HIV persists in the breastmilk of HIV-positive Kenyan mothers on antiretroviral treatment

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HIV-positive Kenyan mothers receiving various antiretroviral drug regimens for the reduction of mother-to-child transmission still carried a detectable reservoir of cell-associated HIV in breastmilk, according to the findings of a study published in the 31st July edition of AIDS. This study underscores the urgency of evaluating alternative interventions for the prevention of mother-to-child transmission in resource-poor settings.

HIV-positive mothers in Africa may not have access to clean water and baby formula, making breastfeeding the only practical means of infant feeding. The dilemma is that breastfeeding accounts for 24-44% of HIV-1 infection in infants of HIV-positive mothers.

Several strategies to prevent mother-to-child transmission have been adopted, consisting of simple antiretroviral regimens taken during pregnancy, during the delivery period or both. These interventions include AZT and single-dose nevirapine (sdNVP) given singly or in combination.

Glossary

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

combination therapy

A therapy composed of several drugs available either as separate tablets, or as fixed-dose combination (FDC).

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

These prophylactic strategies were not specifically designed to reduce mother-to-child transmission through breastmilk. The effect of antiretrovirals which are used for prevention of mother-to-child transmission in resource-poor countries on temporal patterns of cell-associated HIV-1 RNA and DNA in breastmilk is not known.

This issue has been addressed by a team of US and Kenyan investigators. Two randomised clinical trials were carried out at the Mathare North City Council Clinic. The study participants were pregnant women who planned to breastfeed.

In one trial the women received a ‘monotherapy’ of twice daily AZT from 34 weeks of pregnancy until delivery, or sdNVP at the onset of labour with the infant receiving sdNVP within 72 hours of birth.

In the second trial, the women received a ‘combination therapy’ consisting of AZT for six weeks before delivery, sdNVP during labour, and sdNVP in infants after birth (AZT/sdNVP), or triple combination therapy consisting of AZT, NVP and 3TC for six weeks prior to and six months after delivery.

Breastmilk samples were collected two to three times weekly for four–six weeks. HIV-1 DNA was quantified by real-time PCR. Cell-free and cell-associated RNA levels were quantified by the Gen-Probe HIV-1 viral load assay. CD4 counts were measured on blood samples taken at 32 weeks of gestation.

Cell-free HIV-1 RNA levels in breastmilk were significantly suppressed by sdNVP, AZT/sdNVP or triple combination therapy compared with AZT between day three and week four postpartum (P≤ 0.03). However, breastmilk HIV-1 DNA levels, which represent infected cell levels, were not significantly different between the treatment arms at any time-point during the four–six-week follow-up.

At three weeks after the delivery, when the difference between triple combination therapy and AZT in cell-free RNA levels was the greatest (P=0.0001), HIV-1 DNA was still detectable at a level of 2.31-2.78 copies per 106 cells with no significant differences between regimens (P = 0.23). These results indicated that even though they received antiretroviral treatment, HIV-positive women still had a large reservoir of latently infected cells in breastmilk.

Cell-associated HIV-1 RNA levels, which reflect viral expression within infected cells, were modestly suppressed in triple combination therapy versus AZT/sdNVP during week three (3.37 versus 4.02, P= 0.04), as well as over time according to a statistical model.

The persistence of cell-associated HIV RNA in breastmilk despite antiretroviral treatment suggests that the virus expressed in macrophages, the major cell type in breastmilk, may be sequestered away from the drugs in intracellular compartments.

In conclusion, despite the limitations of the study pointed out by the authors, this study demonstrates that although cell-free and, to a lesser extent, cell-associated HIV-1 RNA levels in breastmilk were suppressed by antiretroviral regimens used to prevent mother-to-child transmission in resource-poor countries, these regimens had virtually no impact on the reservoir of infected cells in breastmilk as measured by HIV-1 DNA levels.

The authors suggest that though maternal antiretroviral treatment reduces cell-free HIV RNA, it cannot entirely eliminate the risk of HIV transmission during breastfeeding, due to the poor penetration of antiretroviral drugs into the remaining reservoir of HIV-infected cells in breastmilk.

Several recent studies have shown that where infant prophylaxis is given during the breastfeeding period, the rate of HIV transmission is reduced but still remains in the region of 5% at nine months of age among infants confirmed to be uninfected at birth. The authors conclude that it will be important to continue to examine the role of infant prophylaxis versus maternal treatment in prevention of mother-to-child transmission during breastfeeding.

References

Lehman DA et al. HIV-1 persists in breast milk cells despite antiretroviral treatment to prevent mother-to-child transmission AIDS 22:1475–1485, 2008