Administering ART Immediately After Birth Triggers Innate Immune Response, HIV Reservoir Shrinkage in Infants Born With HIV

Knowing that HIV can kill infants at a faster rate because their immune systems are not fully developed, researchers from the Harvard T.H. Chan School of Public Health and Brigham and Women’s Hospital (B&W), both in Boston, Massachusetts, initiated the Early-Infant Treatment Study (EIT) among infants in Botswana—which has the third highest prevalence of HIV-1 in the world, behind Swaziland and Lesotho, and where approximately 24% of pregnant women are infected—who began antiretroviral treatment (ART) hours after birth. Their initial results appeared in a recent issue of Science Translational Medicine.

Infants can contract HIV in the womb, at birth, or through breast milk. Those showing signs of HIV-positive antibodies should begin treatment within weeks after birth, and not doing so can lead to one-third dying before their first birthday and half before they turn 2 years old, according to the World Health Organization (WHO). Resource-rich countries like the United States are able to perform virological testing on newborns almost immediately. However, in resource-poor countries, such as Botswana, this is usually not possible due to lack of human capital, affordable testing technologies, pediatric medications, and screening—a fact the WHO acknowledges.

“In most lower-income countries, babies aren’t tested until they’re 4 to 6 weeks old,” Roger Shapiro, MD, MPH, from Harvard T.H. Chan and one of the study’s lead investigators, stated.

“What excites me most about this work is that making a comparatively small change in the timing of treatment may have a large impact on long-term outcomes,” noted Mathias Lichterfield, MD, PhD, from B&W and a lead study investigator.

Spurred by the 2010 case of a child from Mississippi who was started on ART within 30 hours of being born and continued the treatment for 18 months, which spurred spontaneous viral control that lasted for 27 months, the investigators studied 3 groups of infants over 2 years:

• Infected infants who began ART an average 7 hours after birth (n = 10)
• Infected infants who began ART an average 4 months after birth (n = 10)
• Infants without HIV (n = 54)

Following positive results from HIV-1 DNA polymerase chain reaction (PCR) assays of the first 10 infants, 9 began initial treatment consisting of nevirapine and zidovudine (± lamivudine) a median of 7 hours after birth (range, 0.2-114.5). Treatment switched to nevirapine, zidovudine, and lamivudine at EIT study enrollment and ritonavir-boosted lopinavir, lamivudine, and zidovudine 2 weeks later. The 10th infant started with the lopinavir regimen at day 31 due to an initial negative PCR at birth.

After following the infants for 2 years (using blood samples first taken weekly, then monthly), the results showed that infants who began ART immediately after birth had smaller numbers of reservoir cells at week 96 compared with infants initiated on treatment later—although both groups achieved viral control and 1 infant had to go off treatment at week 24 because of a low white blood cell count—and HIV-infected adults on ART for an average 16 years, as well as more natural killer (NK) cells and monocytes, the innate immune response previously mentioned. HIV reservoir cells are infected, just not actively producing the virus, a state they can remain in for several years.

In addition, selective subsets of the NK cells had a “higher functionality,” according to the authors. This means these cells have a greater ability to kill viruses, a trait that was heightened in the HIV-positive infants compared with the HIV-negative control group, whose NK cells had “phenotypic properties suggestive of lower cytotoxic potency.”

“I think what these results show is, first of all, how critically important it is to extend studies of HIV cure or long-term remission to infants and children. Very early intervention in neonates limits the size of the reservoir and offers us the best opportunity for future interventions aimed at cure in long-term drug-free remission of HIV infection. We don’t think the current intervention is itself curative, but it sets the stage for the capacity to offer additional innovative interventions in the future,” noted Daniel R. Kuritzkes, MD, chief of the Division of Infectious Disease at B&W, during a November 26 teleconference on the study results..

One major limitation to these initial results is the small group of infants used. Forty were actually recruited for the study after an initial screening of 10,000 HIV-exposed children in Botswana. Data from the remaining 30 infants are currently being analyzed.

Reference

Garcia-Broncano P, Maddali S, Einkauf KB, et al; American Association for the Advancement of Science. Early antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile. Sci Transl Med. 2019;11(520). doi: 10.1126/scitranslmed.aax7350.