Antiretroviral therapy started soon after birth can suppress HIV to extremely low levels and severely restrict the size of the reservoir of HIV-infected cells in peripheral blood, Canadian researchers report in the online edition of Clinical Infectious Diseases.
The findings raise the hope that early suppressive antiretroviral therapy can achieve a "functional cure" for HIV-infected babies. However, the authors caution that the only way to determine this would be to discontinue HIV treatment, a strategy that is not without risks.
An HIV-infected baby who started antiretroviral therapy within 30 hours of birth was recently reported to have no detectable virus after treatment was stopped. The case of the so-called “Mississippi Baby” raised the prospect of a “functional cure” for HIV – control of viral replication after withdrawal of antiretroviral drugs.
Doctors from three hospitals in Canada therefore investigated the impact of early antiretroviral treatment on HIV replication and various measures of the HIV reservoir size in children infected with HIV at birth who achieved sustained virologic suppression with triple antiretroviral therapy.
HIV-exposed infants were eligible for inclusion if they started treatment within 72 hours of life because of incomplete maternal HIV suppression at delivery, the absence of viral load results, or a history of poor adherence.
The eligible infants all had confirmed HIV infection and achieved sustained HIV suppression with antiretroviral therapy consisting of zidovudine, lamivudine and nevirapine.
Follow-up was undertaken after 2.5-7.5 years. Assessments included HIV antibody testing, viral load testing with a lower limit of detection of 1.5 copies/ml, monitoring of cell-associated HIV DNA and RNA, tests for the presence of replication-competent HIV and HLA genotype.
A total of 136 infants started combination antiretroviral therapy soon after birth; twelve (9%) were HIV infected. Of these twelve, four achieved sustained viral suppression, whereas eight had difficulties with adherence. Analysis focused on the four patients with sustained viral suppression. All received their first dose of therapy within 24 hours of birth. Virological suppression was first documented between 66 and 189 days of life. All four infants remained on the same regimen until follow-up and at this time were in good health with normal CD4 counts.
At follow-up, all four infants were HIV-negative using both ELISA and Western blot tests. Viral load was undetectable using the ultra-sensitive assay. No detectable cell-associated HIV DNA (below 2.6 copies/106 CD4 T-cells) was found in the peripheral blood of any of the children. However, low levels of cell-associated HIV RNA (19.5-130 copies/1.5 μg RNA) were detected in all four. No virion-associated HIV RNA was detected in the patients’ CD4 cells. Culture detected replication-competent virus in one child at a concentration of 0.1 infectious units per 106 CD4 cells.
All four children had wild-type CCR5 virus. Three had HLA B*58. The HLA-B sequence has previously been associated with better HIV control.
“The findings in the four children with sustained virologic suppression show that early initiation of cART [combination antiretroviral therapy] in infants can dramatically reduce the level of proviral HIV-1 DNA and replication competent virus in peripheral blood CD4+ T-cells,” comment the authors. “Given that it is not possible to examine every cell in each infant, a structured treatment interruption may be the only practical way to determine if HIV-1 eradication or functional cure can be achieved in such treatment.”
The investigators urge that the pros and cons of this strategy should be carefully assessed.
“If virologic rebound were to occur following cART discontinuation it would likely be accompanied by expansion of the HIV-1 reservoir, potentially making future HIV-1 reservoir eradication more difficult,” they conclude. “Therefore, a thorough discussion of the risks and benefits of stopping cART with patients and caregivers is imperative and, if undertaken, will require long-term follow-up.”
Bitnun A et al. Early initiation of combination antiretroviral therapy in HIV-1-infected newborn infants can achieve sustained virologic suppression with low frequency of CD4+ T-cells carrying HIV in peripheral blood. Clin Infect Dis, online edition, 2014.