Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus

Abstract

Background Early antiretroviral therapy (ART) restricts the size of the HIV reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. Methods We measured total and integrated HIV DNA, as well as the frequency of CD4 T-cells producing multiply-spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically-infected Thai infants. Eighty-five infants were followed longitudinally for up to three years. We compared the size of the reservoir in children who received continuous prophylactic ARV since birth versus those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. Results Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous prophylactic ARV since birth compared to those in whom prophylactic ARV was discontinued or never initiated (p<0.020 and p<0.001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (<0.01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during three years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARV before starting ART and those who delayed ART initiation without receiving prior prophylaxis. Conclusions Neonatal prophylactic ARV with direct transition to ART durably limits the size of the HIV reservoir.

HIV-1 Persistence in Children during Suppressive ART

“…A study of 20 children from the CHER cohort who had viremia well-suppressed on ART for 7-8 years also found significantly lower DNA and RNA loads in those who initiated treatment within two months of birth compared with those who initiated later [53]. These findings are mirrored by others [60][61][62][63][64][65][66][67] and highlight the role of early ART in limiting the size of the HIV reservoir. This finding is well-illustrated by a recent study in children showing a positive correlation between HIV RNA area under the viral load curve in the first year of life and HIV DNA levels at one year of age [68].…”

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand

“…On the other hand, in an Ugandan study, none of the baseline factors investigated (age, sex, CD4 + %, WHO stage, cART regimen, weight-for-age or height-for-age z -scores) were found to predict virological suppression to viral load less than 400 copies/ml [33]. Although there was no significant effect of infant and maternal PMTCT prophylaxis on time to virological suppression, the potential effect of PMTCT on suppression has recently been demonstrated [39].…”

Clinical Validation of a Quantitative HIV-1 DNA Droplet Digital PCR assay: Applications for Detecting Occult HIV-1 Infection and Monitoring Cell-associated HIV-1 Dynamics across Different Subtypes in HIV-1 Prevention and Cure Trials

“…With enhanced HIV-1 prophylactic regimens that include combination antiretrovirals to prevent and empirically treat perinatal HIV-1 infection in high-risk exposure settings, access to more sensitive and precise HIV-1 DNA assays across various HIV-1 subtypes is becoming important. (16,36).Similarly, the use of long-acting, potent antiretrovirals such as with long-acting injectables, including broadly neutralizing antibodies, to prevent adult infection, may alter the sensitivity of RNA and antibody testing, and for which ultrasensitive HIV-1 DNA testing may provide unique opportunities to detect occult, low level infection, enabling early transition to combination ART regimens to limit HIV-1 spread into reservoirs that preclude cure. In summary, this assay has potential applications for assessing therapeutic efficacy in the emerging fields of HIV-1 prevention, where occult HIV-1 infection may become more prevalent (37) and standard HIV-1 RNA and antibody testing methods insufficiently sensitive, and with relevance for HIV-1 cure, especially in perinatal infections, where HIV-1 infected cells concentrations can reach exceedingly low levels.…”

“…With enhanced HIV-1 prophylactic regimens that include combination antiretrovirals to prevent and empirically treat perinatal HIV-1 infection in high-risk exposure settings, access to more sensitive and precise HIV-1 DNA assays across various HIV-1 subtypes is becoming important. (16, 36). Similarly, the use of long-acting, potent antiretrovirals such as with long-acting injectables, including broadly neutralizing antibodies, to prevent adult infection, may alter the sensitivity of RNA and antibody testing, and for which ultrasensitive HIV-1 DNA testing may provide unique opportunities to detect occult, low level infection, enabling early transition to combination ART regimens to limit HIV-1 spread into reservoirs that preclude cure.…”

“…Early antiretroviral treatment (ART) of perinatal HIV-1 infection can lead to low concentrations of circulating HIV-1 infected cells in association with negative HIV-1 antibody and DNA tests by clinical diagnostic assays (5)(6)(7)(8)(9)(10)(11), which can lead to unnecessary ART interruption in later childhood (12). Furthermore, the use of combination antiretroviral (ARV) prophylaxis in high-risk perinatal exposures, along with very early ART within days of age, or directly transitioning from prophylaxis to ART may lead to low infected cell concentrations (7,(13)(14)(15)(16) that require more sensitive HIV-1 DNA assays to confirm infection on ART. HIV-1 DNA concentrations in peripheral blood are also used to determine therapeutic efficacy of cure strategies aimed at eradicating reservoir cells in for ART-free remission and cure (17,18).…”