18.1. Principles
Children with HIV may develop HIV drug resistance as a result of being on ART or through exposure to the maternal or infant ARVs and ART used to prevent MTCT.
WHO does not recommend routine HIV drug resistance testing for individual patient management in settings where other basic laboratory measurements such as CD4 and HIV VL are not yet available.
Countries are encouraged to implement strategies for minimizing the development and spread of HIVDR, by selecting appropriate drug combinations, ensuring reliable ARV drug quality and supply, and providing culturally appropriate support for adherence.
Surveillance and monitoring for HIVDR in paediatric populations at country level is recommended. The use of ART site-based HIVDR early warning indicators (EWIs) of factors that may be associated with the preventable emergence of HIVDR is recommended.
18.2. HIV drug resistance in infants and children
HIV drug resistance (HIVDR) in infants and children with HIV infection may result either from a drug-resistant strain being transmitted from the mother [219-222] or a drug-resistant strain developing due to administration of paediatric ART or maternal or infant ARVs used for PMTCT or maternal ART. The risk of HIV-1 transmission to the infant is reduced from about 35% to about 2 – 20% if the mother receives ARVs or ART during pregnancy and delivery, and the infant is given ARVs in the postpartum period. The success of PMTCT depends on the ARV regimen used, the duration of prophyalxis and the degree of adherence. Extended maternal or infant prophylaxis with ARVs, or continued maternal ART is also required to minimize transmission through breastfeeding where breastfeeding is the selected infant-feeding strategy [20, 102, 223, 224].
Development of HIVDR in children on ART is usually related to poor adherence, use of suboptimal regimens, or to problems with drug absorption of pharmacokinetics [225-227]. All of these factors give rise to subtherapeutic drug levels and the rebound of viraemia with resistant virus.
WHO does not recommend routine HIV drug resistance testing for individual infant, child or adult patient management in settings where other basic laboratory measurements, such as CD4 and HIV VL, are not yet available.
18.3. Minimizing the emergence of HIV drug resistance
The emergence of HIVDR is of increasing concern in countries where ART and ARV prophylaxis is widely used and represents a potential impediment to the achievement of long-term success in treatment outcomes for children, adolescents and adults. Minimizing the emergence and transmission of HIVDR is therefore essential in order to ensure the efficacy of the limited number of ARV drugs available in many countries. As in adults, optimization of adherence is vital for minimizing HIVDR, alongside adherence to standardized protocols for ARV use for prophylaxis and treatment. Specific problems that should be considered in treating children include the need to change dose and formulations as children cross thresholds of weight or age, and limited availability of suitable paediatric ARV for mulations. To avoid emergence of HIVDR in the event of discontinuation of ARVs due to toxicity, it may be necessary to not discontinue all ARVs at the same time.
Countries are encouraged to develop and implement strategies to minimize the development and spread of HIVDR by selecting appropriate drug combinations, ensuring reliable ARV drug quality and supply, and providing appropriate support for adherence. Furthermore, surveillance and monitoring for HIVDR in paediatric populations is recommended as part of the overall monitoring of the effectiveness of ART programmes. These surveys are an important public health tool to assist national, regional and global ART scale-up efforts, and guide programmes about trends in drug resistance patterns with a view to enabling timely policy review so as to minimize the impact of such resistance.
The Global HIV Drug Resistance Network (HIVResNet), a group of international experts on HIVDR that advises WHO, has developed an essential package for a national and global HIVDR prevention and assessment strategy, which complements plans for the implementation of ART scale-up [228].i WHO is supplementing this strategy with approaches that specifically target the paediatric population. The main elements of the strategy include the following:
regular assessment of HIVDR EWIs in paediatric ART sites (See );
monitoring surveys to assess the emergence of HIVDR and associated factors in cohort(s) of treated children 12 months after ART initiation in sentinel paediatric ART sites; and
surveillance for drug-resistant HIV-1 among infants newly diagnosed with HIV prior to treatment initiation.
WHO HIV drug resistance early warning indicators.
18.4. Monitoring HIVDR early warning indicators
ART site-based HIVDR EWIs are identifiable factors that may be associated with the emergence of HIVDR and which, if addressed at either the ART site or programme level (see http://www.who.int/hiv/drugresistance for current documentation and tools), may prevent the development of HIVDR. Implementing an HIVDR EWI monitoring system allows ART programmes to assess the extent to which they are optimally preventing HIVDR.
WHO recommends that countries monitor those EWIs for which current information is readily available from data routinely recorded at the site level. Six EWIs (and two optional indicators) are recommended by WHO.
The EWIs should be monitored in all ART sites in a country when feasible, or from a representative sample of ART sites. Achieving the best possible performance as measured by these indicators will help minimize the preventable emergence of drug-resistant HIV. Sites which do not achieve one or more of the EWI targets may require increased resources, staff training, or additional review to clarify the kind of support needed. Likewise, lessons may be learned from sites achieving and surpassing targets and applied to sites observed to be functioning less well.
18.5. Monitoring emergence of HIVDR transmission in infants and children on ART
The use of ART in high-income countries has been associated with the development of HIVDR [229]. HIV is a retrovirus characterized by very rapid replication, a high mutation rate in the presence of drug-selective pressure, viral recombination, and the need for lifelong treatment [230]. Because of these characteristics, some degree of HIVDR is anticipated to occur among persons on treatment even if appropriate ARV regimens are provided and optimal adherence to therapy is supported [229]. A population-based approach to ART scale-up requires a population-based strategy to assess and prevent the emergence of HIVDR, using an epidemiological approach to evaluate ART programmes. WHO has developed a generic monitoring protocol to monitor the emergence of HIVDR and associated programmatic factors in cohorts of infected children starting first-line ART. The survey is designed for implementation following a rolling three-year cycle in sentinel ART sites treating children. The survey identifies programmatic factors associated with the emergence of HIVDR, which can be adjusted to optimize patient care and minimize the emergence of preventable drug-resistant HIV. The paediatric monitoring survey protocol is based on the adult HIVDR monitoring protocol [231] and is currently being piloted in Mozambique. The final paediatric protocol will be updated based on evidence derived from the pilot.
18.6. Surveillance for HIVDR in newly infected treatment-naive infants
An unwanted outcome related to the use of ARVs for PMTCT is the development of drug-resistance in the small number of infants who do become infected. Administration of one or more ARVs, especially if one NNRTI is administered alone, can lead to the development of drug-resistance in the infant in the event that HIV is transmitted.
Combination regimens for PMTCT have been recommended since 2006; however, many countries continue to provide single-dose nevirapine (sd-NVP), which is associated with development of NNRTI resistance among both HIV-infected mothers and infants who become infected. In relatively small studies (9 – 80 infants), the few infected infants exposed to NVP alone antepartum/intrapartum and postpartum have been shown to have NNRTI resistance at rates between 38% and 92% [221, 232-236]. Maternal prophylaxis regimens with two or more ARVs are not only more effective in preventing transmission but are also less likely to result in maternal HIVDR and infant HIVDR if transmission occurs. Small research studies have evaluated the prevalence of drug-resistant among infants associated with various PMTCT regimens administered to mothers and infants. The very few infected infants exposed to combinations of NVP and one or more NRTIs have been seen to have resistance at rates between 13% and 57% [232, 237 [not in list of refs], 238-241] with lower rates (between 13% and 14%) seen in two other small studies (of 7 and 8 infants, respectively) among infants receiving two NRTIs: AZT/3TC [239].
However, nationwide surveillance systems have not yet been developed to evaluate the association between PMTCT and HIVDR among infants, largely because of the expense and difficulty of collecting specimens and performing resistance assays. With expanding access to infant diagnosis using DBS, many laboratories have stored DBS for quality assurance purposes. These may be useful for drug-resistance testing. Stored DBS present an important opportunity to evaluate resistance systematically among infants newly diagnosed with HIV, and may provide critical information to guide optimal selection of an ART regimen. HIV has been successfully amplified and genotyped for drug-resistance testing from DBS in a large number of studies.
WHO is planning to evaluate the use of stored DBS to determine initial HIVDR among infants diagnosed with HIV as part of national HIVDR surveillance efforts.
The objective of surveillance for HIVDR in newly infected treatment-naive infants is to assess the extent of HIVDR in specific geographical areas where ART and ARVs for maternal and infant PMTCT have been widely available to eligible maternal and paediatric populations for at least three years. The survey results will help to guide policy-makers on the likely future efficacy of currently available or future paediatric ART regimens.
Further details can be provided by the WHO HIVDR programme at http://www.who.int/hiv/drugresistance/.
- i
The WHO/HIVResNet strategy for HIVDR in the paediatric population is being developed under the coordination of WHO in collaboration with HIVResNet.
