Global evidence of lower adherence to ARVs after giving birth

Antiretroviral therapy (ART) adherence levels among pregnant women with HIV, in both high- and low-income countries, during pregnancy and especially after giving birth are significantly below what is recommended for viral suppression and prevention of drug resistance, according to a report published this month in the advance online edition of AIDS.

In a pooled analysis of 51 studies, involving over 20,000 women from the United States, Kenya, South Africa and Zambia, only 73.5% of pregnant women with HIV attained adequate adherence to ART during and after pregnancy (defined as equal to or greater than 80%), Jean B Nachega and colleagues report.

The pooled proportion of women with adequate adherence was greater during pregnancy than after giving birth, 75.7% (95% CI: 71.5-79.7%) compared to 53% (95% CI: 32.8-72.7%).

Reported barriers at the individual level included: physical, economic and social stressors, depression (notably after giving birth), alcohol or drug use and frequency of ART dosage or pill burden. 

Conversely disclosure of HIV status and strong social support was linked to high ART adherence, so where safe and feasible both should be encouraged.

As prevention of mother-to-child transmission (PMTCT) programmes move toward universal lifelong ART for all pregnant women with HIV (World Health Organization [WHO] Option B+) the likelihood of multi-class drug resistance for both the mother and the child will increase and the safety and scale-up of these programmes be compromised.

WHO’s goal of the elimination of mother-to-child transmission (eMTCT) by 2015 will also be weakened; virtual elimination depends not only on access and availability to the most effective regimens but also on women’s ability to take the drugs appropriately and provide their infants with complete prophylactic regimens.

The authors stress “the critical and urgent need to assist HIV providers to more reliably monitor adherence and develop evidence-based interventions to improve and/or maintain adherence…”

Of the estimated 1.4 million women with HIV who give birth each year, 91% live in sub-Saharan Africa. ART during and after pregnancy is essential for the mother’s own health as well as preventing transmission of HIV to the child.

The WHO 2010 guidelines for ART to treat pregnant women and prevent transmission to the child in resource-poor settings included recommendations for more complex combination ART regimens as well as continuation of ART prophylaxis throughout breastfeeding, whether the mother needed it for her own health or not. Rapid scale-up and the availability of more effective regimens led WHO to set the goal of virtual eMTCT by 2015.

Adherence is critical for virologic and clinical success and remains of concern in high- and low-income countries. Poor adherence can lead to treatment-limiting drug resistance.

For women who are pregnant or breastfeeding, non-adherence increases the risk of virologic failure, maternal disease progression, development of drug resistance and risk for vertical (mother-to-child) transmission.

There is evidence that newer antiretroviral regimens achieve viral suppression at lower levels of adherence (70 to 80%) than older regimens, because of increased potency and longer drug half-lives, so forgiving the odd missed ART dose. Nonetheless, consistent adherence over time is linked to better virological outcomes.

Given the limited data and absence of a systematic review, the authors chose to conduct a meta-analysis to estimate the proportion of women with adequate ART adherence during pregnancy and after delivery in high-, middle- and low-income countries.

Fifty-one studies involving 20,153 women with HIV were identified. Forty-eight studies reporting 71 adherence estimates were included in the meta-analysis. The remaining three reported ART adherence as a mean or median so were excluded. The studies took place between 1986 and 2011 and reported between 1998 and 2011.

Close to three-quarters (74%) were observational and 26% were RCTs looking at PMTCT regimens.

Most studies were from the United States (n=14, 27%) followed by Kenya with six (12%), and South Africa (10%) and Zambia (10%) both with five.

Almost half (45%) included pregnant women on triple ART, while 15 (29%) and 12 (24%) reported adherence while on zidovudine and single-dose nevirapine, respectively.

The threshold to define good adherence varied across the studies (greater than 80%, greater than 90%, greater than 95% and 100%).

The authors believe this to be the first systematic review and meta-analysis summarising the available data on ART adherence during and after pregnancy.

They cite a recent literature review of gender and ART adherence in high-income countries which, while not addressing pregnancy issues, concluded that being female was linked to poorer adherence than in men. They suggest this is linked to family and caretaking responsibilities. Women with HIV often first learn of their diagnosis during their pregnancy, so are dealing with the diagnosis when ART is first prescribed.

Their findings confirm the challenge of achieving optimal adherence during pregnancy and after delivery.

The authors suggest that better adherence during pregnancy than after delivery is due to the mother’s concern for the health of the foetus and transmission of the virus to the child. Yet, they note that even during pregnancy adherence was lower than what is thought necessary for viral suppression and prevention of drug resistance.

'Morning sickness', nausea and vomiting commonly affect over 70% of pregnant women in early pregnancy; heartburn is common later in pregnancy. These can adversely affect adherence. The mother may also be concerned that ART may harm the foetus.

Post-partum depression (PPD), the authors note, is a part “of major depressive disorder that crosses cultures and affects 13% of women.” They cite a systematic review that found PPD was 31.3% (95% CI: 21.3%-43.5%) higher among women in resource-poor countries compared to those in resource-rich countries.

The studies in this review reported that reduced ART adherence was linked to advanced AIDS, pregnancy-related symptoms, HIV itself, as well as toxicity of the ART regimen.

The findings also suggest “evaluation and management of mental health and illicit drug use during and after pregnancy be a high priority for health-care workers in charge of all HIV-infected pregnant women.”

Close monitoring and adherence support is critical for the safe and effective scale up of PMTCT.

The authors suggest that non-medical personnel can play an important role but evidence is lacking about the effectiveness and cost-effectiveness of such interventions; some observational studies have suggested peer support can improve adherence among pregnant women.

The role of peer mentors in South Africa to improve maternal adherence during pregnancy and at the time of birth is currently being evaluated. Similarly, a trial looking at the role of male involvement is in process.

And, simplified regimens for ease of use and with better tolerability will improve adherence in this population.

The authors conclude “It is crucial to monitor ART adherence…Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the post-partum period. Further research to investigate specific barriers and interventions to address them are urgently needed globally…to ensure the long-term efficacy of such an approach for both maternal health and PMTCT.”

Nachega JB et al. Adherence to antiretroviral therapy during and after pregnancy in low-, middle- and high-income countries: a systematic review and meta-analysis. Advance online edition AIDS 26, doi: 10.1097/QAD.0b013e328359590f, 2012.