Maternal CD4+ cell count decline after interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV

PLoS ONE, Volume 7, No. 8, Year 2012

Ukuhunyushwa

Background: We evaluated maternal CD4+ cell count (CD4+) decline after PMTCT prophylaxis in a multi-country HIV care program. Methods: Analysis was restricted to antiretroviral therapy (ART)-naive, HIV-infected pregnant women with CD4+ ≥250 cells/mm3 at enrollment. Single-dose nevirapine (sd-NVP) or short-course antiretroviral prophylaxis (sc-ARVp) with zidovudine (AZT) or AZT + lamivudine (3TC) was initiated in 11 programs while 2 programs offered triple-drug antiretroviral prophylaxis (tARVp) (AZT+3TC+ NVP or nelfinavir). All regimens were stopped at delivery. CD4+ decline was defined as proportion of women who declined to CD4+ <350 cells/mm3 or <200 cells/mm3 at 24 months. Weibull regression was used for multivariable analysis. Findings: A total of 1,393 women with enrollment CD4+ ≥250 cells/mm3 initiated tARVp (172; 12%) or sc-ARVp (532; 38%) during pregnancy or received intrapartum sd-NVP (689; 50%). At enrollment, maternal median age was 27 years (interquartile range (IQR) 23-30), median CD4+ was 469 cells/mm3 (IQR: 363-613). At 24 months post-delivery, the cumulative probability of CD4+ decline to <200 cells/mm3 was 12% (95% CI: 10-14). Among a subgroup of 903 women with CD4+ ≥400 cells at enrollment, the 24 month cumulative probability of decline to CD4+ <350 cells/mm3 was 28%; (95% CI: 25-32). Lower antepartum CD4+ was associated with higher probability of CD4+ decline to <350 cells/mm3: 46% (CD4+400-499 cells/mm3) vs. 19% (CD4+ ≥500 cells/mm3). After adjusting for age, enrollment CD4+ and WHO stage, women who received tARVp or sd-NVP were twice as likely to experience CD4+ decline to <350 cells/mm3 within 24 months than women receiving sc-ARVp (adjusted hazard ratio: 2.2; 95% CI: 1.5-3.2, p<0.0001). Conclusion: Decline in CD4+ cell count to ART eligibility thresholds by 24 months postpartum was common among women receiving PMTCT prophylaxis during pregnancy and/or delivery. © 2012. The MTCT-Plus Initiative provided support to 13 clinical programs in eight countries in sub-Saharan Africa (Cameroon, Côte d’Ivoire, Kenya, Mozambique, Rwanda, South Africa, Uganda, and Zambia) and in Thailand to implement HIV/AIDS care and treatment to families identified through PMTCT services [7]. Pregnant or recently postpartum women identified as HIV-infected (HIV+) in PMTCT programs were invited to enroll in the MTCT-Plus Initiative which was built upon existing services and provided HIV-infected women, their partners, and their children, holistic family care with unrestricted access to ART for eligible patients [8], [9]. ART eligibility was based on WHO and national guidelines in effect at the time. Prior to January 2005, criteria included CD4+ <200 cells/mm3, WHO stage 4, or CD4+ between 200 and 350 cells/mm3 and WHO stage 2 or 3 [1]. After January 2005, women with CD4+ between 200 and 350 cells/mm3 and stage 2 were no longer considered ART-eligible. ART-naïve pregnant women who were not eligible for ART, received an ARV prophylaxis regimen, had a CD4+ prior to or within 30 days of delivery ≥250 cells/mm3 and had at least one CD4+ after delivery were included in this analysis. Women receiving ART during pregnancy, or who had CD4+ <250 cells/mm3 at enrollment or who had no ARV prophylaxis or missing documentation of ARV prophylaxis were excluded. The MTCT-Plus Initiative procedures for enrollment and follow-up have been previously described [8]–[10]. In brief, pregnant women received CD4+ cell count at enrollment and maternal clinical and socio-demographic characteristics were recorded. HIV-infected women not eligible for ART were scheduled to attend follow-up visits every three months for the first six months following enrollment then every six months thereafter for clinical examination, WHO staging and CD4+ monitoring. MTCT-Plus Initiative sites followed local guidelines for PMTCT prophylactic regimens. Initially, most programs offered a sd-NVP regimen. By 2004, sites in Bangkok, Thailand, and Eldoret, Kenya, offered triple-drug ARV prophylaxis (tARVp) consisting of zidovudine (AZT) + lamivudine (3TC) + NVP or nelfinavir (NFV) prophylaxis during pregnancy. Over time most sites offered short-course (sc-ARVp) multidrug PMTCT regimens (antepartum AZT with or without 3TC + intrapartum sd-NVP). All ARV prophylaxis initiated antepartum or intrapartum was discontinued after delivery, as per WHO guidelines [1] including tARVp in women not eligible for ART. The primary outcome, CD4+ decline, was defined as: 1) the 12 and 24 month cumulative probability from delivery (time when ARV prophylaxis was discontinued) to decline in CD4+ to <200 cells/mm3 (2006 WHO recommended eligibility criteria for ART initiation) among women with enrollment CD4+ ≥250 cells/mm3; and 2) the 12 and 24 month cumulative probability from delivery to decline in CD4+ to <350 cells/mm3 (current WHO recommended eligibility criteria for ART initiation) among women with enrollment CD4+ ≥40 cells/mm3. Group comparisons were conducted using Student’s t-test or non-parametric Kruskal-Wallis test for continuous variables and the Chi square test or Fisher’s exact test for categorical variables. Kaplan-Meier plots were used to estimate the cumulative probability of reaching outcome. Time was measured from the date of delivery and we right-censored women who were lost-to-follow-up (LTF), (>6 months since last scheduled visit), died, withdrew or were without an event at the date of their last clinical visit or March 31, 2008 when data collection ended. In addition, women who started ART after delivery were censored at the date ART was prescribed. The Log-Rank test was used to compare the probability of CD4+ decline to <200 cells/mm3 or <350 cells/mm3 between the three ARV prophylaxis groups (sd-NVP, sc-ARVp, and tARVp). We used Weibull regression models to identify risk factors for reaching the criteria for ART eligibility at 24 months. The following variables were considered: ARV prophylaxis regimen, age, CD4+ and WHO stage at enrollment. All factors associated with the outcomes at a p-value <0.25 were included in the multivariable analysis. Adjusted hazard ratios (aHR) and their 95% confidence interval (CI) are reported with two-sided p-values. The effect of program site was evaluated using Kaplan-Meier plots and associated Log-Rank tests independently for each ARV prophylaxis regimen. All analyses were performed in intent-to-treat and on-treatment population with SAS software version 9.2 (SAS Institute, Cary, NC, USA). The conduct of the MTCT-Plus Initiative as a service delivery program with data collection for monitoring and evaluation purposes was approved by Columbia University’s Institutional Review Board and local ethics review boards in each country where the study was implemented.

I-AI Digest

Study Justification:

This study aimed to evaluate the decline in maternal CD4+ cell count after the interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV. The study was conducted in multiple countries and focused on HIV-infected pregnant women who were not receiving antiretroviral therapy (ART) at enrollment.

Highlights:

– The study included 1,393 women with CD4+ cell count ≥250 cells/mm3 who received different antiretroviral prophylaxis regimens during pregnancy or intrapartum.
– At 24 months post-delivery, the cumulative probability of CD4+ decline to

Amandla Obufakazi

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is fairly strong, but there are some areas for improvement. The study includes a large sample size and provides detailed information about the methods used. The findings are clearly presented and supported by statistical analysis. However, there are a few suggestions to improve the evidence: 1) Include information about the duration of follow-up for each participant to assess the long-term impact of CD4+ decline. 2) Provide more information about the characteristics of the study population, such as demographic data and HIV treatment history, to better understand the generalizability of the findings. 3) Consider conducting a randomized controlled trial to further strengthen the evidence and establish causality.

Abstract

The MTCT-Plus Initiative provided support to 13 clinical programs in eight countries in sub-Saharan Africa (Cameroon, Côte d’Ivoire, Kenya, Mozambique, Rwanda, South Africa, Uganda, and Zambia) and in Thailand to implement HIV/AIDS care and treatment to families identified through PMTCT services [7]. Pregnant or recently postpartum women identified as HIV-infected (HIV+) in PMTCT programs were invited to enroll in the MTCT-Plus Initiative which was built upon existing services and provided HIV-infected women, their partners, and their children, holistic family care with unrestricted access to ART for eligible patients [8], [9]. ART eligibility was based on WHO and national guidelines in effect at the time. Prior to January 2005, criteria included CD4+ <200 cells/mm3, WHO stage 4, or CD4+ between 200 and 350 cells/mm3 and WHO stage 2 or 3 [1]. After January 2005, women with CD4+ between 200 and 350 cells/mm3 and stage 2 were no longer considered ART-eligible. ART-naïve pregnant women who were not eligible for ART, received an ARV prophylaxis regimen, had a CD4+ prior to or within 30 days of delivery ≥250 cells/mm3 and had at least one CD4+ after delivery were included in this analysis. Women receiving ART during pregnancy, or who had CD4+ <250 cells/mm3 at enrollment or who had no ARV prophylaxis or missing documentation of ARV prophylaxis were excluded. The MTCT-Plus Initiative procedures for enrollment and follow-up have been previously described [8]–[10]. In brief, pregnant women received CD4+ cell count at enrollment and maternal clinical and socio-demographic characteristics were recorded. HIV-infected women not eligible for ART were scheduled to attend follow-up visits every three months for the first six months following enrollment then every six months thereafter for clinical examination, WHO staging and CD4+ monitoring. MTCT-Plus Initiative sites followed local guidelines for PMTCT prophylactic regimens. Initially, most programs offered a sd-NVP regimen. By 2004, sites in Bangkok, Thailand, and Eldoret, Kenya, offered triple-drug ARV prophylaxis (tARVp) consisting of zidovudine (AZT) + lamivudine (3TC) + NVP or nelfinavir (NFV) prophylaxis during pregnancy. Over time most sites offered short-course (sc-ARVp) multidrug PMTCT regimens (antepartum AZT with or without 3TC + intrapartum sd-NVP). All ARV prophylaxis initiated antepartum or intrapartum was discontinued after delivery, as per WHO guidelines [1] including tARVp in women not eligible for ART. The primary outcome, CD4+ decline, was defined as: 1) the 12 and 24 month cumulative probability from delivery (time when ARV prophylaxis was discontinued) to decline in CD4+ to <200 cells/mm3 (2006 WHO recommended eligibility criteria for ART initiation) among women with enrollment CD4+ ≥250 cells/mm3; and 2) the 12 and 24 month cumulative probability from delivery to decline in CD4+ to 6 months since last scheduled visit), died, withdrew or were without an event at the date of their last clinical visit or March 31, 2008 when data collection ended. In addition, women who started ART after delivery were censored at the date ART was prescribed. The Log-Rank test was used to compare the probability of CD4+ decline to <200 cells/mm3 or <350 cells/mm3 between the three ARV prophylaxis groups (sd-NVP, sc-ARVp, and tARVp). We used Weibull regression models to identify risk factors for reaching the criteria for ART eligibility at 24 months. The following variables were considered: ARV prophylaxis regimen, age, CD4+ and WHO stage at enrollment. All factors associated with the outcomes at a p-value <0.25 were included in the multivariable analysis. Adjusted hazard ratios (aHR) and their 95% confidence interval (CI) are reported with two-sided p-values. The effect of program site was evaluated using Kaplan-Meier plots and associated Log-Rank tests independently for each ARV prophylaxis regimen. All analyses were performed in intent-to-treat and on-treatment population with SAS software version 9.2 (SAS Institute, Cary, NC, USA). The conduct of the MTCT-Plus Initiative as a service delivery program with data collection for monitoring and evaluation purposes was approved by Columbia University’s Institutional Review Board and local ethics review boards in each country where the study was implemented.

Izinto zokwakha

Emisha

Based on the information provided, it seems that the study is focused on evaluating the decline in maternal CD4+ cell count after interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV. The study analyzes different antiretroviral prophylaxis regimens and their impact on CD4+ decline.

To improve access to maternal health, some potential innovations or recommendations could include:

1. Implementing comprehensive HIV/AIDS care and treatment programs: Similar to the MTCT-Plus Initiative mentioned in the study, providing holistic family care with unrestricted access to antiretroviral therapy (ART) for eligible patients can improve maternal health outcomes.

2. Strengthening PMTCT services: Enhancing prevention of mother-to-child transmission (PMTCT) programs by ensuring early identification of HIV-infected pregnant women, providing appropriate antiretroviral prophylaxis regimens, and promoting adherence to treatment can help improve maternal health.

3. Increasing availability of antiretroviral prophylaxis options: Offering a range of antiretroviral prophylaxis regimens, including both single-dose nevirapine (sd-NVP) and short-course antiretroviral prophylaxis (sc-ARVp) with zidovudine (AZT) or AZT + lamivudine (3TC), can provide more options for pregnant women and potentially improve maternal health outcomes.

4. Regular monitoring of CD4+ cell count: Implementing regular CD4+ cell count monitoring during pregnancy and postpartum can help identify women at risk of CD4+ decline and ensure timely initiation of ART when necessary.

5. Strengthening healthcare systems: Investing in healthcare infrastructure, training healthcare providers, and improving access to healthcare facilities can contribute to better maternal health outcomes by ensuring timely and quality care for pregnant women.

It’s important to note that these recommendations are based on the information provided and may need to be further evaluated and tailored to specific contexts and healthcare systems.

AI Innovations Description

Based on the provided information, the recommendation to improve access to maternal health is to implement the MTCT-Plus Initiative. This initiative provides holistic family care with unrestricted access to antiretroviral therapy (ART) for eligible patients, including pregnant women identified as HIV-infected. The initiative is implemented in multiple countries in sub-Saharan Africa and Thailand and is built upon existing services in PMTCT programs. It offers regular follow-up visits, clinical examination, WHO staging, and CD4+ monitoring for HIV-infected women. The initiative also follows local guidelines for PMTCT prophylactic regimens, including the use of antiretroviral prophylaxis during pregnancy. By providing comprehensive care and access to ART, the MTCT-Plus Initiative aims to improve maternal health outcomes and prevent mother-to-child transmission of HIV.

AI Innovations Methodology

To improve access to maternal health, here are some potential recommendations:

1. Strengthening healthcare infrastructure: Investing in healthcare facilities, equipment, and trained healthcare professionals in areas with limited access to maternal health services can improve access and quality of care.

2. Mobile health (mHealth) interventions: Utilizing mobile technology to provide information, reminders, and support to pregnant women and new mothers can help improve access to maternal health services, especially in remote areas.

3. Community-based interventions: Implementing community-based programs that provide education, counseling, and support to pregnant women and their families can help increase awareness and utilization of maternal health services.

4. Task-shifting and training: Training and empowering community health workers and midwives to provide basic maternal health services can help bridge the gap in areas with a shortage of healthcare professionals.

5. Financial incentives: Providing financial incentives, such as conditional cash transfers or subsidies, to pregnant women and their families can help reduce financial barriers and improve access to maternal health services.

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

1. Define the target population: Identify the specific population that will be impacted by the recommendations, such as pregnant women in a particular region or country.

2. Collect baseline data: Gather data on the current access to maternal health services, including factors such as distance to healthcare facilities, availability of healthcare professionals, and utilization rates.

3. Develop a simulation model: Create a mathematical model that incorporates the various factors influencing access to maternal health services, such as distance, availability of healthcare professionals, and financial barriers. The model should also consider the potential impact of the recommendations, such as increased availability of healthcare facilities or improved training of healthcare professionals.

4. Input data and parameters: Input the baseline data and parameters into the simulation model, including information on the target population, current access to maternal health services, and the potential impact of the recommendations.

5. Run simulations: Run multiple simulations using different scenarios, such as implementing one or more of the recommendations, to assess the potential impact on access to maternal health services. The simulations should consider factors such as the number of additional healthcare facilities, the number of trained healthcare professionals, and the financial incentives provided.

6. Analyze results: Analyze the results of the simulations to determine the potential impact of the recommendations on improving access to maternal health services. This could include assessing changes in utilization rates, reduction in distance to healthcare facilities, and improvements in the availability of healthcare professionals.

7. Refine and validate the model: Refine the simulation model based on the results and feedback from stakeholders. Validate the model by comparing the simulated results with real-world data, if available.

8. Communicate findings: Present the findings of the simulation study to policymakers, healthcare providers, and other stakeholders to inform decision-making and prioritize interventions for improving access to maternal health services.

By following this methodology, policymakers and healthcare providers can gain insights into the potential impact of different recommendations on improving access to maternal health services and make informed decisions to prioritize interventions.

Ababhali & Co-Ababhali

Statistics:

Citations: 5

Authors: 6

Identifiers:

DOI: 10.1371/journal.pone.0043750

Research Areas:

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

Study Countries:

Cameroon, Kenya, Mozambique, Multi-Countries, Rwanda, South Africa, Uganda, Zambia

Study Design:

Cohort Study, Cross Sectional Study, Grounded Theory

Participants Gender:

Female

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