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Two Children Diagnosed at Birth Test HIV Negative After Very Early Treatment

, by Reilly O'Neal

The “Mississippi baby” who made headlines at last year’s CROI remains in HIV “remission” after 23 months off treatment, and a California child infected at birth and treated extremely early is now testing HIV negative, attendees learned today at the 21st Conference on Retroviruses and Opportunistic Infections (abstract 75LB).

Deborah Persaud at CROI 2014

Deborah Persaud at CROI 2014

In a packed auditorium, Deborah Persaud of Johns Hopkins University provided updates on the Mississippi child, who was diagnosed with HIV and received unusually early antiretroviral therapy (ART), then remained free of detectable virus after treatment was interrupted at roughly 18 months of age. (Read the full story here.) Persaud also reported that a second infant with perinatal HIV infection (that is, infection that occurred during birth) who received extremely early antiretroviral treatment is now testing negative for HIV.

These case studies have implications for pediatric treatment strategies, and for ways to reduce viral “reservoirs”—sources of “hidden” virus that pose a major obstacle to a cure. Earlier in the day, Persaud presented findings from a study showing that children perinatally infected with HIV had a significantly smaller reservoir of non-replicating HIV in immune system cells if they were treated relatively early and their viral load was reduced to less than 400 copies/mL within the first year of life (abstract 72). The two individual case studies described here shed light (and raise questions) on how very early ART affects the size of HIV reservoirs, and how best to use this knowledge going forward.

The Mississippi Child

Now roughly three years old, the Mississippi child has been off ART for 23 months, and “there has been no detectable rebound in plasma virus using standard clinical assays with detection limits of less than 20 copies/mL,” Persaud said in a press conference.

Ultrasensitive assays—the same tests used to monitor HIV persistence in Timothy Brown, the first person cured of HIV—were employed to determine whether HIV’s genetic material, RNA, persists in the child’s blood; none has been detected through 40 months of age. In addition, no reservoir of replication-competent virus (that is, HIV that is capable of making more copies of itself) has emerged in the absence of antiretroviral treatment.

Persaud emphasized that another ultrasensitive assay that looks for viral DNA (the genetic material HIV produces as part of the replication process) has turned up “traces” of HIV DNA in the child’s blood cells. But, she said, “the clinical relevance of this DNA detection remains unclear because the child remains with clinically undetectable plasma viral load levels.”

The California Case Study

Next, Persaud reported on a California infant who was started on ART just four hours after delivery. The child’s mother was prescribed antiretroviral drugs but did not take them during pregnancy; maternal viral load was reported as 138,000 copies/mL.

HIV infection in the infant was confirmed at four hours of age by testing technologies that look for HIV RNA and DNA in blood (by contrast with standard HIV antibody testing, which may detect maternal antibodies in newborns and give false-positive results). Four hours after the child was born, pediatricians began administering a regimen of AZT (zidovudine; brand name Retrovir), 3TC (lamivudine; Epivir), and nevirapine (Viramune)—the same early treatment regimen administered to the Mississippi baby.

The California infant’s viral load at 36 hours of age was 217 copies/mL, Persaud reported. On the sixth day of life (DOL#6), pediatricians drew cerebrospinal fluid to check for a bacterial infection; when the fluid was assayed, HIV RNA was found at 32 copies/mL. By DOL#11, however, HIV RNA was undetectable in blood plasma, and remained undetectable through eight months of age. HIV DNA testing was negative at DOL#6 and remained undetectable at DOL#47 and DOL#67. Replication-competent virus was not detected at one and three months of age.

By contrast with the Mississippi child, who was removed from pediatric care and taken off antiretroviral treatment by her caregivers around 18 months of age, the California infant has continued to take ART. She remains in care and on treatment at nine months old. Therefore, Persaud emphasized, “these tests that we’re doing are really being done under antiretroviral treatment cover, quite unlike the Mississippi child.”

“Having said that, at nine months of age, there’s less than 2 copies of HIV DNA [per mL in blood cells] and we have not detected a replication-competent reservoir,” she added.

Moving Forward

What do these case studies tell us? “There’s a signal here that giving very early antiretroviral drug treatment in neonates [newborns] really restricts HIV spread, to the point that it becomes difficult to detect infection,” said Persaud. “We believe it’s important for the field to begin to identify strategies and to be able to advise how to manage these very-early-treated infants going forward.”

The second child is in care with pediatric infectious disease specialists at Miller Children’s Hospital in Los Angeles County and the University of California at Los Angeles. “At this point, there is no immediate plan” to halt treatment, Persaud stated, but the pediatric team is exploring the possibility of interrupting ART around two years of age “if there is some consensus around what to do with this child.”

Persaud stressed that current ART guidelines lack guidance around treatment interruptions. “The reason we’re presenting these cases is so that we, as a field, can come up with guidelines in managing these kids.”

To this end, Persaud and researchers with the Infant Maternal Pediatric Adolescent AIDS Clinical Trials Network are designing a clinical trial to evaluate very early ART in infants infected with HIV at birth. Planned (and carefully monitored) treatment interruptions will occur at approximately two years of age to assess whether the virus rebounds. The trial will hopefully begin within the next two to three months, Persaud said, with a target enrollment of 54 infants at sites in the U.S. and abroad.

Reilly O’Neal is a freelance writer and former editor of BETA.

Abstracts

72: Virologic Control by 1 Year of Age Significantly Reduces HIV-1 Reservoirs in Perinatal Infection
Deborah Persaud, Kunjal Patel, Brad Karalius, Carrie Ziemniak, Kaitlin Rainwater-Lovett, Ya Chen, Douglas D. Richman, George K. Siberry, Russell VanDyke, Katherine Luzuriaga, Pediatric HIV/AIDS Cohort Study (PHACS) and IMPAACT Network
Background: Reducing proviral reservoir size is an important prerequisite for achieving HIV-1 remission for which antiretroviral therapy can be discontinued without viremic rebound. The extent to which proviral reservoir size can be substantially reduced with long-term, early combination antiretroviral therapy (cART) for perinatally HIV-infected (PHIV+) children is  unknown.
Methodology: We quantified with droplet digital PCR proviral load in peripheral blood mononuclear cells (PBMCs) from 144 PHIV+ children enrolled in the Pediatric HIVAIDS Cohort Study/Adolescent Master Protocol (PHACS/AMP) who were receiving cART for a median of 10 years. Proviral burden, HIV serostatus, 2-LTR circles, and immune activation markers (soluble CD14, CD163, IFN-γ, IL-6, and IL-1β) were compared by age at virologic control (less than 1 vs. 1-5 vs greater than 5 years of age). Immune activation markers were also compared to perinatally-HIV-exposed, uninfected (PHEU) children. Proviral burden was also correlated with HIV serostatus and 2-LTR circles.

Results: When studied at 8-20 years of age, the proviral load of PHIV+ children who achieved virologic control by one year of age was significantly lower than that of PHIV+ children who suppressed between 1-5 years and after age 5 (p<0.001, Table 1); 46% of PHIV+ children who suppressed by one year of age had an undetectable proviral reservoir at <4 copies/million PBMCs compared to 11% of those who suppressed after age 1 (p=0.01). Lower proviral burden was associated with undetectable 2-LTR circles (p<0.001) and HIV-1 seronegative/indeterminate status (p<0.001). Plasma concentrations of soluble CD14, CD163, IFN-γ, and IL-1β were similar across the three age groups of virologic control (Table 1) but sCD14 and IL1 β levels were significantly higher in PHIV+ children than in PHEU (p<0.001 and p=0.004 respectively).
Conclusions: Achieving virologic control by one year of age in perinatal infection leads to significantly smaller proviral reservoirs in those with HIV-negative or indeterminate serostatus and absent 2-LTR circles. It does not reverse immune activation. These findings emphasize the benefits of early therapy in perinatal infection with implications for a viro-immunologic profile for HIV cure-related clinical trials.

75LB: Very Early Combination Antiretroviral Therapy in Perinatal HIV Infection: Two Case Studies
Deborah Persaud, Audra Deveikis, Hannah Gay, Jagmohan Batra, Tempe Chen, David E. Michalik, Kaitlin Rainwater-Lovett, Carrie Ziemniak, Katherine Luzuriaga, Yvonne Bryson
Background: Combination Antiretroviral treatment (cART) by 31 hours of age led to HIV remission in the Mississippi Child where cART cessation did not lead to rebound viremia. We report follow-up virologic and immunologic markers at 21 months off ART in the Mississippi Child and in a second perinatally infected infant who started cART similar to that of the Mississippi Child (by four hours of age) and remains on cART through age 8 months.
Methodology: Standard HIV DNA and RNA tests were used to confirm infection and assess virologic responses to cART. HIV-specific immune responses were assessed by ELISA, western blot and cytotoxic T-cell responses. CD4+ and CD8+ T cell percentages were enumerated by flow cytometry. Droplet digital PCR (DDPCR) was used to quantify proviral burden in peripheral blood mononuclear cells (PBMCs), resting CD4+ T cells, activated CD4+ T cells and monocytes. Replication-competent proviral genomes were identified using a limiting dilution viral outgrowth assay. Non-induced proviral genomes were quantified by DDPCR of culture-negative wells.
Results: The Mississippi Child has remained in remission with undetectable plasma viremia (<20 copies/mL) and normal CD4+ and CD8+ T cell counts at 39 months of age, 21 months after stopping cART. Trace proviral DNA is persistently detectable in PBMCs but replication competent HIV is not; noninduced proviruses were not detected in culture-negative wells. HIV-specific immune responses remain undetectable. A second infant with high-risk exposure to HIV was started on cART at four hours of age. HIV infection was confirmed by positive peripheral blood HIV DNA PCR at four hours of life and HIV RNA of 217 copies/mL at 36 hours of age. HIV RNA was detected in CSF at 32 copies/mL on DOL#6. Plasma HIV RNA was undetectable on DOL#11 and remained undetectable through age 8 months. HIV DNA testing was negative by DOL#6, and remained undetectable at DOL#47 and 67. Replication-competent HIV was not recovered from resting CD4+ T cells at 1 and 3 months of age; non-induced proviral genomes were detected by DDPCR, in culture-negative wells, at one month but not age three months. At age 3 months, HIV antibody is indeterminate (western blot reactivity to gp160). CD4+ T cell percentages remained normal for age.
Conclusions: Very early cART in an HIV-infected infant led to sustained HIV remission through 39 months of age, 21 months after stopping cART. In a second infant, cART by four hours of life led to rapid clearance of replicating virus and an undetectable proviral DNA by clinical assays within 6 days of life, supporting restriction of HIV spread with very early cART. Development of sensitive laboratory markers and standardized approaches will be necessary to guide the optimal management of very early HIV treated infants in order to achieve remission.

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