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Study argues against uniform policy of avoiding dolutegravir in women of child-bearing potential

Although neural tube defect risks may be higher with dolutegravir than efavirenz, dolutegravir will lead to many fewer deaths among women, as well as fewer overall HIV transmissions.

Total deaths for women with HIV and their children are projected to be lower with dolutegravir-based (Tivicay) antiretroviral therapy (ART) versus efavirenz-based (Sustiva) ART, MedPageToday reports a model-based analysis found.

Combined deaths among women and children were estimated to be lowest with dolutegravir (358,000 deaths) compared with efavirenz (367,700) or even the World Health Organisation (WHO) recommendations of efavirenz for women without contraception, and dolutegravir for women with contraception (362,800 deaths), reported Dr Caitlin M Dugdale, of Massachusetts General Hospital in Boston, and colleagues.

Dolutegravir-based ART was also estimated to eliminate the most deaths among women compared with efavirenz-based ART, although there were more paediatric deaths due to more neural tube defects, the authors wrote.

In May 2018, the FDA warned about neural tube defects among women living with HIV who were on a dolutegravir-based regimen at the time of conception, or early in the first trimester. These warnings were based on preliminary data from a study presented at the 2018 International AIDS Conference (IAC), which revealed a higher risk of neural tube defects with dolutegravir compared with non-dolutegravir-based therapy, including efavirenz.

As a result, the authors noted that the WHO released interim guidance stating that efavirenz was "a safe and effective alternative for women of child-bearing potential desiring pregnancy or lacking access to 'consistent and reliable contraception.'"

However, another study presented at IAC found that a higher portion of patients on dolutegravir versus efavirenz-based ART achieved undetectable viral loads. More recently, at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), the DolPHIN trial found that mothers treated with dolutegravir-based ART had viral loads reduced more quickly than those treated with efavirenz.

While the WHO guidance seems to provide a compromise, Dugdale and colleagues suggested that "policymakers in resource-limited settings may face challenges in implementing the WHO guidance, including increased demand for reproductive health services, drug procurement difficulties with several first-line ART options, and providers who lack adequate time and training to help women make an informed ART choice."

They used published data, including literature and abstracts on dolutegravir and efavirenz-based antiretroviral therapy regimens, to create a model of three separate strategies: Efavirenz for all women of childbearing potential; Dolutegravir for all women of child-bearing potential; and WHO interim recommendations for efavirenz without contraception and dolutegravir with contraception.

The target population was 3.1m South African women with HIV, ages 15-49, who were starting or continuing first-line ART, and their children, the authors said. At 5 years, the model projected that compared with efavirenz, dolutegravir resulted in about 70,400 more women with virologic suppression, 39,700 fewer severe opportunistic infections, and 13,700 fewer deaths. The authors also noted that "all outcomes among women were better with (dolutegravir) than with the WHO approach."

Because of "higher rates of durable virologic suppression," dolutegravir resulted in 57,700 fewer projected sexual transmissions and 7,100 fewer paediatric HIV infections versus efavirenz, the authors said.

Compared with efavirenz, the authors found that dolutegravir did lead to 4,400 more paediatric deaths, and 4,100 more paediatric deaths compared to the WHO approach.

In an accompanying editorial, Dr Risa M Hoffman, of the University of California Los Angeles, and Dr Lynne M Mofenson, of the Elizabeth Glaser Paediatric AIDS Foundation in Washington, described these projections as "an elegant model."

The editorialists noted the potential problems with the WHO approach, where asking for women of child-bearing potential to make an informed choice regarding their ART regimen may be difficult in many areas.

"Simplicity has been the key to success of many ART programmes in resource-limited settings, and offering a choice of either efavirenz or dolutegravir (…) adds a layer of complexity to the supply chain with regard to forecasting supply, ensuring the availability of buffer stock, and avoiding drug expirations," Hoffman and Mofenson wrote.

"The WHO approach also may present challenges in the setting of widespread scale-up of differentiated models of care, such as community ART groups and adherence clubs, given that they often are based on a 'one-size-fits-all' ART regimen." However, they commented that the dolutegravir and the WHO approach both "seem better than the efavirenz-for-all strategy."

Hoffman and Mofenson also acknowledged the need for more research about the periconceptional safety of ART, with "innovative strategies," such as "development of large observational cohorts with wide geographic diversity and carefully planned clinical trials that include women of child-bearing potential and that continue to follow those who conceive while receiving therapy."

Dugdale and colleagues noted limitations common to all model-based analyses, namely the "uncertainty" in long-term projections, and the assumption that HIV prevalence, ART uptake, and fertility will all remain consistent over the next 5 years.

The study was supported by the NIH, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Massachusetts General Hospital, and Harvard University Centre for AIDS Research (CFAR).

Background: Dolutegravir is superior to efavirenz for HIV antiretroviral therapy (ART) but may be associated with an increased risk for neural tube defects (NTDs) in newborns if used by women at conception.
Objective: To project clinical outcomes of ART policies for women of child-bearing potential in South Africa.
Design: Model of 3 strategies: efavirenz for all women of child-bearing potential (EFV), dolutegravir for all women of child-bearing potential (DTG), or World Health Organization (WHO)-recommended efavirenz without contraception or dolutegravir with contraception (WHO approach).
Data Sources: Published data on NTD risks (efavirenz, 0.05%; dolutegravir, 0.67% [Tsepamo study]), 48-week ART efficacy with initiation (efavirenz, 60% to 91%; dolutegravir, 96%), and age-stratified fertility rates (2 to 139 per 1000 women).
Target Population: 3.1 million South African women with HIV (aged 15 to 49 years) starting or continuing first-line ART, and their children.
Time Horizon: 5 years.
Perspective: Societal.
Intervention: EFV, DTG, and WHO approach.
Outcome Measures: Deaths among women and children, sexual and pediatric HIV transmissions, and NTDs.
Results of Base-Case Analysis: Compared with EFV, DTG averted 13 700 women's deaths (0.44% decrease) and 57 700 sexual HIV transmissions, but increased total pediatric deaths by 4400 because of more NTDs. The WHO approach offered some benefits compared with EFV, averting 4900 women's deaths and 20 500 sexual transmissions while adding 300 pediatric deaths. Overall, combined deaths among women and children were lowest with DTG (358 000 deaths) compared with the WHO approach (362 800 deaths) or EFV (367 300 deaths).
Results of Sensitivity Analysis: Women's deaths averted with DTG exceeded pediatric deaths added with EFV unless dolutegravir-associated NTD risk was 1.5% or greater.
Limitation: Uncertainty in NTD risks and dolutegravir efficacy in resource-limited settings, each examined in sensitivity analyses.
Conclusion: Although NTD risks may be higher with dolutegravir than efavirenz, dolutegravir will lead to many fewer deaths among women, as well as fewer overall HIV transmissions. These results argue against a uniform policy of avoiding dolutegravir in women of child-bearing potential.

Caitlin M Dugdale; Andrea L Ciaranello; Linda-Gail Bekker; Madeline E Stern; Landon Myer; Robin Wood; Paul E Sax; Elaine J Abrams; Kenneth A Freedberg; Rochelle P Walensky

[link url=""]MedicalPageToday report[/link]
[link url=""]Annals of Internal Medicine abstract[/link]
[link url=""]Annals of Internal Medicine editorial[/link]

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