Prevalence of HIV-1 drug resistance amongst newly diagnosed HIV-infected infants age 4-8 weeks, enrolled in three nationally representative PMTCT effectiveness surveys, South Africa: 2010, 2011-12 and 2012-13

BMC infectious diseases, Volume 19, Year 2019

Interpretation

BACKGROUND: South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. METHODS: Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. RESULTS: Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. CONCLUSIONS: These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years. Data for this resistance sub-study were drawn from the three nationally representative, cross-sectional SAPMTCTE, conducted amongst infants aged 4–8 weeks receiving their first immunisation. Data were collected at 580 public primary health care clinics and community health centres in all nine South African provinces between June – December 2010 (2010 survey), August 2011 – March 2012 (2011 survey), and October 2012 – May 2013 (2012 survey), respectively [13]. Caregiver/infant pairs of known or unknown HIV and PMTCT status were consecutively or systematically selected depending on facility size. Data were gathered from patient-held charts (“Road to Health Charts/Booklets”) and during interviews (self-reported maternal HIV testing and HIV status, infant feeding practices and ARV regimen). Infant dried blood spots (iDBS) were collected by heel-prick from all consented infants and assessed for HIV-exposure using a biomedical marker HIV Enzyme immunoassay (EIA). The iDBS with positive EIA or discordant EIA results were compared with self-reported results or were tested using a qualitative total nucleic acid (TNA) PCR to determine infant’s HIV infection. All DBS cards were stored at -20 °C before analysis. HIVDR genotyping was performed on all adequate HIV PCR positive iDBS specimens from participants that had consented for further testing. Specimens from participants from whom consent for further testing was not received, or iDBS cards with insufficient or unusable blood spots were excluded. Genotyping for resistance mutations to the NRTI, NNRTI and protease inhibitor (PI) drug classes was performed using a validated in-house sequencing method recommended by the CDC [14] as previously described [15]. Briefly, total viral nucleic acid was extracted from two spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3 [16]. Resistance was defined as the presence of mutations associated with impaired drug susceptibility using the Stanford algorithm (https://hivdb.stanford.edu/) and the 2015 IAS-USA drug resistance mutation list [17]. Group comparisons for categorical data were performed using chi-square tests. Binomial regression models were applied to estimate absolute differences in resistance prevalence over the different years and exposure categories. The analyses performed are unweighted and did not take the survey design into account due to the small number of HIV positive participants involved. Summary statistics were calculated using STATA v14 (StataCorp. 2015 Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). For the purpose of this analysis we categorised maternal and infant antiretroviral access into five main groups: maternal ART with infant prophylaxis (NVP or AZT); maternal ARV prophylaxis with infant prophylaxis (NVP or AZT); infant prophylaxis only (mother reported not receiving any antiretroviral drug), any other antiretroviral combination including maternal ART only or maternal ARV only (no infant prophylaxis) or maternal ART and ARV (not one or the other) for some duration of pregnancy, and no known maternal antiretroviral exposure. The SAPMTCTE was approved by the institutional review board of the SA Medical Research Council (MRC), study number EC09–002. The project was reviewed according to the CDC human research procedures and was determined to be research, but CDC was not engaged. The resistance sub-analysis study was approved by the Institutional Review Board of the University of the Witwatersrand (M110737).

AI Digest

Study Justification:

The study aims to investigate the prevalence of HIV-1 drug resistance among newly diagnosed HIV-infected infants aged 4-8 weeks in South Africa. This is important because despite efforts to reduce mother-to-child transmission of HIV, there is limited data on infant HIV drug resistance. Understanding the prevalence of drug resistance patterns can help inform national programs to prevent mother-to-child transmission of HIV.

Highlights:

– The study analyzed data from three nationally representative surveys conducted in South Africa between 2010 and 2013.
– The surveys included mothers with known, unknown, or no exposure to antiretrovirals for prevention of mother-to-child transmission (PMTCT) and their infants.
– HIV drug resistance was detected in 51% of HIV-positive infants, with the highest prevalence of resistance observed in infants whose mothers received antiretroviral therapy (ART).
– The prevalence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was particularly high.
– Concerningly, resistant virus was also detected in infants whose mothers were not exposed to antiretroviral drugs, raising questions about circulating resistant virus.

Recommendations:

– Strengthen efforts to prevent mother-to-child transmission of HIV by ensuring optimal antiretroviral therapy coverage for HIV-positive pregnant and lactating women.
– Monitor and address the increasing prevalence of NNRTI resistance among newly diagnosed infants.
– Investigate the sources of circulating resistant virus in infants whose mothers were not exposed to antiretroviral drugs.

Key Role Players:

– National Department of Health: Responsible for implementing and coordinating national programs to prevent mother-to-child transmission of HIV.
– Healthcare providers: Involved in providing antiretroviral therapy and care to HIV-positive pregnant and lactating women.
– National Institute of Communicable Diseases: Conducted the analysis of infant dried blood spots for HIV drug resistance.
– Centers for Disease Control and Prevention: Provided validation for the in-house assay used to analyze HIV drug resistance.

Cost Items for Planning Recommendations:

– Antiretroviral drugs: Budget allocation for ensuring optimal antiretroviral therapy coverage for HIV-positive pregnant and lactating women.
– Laboratory equipment and supplies: Funding for the National Institute of Communicable Diseases to conduct analysis of infant dried blood spots for HIV drug resistance.
– Training and capacity building: Investment in training healthcare providers on the latest guidelines and best practices for preventing mother-to-child transmission of HIV.
– Research and surveillance: Funding for ongoing monitoring and research to track the prevalence of HIV drug resistance and identify emerging trends.
Please note that the provided information is based on the description and findings of the study. For specific details and accurate budget estimates, it is recommended to refer to the original publication in BMC Infectious Diseases, Volume 19, Year 2019.

Strength of Evidence

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong, but there are some areas for improvement. The study design is cross-sectional, which limits the ability to establish causality. Additionally, the sample size for certain subgroups is small, which may affect the generalizability of the findings. To improve the strength of the evidence, future studies could consider using a longitudinal design to better assess trends over time. Additionally, increasing the sample size for underrepresented subgroups would provide more robust data. Finally, incorporating a control group of HIV-negative infants could help establish a baseline for comparison.

Abstract

Data for this resistance sub-study were drawn from the three nationally representative, cross-sectional SAPMTCTE, conducted amongst infants aged 4–8 weeks receiving their first immunisation. Data were collected at 580 public primary health care clinics and community health centres in all nine South African provinces between June – December 2010 (2010 survey), August 2011 – March 2012 (2011 survey), and October 2012 – May 2013 (2012 survey), respectively [13]. Caregiver/infant pairs of known or unknown HIV and PMTCT status were consecutively or systematically selected depending on facility size. Data were gathered from patient-held charts (“Road to Health Charts/Booklets”) and during interviews (self-reported maternal HIV testing and HIV status, infant feeding practices and ARV regimen). Infant dried blood spots (iDBS) were collected by heel-prick from all consented infants and assessed for HIV-exposure using a biomedical marker HIV Enzyme immunoassay (EIA). The iDBS with positive EIA or discordant EIA results were compared with self-reported results or were tested using a qualitative total nucleic acid (TNA) PCR to determine infant’s HIV infection. All DBS cards were stored at -20 °C before analysis. HIVDR genotyping was performed on all adequate HIV PCR positive iDBS specimens from participants that had consented for further testing. Specimens from participants from whom consent for further testing was not received, or iDBS cards with insufficient or unusable blood spots were excluded. Genotyping for resistance mutations to the NRTI, NNRTI and protease inhibitor (PI) drug classes was performed using a validated in-house sequencing method recommended by the CDC [14] as previously described [15]. Briefly, total viral nucleic acid was extracted from two spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3 [16]. Resistance was defined as the presence of mutations associated with impaired drug susceptibility using the Stanford algorithm (https://hivdb.stanford.edu/) and the 2015 IAS-USA drug resistance mutation list [17]. Group comparisons for categorical data were performed using chi-square tests. Binomial regression models were applied to estimate absolute differences in resistance prevalence over the different years and exposure categories. The analyses performed are unweighted and did not take the survey design into account due to the small number of HIV positive participants involved. Summary statistics were calculated using STATA v14 (StataCorp. 2015 Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). For the purpose of this analysis we categorised maternal and infant antiretroviral access into five main groups: maternal ART with infant prophylaxis (NVP or AZT); maternal ARV prophylaxis with infant prophylaxis (NVP or AZT); infant prophylaxis only (mother reported not receiving any antiretroviral drug), any other antiretroviral combination including maternal ART only or maternal ARV only (no infant prophylaxis) or maternal ART and ARV (not one or the other) for some duration of pregnancy, and no known maternal antiretroviral exposure. The SAPMTCTE was approved by the institutional review board of the SA Medical Research Council (MRC), study number EC09–002. The project was reviewed according to the CDC human research procedures and was determined to be research, but CDC was not engaged. The resistance sub-analysis study was approved by the Institutional Review Board of the University of the Witwatersrand (M110737).

Materials

N/A

Innovations

Based on the provided description, it seems that the focus of the study is on tracking the prevalence of HIV drug resistance among newly diagnosed HIV-infected infants in South Africa. The study analyzes data from three nationally representative surveys conducted between 2010 and 2013. The surveys collected data on maternal and infant antiretroviral access, HIV exposure, and HIV drug resistance.

In terms of potential innovations to improve access to maternal health, here are some recommendations:

1. Strengthening Antiretroviral Therapy (ART) Programs: Enhance the availability and accessibility of ART for pregnant women living with HIV to prevent mother-to-child transmission of HIV. This can include expanding ART coverage, improving supply chain management, and ensuring consistent availability of antiretroviral drugs.

2. Early HIV Testing and Diagnosis: Implement strategies to increase early HIV testing and diagnosis among pregnant women, such as routine HIV testing during antenatal care visits or offering HIV self-testing options. Early diagnosis allows for timely initiation of antiretroviral treatment and prevention of mother-to-child transmission.

3. Integrated Maternal and Child Health Services: Integrate maternal and child health services to provide comprehensive care for pregnant women and their infants. This can include integrating HIV testing, antenatal care, postnatal care, and pediatric HIV services to ensure continuity of care throughout the pregnancy and postpartum period.

4. Community-Based Approaches: Implement community-based interventions to improve access to maternal health services, particularly in remote or underserved areas. This can involve training community health workers to provide antenatal and postnatal care, conducting outreach programs, and promoting community awareness about maternal health and HIV prevention.

5. Health Information Systems: Strengthen health information systems to improve data collection, monitoring, and evaluation of maternal health programs. This can help identify gaps in service delivery, track progress, and inform evidence-based decision-making for improving access to maternal health services.

These recommendations aim to address the challenges identified in the study and improve access to maternal health, particularly for pregnant women living with HIV.

AI Innovations Description

Based on the provided description, the recommendation to improve access to maternal health would be to strengthen the implementation of antiretroviral therapy (ART) for pregnant women living with HIV. This recommendation is based on the findings that show increasing HIV drug resistance among newly-diagnosed infants in South Africa, despite improved ART regimens and coverage.

To implement this recommendation, the following steps can be taken:

1. Enhance awareness and education: Increase awareness among healthcare providers and pregnant women about the importance of early initiation of ART during pregnancy to prevent mother-to-child transmission of HIV.

2. Improve access to HIV testing and counseling: Ensure that all pregnant women have access to HIV testing and counseling services, and that they receive accurate information about the benefits of ART for both their own health and the health of their infants.

3. Strengthen antenatal care services: Integrate HIV testing and ART initiation into routine antenatal care services to ensure that pregnant women are identified early and provided with appropriate treatment.

4. Expand access to ART: Ensure that all pregnant women living with HIV have access to ART, regardless of their CD4 cell count or clinical stage. This can be achieved by increasing the availability of ART medications and improving the supply chain management system.

5. Provide comprehensive support: Offer comprehensive support services to pregnant women living with HIV, including adherence counseling, psychosocial support, and access to maternal and child health services.

6. Strengthen monitoring and evaluation: Establish a robust monitoring and evaluation system to track the implementation of ART for pregnant women and assess its impact on reducing mother-to-child transmission of HIV.

By implementing these recommendations, it is expected that access to maternal health will be improved, leading to a reduction in mother-to-child transmission of HIV and improved health outcomes for both mothers and infants.

AI Innovations Methodology

Based on the provided information, here are some potential recommendations to improve access to maternal health:

1. Strengthening Antiretroviral Therapy (ART) Programs: Enhance the availability and accessibility of ART for pregnant women living with HIV, ensuring early initiation and consistent adherence to treatment.

2. Integrated Maternal and Child Health Services: Integrate maternal health services with child health services to provide comprehensive care for both mother and child, including antenatal care, postnatal care, immunizations, and family planning.

3. Community-Based Interventions: Implement community-based interventions to increase awareness and knowledge about maternal health, promote early antenatal care visits, and provide support for pregnant women in accessing healthcare services.

4. Mobile Health (mHealth) Solutions: Utilize mobile health technologies to deliver maternal health information, reminders, and appointment notifications to pregnant women, especially in remote or underserved areas.

5. Capacity Building for Healthcare Providers: Provide training and support for healthcare providers to improve their knowledge and skills in providing quality maternal healthcare, including HIV prevention, treatment, and care.

To simulate the impact of these recommendations on improving access to maternal health, a possible methodology could include the following steps:

1. Define the indicators: Identify key indicators to measure the impact of the recommendations, such as the number of pregnant women receiving ART, the percentage of pregnant women attending antenatal care visits, or the rate of mother-to-child transmission of HIV.

2. Collect baseline data: Gather data on the current status of maternal health access, including the number of pregnant women receiving ART, antenatal care attendance rates, and other relevant indicators.

3. Implement the recommendations: Roll out the recommended interventions and monitor their implementation, ensuring that they are reaching the target population.

4. Collect post-intervention data: After a sufficient period of time, collect data on the indicators again to assess the impact of the recommendations. This could involve surveys, interviews, or analysis of existing health records.

5. Analyze the data: Compare the baseline data with the post-intervention data to determine the changes in the indicators. Use statistical analysis to assess the significance of the changes and quantify the impact of the recommendations.

6. Interpret the results: Interpret the findings to understand the effectiveness of the recommendations in improving access to maternal health. Identify any challenges or limitations encountered during the implementation process.

7. Adjust and refine: Based on the results, make any necessary adjustments or refinements to the recommendations to further improve access to maternal health.

8. Monitor and evaluate: Continuously monitor and evaluate the impact of the recommendations over time to ensure sustained improvements in access to maternal health.

It is important to note that the specific methodology may vary depending on the context and available resources.

Author

Dima Health

Statistics:

Citations: 8

Identifiers:

DOI: 10.1186/s12879-019-4339-y

Research Areas:

Cancer, Community Interventions, Health System and Policy, Infectious Diseases, Maternal and Child Health, Quality of Care, Sexual and Reproductive Health, Social Determinants

Study Countries:

South Africa

Study Design:

Cross Sectional Study

Study Approach:

Mixed-methods, Qualitative, Quantitative

Participants Gender:

Female