Pregnancy: growing body of evidence supports treating maternal disease

10 April 2002. Related: Conference reports, Pregnancy, CROI 9th (Retrovirus) 2002.

Polly Clayden, HIV i-Base

The 9th CROI provided an impressive volume of research into maternal/child health and managing pregnancy and mother to child transmission (MTCT) across a diverse range of access levels and resources (we will also include reports on paediatrics and women-specific research in the next issue of HTB).

For those living in countries with access to treatment, the body of data continues to grow supporting the treatment of maternal disease, appropriately with fully suppressive therapy, to offer the best outcome to mother and baby.

As part of a symposium entitled ‘Controversies in Antiretroviral Therapy’, Judith Currier gave an overview of the state-of the-art ‘Challenges to managing antiretroviral therapy during pregnancy’ [1]. She began by reminding us that HIV continues to have a major impact on women of childbearing age worldwide, and explained that the “need to treat a woman for her HIV infection both in the short term and over the course of her lifetime, must be balanced with the goals of preventing infection”. Globally however only a small fraction of women with HIV have access to treatment and the primary use of antiretrovirals in settings where they are available has been for prevention of transmission and not for maternal benefit. Dr Catherine Wilfert from the Elizabeth Glaser Pediatric AIDS Foundation made this the subject of her plenary talk in which she outlined the programmes that this organisation have sponsored in Africa [2]. She spoke encouragingly of the work emphasising that prevention of MTCT should be the “…gateway to international care and support to entire families” and that “health of mothers needs to be optimal to enhance their lives and provide the best care for their children.”

Dr Currier also stressed that efforts to expand access to triple therapy must include provision of this treatment to pregnant women worldwide. Within settings with access to antiretrovirals she summarised the goals of care as: an uncomplicated pregnancy, a healthy uninfected baby and a healthy mother who has not compromised her future treatments for the management of her own disease.

Antiretroviral use during pregnancy

Enormous progress has been made since reduction of transmission from 25% to 8.3% using ZDV monotherapy prophylaxis and caesarean section was demonstrated in the 1994 076 trial [3]. Today since the introduction of potent HAART this rate has dropped to less than 2% [4, 5].

Two posters evaluated the pharmacokinetics of protease inhibitors used in pregnancy. Scott and colleagues from the PACTG 354 team looked at ritonavir in combination with ZDV and 3TC [6]. They found a dose of 600mg BID to provide therapeutic maternal levels at delivery but the drug was poorly tolerated and this would certainly be an unlikely combination to use in real life clinical practice.

Bryson and colleagues studied the PK of nelfinavir in combination with ZDV and 3TC. This drug has been used quite widely in pregnancy [7]. Anecdotally it appears that the gastrointestinal changes that occur in pregnant women may make this drug more tolerable as far as nelfinavir-induced diarrhoea is concerned, compared to non-pregnant patients [8]. The investigators reported that a dose of 750mg TID failed to reach optimal levels (only 3/9 women achieved the target AUC), and that a dose of 1250 BID met target AUC in 14/17 women. They also reported suboptimal levels in 5/18 (28%) of infants at a 40mg/kg BID dose.

The importance of reporting any adverse events associated with antiretroviral use was stressed in a presentation from Dr Markus describing the FDA’s Adverse Event Reporting System (AERS) [9]. Following a report to the FDA from BMS in November 2000 of two maternal and one infant death due to lactic acidosis that occurred during a clinical trial in which both patients were receiving ddI and d4T, the AERS database was searched for maternal adverse events. 10 reports of any maternal drug toxicity were found, of which two cases of lipodystrophy were excluded. 7/8 cases of lactic acidosis had received d4T and ddI and 1/8 received d4T and 3TC. There were three maternal and three infant deaths. All cases occurred after 32 weeks of pregnancy and the duration of ARV use was approximately five to eight months. This led to labelling changes for both d4T and ddI recommending that this combination only be used if the benefits clearly outweigh the maternal risks, and a ‘Dear Healthcare Provider’ letter was sent.

In addition Dr Currier also included a description of the Antiretroviral Pregnancy register focusing on an analysis assessing the teratogenic potential of antiretroviral drugs [10]. These data did not indicate an increase risk of birth defects with exposure to ARV overall or for the first trimester ZDV or 3TC exposures. Both presentations emphasise the continual critical importance of reporting exposure to antiretrovirals during pregnancy and the outcomes.

C-section – controversy still rages

Two reports from this meeting looked at mode of delivery. Dr Patel and colleagues examined the ‘Role of combination antiretroviral therapy and mode of delivery in perinatal HIV transmission’ for the Pediatric Spectrum of Disease Project in the US from 1995 to 2000 [11]. This large study collected prospectively data from 6274 HIV-exposed infants (amongst which HIV status was known for 5009) in six areas of the US.

They reported that in 1998 the number of elected caesarean section (ECS) deliveries began to increase as results from studies showing benefit in reducing MTCT were presented for women receiving either no antiretrovirals or ZDV monotherapy. They assessed the added benefit of C-section for women receiving combination therapy. During the study period there were significant increases in both interventions: 1.3% to 65.5% in use of combination therapy and 18.9% to 46.8% increase in C-section.

Overall the rate of MTCT was found to be lower in those receiving combination therapy than monotherapy, 4.9% and 9.4% (p<0.001). In addition the rate of transmission was lower with C-section than vaginal delivery, 13.0% vs 15.9% (p=0.676). With vaginal delivery the rate of transmission was lower in those receiving combination therapy than monotherapy, 5.5% vs 9.6% (p=0.015). The rates of transmission with C-section or vaginal delivery were similar in women receiving combination therapy ie 4.5% vs 5.5% (p=0.676). They also reported no significant benefit from C-section for women receiving no antiretroviral therapy but these data do not indicate whether these interventions were scheduled before onset of ruptured membranes and labour.

The investigators concluded that from this database that “…no additional benefits of caesarean section in women were noted in reducing transmission risk’. They also noted that further analyses are needed to better understand the role of maternal viral load, CD4+ T cell count and indication for C-section.

In addition, in an oral presentation, Dr Shapiro from Harvard presented data from PACTG 367, which analysed transmission rates from 2087 pregnancies according to antiretroviral therapy, mode of delivery and viral load [12]. In this study data from 67 US clinical sites resulting in live births between January 1998 and August 2000 were reviewed, from which 76 babies were HIV positive giving an overall transmission rate of 3.6% (95% CI [2.9%-4.5%]).

Dr Shapiro reported a reduction in transmission rate during the study period from 4.3% in 1998 to 1.6% in 2000 (p=0.03), during which time the use of multi-agent therapy in the third trimester and ECS both rose (from 76% in 1998 to 86% in 2000; p<0.001 and from 12% in 1998 to 29% in 2000; p<0.001 respectively). He also reported that with use of multi-agents the association with mode of delivery was “weaker”.

This observation provoked the comment from Dr Karen Beckerman from San Francisco General, that she was, “…glad that you concluded that the association with mode of delivery is “weaker” whereas I would conclude that it is absent”, and continued by emphasising the importance of counselling women to take care of their own disease as this will also have the most significant impact on their babies’ outcome. However, in the written abstract the authors conclude that “Over time, transmission rates decreased and multi-agent use and ECS increased. Transmission rates were significantly lower with more intensive ART and lower plasma HIV RNA level, but did not differ according to delivery mode…” In her overview Judith Currier also reminded us that, “clearly there is morbidity associated with this procedure”. Use of C-section remains controversial and as long as transmission rates remain as low as 2% or less, as has been demonstrated with appropriate use of complex therapy, it is unlikely that data to demonstrate either maternal or neonatal benefit with this procedure within this setting will be generated.

Rousseau C, Richardson B, Steele M et al. Breastmilk HIV-1 viral load is associated with viral load in other compartments, host genotype and perinatal transmission. Abstract 792-w. 9th CROI

Resistance

Two further reports from the HIVNet 012 (012) study were presented at this meeting. Previous results from this study performed in Uganda demonstrated that an intrapartum and postpartum single dose of nevirapine given to the mother and infant respectively, significantly reduced the rate of MTCT and was more effective than a short course ZDV regimen [13]. In an oral presentation Mary Glenn Fowler described transmission rates from a subgroup of 583 women stratified by their high viral loads (>50, 000 RNA copies/mL) and low CD4 (<200) [14].

Although this analysis demonstrated significantly lower transmission rates among women receiving nevirapine than those receiving ZDV (24.9% vs 44.6%), and the investigators concluded that “these data support the efficacy of the simple NVP 2-dose peripartum regimen even among the women with the most advanced HIV disease.” However, these transmission rates are still rather alarming. This analysis did not include any resistance data for this high viral load group. Previous studies have shown that this strategy rapidly selected for nevirapine mutations, which was somewhat sobering after the original excitement that this trial generated. Several of us were poised to comment on this as the question time ran out. There remain huge concerns about the risk of using nevirapine monotherapy in this setting particularly for someone with very advanced disease.

A second report combined data from the 012 and HIVNet 023 to characterise the effect of single dose nevirapine on MTCT and on the selection for resistance in women infected with HIV-1 subtype C, n=36 (the majority of women in 012 were subtype A or D) [15]. HIVNet 023 is a phase I/II study conducted in South Africa and Zimbabwe — where C is the predominant subtype, which evaluates the safety and plasma concentrations of various prophylaxis dosing regimens given to breastfeeding infants. As part of the protocol, women found to be HIV positive at screening were offered the 012 regimen for prevention of MTCT.

At 24 weeks 31/121 (36%) of the infants were infected by MTCT across all subtypes and the investigators report no difference between subtypes in rates of transmission. Nevirapine mutations were present at 8 weeks in 27/121 (22%) of the women studied and higher rates of mutations were detected in subtype C 10/36 (28%) and D 11/37 (30%) compared to subtype A 6/48 (13%). Patterns of resistance were similar between groups; viral load and CD4 stratifications were not included in the analysis. The investigators concluded that different selections of resistance between subtypes ‘…could potentially limit the use of nevirapine or other NNRTIs for treatment of HIV-1 infection in certain circumstances and may have implications on therapy selection.’

In addition resistance data was reported from the PETRA study performed in South Africa, Tanzania and Uganda, which investigated different ZDV/3TC regimens [16]. Early analysis at 6 weeks showed that arm A reduced transmission by 50% and arm B by 37%.

PETRA Study design:

Women from arms A and B were studied from one participating site. 64 (32 from each treatment arm) samples were collected from mothers at one week, 82% were sequenced. In 2/24 (8.3%) of samples from women in arm A the M184V mutation was detected one week after delivery. In both cases this mutation was not detected at enrolment and disappeared after three months. In one further sample the M41L was detected at week one and was still present after three months. No NRTI mutations were detected in samples from arm B or in the infected infants.

Rapid testing

Although almost no one would dispute the paramount importance of antenatal care in an ideal setting, many women present in early stages of labour with their HIV status unknown. Two studies evaluated rapid HIV-1 testing presenting in early stages of labour in different settings. A study from Santos and colleagues in Brazil analysed the first 1729 rapid tests using the Determine test from Abbott Laboratories for determining HIV1/2 antibodies in plasma [17]. They looked at sensitivity, specificity, positive predictive value, negative predictive value and acceptability of the test.

All but one woman (0.6%) offered testing accepted and 61 (3.5%) tests were positive. In addition there were two (0.1%) false positives, one indeterminate and no false negatives. The sensitivity of the rapid test was 100%; specificity 99%; positive predictive value 99.3% and negative predictive value 100%. They also report a high rate of acceptance by pregnant women unaware of their HIV status in their cohort. Based on their findings the investigators also reported that they felt confirmatory tests for those who test negative according to this assay to be unnecessary due to the high negative predictive value. Despite these encouraging findings for the accuracy of the test, they also stressed that “Patients would benefit most if HIV testing occurred during antenatal care, when a better pre and post test counselling can be done in a much more caring environment.”

The second study, performed in Lima, Peru also evaluated the Abbott Determine and in addition a saliva test called OraQuick from Orasure [18]. 3,543 women were tested and from this group 26 (0.7%) had positive results and two (0.06%) were invalid using the Determine assay. Using the OraQuick saliva test the results were 26 (0.7%) positive and five (0.14%) invalid. The combined results were – 25 positive using both assays, one positive saliva/negative blood and one positive blood/invalid saliva.

This study also looked at the women’s opinion as to the acceptability of these tests. They report that with the Determine, 0.7% felt the test caused a lot of pain, 94% a little and 4.4% none. With the OraQuick, 0.1% reported a lot of discomfort, 2.1% a little and 97% no discomfort. Overall 33% found the saliva test more comfortable, 66% felt it made no difference, 0.6% preferred the blood test and 0.1% found neither acceptable. Overall the investigators concluded that “While HIV counselling and testing at the beginning of pregnancy is preferable, rapid testing in labour is feasible and allows for intervention prior to delivery to prevent maternal child HIV transmission.”

Breast milk

Breastfeeding increases the risk of mother to child transmission by approximately 14%. Therefore understanding the mechanism of breastfeeding transmission is important in the establishment of effective interventions to prevent postpartum MTCT.

Since CTL responses have been shown to have a role in controlling HIV levels in peripheral blood, in an oral abstract, Dr Sabbaj from the University of Alabama presented findings from a study in which it was sought to determine the presence of CD8+ T cells in breast milk from HIV positive women [19].

Colostrum was obtained from five HIV positive and four HIV negative women. Breast milk cells (BMC) were stimulated with clade B peptides spanning gag, pol, nef and env and they used responses to tetanus toxoid (TT), CMV and PHA as positive controls. All women in the study were reported as having strong responses to PHA and the HIV negative women had responses to CMV but not to any of the HIV peptides. All five of the HIV positive women had responses to gag, four to pol, three to nef and two to env.

This is the first study to demonstrate HIV-specific MHC class 1 restricted CD8+ T cell responses to HIV antigens in breast milk from HIV positive women and to show antigen-specific CD8+ T cell response. The investigators noted that “Their presence suggests that they play a role in limiting transmission and provide a rationale for vaccine studies enhancing these responses.”

Christine Rousseau and colleagues from the Fred Hutchinson Cancer Research Centre reported findings from a study conducted in Nairobi where almost 50% of cases of vertical transmission are attributed to breastfeeding [20].

Analysis of 648 samples from 273 women (collected at birth, six weeks, 14 weeks, and at three month intervals for up to two years) found increased breast milk viral load levels to be associated with frequency of MTCT through feeding. They also found breast milk viral load to correlate with that in plasma and the genital tract.

They observed that the range of breast milk viral load among those that transmitted was similar to those that did not, indicating that, as with maternal plasma viral load, there is no low level at which transmission never occurs. This, they report, demonstrates that there are other factors involved such as protective maternal antibodies, viral factors and/or host genetic factors.

In addition they reported that the “…SDFI 3’A allele is shown to be associated with increased breast milk viral levels, indicating that the allele might have an effect on viral replication in breast milk, providing a potential explanation for the increased risk of late transmission” (more than two months after delivery).

Conclusion

This conference provided further insights into the treatment of maternal health and the prevention of mother to child transmission. But as emphasised at the start of this article – programmes for access to HAART worldwide must also include pregnant women. No amount of mother to child transmission data alone will tackle the continuing global increase of orphans.

References:

1. Currier JS. Challenges to managing antiretroviral therapy during pregnancy. Abstract.S19. 9th CROI.
2. Wilfert CM. Prevention of mother-to-child-transmission: Implementation, programs and treatment of mothers and children. Abstract.S26. 9th CROI
3. Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. PACTG 076. N Engl J Med 1994; 1173-1180
4. Blattner WA, Cooper E, Charurat M et al. Effectiveness of potent antiretroviral therapies on reducing perinatal transmission of HIV-1. Abstract LBOr4. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa
5. Beckerman KP, Shannon M et al. The impact of combination antiretroviral therapy on maternal health and pregnancy outcome [Abstract MoPeB2198]. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa
6. Scott G, Rodman J, Scott W et al. Pharmacokinetic and virologic response to ritonavir in combination with zidovudine and Lamivudine in HIV-1 infected pregnant women and their infants. Abstract 794-w 9th CROI
7. Bryson Y, Stek A, Mirochnick M et al. Pharamacokinetics, antiviral activity and safety of nelfinavir with ZDV/3TC in pregnant HIV-infected women and their infants. Abstract 795-w. 9th CROI
8. Beckerman KP. Principles of management of HIV disease during pregnancy. Topics in HIV Med 2000 vol8, issue 7,18-25
9. Marcus K, Truffa M, Boxwell D. Cases from the FDA’s adverse event reporting system (AERS). Abstract LB 14 9th CROI
10. Garcia P, Beckerman KP, Watts HW et al. Assessing the teratogenic potential of antiretroviral drugs. Abstract 1325, ICAAC, Dec 2001
11. Patel J, Melville S, Heath C et al. Role of combination antiretroviral therapy and mode of delivery in perinatal HIV transmission. Abstract 798-w 9th CROI
12. Shapiro D, Tuomala R, Samelson R et al. Mother-to-child HIV transmission rates according to antiretroviral therapy, mode of delivery and viral load. Abstract 114 9th CROI
13. Jackson JB, Mracna M, Guay L et al. Selection of nevirapine resistance mutations in Ugandan women and infants receiving NVP prophalaxis to prevent HIV-1 vertical transmission. Abstract LBOr 13. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa
14. Fowler MG, Mwatha A, Guay L et al. Effect of nevirapine for perinatal HIV prevention appears greatest among women with most advanced disease. Abstract 120. 9th CROI
15. Kantor R, Lloyd R, Shafer R et al. Comparison of mother-to-child- transmission and genotypic resistance in HIV-1 subtypes A,C and D after single dose nevirapine in Africa. Abstract 801-w 9th CROI
16. GiulianoM, Galluzzo T, Amici R et al. Selection of resistance mutations in pregnant women receiving short-course antiretroviral regimens with ZDV and 3TC to prevent perinatal transmission. Abstract 802-w 9th CROI
17. Santos BR, Canti IT, Guerin YLS et al. Evaluation of an anti-HIV rapid test (Determine/Abbott) offered to pregnant women not tested before delivery in a large public hospital in Porto Alegre, Brazil. Abstract 788-w 9th CROI
18. Melvin AJ, Alarcon J, Velasquez C et al. Rapid HIV-1 testing of pregnant women presenting in labour with unknown HIV status in Lima, Peru. Abstract 789-w 9th CROI
19. Sabbaj S, Edwards B, Ghosh M et al HIV-specific CD8+ T cells are present at a high frequency in breast milk from HIV-infected women. Abstract 117 9th CROI