BAN study: Giving ART to mothers or ARV prophylaxis to infants during breastfeeding equally effective at reducing HIV transmission
by Theo Smart
Maternal antiretroviral therapy (ART) or infant prophylaxis during the time of breastfeeding are equally safe and effective in reducing post-natal mother-to-child transmission of HIV, Dr Charles Chasela of the University of North Carolina Project in Lilongwe, Malawi, reported to the Fifth International AIDS Society conference on Wednesday.
He presented the findings of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study as a late-breaker at IAS 2009 in Cape Town - making it the fifth major study at the conference evaluating ways to make it possible for an HIV-infected mother to breastfeed her infant without passing on HIV.
Breastfeeding in HIV
Breastfeeding is generally the best way of feeding a baby, but when the mother is HIV-positive there is a risk of vertical transmission of the virus to her infant. WHO guidelines recommend exclusive breastfeeding for HIV-infected women for the first six months of life unless replacement feeding is acceptable, feasible, affordable, sustainable and safe (AFASS) for them and their infants before that time.
Unfortunately, replacement feeding is rarely possible in resource-limited settings. Formula is expensive and reliable supplies are difficult to maintain in countries with limited infrastructure for transport and storage. Even when formula feed is freely provided it may not be culturally acceptable and often puts the mother at risk of having her HIV status disclosed involuntarily to her family and community and of being stigmatised.
Finally, the water to prepare it with may not always be safe or it may be difficult to keep the babies’ environment hygienic. As a result, some programmes have reported diarrhoea outbreaks.
Breastfeeding reduces diarrhoea-related morbidity and mortality. Even early weaning poses problems. In fact, in another presentation at the conference, Dr Ashraf Fawzy of Columbia University reported that diarrhoea and morbidity increased among uninfected infants of HIV-infected mothers in the Zambia Exclusive Breastfeeding Study (ZEBS). The effect was most pronounced in children who stopped breastfeeding earlier. What was worse? “Among children who weaned early, severe diarrhoeal morbidity and mortality continued to be higher between 6 and 18 months,” Dr Fawzy reported.
“Formula is not recommended in Malawi since it is expensive, and if used in the first six months, yields high infant mortality. Therefore, there is an urgent need for interventions to make breastfeeding safer for infants of HIV-infected women,” said Dr Chasela.
The BAN Study
So investigators from Malawi, the University of North Carolina and the US Centers for Disease Control (CDC) launched the BAN study, a randomised controlled trial to evaluate two interventions given to HIV-infected mothers or their infants during a 24-week period of exclusive breastfeeding.
To prevent mother-to-child transmission of HIV, all the mothers were treated with a single dose of nevirapine during labour, followed by a week of twice-daily treatment with 3TC and AZT. All the women participating in the study were given nutritional supplementation to prevent maternal depletion.
To be eligible for the study, all the mothers had a CD4 cell count above 250 cells/mm3 and the infants weighed at least 2 kg. Then within the first week after delivery, the mothers and their infants were randomised into one of three treatment arms:
- Maternal daily treatment with nevirapine (after they were switched to nelfinavir, then the protease inhibitor lopinavir/ritonavir) in combination with 3TC and AZT
- Infant nevirapine (NVP) that the mother administered to her infant through 28 weeks
- A control arm. No antiretroviral treatment, but nutritional support.
All the mothers breastfed for 24 weeks, followed by rapid weaning by 28 weeks. Weaning food Plumpy Nut was provided until week 48.
The study outcomes were HIV infection or death in infants at week 28 amongst those who were HIV-uninfected a week after birth.
Results
A total of 2367 HIV-positive mothers and their infants were included in the study: 851 were on maternal ART, 848 were randomised to infant NVP, and 668 to the enhanced control. Fewer women were in the enhanced control arm since randomisation to the control arm was stopped after March 2008 based on a Data Safety and Monitoring Board recommendation.
There were no statistical significant differences in age, body mass index, CD4 count, haemoglobin and infant birth weight at baseline.
Severe side-effects were rare. There were no significant differences in terms of grade three or four toxicities except for low neutrophil count in mothers on the maternal ART arm (this is a known side-effect of AZT). And out of the 848 infants on the infant NVP arm, there were 16 possible cases of NVP hypersensitivity that were mild and all were resolved when NVP was discontinued. There appeared to be one additional case of NVP hypersensitivity in a breastfeeding infant whose mother was receiving NVP.
According to Dr Chasela, there had been concerns about NVP hypersensitivity (reactions that includes rash, eosonophilia, sometimes liver toxicity and Stevens Johnson Syndrome), which has been well documented in NVP use in adults, usually within the first weeks of treatment, but there is less information on its use in infants.
HIV infection status was assessed by testing the infant at birth, 2, 12, 28 and 48 weeks by DNA PCR. Dried Blood Spots (DBS) were obtained at each visit and tested to narrow the window of transmission to less than four weeks. All positives were confirmed with a second specimen. The rate of mother-to-child transmission of HIV one week after delivery (before randomisation) was 5%.
“Using standard survival methods - both the infant NVP and maternal ART regimens significantly reduced 28 week HIV transmission, compared with the enhanced control arm,” said Dr Chasela.
At the end of the study, 6.4% of the infants in the control arm were HIV-positive. This was significantly higher (p = 0.003) than the 3% rate of mother-to-child transmission observed in the infants of mothers who took antiretroviral therapy during breastfeeding, and the 1.8% transmission rate seen in infants treated with nevirapine (p < 0.001).
The overall risk of HIV transmission or death was 7.6% for infants in the control arm, compared to 4.7% for the maternal HIV treatment arm (p = 0.03) and 2.9% for the nevirapine arm (p < 0.0001).
The study was not powered to directly compare the maternal and infant interventions, but there was some suggestion that HIV-free survival was lower among infants who were treated with NVP for 28 weeks (p = 0.07).
Implications
“The BAN results give global and national policy makers the choice of which interventions to implement: either maternal ART or infant NVP, based on the appropriateness of their particular setting,” said Dr Chasela.
Indeed, this was just one of five studies presented at IAS on interventions that could make breastfeeding safer for women with HIV and their infants. The first was a retrospective analysis of the DREAM cohort in Malawi and Mozambique, which found that giving ART during pregnancy and breastfeeding reduces the risk of a woman transmitting HIV to her infant to just 2%.
The other studies were all randomised controlled studies.
In the Mma Bana study in Botswana, there was about a half a percent risk of transmission during breastfeeding.
The PEPI-Malawi study was presented as a poster, and showed that extended antiretroviral prophylaxis of breastfeeding HIV-exposed infants for 14 weeks reduced postnatal transmission by 67% at age 14 weeks and 50% at age 9 months (Mofenson). However, continued transmission after 14 weeks suggested that infant prophylaxis needs to last at least as long as the mother continues to breastfeed.
Finally the Kesho Bora study used the same regimen as the BAN Study but commenced treatment between week 28 and 36 of pregnancy, rather than after delivery, and showed about a two percent risk of transmission during breastfeeding.
Taken together these findings have clear policy implications. Noting that transmission from women with CD4 counts of 200-350 cells/mm3 is still unacceptably high, Mofenson et al. wrote: Use of infant prophylaxis should be considered to reduce breast milk transmission risk in infants born to women with CD4 [cell counts] over 350, while women with CD4s [below] 350 should receive ART for their own health… which would be continued after breastfeeding cessation for maternal health.”
References
Chasela C et al. Both maternal HAART and daily infant nevirapine are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBC103, 2009.
Fawzy A et al. Diarrhea morbidity and mortality increases with weaning prior to 6 months among uninfected infants born to HIV-infected mothers in Zambia. . 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUAC104, 2009.
Mofenson LM et al. Infant Extended Antiretroviral (ARV) Prophylaxis is Effective in Preventing Postnatal Mother-to-Child HIV Transmission at All Maternal CD4 Counts. . 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUPEC053, 2009.
Further information
A powerpoint presentation by Charles Chasela and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.
A powerpoint presentation by Ashraf Fawzy and a webcast of the conference session in which it was presented are also available on the IAS 2009 website here.
Kesho Bora study: Maternal ART during pregnancy and breastfeeding prevents more infections than short-course prophylaxis
by Keith Alcorn
Antiretroviral treatment for mothers started during pregnancy and continued throughout the breastfeeding period resulted in a significantly lower rate of mother-to-child HIV transmission when compared with the standard short-course regimen, investigators on the Kesho Bora study reported this week at the Fifth International AIDS Society conference in Cape Town.
The Kesho Bora study, conducted in Kenya, South Africa and Burkina Faso, found that antiretroviral treatment for the mother with a protease inhibitor-based regimen was significantly more effective than short-course treatment in which the mother took AZT from week 28 to 36 of pregnancy with AZT/3TC and single dose nevirapine at the onset of labour, and AZT/3TC for one week, while the infant received single dose nevirapine with one week of AZT/3TC, and was either formula fed or breastfed with weaning at 6 months.
The differing short-course regimens studied reflect variations in practice as a result of previous clinical trial results.
In the Kesho Bora study 824 pregnant women not currently eligible for antiretroviral treatment for their own health, with CD4 counts between 200 and 500 cells/mm3, were randomised to one of two regimens.
Women in the triple therapy group (n=413) received AZT/3TC and lopinavir/ritonavir (Kaletra) from the third trimester of pregnancy until six months postpartum, the point at which breastfeeding was recommended to cease.
Women in the short-course group received AZT (zidovudine) from week 28 to 36 of pregnancy until the onset of labour, when they received AZT/3TC and single dose nevirapine. They continued to take AZT/3TC for one week after delivery, an amendment introduced to the study in December 2007.
All infants received single dose nevirapine within 72 hours of delivery, and one week of AZT treatment was added from December 2007.
Women were counselled on the risk of transmission through breastfeeding and offered the choice of free formula for bottle feeding, or exclusive breastfeeding with weaning over a two-week period commencing at five and a half months. During the study 76 and 78% of mothers in the two study arms breastfed at some point, with around 45% in each arm breastfeeding exclusively during the first three months after delivery. The average duration of breastfeeding was 21 weeks.
Study recruitment began in June 2005 and the study was fully recruited by August 2008, with the result that the majority of births in the study occurred in the period before the December 2007 protocol amendment.
In the triple ART arm there were 402 live births, and infant HIV infections as measured by real-time PCR were detected in 1.8% at birth, 3.3% at six weeks, 4.9% at six months and 5.5% at one year. The reduction in the risk of transmission at one year was 42% when compared to the short-course regimen. A log rank test at 12 months showed this difference to be statistically significant (p = 0.039).
In comparison there were 411 live births in the short-course arm, and infant HIV infections were detected in 2.2% at birth, 4.8% at six weeks, 8.5% at six months and 9.5% at one year.
A difference in infant survival became apparent after six months: 6.3% of infants born to mothers in the triple therapy arm had died after 12 months of follow-up, compared to 10% of infants in the short-course arm, a reduction in risk of 37%. However a log rank test at 12 months did not show this difference to be statistically significant (p = 0.086).
Subgroup analysis showed that the reduction in HIV infection rate associated with the triple therapy regimen was statistically significant only in the group of mothers with baseline CD4 counts between 200 and 350 cells/mm3. In the infants born to these mothers there was a cumulative HIV infection rate of 5.5% by six months in the triple ART group and 10.5% in the short-course group, rising to 6.1 and 11.1% at 12 months (p = 0.044).
A significant difference was not detected in infants born to mothers with baseline CD4 counts between 350 and 500 cells/mm3, and there was no significant difference in HIV infections according to regimen in the infants of mothers who ever breastfed during the study (5.9% vs 10.2%, p = 0.064).
The study authors note that the biggest effect of triple ART was detected between six weeks and six months after delivery, and in mothers with CD4 counts between 200 and 350 cells/mm3, reinforcing the view that if earlier treatment is to be recommended in resource-limited settings, this group should be a priority. The median CD4 count in this study population was 335 cells/mm3.
The authors also noted that a small number of postnatal transmissions occurred after six months, the point at which breastfeeding was recommended to stop, indicating the importance of continuing ART until breastfeeding stops completely.
Analyses of adherence and the long-term impact of treatment on maternal health will take place, and full results of the study, with 12-month and 18-month follow-up on all participants, are expected in 2010.
References
Kesho Bora Study Group. Triple-antiretroviral prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent mother-to-child transmission of HIV-1: the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. Fifth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBPeC01, 2009
Chasela C et al. Both maternal HAART and daily infant nevirapine are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28 week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. Fifth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLBC103, 2009.
Further information
A powerpoint presentation by Charles Chasela and a webcast of the conference session in which it was presented are available on the IAS 2009 website.
Mma Bana study: Mother-to-child transmission reduced below 1% in breastfeeding mothers who receive ART
by Keith Alcorn
Antiretroviral treatment during pregnancy and breastfeeding resulted in a mother-to-child transmission rate of less than 1% in a large randomised comparison of two triple combinations in women with CD4 counts above 200 cells/mm3, the Mma Bana study, presented this week at the Fifth International AIDS Society conference in Cape Town.
The study also showed that a triple-nucleoside analogue regimen containing abacavir is just as effective as a protease inhibitor-based regimen in a population of women with relatively low viral load (Trizivir has previously shown itself to be less effective than efavirenz-based ART in people with viral loads above 100,000 copies/ml, leading to its withdrawal from the list of recommended first-line regimens in the United States and Europe).
However it should be noted that women in this study were followed for a little less than nine months, which may not be long enough to evaluate the suitability of Trizivir as a long-term regimen for women in sub-Saharan Africa.
The Mma Bana study was a randomised comparison of the virologic efficacy and PMTCT (prevention of mother-to-child transmission) efficacy of two antiretroviral regimens taken during pregnancy and breastfeeding by women with CD4 counts above 200 cells/mm3.
The investigators randomised 560 HIV-positive pregnant women with CD4 cell counts above 200 cells/mm3 to start one of two antiretroviral regimens between weeks 26 and 34 of pregnancy. This treatment was continued until weaning six months after giving birth.
Women in the first arm were provided with a combination of drugs that comprised the three nucleoside reverse transcriptase inhibitors (NRTIs) 3TC, abacavir and AZT, dosed as Trizivir. Nevirapine-based ART is unsuitable for women with CD4 counts above 250 cells/mm3 due to an increased risk of liver toxicity, so alternative regimens need to be identified to enable treatment in pregnancy to be extended to women with higher CD4 counts.
Women in the other arm were treated with the protease inhibitor lopinavir/ritonavir (Kaletra) in combination with 3TC and AZT (dosed as Combivir).
Also included in the study were 170 women with a CD4 cell count below 200 cells/mm3. In accordance with treatment guidelines at that time, to protect their own health they started a combination of anti-HIV drugs consisting of nevirapine with 3TC and AZT between weeks 18 and 34 of pregnancy.
All mothers received supplemental AZT (zidovudine) during labour.
Infants received single dose nevirapine after delivery and one month of treatment with AZT (zidovudine).
Women in the randomisation arms had median CD4 counts of approximately 400 cells/mm3, and were enrolled to the study around week 27 of their pregnancy. Median viral loads were relatively low in the randomisation arm; 13,300 and 9100 copies in the Trizivir and Kaletra arms respectively, with only 15% of women having a baseline viral load above 100,000 copies/ml.
In the observational group receiving nevirapine-based ART the median CD4 cell count was 147 cells/mm3 and the median viral load 51,000 copies/ml. Thirty-seven per cent had baseline viral load above 100,000 copies/ml.
There were two main study outcomes: the proportion of women with a viral load below 400 copies/ml at delivery and throughout breastfeeding at months 1, 3 and 6; and the rate of mother-to-child transmission of HIV assessed at birth and then months 1, 3 and 6 of feeding. Data were also gathered on adverse events, including still births and the number of babies born prematurely or with a low birth weight.
At the time of birth, equal proportions of women taking triple NRTI treatment (96%), protease inhibitor-based therapy (93%) and treatment that included nevirapine (94%) had a viral load below 400 copies/ml. The median duration of treatment was 11 weeks in the randomisation arm, and 13 weeks in the observational arm.
Moreover, similar proportions of women maintained viral suppression throughout breastfeeding, regardless of the HIV treatment they were taking (92% vs 93% vs 95%).
The cumulative rates of mother-to-child transmission of HIV were equally low in all three groups of women (2% in the triple NRTI arm vs below 0.4% in the Kaletra group and 0.6% in the nevirapine group). This difference was not statistically significant.
The very small number of transmissions in the study occurred almost entirely in utero, in women who had high baseline viral loads and shorter than average periods on ART prior to delivery, and in some cases, a history of self-reported adherence problems. Insufficient viral suppression is likely to explain these cases of transmission, and indicates the need for ART to be initiated promptly in pregnancy in order to achieve rapid viral suppression before delivery.
Only two transmissions occurred during the breastfeeding period, in one case from a mother who had viral load below 50 copies/ml at months 1 and 3 and no evidence of adherence problems.
There was no difference in the number of babies born with a low birth weight between the arms of the study, although babies born to mothers in the Kaletra arm were more likely to be premature (p = 0.04).
Furthermore, there was a comparable rate of still births amongst the women treated with three NRTIs (3%) and those receiving a protease inhibitor (2%). However, 7% of the babies of mothers taking nevirapine were still births.
Side-effects causing a change of treatment were recorded in 2% of women taking both the triple NRTI treatment or the protease inhibitor-based treatment. Nevirapine-based treatment was associated with a much higher rate of treatment changes, with 11% changing because of side-effects.
Approximately 75% of women breastfed for over five months. Nearly all infants had been weaned six months after birth. Infant mortality during breastfeeding was 2% amongst women who took triple NRTI treatment, 3% amongst those taking a protease inhibitor, and 4% amongst those who started nevirapine-based therapy because they had a low CD4 cell count.
The mother-to-child transmission rate in the Mma Bana study is the lowest yet seen in any randomised study of antiretroviral treatment during pregnancy and breastfeeding, and despite the higher rate of drug substitution in the nevirapine arm, shows that in mothers with higher viral load and low CD4 counts, nevirapine-based ART is remarkably effective in preventing mother-to-child transmission.
Reference
Shapiro R et al. A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child transmission among breastfeeding women in Botswana (The Mma Bana Study). 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeLLB101, 2009.
Further information
A webcast of the conference session in which this study was presented is available on the IAS 2009 website >here.
DREAM study: Extended prenatal ART protects against mother-to-child transmission of HIV at low and high CD4 levels
by Theo Smart
Antiretroviral therapy (ART) administered during pregnancy and breastfeeding reduces the risk of a woman transmitting HIV to her infant to just 2% by the time the child is six months of age – even without caesarean sections or formula feeding, according to a retrospective analysis of participants in the Drug Resource Enhancement against AIDS and Malnutrition (DREAM) programme in sub-Saharan Africa, presented this week at the International AIDS Society conference in Cape Town.
Without ART, even women with CD4 cell counts over 350 cells/mm3 were at high risk of transmitting the virus to their infants: “In our cohort, 37% of the transmissions that occurred were in this group with CD4 cell counts over 350,” said Professor Leonardo Palombi, of the University of Tor Vergata in Rome, who presented on behalf of the DREAM Programme.
But the benefit of ART was observed regardless of whether the mother had a low or high CD4 cell count when she went on treatment – and the longer that she was on treatment, the better. In fact, a shorter course of pre-delivery ART (less than 30 days) was strongly associated with HIV transmission and death at 1 month and between 1 and 6 months of age. Again, “this effect was also apparent in the women with higher CD4 cell counts,” said Prof. Palombi.
Going on ART during pregnancy was also associated with a dramatic reduction in adverse pregnancy outcomes, including a 70% reduction in the rates of spontaneous abortion and stillbirths, a 72% reduction in prematurity rates and a significant reduction in maternal mortality regardless of baseline CD4 cell counts. Toxicity was infrequent and mainly associated with AZT and d4T, even though there were concerns of nevirapine-related hypersensitivity in women with higher CD4 cell counts.
DREAM
The DREAM programme supports HIV care and treatment for around 75,000 adults and children in 10 countries within sub-Saharan Africa. Their approach to the prevention of mother-to-child transmission (PMTCT) is much closer to the norm in industrialised countries than the typical African PMTCT regimen (a short course of AZT monotherapy during late pregnancy, followed by single-dose nevirapine [sdNVP] as the woman goes into labour).
“In DREAM, we start as soon as possible and continue for at least six months while women are breastfeeding,” said Prof. Palombi. Women with CD4 cell counts below 350 cells/mm3 are deemed to need ART for their own health, and given nevirapine with either AZT/3TC or d4T/3TC as early as the 14th week of gestation and continuing for life (or treatment switch). Those with CD4 cell counts over 350 cells/mm3 are given the same regimen, starting from the 25th week of pregnancy, and continuing during breastfeeding and stopping after weaning (about six months after birth).
Since nevirapine has a long half-life, the women then continue to take a AZT/3TC ‘tail’ for three weeks to reduce the risk of becoming resistant to nevirapine. All infants are also given sdNVP within 72 hours of birth.
Participants in the programme also receive more intensive monitoring than is routinely available in their countries (with routine viral load, CD4 cell counts and toxicity monitoring).
Impact on vertical transmission
The retrospective analysis presented by Prof. Palombi involved a record review for 3148 live births among 3273 HIV-positive women enrolled in the programme in Malawi and Mozambique from July 2005 to December 2008.
Of the live births, at one month, 93 infants were lost to follow-up and seven had died (for a neonatal mortality rate of 0.23%) but 2994 infants were tested by bDNA (and testing was still pending for 54 at the time of analysis).
Out of the 2994 infants tested at one month, 22 have been confirmed as being HIV-positive (and five with positive results await confirmation), for an HIV transmission rate of 0.7%.
At month 6, 2120 of the children who were HIV negative at month 1 were again tested (another 642 are waiting to be tested, while between month 1 and 6, 143 have been lost to follow-up and 41 have died (for a 1-6 month mortality rate of 1.9%). At this timepoint, 15 more children have been confirmed to be positive, and 5 are waiting to be confirmed as positive.
The cumulative transmission rate at 6 months is between 1.4 and 1.9%, the cumulative mortality rate at 6 months is 2.1% and the loss to follow-up rate at six months is 7.5%. These are rates as low as typically reported in well-resourced countries – but again, these are breastfeeding women who would be more likely to transmit HIV if not on treatment.
Benefit associated with time on ART
Because of factors such as late diagnosis and presentation, not every women started treatment as per protocol. This enabled the researchers to detect an association between outcomes and length of time on ART.
At one month, there was a 0.9% transmission rate for infants whose mothers had received at least one dose of ART before delivery (these women had a viral load of 3.55 log) but a 5.1% transmission rate among infants whose mothers waited until delivery to begin ART (with a viral load of 4.51 log, p = 0.001). The one-month HIV-free survival rate for infants was 97.6%.
When infant outcomes were stratified according to maternal baseline CD4 level, pre-delivery ART use appeared to have an impact regardless of whether mothers had low or high CD4 cell counts. Among 1388 children of women whose baseline CD4 levels were below 350 cells/mm3, there was a 1.3% rate of HIV transmission or death with 30-plus days of maternal ART use (16 of 1231 infants) versus a 3.8% rate when maternal ART was used for 30 days or less (six of 157 infants) (odds ratio [OR] 0.33, confidence interval [CI] 0.12-0.86). Among 1533 children of women whose baseline CD4 levels were 350 cells/mm3 or higher, there was a 0.7% rate of either HIV transmission or death with 30-plus days of maternal ART use and a 2.0% rate with a shorter duration of maternal ART use (OR 0.33, CI 0.10-1.09).
In multivariate analysis, 30 days or less of pre-delivery ART was found to be associated with either infant death or HIV transmission at one month postpartum after adjusting for baseline viral load, CD4 cell count, haemoglobin and body mass index.
During the period of breastfeeding – between 1 to 6 months – the association between the length of time on ART pre-delivery was significantly associated with both HIV transmission on its own and the combined endpoint of transmission and death – again, this was apparent in both CD4 cell strata, but most pronounced in the women with lower CD4 cell counts.
Among the 990 children of women whose baseline CD4 levels were below 350 cells/mm3 who were tested for HIV at month 6, there was a 3.1% rate of HIV transmission or death with 30-plus days of maternal ART use (27 of 876 infants) but an 8.8% rate when maternal ART was used for 30 days or less (10 of 114 infants) (OR 0.33, CI 0.16-0.70).
Among 1105 children of women whose baseline CD4 levels were 350 cells/mm3 or higher, there was a 1.8% rate of either HIV transmission or death with 30-plus days of maternal ART use and a 2.1% rate with a shorter duration of maternal ART use (OR 0.81, CI 0.24-2.83).
In a multivariate analysis, both baseline maternal viral load and receiving 30 days or less of pre-delivery ART were found to be associated with either infant death or HIV transmission at 1-6 months postpartum after adjustments.
The six-month estimated HIV-free survival for the children of women who received less than 30 days of ART was 90.9%, while it was 96% in those who received extended therapy.
Finally, “the infant mortality rate and other parameters of infant health (such as birth weight, weight for age) were also positively affected by the approach,” said Prof. Palombi. “Breastfeeding under ART is a safe, feasible and acceptable choice in resource-limited settings where the health risks associated with no breastfeeding are extremely high.”
ART results in favourable pregnancy outcomes
The DREAM researchers also looked pregnancy outcomes (such as spontaneous abortion, stillbirth and prematurity), maternal mortality, toxicity and resistance to ARVs to determine how the approach impacted on the mother’s health.
Out of the 3273 pregnancies in the cohort, 42 died, for a maternal mortality rate of 1.2%. 3.1% of the pregnancies ended in stillbirth, 2.1% were spontaneous abortions (9 of these coincided with the mother’s death), and 19.1% of the infants were premature.
Of the entire cohort, 68 women received no ART, and 365 received less than 30 days of ART – and again, there were clear differences in outcomes. While only 5.2% of those on ART for more than 90 days had stillbirths, the rate was 26.5% in women who received no ART, and 7.1% in those who received ART for less than 30 days. The rate of stillbirth and abortion in those who received less than 30 days of ART was higher regardless of the CD4 cell count but those with CD4 cell counts below 200 cells/mm3 were most likely to have poor outcomes. Likewise, prematurity was strongly associated with shorter duration of ART – regardless of CD4 cell strata. And although the numbers were rather small, maternal mortality followed the same pattern.
ART-related adverse reactions were rather uncommon. Grade 3/4 anaemia was reported in 8.6% of subjects. Likewise, d4T-related peripheral neuropathy was observed in 6.9% of subjects – mostly after pregnancy. Nevirapine-related toxicity was less common. Grade 3/4 liver toxicity was observed in only 2.2% (one patient's LFT increased more than 5 times the upper limit of normal within six weeks of ART). There were 39 cases of Stevens-Johnson Syndrome (1.2%), while grade 3/4 rash was reported in 2.4% of the subjects.
Finally, no viral resistance has been detected among a substudy of 26 women who discontinued ART after weaning.
Limitations
Prof Palombi conceded that as a retrospective study, there is a potential for selection bias. Some in the audience pointed out that the better outcomes seen in the women who accessed ART earlier might simply be due to better access to care. However, Prof. Palombi doesn’t think this is likely – the various benefits are too consistently associated with longer ART across CD4 strata.
References
Marazzi MC et al. Extended use of highly active antiretroviral therapy (HAART) during pregnancy in Southern Africa is highly protective in HIV-1 prevention of mother-to-child-transmission (PMTCT) also in women with higher CD4 cell counts. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract TUC101, 2009.
Increased risk of HIV transmission in serodiscordant couples wishing to conceive
by Lesley Odendal
Harm reduction interventions to avoid HIV transmission in heterosexual, serodiscordant couples who wish to have children are urgently needed, according to Dr Sara Brubaker, from Kenya, as reported at the Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town.
A study conducted in Kisumu, Kenya, found that HIV-serodiscordant couples, where one partner is HIV-infected and the other is not, continue to conceive despite knowledge of their serostatus. In this cohort, couples who conceived were at 80% increased risk of HIV transmission between the partners.
A large proportion of new HIV infections in sub-Saharan Africa occur in stable heterosexual partnerships.The Kenya AIDS Indicator Survey of 2007 showed that half of HIV-infected Kenyans have partners who are HIV-uninfected.
Prevention efforts have focused on couples-based HIV testing. Although couples studies in central Africa have shown that condom use increases when couples learn about their discordant status, these same studies had shown that 20 to 43% of couples continue to have unprotected intercourse despite knowledge of their serostatus. This behaviour is often motivated by the desire to have children.
A systematic review of factors influencing fertility desires in HIV-infected people showed the factors that positively influence the desire and intention to have children are young age, having few or no previous children and having access to antiretroviral treatment (ART).
Five hundred and thirty-two heterosexual HIV-serodiscordant couples were enrolled in the study. Forty-one (7.6%) of the HIV-uninfected partners seroconverted, at a rate of 4.6 per 100 person years. In 328 (61.7%) of the couples, the female was HIV-infected, compared to 204 (38.3%) where the male was HIV-infected. 95.3% of study participants were married to their partner.
There were 373 pregnancies during the study period (this number included men if their partner conceived) compared to 698 individuals who did not become pregnant.
A comparison of those who conceived and those who did not showed that 10.8% of individuals who conceived or whose partner conceived aquired HIV, compared to only 5.9% in those where no pregnancy occurred.
The relative risk of a partner aquiring HIV was 1.8 times greater in serodiscordant couples where pregnancy did not occur than in those where pregnancy did occur.
Individuals who conceived were significantly younger with a median age of 27 compared to 34 in those who did not become pregnant (p<0.01).
The study investigators could not assess intentionality or if the pregnancies were unplanned. Researchers suggested that rather than people acquiring HIV while attempting to become pregnant, they may acquire HIV because of possible increased susceptibility to HIV due to pregnancy.
An analysis of timing of pregnancy in relation to seroconversion showed that approximately 30% of seroconversions occurred six months before conception, 35% in the six months after conception and the remaining 35% were remote from conception.
A second study in Kenya, carried out among a cohort of 296 stable, HIV-discordant couples at Kenyatta National Hospital in Nairobi, already participating in a study of immune responses in exposed but uninfected partners, found a one-year cumulative pregnancy rate of 10.5%, with no difference in pregnancy rates between HIV-positive and uninfected women. This study did not evaluate HIV incidence.
The study found a particularly high rate of pregnancy in women below the age of 30 who wanted children: after 500 days of follow-up, 30% of this group had become pregnant, compared with fewer than 5% of women under 30 who did not want children. Women in the earlier stages of relationships were significantly more likely to become pregnant, with the incidence of pregnancy falling by 16% for each year the couple had been together by the time of recruitment to the study.
Implications for service delivery
Despite being unable to assess intentionality for pregnancy in the first cohort, if a portion of these pregnancies were intentional, these couples were risking HIV transmission in order to conceive. In high-income settings there are high-tech interventions such as sperm washing available that make conception for serodiscordant couples safe. However, even in free-at-the-point-of-care health systems like the United Kingdom, assisted conception procedures like sperm washing are charged for.
Antiretroviral treatment may also reduce the risk of transmission when it is fully suppressive, and some clinics, particularly in Switzerland and the United Kingdom, have already begun counselling couples about how to time unprotected intercourse in order to maximise the potential for conception once undetectable viral load has been achieved on treatment.They may also offer antiretroviral drugs to the uninfected partner as pre- and post-exposure prophylaxis, an approach to managing conception that would be feasible and affordable in settings where it is possible to measure viral load and provide results promptly.
Interventions and public health campaigns addressing the desire to have children in serodiscordant couples need to be designed and implemented in low-income settings in order to address this issue. As researchers from the University of Washington and Kenyatta National Hospital norte, it is not enough to say “avoid unprotected sex”.
References
Nattabi B et al. A systematic review of factors influencing fertility desires and intentions among people living with HIV/AIDS: implications for policy and service delivery. AIDS Behaviour, DOI 10.1007/s10461-00909537-y, March 2009.
Brubaker S et al. Pregnancy and HIV transmission among HIV discordant couples in a clinical trial in Kisumu. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract WELBC105, 2009.
Guthrie BL et al. Predicting pregnancy among HIV-1 discordant couples. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract LBPEC08, 2009.
Further information
A powerpoint presentation by Sara Brubaker and a webcast of the conference session in which it was presented are available on the IAS 2009 website here.