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, 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 Organization (WHO) recommendations of efavirenz for women without contraception, and dolutegravir for women with contraception (362,800 deaths), reported Caitlin M. Dugdale, MD, 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 pediatric deaths due to more neural tube defects, the authors wrote in Annals of Internal Medicine.
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
- WHO interim recommendations for efavirenz without contraception and dolutegravir with contraception
The target population was 3.1 million 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 pediatric HIV infections versus efavirenz, the authors said.
Compared with efavirenz, the authors found that dolutegravir did lead to 4,400 more pediatric deaths, and 4,100 more pediatric deaths compared to the WHO approach.
In an accompanying editorial, Risa M. Hoffman, MD, MPH, of the University of California, Los Angeles, and Lynne M. Mofenson, MD, of the Elizabeth Glaser Pediatric 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 programs 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 Center for AIDS Research (CFAR).
Dugdale disclosed support from the NIAID and Harvard University CFAR, and grants from the NIMH and NIH/IMPAACT Network. Co-authors disclosed support from the NIH, the Elizabeth Glaser Pediatric AIDS Foundation, the Foundation for AIDS Research (amfAR), WHO, Merck, Gilead, Bristol-Myers Squibb, ViiV/GlaxoSmithKline, Janssen, and WHO/Unitaid. One co-author disclosed being a Steve and Deborah Gorlin MGH Research Scholar.
Hoffman disclosed no relevant relationships with industry. Mofenson disclosed support from WHO.
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