considered equivalent to LPV/r as a second-line option for children for whom NNRTI-based regimens are failing.
Because of the lack of dosing information and regulatory approval for use in these populations, DTG was only recommended for third-line ART (2).
WHO continues to promote the optimization of second-line regimens to lower toxicity and pill burden and once-daily dosing, minimal or no cross-class resistance and a preference for regimens that can be used across all populations (84,85).

# Supporting evidence

# Adults and adolescents
An updated systematic review conducted in 2018 assessed the efficacy and safety of DTG in combination with an optimized NRTI backbone among individuals with HIV for whom a NNRTIor PI-based first-line regimen is failing (Web Annex F). All studies investigating the use of DTG in second-line ART typically choose the best available NRTI backbone based on history or genotyping results (Box 7).
The review included seven trials involving 3877 people randomized to 16 treatment arms.
The analysis showed high-to moderate-quality evidence that two NRTIs + DTG is generally a more effective regimen, with higher viral suppression and lower risk of treatment discontinuation because of adverse events, compared with two NRTIs + LPV/r, as well as evidence that DTG has the strongest suppressive efficacy compared with other integrase inhibitors. No differences were found in terms of mortality, AIDS-defining illnesses and occurrence of serious adverse events.
As noted above, DTG has other advantages compared with other second-line options, including lower cost, better tolerability, less potential for drug-drug interactions, lower pill burden and availability in once-daily fixed-dose combinations (9,82).
Experience with DTG in low-and middle-income countries as a second-line option is very limited compared with LPV/r and other boosted PIs. More than 70% of the people in low-and middle-income countries taking second-line ART are receiving a LPV/r-based regimen (58).
There are also concerns about DTG safety during conception and complexity related to the need to double dose in the presence of rifampicin.
Since the 2016 WHO consolidated ARV guidelines were published, the Paediatric Antiretroviral Drug Optimization group has endorsed the rapid introduction of integrase inhibitors for infants and children, with a preference for DTG over RAL. The group has also supported the use of DTG in second-line treatment and promoted the extrapolation of efficacy data from trials involving adults when direct comparative evidence is not available for children (18).
Although the use of DTG as second-line ART for children is still under evaluation (with results expected in 2020), based on extrapolation from data for adults, the Guideline Development Group agreed that DTG in combination with an optimized backbone regimen should be recommended as a preferred second-line regimen for all children for whom an approved DTG dosing is available. DTG can currently only be used for children older than six years and weighing at least 15 kg, with approved dosing down to four weeks expected by the end of 2019. Because experience with DTG among children is limited, the Guideline Development Group also recommended that routine toxicity monitoring be ensured when this recommendation is implemented.
For children for whom approved DTG dosing is not available, boosted PI-and RAL-based regimens continue to be preferred for children for whom an NNRTI-or PI-based first-line regimen is failing, respectively (2).  b Women and adolescent girls of childbearing potential with consistent and effective contraception and who are fully informed of the benefits and risks can use DTG. Women beyond the first trimester of pregnancy are not at risk on NTD and DTG-based ART is a safe option for those starting ART or those switching to second-line. Women of childbearing potential who intend to become pregnant or who are not otherwise using contraception should be informed of the potential increase in the risk of neural tube defects (at conception and up to the end of first trimester) before being offered DTG. c If population-level pretreatment resistance to EFV or NVP is 10%, the choice of alternative options to EFV needs to be made weighing the drug availability and toxicity profile. Women of childbearing potential who intend to become pregnant or who are not otherwise using contraception should be informed of the potential increase in the risk of neural tube defects (at conception and up to the end of first trimester) before being offered DTG. d ATV/r can be used as an alternative to LPV/r among children older than three months, but the limited availability of suitable formulations for children younger than six years, the lack of a fixed-dose formulation and the need for separate administration of a ritonavir booster should be considered when choosing this regimen. e This applies to children for whom approved DTG dosing is available. RAL should remain the preferred second-line regimen for the children for whom approved DTG dosing is not available (Annex 3). f ATV/r or LPV/r should remain the preferred second-line treatment for the children for whom approved DTG dosing is not available. This applies to children for whom approved DTG dosing is available. g For PI-experienced people, the recommended DRV/r dose should be 600 mg/100 mg twice daily. h Children younger than three years should not use DRV/r. i DTG-based third-line ART following the use of integrase inhibitors must be administered with DTG twice daily.

# Second-line ARV drug regimens
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# Rationale for the recommendation

# Cost and cost-effectiveness
The median price of DTG is significantly lower than that for the boosted PIs currently used for second-line ART, especially in low-and middle-income countries (58). However, some uppermiddle-income countries have no access to generic DTG formulations at reduced prices as a result of patent and licensing restriction.
Four studies, including one from sub-Saharan Africa, have evaluated the cost-effectiveness of DTG as second-line ART (44)(45)(46)53). All studies concluded that using DTG-based regimens is highly cost-effective compared with the standard of care (either for a national treatment policy or compared with current WHO guidelines), had lower total costs, offered significant cost savings and improved clinical outcomes.
For children, cost and cost-effectiveness are less clear. Formulations of DTG for children are not widely available and are being registered nationally by the originator company. While paediatric formulations of DTG are currently only manufactured by the originator company, access prices have been negotiated and appear to be comparable to other recommended ARV drugs and represent good value for money (58).

# Equity and acceptability
The selection of second-line ART has important public health and programmatic implications. Effectiveness, tolerability and safety of regimens remain key considerations; issues such as cost, monitoring and drug delivery and storage should also be considered to ensure a equitable and acceptable selection of second-line and salvage ART.
For first-line ART, the Guideline Development Group, supported by a contribution from a representative of the WHO Department of Global Health Ethics, discussed at length the potential impact of the recommendation on equity. The group agreed that providing DTG to everyone who can safely use it is the most equitable approach. They also noted that, given the DTG safety signal, providing an alternative effective regimen, such as a boosted PI-based regimen, would remain equitable. Using DTG instead of boosted PIs was therefore considered to increase equity across populations in low-and middle-income countries. Among adolescents and children, fixed-dose combinations are typically more acceptable, but similar to other second-line regimens, no fixed-dose combination for children currently contains DTG (86). Meanwhile, once-daily administration of a small DTG tablet in combination with an age-appropriate NRTI backbone in a fixed-dose combination is expected to be acceptable, especially compared with an ATV/r regimen, which would require separate administration of ATV and ritonavir.
Among low-and middle-income countries, Botswana, Brazil and Kenya have been early adopters of DTG as a preferred first-line option and are implementing programmatic transition to DTG (5). Only Botswana is planning to use DTG in second-line ART.
Introducing DTG-based regimens for children older than six years appears to be feasible, especially given the possibility of adopting a simplified dosing approach using a 50-mg generic DTG formulation from at least 25 kg.

# Box 7. Use of TDF + 3TC + DTG in second-line ART following failure of TDF + 3TC (or FTC) + EFV: HIV drug resistance considerations
The use of DTG in combination with an optimized NRTI backbone is preferable and recommended as good practice (AZT + 3TC should be used as the NRTI backbone in a second-line regimen if TDF + 3TC (or FTC) was used in the failing first-line regimen and vice versa). Indeed, using TDF + 3TC + DTG in second-line ART following failure of TDF + 3TC (or FTC) + EFV, although it may have programmatic advantages, also raises concerns about the potential use of a suboptimal therapy. Viral resistance to TDF and 3TC is common among people for whom NNRTI-based ART is failing; up to two thirds of individuals have viral resistance to TDF, and in the vast majority of these resistance to 3TC is also present (76).
There is currently no evidence on the efficacy of DTG when used in combination with an NRTI backbone whose activity is compromised by the presence of one or more major resistance-associated mutations; DTG in combination with an optimized backbone is therefore recommended.
The apparent high genetic barrier of DTG to HIV resistance has prompted the investigation of DTG as part of two-drug therapy or monotherapy and in regimens with a partly active NRTI backbone.
Although the efficacy of DTG in combination with 3TC appears to be promising among ART-naive individuals and may potentially be highly effective as maintenance therapy in people with suppression of viral loads (87,88), limited evidence currently supports using it among people with failure to suppress viral loads and documented resistance to 3TC.
In the DAWNING study, people were switched from NNRTI to DTG-based ART with at least one active NRTI predicted by genotypic resistance testing. Although DTG seems to be effective with at least one active NRTI for people for whom NNRTI-based ART is failing, a retrospective analysis suggests that selecting NRTI backbone sequencing according to WHO guidelines achieved modest but significantly greater suppression of viral loads (85).
Further, there has been no direct evaluation of DTG with an NRTI backbone predicted to be inactive by genotypic resistance testing, but findings from DTG monotherapy studies have demonstrated the rapid accumulation of integrase inhibitor mutations (89,90).
Overall, insufficient evidence supports using DTG in combination with TDF and 3TC as second-line ART for people for whom TDF + 3TC (or FTC) + EFV is failing as a first-line regimen. More data are needed on the efficacy of DTG among people with resistance to 3TC and TDF (78).

# Second-line ARV drug regimens
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# Research gaps
Further evidence is needed to inform the routine use of TDF + 3TC + DTG in second-line regimens following the failure of TDF + 3TC (or FTC) + EFV. Additional research is also required to better understand the choice and sequencing strategies in second-and third-line ART, especially for children and adolescents. Ongoing studies comparing the use of DTG and other integrase inhibitors combined with other ARV drug classes will provide more data on appropriate second-line regimens, including NRTI-sparing and NRTI-limiting approaches.
Finally, more data is needed to inform the recycling of the NRTI backbone in DTG-based second-line regimens following the failure of first-line TDF + 3TC (or FTC) + EFV. Several trials are underway to examine induction and maintenance using integrase inhibitors (including DTG), either in monotherapy or in combination with 3TC (or FTC).
Further studies are needed to assess the possible impact of resistance to the NRTI backbone on the long-term effectiveness and durability of second-line DTG-containing ART regimens.
Residual NRTI activity (activity of TDF, 3TC and FTC) or reduced viral fitness is likely in the presence of certain resistance mutations, and could provide some protection against the selection of DTG resistance, but no clinical trials or observational studies have assessed their impact among people receiving this regimen.

# WHAT TO USE IN HIV POST-EXPOSURE PROPHYLAXIS 4.1. Background
WHO guidelines for HIV post-exposure prophylaxis, formulated in 2014, aimed to provide a simplified approach to delivering post-exposure prophylaxis, given the suboptimal uptake and completion of post-exposure prophylaxis (PEP) (91-93). The guidelines aimed to align recommendations for HIV PEP with the ARV drugs available in low-and middle-income countries for treating and preventing HIV.
The 2014 guidelines recommended TDF + 3TC (or FTC) as the preferred backbone regimen for HIV PEP for adults and adolescents, and for children 10 years and younger, AZT + 3TC was the recommended backbone regimen. The recommended third drugs included ATV/r or LPV/r for adults and LPV/r for children, with several alternatives provided according to availability, including current age restrictions and the availability of age-appropriate formulations for

# Recommendations Overall
An HIV post-exposure prophylaxis regimen with two ARV drugs is effective, but three drugs are preferred (conditional recommendation, low-certainty evidence) a

# Adults and adolescents TDF + 3TC (or FTC) is recommended as the preferred backbone regimen for HIV post-exposure prophylaxis (strong recommendation, low-certainty evidence) a

# DTG is recommended as the preferred third drug for HIV post-exposure prophylaxis (strong recommendation, low-certainty evidence) b
When available, ATV/r, DRV/r, LPV/r and RAL may be considered as alternative third drug options for post-exposure prophylaxis (conditional recommendation, low-certainty evidence)

# AZT + 3TC is recommended as the preferred backbone regimen for HIV post-exposure prophylaxis for children. ABC + 3TC or TDF + 3TC (or FTC) can be considered as alternative regimens (strong recommendation, low-certainty evidence) a

# DTG is recommended as the preferred third drug for HIV post-exposure prophylaxis for children for whom an approved DTG dosing is available (strong recommendation, low-certainty evidence)
When available, ATV/r, DRV/r, LPV/r and RAL may be considered as alternative third drug options for post-exposure prophylaxis (conditional recommendation, low-certainty evidence)
a WHO 2016 consolidated guidelines on the use of ARV drugs for treating and preventing HIV infection. b See Box 1 on women and adolescent girls of childbearing potential using DTG. c The choice of ARV drugs for children will depend on the availability of approved dosing and age-appropriate formulations for children. Use of DTG applies to all infants and children for whom an approved DTG dosing is available.

# N E W N E W N E W N E W
What to use in HIV post-exposure prophylaxis Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV children. Since then, additional studies have been published that provide information about the tolerability and completion rates of the WHO-recommended HIV PEP regimens and data on newer ARV drugs, notably DTG.

# Supporting evidence
An updated systematic review assessed the tolerability of HIV PEP and completion of different ARV regimens recommended by the 2016 WHO consolidated guidelines (Web Annex G). The systematic review identified 16 studies reporting the outcomes of different HIV PEP regimens using TDF + 3TC (or FTC) backbones. All studies involved adults, and no additional evidence was retrieved for post-exposure prophylaxis regimens for children or adolescents. Overall, the highest completion rates for HIV PEP were reported for TDF + 3TC (or FTC) in combination with DRV/r (93%, 95% confidence interval 89-97%) or DTG (90%, 95% confidence interval 84-96%). These regimens were also associated with the lowest rates of discontinuation or substitutions because of adverse events (1%, 95% confidence interval 0-2% for DRV/r; 1%, 95% confidence interval 1-4% for DTG).
For adults, the Guideline Development Group recommends that DTG may be used as the preferred third drug for HIV post-exposure prophylaxis. This recommendation considered the high rates of post-exposure prophylaxis completion and low rates of adverse events as well as the established high tolerability of DTG when used in ART (Web Annex B). This preference also considered cost, current and anticipated availability, low potential for drug-drug interactions and the desirability of aligning with recommendations for ART. Alternative third drug options include ATV/r, DRV/r, LPV/r and RAL, with the choice to be based on considerations of tolerability and completion rates as well as cost, availability and acceptability (Table 3).
The 2014 WHO guidelines on PEP noted that data on using EFV in HIV post-exposure prophylaxis were lacking and that there are concerns about giving a drug associated with early central nervous system and mental health adverse events to HIV-negative people who may have anxiety related to HIV exposure. Since then, data have been published suggesting that EFV is associated with high rates of discontinuing PEP because of central nervous system events (95). EFV should therefore only be used as a third drug option when no other options are available.
For children, no new evidence has been published since the review carried out for the 2014 guidelines. However, the recommendation to provide DTG as a preferred drug option for this population is now included, extrapolating from data for adults with the goal of aligning the recommendations for adults and adolescents. DTG is currently only recommended for children older than six years and weighing more than 15 kg. However, approval for use in younger age groups is anticipated, and the recommendation may extend further as dosing approval becomes available. Since other recommended ARV drugs for children also have age restrictions, the choice of ARV drugs for children depends on current age restrictions and the availability of age-appropriate formulations.

# Considerations for adolescent girls and women of childbearing potential
The use of DTG in HIV PEP is conditional upon access to consistent and reliable contraception, considering concerns regarding the safety of DTG in the periconception period (see Box 1). As part of comprehensive PEP services, all women should be offered pregnancy testing at baseline and follow-up. Emergency contraception should be offered to girls and women as soon as possible and within five days of sexual exposure. For women not wishing to take emergency contraception, an alternative to DTG should be provided.

# Implementation considerations
The uptake and completion rates for HIV PEP are suboptimal, and the recommendations for HIV PEP regimens should be considered together with existing WHO recommendations aimed at improving completion rates for HIV PEP, including adherence support and providing a full 28-day course of medication at the first clinic visit (2,91).
Choice of HIV PEP regimen should consider the ARV drugs already being procured within national HIV programmes. Additional considerations include the availability of heat-stable formulations, daily dosing, availability and affordability (Table 3).
People may be subject to ongoing high risk of exposure to HIV, leading to multiple prescriptions for PEP. In such situations, health providers should discuss with their clients the potential benefits of transitioning to HIV pre-exposure prophylaxis (PrEP) (96,97).

# Research gaps
Ongoing research is needed to document completion and drug-related discontinuation rates associated with different ARV drug regimens used in HIV PEP.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# EARLY INFANT DIAGNOSIS
In 2016, WHO recommended that HIV nucleic acid-based testing (NAT) be used to diagnose HIV infection among infants and children younger than 18 months of age and that ART be started without delay while a second specimen is collected to confirm the initial positive NAT result (2). Confirmatory testing is critical because of the risk of false-positive results, potential contamination with maternal blood (and virus), specimen mislabelling or mix-up, laboratory or cross-sample contamination and an observed trend of low detection of HIV among both mothers and infants because of increased exposure to maternal treatment and enhanced infant prophylaxis (98). The potential for false-positive results is of particular concern in settings in which the mother-to-child transmission rate is less than 5%, since the positive predictive value of highly sensitive nucleic acid-based technologies may decrease to nearly 70% (99). However, in some countries in sub-Saharan Africa, less than 10% of infants with an initial positive test result receive a confirmatory test, potentially resulting in a significant proportion (12.5%) of infants starting lifelong treatment unnecessarily.
Although a variety of causes may result in a false-positive test result, most infants with false-positive test results have low levels of viraemia; however, guidance is limited on how to interpret low levels of viraemia detected in early infant diagnostic assays. All test results reported as detectable by the NAT technology are generally considered to be positive, relying on the thresholds of detection provided by the manufacturers. To ensure that infants do not start lifelong treatment unnecessarily, various approaches have been considered. Guidelines in the United States of America suggest that infants should not be considered HIV-positive unless they have the equivalent of at least 5000 viral copies/ml (100), and South Africa has introduced an indeterminate range that requires further testing before a definitive diagnosis is provided and treatment is initiated (101).
Previous WHO guidelines do not specifically address this growing concern about false-positive test results. Further, there is currently no specific recommendation on what level of viraemia should be considered a true positive result in infants.

# Supporting evidence
A systematic review of 32 studies using an indeterminate range found 14 753 non-negative test results, of which 2436 (16.5%, 95% confidence interval 15.9-17.1%) were indeterminate (Web Annex H). One study reporting the final diagnoses of indeterminate cases found that 76% of
An indeterminate range a should be used to improve the accuracy of all nucleic acid-based early infant diagnosis assays (strong recommendation, moderate-certainty evidence)
a Indeterminate range: a range of viral copy equivalents that would be too low to be accurately diagnosed as HIV infected.
The indeterminate range suggested is currently estimated to be approximately equivalent to a cycle threshold of 33 on the Roche COBAS  Ampliprep/COBAS  TaqMan  HIV-1 Qualitative Test v2.0 assay.

# N E W
infants with an initial indeterminate test result were negative on repeat testing, suggesting that most infants were not HIV-infected despite the initial non-negative test result. These data indicate that, in countries not implementing an indeterminate range to manage early infant diagnosis test results, up to 12.5% (76% of 16.5%) of non-negative results could be false positive on initial testing with affected infants being potentially started on lifelong treatment unnecessarily.
The optimal indeterminate range is considered to be the approximate equivalent of a cycle threshold of 33 on the Roche COBAS  Ampliprep/COBAS  TaqMan  HIV-1 Qualitative Test v2.0 assay. This represented a balance between the proportion of infants living with HIV that would be incorrectly identified as indeterminate (about 8-13%) and the proportion of HIV-uninfected infants that would potentially start treatment unnecessarily (about 2-7%). The cycle threshold values vary by the assay used and cannot be directly applied between technologies or assays. Because true-positive infants with low levels of viraemia generally have less rapid disease progression and need to be followed up until final diagnosis is ascertained, the Guideline Development Group determined that it is more acceptable to have a higher proportion of true-positives incorrectly classified as indeterminate than false-positives, since all indeterminate test results should be followed up and repeat tested as soon as possible before lifelong treatment is administered.
Implementing an indeterminate range will support more accurate nucleic acid-based early infant diagnosis. Fewer HIV-negative infants will probably start unnecessary lifelong treatment, since most false-positives will fall within the indeterminate range rather than being identified as positive. This will limit confusion and challenges in interpreting potential subsequent discordant test results if the infant was classified as positive and already initiated treatment. Finally, in addition to reducing unnecessary treatment by limiting false-positive results, an indeterminate range will promote increased attention to confirmatory testing of all nonnegative test results and trigger corrective action to minimize potential contamination at the point of collection or in the laboratory.
Possible harm identified includes the potential requirement for additional specimens, which could result in delays to treatment initiation, and the associated risk of loss to care for HIV-positive infants with indeterminate results on the first sample. However, infants with low levels of viraemia (a small proportion of HIV-positive infants who would fall within the indeterminate range) are expected to progress more slowly to morbidity and mortality (102). Further, implementing an indeterminate range may reduce the confidence of health-care workers in early infant diagnosis testing programmes if high rates of resampling and retesting are required.

# Rationale for the recommendation

# Cost and cost-effectiveness
Implementing an indeterminate range has been determined to save costs since minimum additional resources will be required to repeat test all non-negative specimens, especially those with an initial indeterminate test result, compared with the cost of unnecessary lifelong treatment.
A cost-effectiveness model compared the standard of care (no indeterminate range) to a variety of indeterminate range options and concluded that implementing an indeterminate range is far more effective than the standard of care across a variety of viral ranges (data unpublished). As the prevalence, positivity and mother-to-child transmission rate at each testing time point decrease, the cost-effectiveness of an indeterminate range increases and saves more costs than no indeterminate range.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# Equity and acceptability
Implementing an indeterminate range may improve equity by ensuring that HIV-negative infants do not start lifelong treatment unnecessarily. This may also enable access to available treatment for infants correctly identified as HIV-positive.
A survey of values and preferences that included people living with HIV, health-care workers and programme managers found an indeterminate range to be highly acceptable. Most respondents preferred that the meaning of an indeterminate test result be clearly explained to mothers and other caregivers. The primary concern for all groups was the potential for confusion arising from inadequate explanations about the need to resample and retest the infant. However, as long as clear guidance on the meaning of an indeterminate test result is provided to mothers and other caregivers, there will be limited uncertainty about the acceptability of implementation.
Implementing an indeterminate range is expected to be feasible, especially if indeterminate test results are repeat tested using the same specimen. In the survey of programme managers, slightly more than half indicated that their country already has a written standard operating procedure for requesting a second specimen for invalid test results. However, there were some concerns regarding the additional time required for repeat testing all indeterminate test results and the need for storing specimens at the laboratory.
To ease the acceptability, feasibility and implementation of an indeterminate range, a standard operating procedure has been developed to support and guide countries based on expert opinion and values and preferences surveys (Annex 4 and Web Annex D). This standard operating procedure suggests that all indeterminate tests be repeat tested on the same specimen, if and when available. Most indeterminate test results are expected to be resolved with a repeated test on the same specimen, which would alleviate the need for and delay incurred in requesting a new specimen from the infant (98). If the same specimen cannot be repeat tested, then a new specimen should be requested and tested as quickly as possible. Repeat testing of the same sample may not be possible with point-of-care or near point-of-care technologies when the sample is directly applied from the heel to the cartridge; however, in such instances a new sample should be taken and immediately tested to confirm a positive test result.
This recommendation to use an indeterminate range to support more accurate diagnosis of infants should be implemented for any nucleic acid-based test performed for infants younger than 18 months, including testing at birth and at six weeks of age. In addition, recent evidence indicates that using HIV serology assays to rule out HIV infection among asymptomatic HIV-exposed infants at nine months of age should be reconsidered. Changes in transmission dynamics as well as in policy and practice have complicated RDT use for determining infection status. Substantial drug exposure for infants with implementation of the treat all policy for mothers and enhanced postnatal prophylaxis of HIV-exposed infants have resulted in viral load reduction and delayed antibody development in HIV-infected infants. Finally, the occurrence of maternal infection in late pregnancy or during the postnatal period may be responsible for a lack of passive HIV antibody transfer to the HIV-exposed infant. These concerns are supported by findings from Uganda and Kenya, where 15-40% of children under the age of two years and identified as HIV-infected had positive NAT but negative RDT (103,104). In this context, an expert group convened by WHO in May 2018 confirmed the importance of testing mothers to accurately assess infant exposure status and advocated undertaking nucleic acid-based testing instead of a serology test at nine months for all known symptomatic and asymptomatic HIV-exposed infants to determine HIV diagnosis before 18 months of age (Annex 5 shows the algorithm).

# Implementation considerations
Generally, early infant diagnostic assays measure the presence of virus using real-time nucleic acid-based technologies that often report cycle thresholds. The cycle threshold -the polymerase chain reaction (PCR) cycle when amplification is observed -is inversely correlated with the amount of virus in a sample.
Based on the meta-analysis and cost-effectiveness modelling, the Guideline Development Group assessed that detecting an approximate equivalent of a cycle threshold of 33 on the Roche COBAS  Ampliprep/COBAS  TaqMan  HIV-1 Qualitative Test v2.0 assay would be the most appropriate value to balance the risks and benefits of introducing an indeterminate range. Note that the cycle threshold values vary by assay used and cannot be directly applied between technologies or assays. Further, additional consideration may be necessary for countries using plasma as a sample type for infant testing rather than whole blood or dried blood spots, since the latter sample types typically capture and amplify intracellular nucleic acids that may increase detected viral levels.

# Research gaps
Research priorities regarding using an indeterminate range include the need for more detailed evidence on the impact of implementing an indeterminate range in populations with increased drug exposure and enhanced infant prophylaxis, the time of testing (earlier testing near birth), various sample types, differences in prevalence and different virus subtypes. More research would be valuable on the best messaging for health-care workers and mothers and other caregivers and on the optimal standard operating procedure for managing indeterminate test results. Further, understanding the feasibility of implementing an indeterminate range with all available nucleic acid-based technologies for early infant diagnosis and in various programmatic settings will be critical.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# PLANS FOR UPDATING, DISSEMINATION AND EVALUATION
These guidelines will be produced for dissemination as both printed hard-copy and webbased products and will be supported by peer-reviewed publication of the systematic reviews on which the recommendations are based. A policy brief will accompany the publication of the guidelines.
WHO will also incorporate these guidelines into the next full update of the WHO consolidated ARV guidelines planned for 2019. WHO will closely monitor data on the potential association between DTG and neural tube defects and regularly review emerging data. WHO will update recommendations related to DTG use as soon as relevant evidence becomes available.
WHO will work closely with WHO regional and country offices, national health ministries, implementing partners and networks of people living with HIV to plan for rapidly disseminating, adapting and implementing the new recommendations. Key steps in the dissemination include: presenting the recommendations at international conferences; holding workshops to support country adaptation; developing adaptation tools to assist countries in setting priorities; and ensuring briefings and joint planning with international and national implementing partners. The uptake of the recommendations in national guidelines will be assessed in 2020.
- Vitoria M, Hill A, Ford N, Doherty M, Clayden P, Venter F et al. The transition to

# ANNEX 1. METHODS FOR DEVELOPING THESE GUIDELINES
Methods for evidence synthesis

# Key information sources
The WHO Guideline Steering Group formulated PICO (population, intervention, comparator and outcome) questions to guide the systematic reviews used in developing these guidelines (101).
The following four PICO questions relevant to these guidelines were identified.
- Should DTG (or RAL for children without approved DTG dosing) be recommended in combination with an age-appropriate NRTI backbone as the preferred first-line ARV agent for treating HIV infection?
- Should DTG in combination with an optimized NRTI backbone be recommended as the preferred second-line ARV agent for treating HIV infection?
- Should DTG be recommended as the preferred ARV agent in combination with tenofovir disoproxil fumarate (TDF) and 3TC or FTC (XTC) for HIV post-exposure prophylaxis?
- Should an indeterminate range be implemented for more accurate molecular diagnosis of infants younger than 18 months?
A list of potential outcomes of interest for each question was circulated to all members of the Guideline Development Group, and members scored the importance on a scale of 1 (not important) to 9 (critical). The median score for each outcome was used to inform decision-making.
Systematic review teams developed protocols and conducted reviews in accordance with PRISMA reporting items for systematic reviews and meta-analyses.

# Assessing the risk of neural tube defects associated with using DTG in the periconception period
As part of retrieving the evidence for these guidelines, a systematic review was carried out to assess the evidence for the safety of DTG in pregnancy. As part of this review, the investigators of an ongoing study in Botswana were requested to provide information on pregnancy and birth outcomes for women exposed to different ART regimens during the periconception period. The results of this analysis identified a potential association between DTG use at conception and neural tube defects discussed in these guidelines.
The reviewers then comprehensive reviewed other databases, surveillance systems and other data sources to determine whether any other cases of neural tube defects associated with DTG use had been identified. These included post-marketing surveillance data from the manufacturers, pregnancy registries (the Antiretroviral Pregnancy Registry) and birth outcomes registries (the National Study of HIV in Pregnancy and Childhood in the United Kingdom and Ireland and the European Pregnancy and Paediatric HIV Cohort Collaboration study group) and drug regulatory authorities.
The results of the review, which included the analysis from the Botswana study, were presented to the Guideline Development Group under a confidentiality agreement.

# Values and preferences
To assess values and preferences, an online survey of people living with HIV was conducted to determine their views on recommendations that could be formulated. The survey was disseminated through networks of civil society organizations and organizations of people living with HIV. These surveys were carried out before a signal emerged of a potential risk of neural tube defects with DTG use in the periconception period. Following the dolutegravir drug safety alert, information regarding the values and preferences of women of reproductive age has been made available and has been integrated into these guidelines (2).
Web Annex D reports the results of the initial surveys. Web Annex D also reports on a pilot survey of women living with HIV carried out after the dolutegravir safety signal emerged (/).

# Feasibility and acceptability
To explore the feasibility and acceptability of the possible recommendations, online surveys were conducted among health-care workers and of HIV programme managers. Health-care workers were contacted through existing networks of organizations of health-care workers. Programme managers were contacted through WHO regional advisers, who disseminated the surveys to country programme managers in their region. These surveys were carried out before a signal emerged of a potential risk of neural tube defects with DTG use in the periconception period. In addition, a specific acceptability and feasibility assessment was undertaken to inform deliberations on the use of RAL granules. This evaluation was undertaken in KwaZulu-Natal in collaboration with a local academic institution.
Web Annex D reports the results of this survey.

# Certainty of the evidence and the strength of the recommendations
The GRADE method (3) was used to rate the certainty of the evidence and determine the strength of the recommendations. The GRADE approach to developing recommendations, which WHO has adopted, defines the certainty of evidence as the extent to which one can be confident that the reported estimates of effect (desirable or undesirable) available from the evidence are close to the actual effects of interest. The strength of a recommendation reflects the degree of confidence of the Guideline Development Group that the desirable effects of the recommendation outweigh the undesirable effects. Desirable effects (potential benefits) may include beneficial health outcomes (such as reduced morbidity and mortality), reducing the burden on the individual and/or health services and potential cost savings. Undesirable effects (potential harm) include those affecting individuals, families, communities or health services. Additional burdens considered include the resource use and cost implications of implementing the recommendations and clinical outcomes (such as drug resistance and drug toxicity).
The strength of a recommendation can be either strong or conditional. A strong recommendation (for or against) is one for which there is confidence that the desirable effects of adhering to the recommendation clearly outweigh the undesirable effects.
A conditional recommendation (for or against) is one for which the certainty of the evidence may be low or may apply only to specific groups or settings, Guideline Development Group concludes that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects or are closely balanced, but the Guideline Development Group is not confident about these trade-offs in all situations.
The certainty of the evidence, values and preferences of the end-users, feasibility, resource implications and considering the potential benefits and harm contribute to determining the strength of a recommendation.

# ANNEX 2. DRUG TOXICITY AND DRUG-DRUG INTERACTIONS OF ARV DRUGS

# WEIGHT-BASED DOSING FOR ARV FORMULATIONS FOR INFANTS AND CHILDREN

# Prescribing information and weight-based dosing of available ARV formulations for infants and children
This annex contains information on ARV drugs for which there are paediatric indications, formulations or sufficient information and evidence to provide guidance on prescribing and dosing in infants, children and adolescents less than 18 years of age. The work to develop and update simplified guidance on ARV drugs for use in children has been undertaken by WHO through the Paediatric Antiretroviral Working Group. 1
For simplification and ease of implementation, doses are expressed per weight-band rather than per kilogram or per square metre of body surface area. When this simplified weightband dosing was developed, careful consideration was given to the expected body surface area of children from low-and middle-income countries in each weight band. The primary source of information for the guidance provided is the manufacturer's package insert. This was supplemented with data from other clinical studies as well as expert paediatric pharmacology consultations. For fixed-dose combinations, a dose-modelling tool (. who.int/hiv/paediatric/generictool/en/index.html) was used to predict the dose delivered for each component drug against the recommended dosing schedule. In some cases the dose for a component in a particular weight band may be somewhat above or below the target dose recommended by the manufacturer. This is inevitable given the limitations imposed by a fixeddose combination, but care was taken to ensure that in no case would a child receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. PK efficacy and safety studies have also confirmed the overall safety of this dosing approach. For simplification, ARV drugs no longer considered preferred or alternative options for children have been removed from the dosing guidance.
In the context of increasing implementation of virological testing at birth, and the shift towards treating infants earlier in an effort to reduce early mortality, these guidelines include weight-based dosing for term infants aged <4 weeks, including those weighing less than 3 kg. However, there is limited experience with initiating treatment in HIV-infected newborns aged <2 weeks, and a paucity of PK data to fully inform accurate dosing for most drugs in neonates, who are undergoing rapid growth and maturation in renal and liver function. PK data in preterm infants are available only for AZT; there is considerable uncertainty of appropriate dosing for NVP, RAL and 3TC in preterm and low birth weight infants. In addition, LPV/r solution should not be given to preterm infants until they have reached 42 weeks gestational age, because of the risk of adverse effects that may occur in this population. The management of HIV treatment in preterm neonates extremely is challenging because of the lack of appropriate pharmacokinetic, safety, and dosing information as well as suitable formulations. Dosing for postnatal prophylaxis for HIV-exposed infants is not provided here but can be found at .      RAL granules are approved from birth. Feasibility and acceptability of such formulations has not been widely investigated and concerns have been raised regarding administration in resource limited settings. Due to the administration challenges presented by the granule formulation the use of the 25 mg chewable tablets as dispersible has been endorsed by the PAWG for infants and children older than 4 weeks and weighting at least 3 kg. This was largely based on in vitro data on solubility and bioequivalence between tablets and granules vi as well as considering the limited availability of adequate alternatives for this age group. However, findings from a feasibility and acceptability assessment conducted in South Africa demonstrate that administration of RAL granules in rural settings is feasible as long as supported with adequate training and counselling.  Suggested RTV dose for super-boosting to achieve the same dose as LPV in mg, in a ratio equal or approaching to 1:1. This dosing approach is supported by a study which explored this approach in young children receiving LPVr x.

# Strength of paediatric tablets
The LPV/r heat-stable tablet formulation must be swallowed whole and should not be split, chewed, dissolved or crushed. Adult 200/50 tablet could be used for patients 14-24.9kg (1 tab qam and 1 tab qpm) and for patients 25

# Optimal Paediatric ARV Formulary
In recent years, a number of improved ARV formulations have become available, such as dispersible, scored FDC tablets in place of the traditional liquid formulations. These products have greatly simplified the delivery of paediatric HIV care in low-income settings; however, the proliferation of options, has resulted in a multiplicity of formulations across regimens and weight-bands. Economies of scale are used by generic manufacturers to maintain affordable pricing but fragmentation of demand across too many duplicative products creates instability in the reliable supply of paediatric ARV dosage forms and complicates procurement and supply chain management.
Partners of the ARV procurement working group (APWG) and of the Global Accelerator for paediatric formulations (GAP-f) xi provide formulary guidance to programmes on selection of optimal paediatric ARVs defined using a robust set of criteria. The Optimal formulary is currently a list of 8 products that delivery recommended and appropriate first and second line regimens across all paediatric weight bands. The formulary was first developed in 2011 but is routinely revised to correspond to current WHO guidelines and available products. Programs are encouraged to procure paediatric dosage forms that are included on the Optimal Paediatric ARV Formulary. During periods of transitions or in special circumstances (eg. Neonatal treatment, TB co treatment and third line), dosage forms included on the ARV Limited-use formulary provide appropriate coverage xvi.

# The need for new formulations
The work of the Paediatric Antiretroviral Working Group and the Paediatric ARV Drug Optimisation xii xiii groups continue to highlight the urgent need for better age appropriate formulations for infants and children living with HIV. A number of solid formulations are under final stage of development (ABC/3TC/LPVr granules as well as ABC/3TC/EFV and DTG 10 mg scored dispersible tablets). In addition, the availability of co-formulated DRV/r in heat-stable fixed-dose combination formulations is critical to facilitate treatment sequencing and uptake of future 2nd and 3rd line treatment. A number of formulations containing approved ARVs for paediatric use have been formally prioritised and are listed in table 6. Finally, additional formulations containing newer drugs for which there is currently no paediatric indication were considered and the central future role of DTG and TAF in optimizing dose, sequencing and harmonization across age groups was highlighted.
In moving towards promoting drug optimisation for children and adolescents, WHO will continue to work to simplify prescribing, dispensing and dosing guidance and work with the pharmaceutical industry (originator and generic) and other partners to develop more practical recommendations on the range of formulations required to safely accelerate the scaling up of ART for children. this proposed dosing will be revised as soon as more evidence is gathered from ongoing studies.
This dosage form is the one identified by the PADO group viii as the most likely to deliver appropriate dose based on the best available information. However, the group strongly emphasized the importance of validating this dosing and ratio as soon as final dosing for DTG is approved down to 4 weeks of age, Scored tablets with doubled-strength of each component drug (ABC/3TC/DTG 120/60/10 mg) would enable reduction of the pill burden for children, but difficulties with assuring accuracy of dosing when scoring a triple-drug FDC will need to be addressed. Importantly, manufacturers interested in developing ABC/3TC/DTG could start development of a prototype, but will need to delay advancing their development plans until the dosing and the ratio are confirmed (expected in early 2019).

# ANNEXES 52
Annex 1. Methods for developing the guidelines Annex 2. Drug toxicity and drug-drug interactions of ARV drugs Annex 3. Dosages of ARV drugs Annex 4. Standard operating procedure for early infant diagnosis testing Annex 5. Revised simplified early infant diagnosis algorithm

# Guideline Development Group meeting
The Guideline Development Group met for three days in Geneva, Switzerland on 16-18 May 2018. Three members of the group participated via videoconference. The systematic reviews and supportive evidence, including values and preferences, acceptability, feasibility and cost, were presented to the group. Evidence-to-decision-making tables were prepared in accordance with the GRADE process and presented to the group, and the methodologist facilitated discussions. The Group agreed at the start of the meeting that 70% of votes from members would be required for a decision. Voting was required for the recommendations on DTG as the preferred first-line regimen. All recommendations were formulated with the consensus of Group members.
Following the Guideline Development Group meeting in Geneva, a follow-up meeting was held via videoconference on 13 June 2018. The meeting was intended to confirm the recommendations of the Group, since drug regulatory authorities and other agencies had made several statements regarding the safety of DTG for women and adolescent girls of childbearing potential after the meeting in May. The Guideline Development Group confirmed the recommendations it made during the May meeting.

# Peer review
A draft of the guidelines was circulated for review to members of the Guideline Development Group and the External Review Group. The Guideline Development Group reviewed the comments and incorporated them into the final document with due consideration of any conflicts of interest. Comments were interpreted in the light of any conflicts of interest declared (Web Annex A). Any conflicting or controversial comments were discussed with the WHO Guideline Steering Group. Disagreements were resolved through consensus of the WHO Guideline Steering Group.

# Declarations of interest and biographies of Guideline Development Group members
All external contributors to the development of these guidelines completed a WHO declaration of interests form. This included systematic reviewers and contributors to the supporting evidence as well as all members of the Guideline Development Group and External Review Group. In accordance with the WHO declaration of interests policy for experts, a brief biography of each Guideline Development Group member was published on the WHO HIV website with a description of the objective of the meeting. No public comments or objections were received concerning any Group members.
The responsible technical officers reviewed all the declaration of interests forms completed by the Guideline Development Group members. Every effort was made to ensure that the representation of the Guideline Development Group minimized conflicts of interest. A management plan for each declared conflict was agreed. All declared interests and management strategies were discussed with the chairs and methodologist before the Guideline Development Group meeting. Conflicts of interest were shared with the Guideline Development Group at the start of the meeting, with participation closely monitored by the responsible technical officers and GRADE methodologist.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV Review of declaration of interest forms identified two members who were principal investigators of two clinical trials of DTG-containing regimens (Francois Venter and Pablo Rojo). They were excluded from making recommendations on drug regimens but could make recommendations on early infant diagnosis of HIV.
Another member of the Guideline Development Group was excluded from making recommendations on ARV regimens because of a financial conflict of interest deemed significant (Mark Boyd). He declared being on the HIV advisory board of Gilead and had received US$ 7500. He was also participating in the advisory board of ViiV (current) and had received US$ 15 000. That member could make recommendations on early infant diagnosis of HIV. Web Annex A details the declared conflicts of interest and management plans.
Other declaration of interests were managed as follows. Thuy Le declared being a coinvestigator of two trials that received funding from industry. However, she did not personally receive funding as funding went to the research institution. The WHO Guideline Steering Group and responsible technical officer reviewed the information and determined that full participation was appropriate. Thanyawee Puthanakit received funding through the PENTA foundation from industry. Research funding went to her institution and no personal funding was received. The WHO Guideline Steering Group and responsible technical officer reviewed the information and determined that full participation was appropriate. Wendy Stevens received funding for research relating to TB diagnostics (not directly relevant to the guidelines) from the Bill & Melinda Gates Foundation and MRC. This was not deemed a conflict of interest by the WHO Guideline Steering Group and responsible technical officer, and full participation was allowed.
The responsible technical officers assessed all completed declaration of interest forms for other external contributors to the guidelines, including the External Review Group. Individual participation was reviewed with regard to the interests declared.

# External Review Group
Each member of the External Review Group was asked to complete and sign a declaration of interest form. This included members from partner organizations, including the United States Centers for Disease Control and Prevention and UNICEF. The responsible technical officers reviewed these to determine any conflicts of interests. Comments from the External Review Group were interpreted in the light of any conflicts of interest. Web Annex A details the declaration of interests and the management plan for External Review Group members.
All declaration of interest forms are on electronic file at the WHO Department of HIV and will be maintained for at least 10 years.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# Proteases inhibitors (PIs)
Atazanavir + ritonavir (ATV/r) 300 mg + 100 mg once daily Darunavir + ritonavir (DRV/r) 800 mg + 100 mg once daily or 600 mg + 100 mg twice daily Lopinavir + ritonavir (LPV/r) 400 mg + 100 mg twice daily

# Considerations for individuals receiving TB therapy
In the presence of rifampicin, adjusted dose of LPV/r (LPV 800 mg + ritonavir 200 mg twice daily or LPV 400 mg + ritonavir 400 mg twice daily), with close monitoring. In the presence of rifabutin, no dose adjustment required.

# Integrase strand transfer inhibitors InSTI
Dolutegravir (DTG) 50 mg once daily Raltegravir (RAL) 400 mg twice daily

# Considerations for individuals receiving TB therapy
In the presence of rifampicin, adjusted dose of DTG (50 mg twice daily) and RAL (800 mg twice daily), with close monitoring. In the presence of rifabutin, no dose adjustment required.
TLD (Tenofovir 300 mg, Lamivudine 300 mg, Dolutegravir 50 mg fixed dose combination) can be used once daily in adolescents living with HIV weighting at least 30 kg.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV

# General principles
The principles followed in developing the WHO simplified tables include the following:
- Use of an age-appropriate fixed dose combination is preferred for any regimen if such a formulation is available. DTG 25mg (FCT) in this weight band, more data to confirm this and further inform optimal dosing in the 14 to 25 kg weight bands is expected at the beginning of 2019 and will be included in an updated version of this annex. For adolescents living with HIV weighting more than 30 Kg a fixed dose formulation of TDF 300mg/3TC 300mg/DTG 50mg (TLD) can be used and is preferred.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV All indeterminate tests should be repeat tested on the same specimen, if and when available.
If the same specimen cannot be repeat tested, then a new specimen should be requested and tested as quickly as possible.
For specimens with two indeterminate test results, a new specimen should be requested.
For infants repeatedly testing indeterminate, it is suggested that a team of experts review clinical and test information to determine the best follow-up care.
Annex 5. Revised simplified early infant diagnosis algorithm

# ANNEX 5. REVISED SIMPLIFIED EARLY INFANT DIAGNOSIS ALGORITHM
The key principles for establishing whether HIV-exposed infants and children younger than 18 months are infected with HIV in low-and middle-income countries are based on existing WHO recommendations.
- Assess HIV exposure status by antibody testing the mother.
- Perform NAT test for any HIV exposed child that presents outside of national infant testing algorithm with clinical symptoms irrespective of previous NAT results.
- At 9 months, perform NAT for HIV-exposed infants, symptomatic and asymptomatic, regardless of previous NAT results after delivery.
- Ensure that confirmatory testing is undertaken following any positive result.
- Ensure that indeterminate test results are repeat tested immediately and given priority for rapid resolution.
- Ensure regular follow-up for all HIV-exposed infants until final diagnosis, including providing co-trimoxazole prophylaxis and clinical and nutritional assessment.
Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV  The risk of HIV transmission remains as long as breastfeeding continues. If the nine-month test is conducted earlier than three months after cessation of breastfeeding, infection acquired in the last days of breastfeeding may be missed. Retesting at 18 months or three months after cessation of breastfeeding (whichever is later) should be carried out for final assessment of HIV status.
f If breastfeeding extends beyond 18 months, the final diagnosis of HIV status can only be assessed at the end of breastfeeding. If breastfeeding ends before 18 months, final diagnosis of HIV status with antibody testing can only be assessed at 18 months. Antibody testing should be undertaken at least three months after cessation of breastfeeding (to allow for development of HIV antibodies). For infants younger than 18 months of age, NAT should be performed to confirm infection. If the infant is older than 18 months, negative antibody testing confirms that the child is uninfected; positive antibody testing confirms that the infant is infected.

# Web annexes