Meeting News CoveragePerspective

Early ART may achieve ‘functional cure’ in children with HIV

Early application of antiretroviral therapy may prevent establishment of a latent reservoir and achieve cure in HIV-positive children, according to results of a case report presented at the 2013 Annual CROI Meeting in Atlanta.

Researchers from Johns Hopkins Children’s Center, the University of Mississippi Medical Center and the University of Massachusetts Medical School presented a novel case of a “functional HIV cure” in a 26-month-old infected child who commenced ART at 30 hours of age.

“Prompt antiviral therapy in newborns that begins within days of exposure may help infants clear the virus and achieve long-term remission without lifelong treatment by preventing such viral hideouts from forming in the first place,” Deborah Persaud, MD, a Johns Hopkins Children’s Center virologist, said in a press release.

The researchers confirmed infant exposure to HIV through review of maternal HIV antibody and plasma viral load tests, together with HIV drug resistance testing. Infant infection was identified using standard HIV DNA polymerase chain reaction and plasma viral load.

The researchers established ART administration with medical and pharmacy records and maternal report of medication adherence. In addition, the researchers evaluated persistence of HIV infection after treatment termination using standard clinical assays that included plasma viral load, proviral DNA and HIV antibody testing.

Ultrasensitive HIV DNA, plasma viral load assays and quantitative co-culture assays were performed at 24 and 26 months to further review HIV persistence.

The researchers verified maternal infection with wild-type subtype B HIV, and both mother and infant shared human leukocyte antigen (HLA) haplotypes. Infant infection was confirmed by positive HIV DNA and RNA testing on two separate blood samples obtained on the second day of life.

Three additional plasma viral load tests — obtained on days 7, 12 and 20 — were positive before reaching undetectable levels at age 29 days.

According to researchers, plasma HIV RNA remained undetectable (<20 copies/mL) on 16 different measurements obtained from 1 to 26 months of age, despite ART discontinuation at age 18 months.

The researchers observed replication-competent virus after co-culture of 22 million purified resting CD4+ T cells. At age 26 months, HIV DNA was detected at 4 copies/million peripheral blood mononuclear cells (PBMC) but with no 2-long terminal repeat (2-LTR) circles. Plasma viral load, PBMC DNA and HIV-specific antibodies remained undetectable with standard clinical assays, confirming a state of functional HIV cure.

“Complete viral eradication on a large scale is our long-term goal but, for now, remains out of reach, and our best chance may come from aggressive, timely and precisely targeted use of antiviral therapies in high-risk newborns as a way to achieve functional cure,” Katherine Luzuriaga, MD, immunologist and professor at the University of Massachusetts Medical School, said in a press release.

For more information:

Persaud D. Abstract #48LB. Presented at: 2013 Annual CROI Meeting; March 3-6, 2013; Atlanta.

Early application of antiretroviral therapy may prevent establishment of a latent reservoir and achieve cure in HIV-positive children, according to results of a case report presented at the 2013 Annual CROI Meeting in Atlanta.

Researchers from Johns Hopkins Children’s Center, the University of Mississippi Medical Center and the University of Massachusetts Medical School presented a novel case of a “functional HIV cure” in a 26-month-old infected child who commenced ART at 30 hours of age.

“Prompt antiviral therapy in newborns that begins within days of exposure may help infants clear the virus and achieve long-term remission without lifelong treatment by preventing such viral hideouts from forming in the first place,” Deborah Persaud, MD, a Johns Hopkins Children’s Center virologist, said in a press release.

The researchers confirmed infant exposure to HIV through review of maternal HIV antibody and plasma viral load tests, together with HIV drug resistance testing. Infant infection was identified using standard HIV DNA polymerase chain reaction and plasma viral load.

The researchers established ART administration with medical and pharmacy records and maternal report of medication adherence. In addition, the researchers evaluated persistence of HIV infection after treatment termination using standard clinical assays that included plasma viral load, proviral DNA and HIV antibody testing.

Ultrasensitive HIV DNA, plasma viral load assays and quantitative co-culture assays were performed at 24 and 26 months to further review HIV persistence.

The researchers verified maternal infection with wild-type subtype B HIV, and both mother and infant shared human leukocyte antigen (HLA) haplotypes. Infant infection was confirmed by positive HIV DNA and RNA testing on two separate blood samples obtained on the second day of life.

Three additional plasma viral load tests — obtained on days 7, 12 and 20 — were positive before reaching undetectable levels at age 29 days.

According to researchers, plasma HIV RNA remained undetectable (<20 copies/mL) on 16 different measurements obtained from 1 to 26 months of age, despite ART discontinuation at age 18 months.

The researchers observed replication-competent virus after co-culture of 22 million purified resting CD4+ T cells. At age 26 months, HIV DNA was detected at 4 copies/million peripheral blood mononuclear cells (PBMC) but with no 2-long terminal repeat (2-LTR) circles. Plasma viral load, PBMC DNA and HIV-specific antibodies remained undetectable with standard clinical assays, confirming a state of functional HIV cure.

“Complete viral eradication on a large scale is our long-term goal but, for now, remains out of reach, and our best chance may come from aggressive, timely and precisely targeted use of antiviral therapies in high-risk newborns as a way to achieve functional cure,” Katherine Luzuriaga, MD, immunologist and professor at the University of Massachusetts Medical School, said in a press release.

For more information:

Persaud D. Abstract #48LB. Presented at: 2013 Annual CROI Meeting; March 3-6, 2013; Atlanta.

    Perspective

    If this case report actually represents a “functional cure,” it would suggest a role of early therapy in treating towards a cure. My concerns are whether this infant was ever really infected. My concerns are that PCR technology can detect non-viable genetic material or viral genetic material passively transferred from the mother but not actually infecting the infant, i.e. replicating in the infant’s cells. The HIV DNA by PCR was positive at 2 days of life, which could be infected infant CD4 cells or passively transferred maternal-infected CD4 cells. 

    The viral load results suggest the presence of a cell-free virus in the plasma, however, the level of the viral load is not noted in the abstract. If the viral load is low and not suggesting a rising number, one has to be concerned that this was also a result of transfer of the virus (viable or non-viable) from the mother. 

    The last positive HIV RNA by PCR was at 20 days of life while the first negative result was at 29 days of life. This could represent the initial infection of a small number of cells in the infant prior to the development of reservoir cell infection with elimination of infected cells by providing early antiretroviral therapy. However, it could also represent post-exposure prophylaxis of infection that would be consistent with what is accomplished following blood exposures by health care workers or sexual exposures. This second scenario would be different than a “functional cure” since it would represent post-exposure prophylaxis. However, I hope that this is actually evidence that early therapy can result in long-term eradication of HIV infection and a cure.

    • Michael T. Brady, MD
    • Chair of the AAP's Red Book Committee Physician-in-Chief, Nationwide Children's Hospital Professor and chair, Department of pediatrics The Ohio State University
    Perspective
    Elizabeth Connick

    Elizabeth Connick

    More long-term follow-up is necessary to confirm that the child truly does not have HIV infection, but the case is fairly convincing. Anomalous cases such as this can provide important insights. The challenge will be to determine what led to this remarkable result.

    • Elizabeth Connick, MD
    • Professor, Division of Infectious Diseases University of Colorado School of Medicine

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