HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study

Abstract

Background: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission.

Methods: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m² and lopinavir 300 mg/m² from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255.

Findings: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2.

Interpretation: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission.

Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Figure 1:

Schedule of evaluations and study profile (A) Schedule of evaluations. Study weeks correspond approximately to infant age due to enrolment within 48 h of age for cohort 1 and 10 days of age for cohort 2. (B) Study profile. ART=antiretroviral therapy.

Figure 1:

Schedule of evaluations and study profile (A) Schedule of evaluations. Study weeks correspond approximately to infant age due to enrolment within 48 h of age for cohort 1 and 10 days of age for cohort 2. (B) Study profile. ART=antiretroviral therapy.

Figure 2:

HIV-1 plasma viral load (A) Plasma HIV-1 RNA levels (log10 copies per mL) in the first 26 weeks of life by cohort and by reaching study-defined criteria to stay in study follow-up. The first, second, and third horizontal lines correspond to plasma HIV-1 RNA of 200 copies per mL (log10 HIV-1 RNA of 2·3), 40 copies per mL (log10 HIV-1 RNA of 1·6), and 20 copies per mL (log10 HIV-1 RNA of 1·3). The downward grey arrows indicate samples that required dilution for viral load testing due to low plasma volume. (B) Kaplan-Meier plot showing the estimated probability of maintaining strict virological control (plasma HIV-1 RNA <200 copies per mL at study week 24 or no confirmed detectable plasma HIV-1 RNA after that) through to 114 weeks of age. In cohort 1, there were 21 total events and in cohort 2, there were six total events. 95% CIs are shown in the shaded red areas. Tick marks indicate a participant was censored.

Figure 2:

HIV-1 plasma viral load (A) Plasma HIV-1 RNA levels (log10 copies per mL) in the first 26 weeks of life by cohort and by reaching study-defined criteria to stay in study follow-up. The first, second, and third horizontal lines correspond to plasma HIV-1 RNA of 200 copies per mL (log10 HIV-1 RNA of 2·3), 40 copies per mL (log10 HIV-1 RNA of 1·6), and 20 copies per mL (log10 HIV-1 RNA of 1·3). The downward grey arrows indicate samples that required dilution for viral load testing due to low plasma volume. (B) Kaplan-Meier plot showing the estimated probability of maintaining strict virological control (plasma HIV-1 RNA <200 copies per mL at study week 24 or no confirmed detectable plasma HIV-1 RNA after that) through to 114 weeks of age. In cohort 1, there were 21 total events and in cohort 2, there were six total events. 95% CIs are shown in the shaded red areas. Tick marks indicate a participant was censored.

Figure 3:

HIV-1 DNA load (A) Boxplots of HIV-1 infected cell concentrations in the first 26 weeks of life by cohort with repeated measures regression slopes. Outliers are defined as points more than 1·5 × IQR above Q3 or 1·5 × IQR below Q1. Whiskers correspond to the lesser

of 1·5 × IQR or most extreme observed value. The horizontal grey line shows the limit of detection of the HIV-1 DNA assay at 0·612 log10 copies per 10⁶ PBMCs. Levels lower than the limit of detection were set to ½ (limit of detection). The blue triangles and blue lines represent the data from each participant throughout very early ART. Regressions treated time as a linear, fixed effect. Splines were evaluated at ages

2 weeks (cohort 1, corresponding to HIV-1 infection confirmation) and 13 weeks (cohorts 1 and 2, corresponding to the week 12 visit). Akaike Information Criterion was minimised for random intercept and fixed slope (eg, the model for each cohort fit best without splines). (B) HIV-1 DNA through to 114 weeks of age, by cohort and by study status (on or off study). The horizontal grey line shows the limit of detection of

the HIV-1 DNA assay at 0·612 log10 copies per 10⁶ PBMCs. Only infants meeting study-defined virological control criteria stayed in the study past week 24 (corresponding to 26 weeks of age).

ART=antiretroviral therapy. PBMC=peripheral blood mononuclear cell.

Figure 3:

HIV-1 DNA load (A) Boxplots of HIV-1 infected cell concentrations in the first 26 weeks of life by cohort with repeated measures regression slopes. Outliers are defined as points more than 1·5 × IQR above Q3 or 1·5 × IQR below Q1. Whiskers correspond to the lesser

of 1·5 × IQR or most extreme observed value. The horizontal grey line shows the limit of detection of the HIV-1 DNA assay at 0·612 log10 copies per 10⁶ PBMCs. Levels lower than the limit of detection were set to ½ (limit of detection). The blue triangles and blue lines represent the data from each participant throughout very early ART. Regressions treated time as a linear, fixed effect. Splines were evaluated at ages

2 weeks (cohort 1, corresponding to HIV-1 infection confirmation) and 13 weeks (cohorts 1 and 2, corresponding to the week 12 visit). Akaike Information Criterion was minimised for random intercept and fixed slope (eg, the model for each cohort fit best without splines). (B) HIV-1 DNA through to 114 weeks of age, by cohort and by study status (on or off study). The horizontal grey line shows the limit of detection of

the HIV-1 DNA assay at 0·612 log10 copies per 10⁶ PBMCs. Only infants meeting study-defined virological control criteria stayed in the study past week 24 (corresponding to 26 weeks of age).

ART=antiretroviral therapy. PBMC=peripheral blood mononuclear cell.