R4P2018 conference session reviews U=U

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One of the last sessions at R4P2018 included six talks about U=U, one of which reviewed the evidence about breastfeeding. This is important because rather than just sexual transmission, U=U is sometimes wrongly interpreted as covering all ways that HIV can be transmitted.

Lena Serghides from University Health Network and University of Toronto answered the opening question of whether ART eliminates HIV transmission with a clear “no”. While it is easy to show that ART dramatically reduces the risk for all routes of transmission, it is only sexual transmission where the risk is proven to be effectively zero.

This talk emphasised that cases of HIV transmission have already been reported when mothers are on ART with undetectable viral load, notably in the PROMISE trial. Latest results presented at AIDS 2018 reported that 2/8 cases when transmission occurred form breastfeeding were in women whose most recent viral load was <40 copies/mL.

So, although HIV treatment reduces the risk of transmission during breastfeeding, this risk is not zero. None of the studies looking at this risk have reported a zero result, with a meta analysis that drove WHO guidelines reported risk of 1.1% and 2.9% with 6- and 12-months breastfeeding in mothers on ART.

Possible explanations for this residual risk include: high lifetime exposure volume compared to sexual fluid: 3-4 cups of milk a day is 150 litres over six months; breast milk is likely to include 1 million immune cells/day and 150 million over six months; breast milk induces immune activation and HIV replication is 10-fold higher in milk vs blood; cell associated HIV DNA persists on ART and latently infected resting cells are transmitted (and then activated) in milk; breast inflammation can activate HIV (mastitis, abscess, engorgement etc); great immune vulnerability in infant GI tissue; and adherence difficulties post partum (erratic sleep, depression, support) are well documented in all settings, including high-income countries.

Breastfeeding starts off with a much higher risk of transmission because the infant is exposed to far higher amounts of infectious fluid.

Crucially, context for risk drives current WHO recommendations. In low-income settings with limited access to clean water, formula feed and medical care the recommendation to breastfeed on ART means the positive benefits from breast milk in fighting malnutrition, diarrhoea and pneumonia outweigh the low risk of HIV transmission.

In high-income settings where the rates of infant mortality from background health risks are much lower, the recommendation to use formula feed has the best outcome in terms of infant health and the higher risk comes from HIV via breastfeeding.

Comment: This is an area where more data on transmission risk from mothers on ART will become increasingly available now that the WHO recommends both continued ART and breastfeeding in low income countries. Earlier evidence reviews on risk showed heterogenicity of approaches with many studies not fully reporting timing and use of ART and importantly, maternal viral load data.

Prospectively collecting cases in large observational databases, similar to the approach in the PARTNER studies for sexual transmission, is not only ethical, but essential.

Although a recent discussion paper from some of the doctors involved in the original Swiss Statement, suggested there might be equipoise on risk for women in high-income countries, this was published before the cases were presented from the PROMISE study.
Currently, National guidelines, including in the UK (and Switzerland), continue to recommend that the safest option for the baby in high-income countries is to use formula feed and not to breastfeed.

Abstract 1
Infant feeding choices should support the greatest likelihood of HIV-free survival, i.e., meeting the nutritional needs of the infant and protecting the infant from HIV infection and non-HIV morbidity and mortality. The choice to breastfeed is a balancing act where context is important and multiple factors need to be considered, including whether the benefits of breast milk justify the risk of HIV transmission. In the context of the U=U movement, mothers living with HIV are reassessing their infant feeding choices and are considering breastfeeding, even if their country’s guidelines recommend against it. This presentation will explain the basic science of HIV transmission through breast milk in untreated HIV infection and in HIV infection that is fully suppressed with antiretroviral therapy. It will also summarize available clinical data on HIV transmission risk through breast milk, and discuss factors that increase the risk of transmission.

Lena Serghides

Abstract 2
Background: In the PROMISE 1077BF trial, breastfeeding women with CD4 >350 cells/mm3 (or >country-specific ART threshold if higher) and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) until breastfeeding cessation or 18 months post-delivery, (whichever occurred first) and had low infant HIV-1 infection rates (0.7% overall). We assessed whether maternal viral load (MVL) or CD4 were associated with perinatal HIV transmission risk.
Methods: MVL was measured retrospectively on batched specimens collected at entry (7-14 days postpartum) and weeks 6, 14, 26, and 50 postpartum. CD4 was measured real-time at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 NAT was obtained at weeks 1, 6, every 4 weeks until week 26, then every 12 weeks. Infant infection was defined as a positive HIV-1 NAT at any two post-entry timepoints. The associations of baseline and time-varying MVL and CD4 with transmission risk were assessed using proportional hazards regression models by randomized treatment arm, with MVL categorized as < 1000 or ≥1,000 copies/ml and CD4 categorized as < 500 or ≥ 500 cells/mm3, and adjustment for mART receipt during pregnancy.
Results: 2431 mother-infant pairs were randomized. Baseline MVL and CD4 are shown in Table 1. Baseline MVL (p= 0.11) and CD4 (p=0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection in the mART arm (hazard ratio (95% CI): 12.04 (2.54, 57.06) but not in the iNVP arm (hazard ratio (95% CI): 1.04 (0.20 – 5.52)). Time-varying CD4 was not significantly associated with infant HIV-1 infection in either arm (hazard ratio (95% CI): 0.29 (0.05-1.59) in mART arm and 0.33 (0.07-1.57) in iNVP arm). Of 7 postnatal infections in mART arm, 2 had proximal MVL< 40 copies/ml.
Conclusions: With iNVP, MVL was not significantly associated with HIV-1 transmission during breastfeeding. However, among women receiving mART, increased MVL during breastfeeding was associated with increased risk of infant HIV-1 infection. These data emphasize the important role of adherence to mART in controlling MVL and preventing infant infection and suggest that iNVP should be considered in situations with documented poor maternal ART adherence.

P Flynn, T Taha, M Cababasay, K Butler, MG Fowler, L Mofenson, M Owor, S Fiscus, L Stranix-Chibanda, A Coutsoudis, D Gnanashanmugam, N Chakhtoura, K McCarthy, C Mukuzunga, B Makanani, D Moodley, T Nematadzira, B Kusakara, S Patil, T Vhembo, R Bobat, B Mmbaga, M Masenya, M Nyati, G Theron, H Mulenga, D Shapiro

Abstract 3
Introduction: To systematically review the literature on mother-to-child transmission in breastfed infants whose mothers received antiretroviral therapy and support the process of updating the World Health Organization infant feeding guidelines in the context of HIV and ART.
Methods: We reviewed experimental and observational studies; exposure was maternal HIV antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were analysed by narrative synthesis; data were pooled in random effects meta-analyses. Postnatal transmission was assessed from four to six weeks of life. Study quality was assessed using a modified Newcastle-Ottawa Scale (NOS) and GRADE.
Results and discussion: Eleven studies were identified, from 1439 citations and review of 72 abstracts. Heterogeneity in study methodology and pooled estimates was considerable. Overall pooled transmission rates at 6 months for breastfed infants with mothers on antiretroviral treatment (ART) was 3.54% (95% CI: 1.15–5.93%) and at 12 months 4.23% (95% CI: 2.97–5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32–1.85) at six and 2.93 (95% CI: 0.68–5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue beyond six months postpartum. No study provided data on mixed feeding and transmission risk.
Conclusions: There is evidence of substantially reduced postnatal HIV transmission risk under the cover of maternal ART. However, transmission risk increased once PMTCT ART stopped at six months, which supports the current World Health Organization recommendations of life-long ART for all.

Stephanie Bispo, Lana Chikhungu, Nigel Rollins, Nandi Siegfried, Marie-Louise Newell

Abstract 4
Combined antiretroviral treatment (cART) has reduced mother-to-child transmission (MTCT) of the human immunodeficiency virus (HIV) to virtually zero in industrialised countries, where strictly bottle feeding is recommended for HIV-infected mothers, and to as low as 0.7% after 12 months in low-resource settings, where breastfeeding is strongly encouraged. Given the theoretically very low risk of transmission by breastfeeding with cART, and the advantages and benefits of breastfeeding, also in industrialised countries, the strong recommendation to HIV-infected mothers to refrain from breastfeeding in this setting may no longer be justified.
We have evaluated risks of breastfeeding for HIV MTCT in the light of accessible cART, the general benefits of breastfeeding, and the women’s autonomy to consent to any intervention. As we found no evidence in the literature of HIV MTCT via breastfeeding whilst on effective cART, we identified a situation of clinical equipoise.
We propose how to proceed in Switzerland when HIV-infected women consider breastfeeding. We advocate a shared decision-making process and suggest a list of topics on which to provide unbiased information for the HIV-infected mother to enable her comprehensive understanding of one or the other decision.
Although breastfeeding still should not be actively recommended in Switzerland, any HIV-infected mother, regardless of her geographical and cultural background, who decides to breastfeed should be supported by the best strategy to achieve optimal medical care for both herself and her child. This includes continuous support of cART adherence and regular maternal HIV plasma viral load monitoring.

Kahlert Christian R, Aebi-Popp Karoline, Bernasconi Enos, Martinez de Tejada Begoña, Nadal David, Paioni Paolo, Rudin Christoph, Staehelin Cornelia, Wagner Noémie, Vernazza Pietro

Abstract 5
Objective: To estimate antiretroviral therapy (ART) adherence rates during pregnancy and postpartum in high-income, middle-income, and low-income countries.
Design: Systematic review and meta-analysis.
Methods: MEDLINE, EMBASE, SCI Web of Science, NLM Gateway, and Google scholar databases were searched. We included all studies reporting adherence rates as a primary or secondary outcome among HIV-infected pregnant women. Two independent reviewers extracted data on adherence and study characteristics. A random-effects model was used to pool adherence rates; sensitivity, heterogeneity, and publication bias were assessed.
Results: Of 72 eligible articles, 51 studies involving 20 153 HIV-infected pregnant women were included. Most studies were from United States (n = 14, 27%) followed by Kenya (n = 6, 12%), South Africa (n = 5, 10%), and Zambia (n = 5, 10%). The threshold defining good adherence to ART varied across studies (>80, >90, >95, 100%). A pooled analysis of all studies indicated a pooled estimate of 73.5% [95% confidence interval (CI) 69.3–77.5%] of pregnant women who had adequate (>80%) ART adherence. The pooled proportion of women with adequate adherence levels was higher during the antepartum (75.7%, 95% CI 71.5–79.7%) than during postpartum (53.0%, 95% CI 32.8–72.7%; P = 0.005). Selected reported barriers for nonadherence included physical, economic and emotional stresses, depression (especially postdelivery), alcohol or drug use, and ART dosing frequency or pill burden.
Conclusion: Our findings indicate that only 73.5% of pregnant women achieved optimal ART adherence. Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the postpartum period. Further research to investigate specific barriers and interventions to address them is urgently needed globally.

Nachega, Jean B; Uthman, Olalekan A; Anderson, Jean; Peltzer, Karl; Wampold, Sarah; Cotton, Mark F; Mills, Edward J; Ho, Yuh-Shan; Stringer, Jeffrey SA; McIntyre, James A; Mofenson, Lynne M

i-base material
HIV4RP 2018 abstract
AIDS 2018 abstract
Journal of the International Aids Society abstract
Swiss Medical Weekly article summary
AIDS abstract
BHIVA guidelines

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