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Background


Currently, the WHO recommends that HIV positive mothers or their infants take antiretroviral medication throughout the period of breastfeeding, with the safe introduction of complementary foods at six months and to continue breastfeeding until the baby is 12 months old.1 The benefit is that the risk of death from illnesses such as diarrhoea and pneumonia, is reduced with a low risk of HIV transmission.
However, strategies to prevent mother-to-child postnatal transmission of HIV-1 in Africa, including infant prophylaxis, have never been evaluated for the entire recommended period of breastfeeding, i.e., 12 months, hence the need for relevant trials.
Lamivudine and Lopinavir/ritonavir were the chosen antiretroviral drugs for the PROMISE PEP trial. Besides lamivudine, which proved safe and efficacious during 6 months for PMTCT2, lopinavir/ritonavir is a good candidate for infant prophylaxis due to its good safety profile in infants, its potent antiretroviral activity and its high genetic barrier to HIV resistance mutations3.

Methodology


The ANRS 12174 study is a randomised controlled clinical trial comparing the efficacy and safety of prolonged infant peri-exposure prophylaxis (PEP) with lopinavir/ritonavir (LPV/r) versus lamivudine (3TC) to prevent postnatal HIV-1 transmission during the full duration of breastfeeding (50 weeks), in children born to HIV-1-infected mothers not eligible for HAART (i.e., with CD4 >350 cells/µl). Mother’s eligible for HAART were not considered because HAART is effective in reducing post natal transmission of HIV; and breastfed infants of HAART-treated mothers have been shown to ingest sufficient amounts of ARTs to reach plasma therapeutic levels.
The trial was conducted in 4 African countries: Burkina Faso, South Africa, Uganda and Zambia with support from university based institutions in Sweden, Norway and France. Sponsorship was through the French ANRS agency. Figure 1 depicts the trial design schematically.
All women who agreed to participate in the study were counselled to exclusively breastfeed their babies up to 6 months of age, after which they would introduce complementary food over a maximum period of 2 months, and to stop breastfeeding at 8-11 months. Continuous counselling on a nutritionally balanced diet was made available up to 50 weeks of age.
For those infants meeting the inclusion criteria, (HIV-uninfected breastfed newborns with a birth weight > 2000g amongst others) randomization occurred on day 7, after country specific infant PMTCT, and one of the two medications was provided to each infant’s mother in a 1:1 ratio. Routine visits were scheduled at 2 weeks, then every 4 weeks throughout the trial to screen for any adverse events, monitor growth and encourage adherence.
The primary outcome was infant HIV infection until 50 weeks, diagnosed every 3 months by HIV-1 DNA PCR. Secondary outcomes included mortality, HIV-free survival and severe adverse events, including routine biological parameters. Outcomes were analysed using Kaplan-Meier survival methods with an intention-to-treat approach.
Figure 1 Schematic trial design.


w2
w10

w6

w14

w18

w22

w26

w30

w34

w38

w42

w46

w50


Feeding counselling

Infant trial: Day 7 – Week 50

Infant HIV-1 PCR

Infant medication
Country specific PMTCT

Maternal medication


Scheduled visits

Randomisation

PEP trial

3TC vs. LPV/r

Country

specific

PMTCT

Day 7

Birth

w28

National care



No BF

Cessation

Counselling on EBF






Only for infants still breastfeeding after 46 weeks




Results:

Overall, 1273 children were enrolled in the trial, 636 in the LPV/r arm and 637 in the 3TC arm. Baseline infants’ characteristics were similar between arms. Antenatal maternal median CD4 count was 529 (IQR: 432-669).


At final follow-up (completed in May 2013), 1119 (88.32%) infants had attended the final visit and 115 (9.08%) were lost to follow-up. The median duration of breastfeeding was 42 weeks (IQR: 41-42). Drug adherence was determined to be 90% or more in both arms.
Overall, 17 HIV infections were diagnosed (8 by 6 months), 8 in the LPV/r arm and 9 in the 3TC arm, giving HIV infection rates of 1.39% (0.70-2.76) and 1.53% (0.80-2.91) at 50 weeks, respectively (p=0.83).
Overall, 18 (2.83%) died in the LPV/r arm and 15 (2.35%) in the 3TC arm (p=0.57). HIV-free survival was similar between arms, at 96.5% (94.6-97.7) and 96.3% (94.4-97.5) in the LPV/r and 3TC arms respectively (p=0.85). Medical or biological severe adverse events were not different between arms. These results are summarized in Table 1.
The ANRS PROMISE PEP trial is the first to cover the WHO recommended period of 12 months of breastfeeding and produced extremely low transmission rates of <1.0% for the first 6 months and 1.4% overall over the year.
Table 1 Summary of results.





LPV/r

(N = 604)

3TC

(N = 607)

P

HIV (Intention to Treat Analysis)










  • Number of Infections

8

9




  • Transmission rate @ 26 wks

0.7% (0.3-1.8)

0.8% (0.3-2.0)




  • Transmission rate @ 50 wks

1.4% (0.7-2.8)

1.5% (0.8-2.9)

0.83

  • Transmission if Antenatal CD4 ≥ 500c/µl

4/335 (1.3%)

2/356 (0.6%)

0.19

  • Transmission if Antenatal CD4 < 500c/µl

4/269 (1.5%)

7/251 (2.9%)

0.19

HIV (Per Protocol Analysis)

1/475 (0.2%)

4/516 (0.8%)

0.22

Deaths

18

15




Mortality Rate

3.0%

(1.9-4.8)



2.5%

(1.5-4.1)



0.57

1 SAE

34.6%

32.6%

0.82





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