Benefits of adding 4 or 7 days of AZT/3TC to single-dose nevirapine to prevent MTCT: further analysis from TOPS
14 September 2005. Related: Conference reports, Pregnancy, IAS 3rd Rio de Janeiro 2005.
Polly Clayden, HIV i-Base
James McIntyre from the Perinatal HIV Research Unit, Johannesburg, presented further analyses from the Treatment Options Preservation Study (TOPS). This is a randomised three-arm trial in which either 4 or 7 days of Combivir were added to the single dose nevirapine received by pregnant women (and the infants received single dose nevirapine or single dose nevirapine plus 4 or 7 days AZT/3TC syrups). We have reported earlier results of this important study in previous issues of HTB. [1, 2, 3]
The single dose nevirapine only arm (sd) closed after preliminary analysis showed significantly higher rate of resistance in this group. Dr McIntyre presented 6-week follow up data on all mothers (n=226) and infants (n=228) enrolled in the study at the time of single dose arm closure.
A total of 203 mothers were included in the resistance analysis; 68, 67 and 68 in the nevirapine only (sd), nevirapine plus 4 days Combivir (sd+4) and nevirapine plus 7 days Combivir (sd+7) respectively). The mothers median age was 27 years and 99.6% were black, 25.2% women had Caesarean sections and 24% received single dose nevirapine <2hrs before delivery. Median CD4 count and viral load was 314 cells/mm3 and 4.49 log10 copies/mL, respectively. 3/226 mothers had detectable NNRTI-associated mutations at baseline.
Six weeks after treatment, mutations were found in 41/68 (60%), 8/67 (12%) and 7/68 (10%) of mothers in the sd, sd+4 and sd+7 arms respectively.
The presentation included viral load data. The median baseline/nadir viral loads of the mothers were: 23,200/8,300 copies/mL, 24,700/<400 copies/mL, and 35,000/436 copies/mL in sd, sd+4 and sd+7 arms respectively. Dr McIntyre suggested that this might answer the question: Why is short course Combivir working?
Median baseline and nadir viral loads for women receiving single dose nevirapine were 10,600/4,460 copies/ml and 43,650/16,600 copies/ml for mothers with wild type and emergent resistance respectively. The median baseline and nadir viral loads overall were 23,200/8,300 copies/ml.
Infant resistance data was also presented and a poster from Glenda Gray and co-workers looked at infant resistance in more detail. [3]
The overall transmission rate at 6 weeks was 10.5% (24/228). In utero transmission occurred in 9.2% (21/228) and 3 infants (1.3%) were infected at 6 weeks. NNRTI resistance was only found in infants infected in utero. Two infants had detectable resistance at birth 1/6 in the single dose nevirapine and 1/7 in the nevirapine plus 4 days maternal Combivir arms.
The addition of AZT/3TC decreased the emergence of new resistance mutations to zero in both the 4 or 7 days arms while 66.7% (6/9) had resistance in the single dose nevirapine arm. There was no evidence of transmission of NNRTI-resistant virus. Three infants with mutations were born to mothers with no NNRTI mutations. None of the mother-infant pairs with mutations had identical resistance patterns.
The investigators concluded that the rate of detectable maternal resistance is reduced from 60% for single dose nevirapine to 12% and 10% by 4 and 7 days of Combivir respectively (p=0.0001).
Additionally, Single dose nevirapine and 4 to 7 days of Combivir can produce a transient reduction of plasma HIV-1 to <400 copies/ml and avoid 80% of the emergence of NNRTI resistance in mothers seen with single dose nevirapine.
Furthermore the addition of AZT/3TC to single dose nevirapine resulted in substantial reduction in new NNRTI associated mutations in HIV-1 infected infants.
Impact on response to subsequent HAART?
Following a presentation in which single dose nevirapine exposure or non-exposure was reported to make no difference to immunological response in women receiving nevirapine containing HAART, Dr McIntyre suggested that this may be explained by the addition of AZT and 3TC in 66/115 (57.45%) of the women studied [5].
This study conducted in Abidjan, Cote dIvoire enrolled 209 women between August 2003 and February 2005, 115 women had previously received nevirapine as MTCT prophylaxis, 49 received AZT in addition and 66 had received nevirapine in combination with AZT and 3TC.
The investigators reported that the majority of women initiated therapy with an NNRTI-containing regimen and that 97% of women received a nevirapine-containing regimen. The median delay for women who had received nevirapine prophylaxis prior to HAART initiation was 17 months.
At six months follow up the median increase in CD4 for the 176 women for whom those data were available was 229 cells/mm and there was no significant difference between the group that had received nevirapine (n=97) and those that had not (n=79). For the 42 women for whom 12-month data were available (15 and 27 in the nevirapine exposed and non exposed arms respectively) the median CD4 increase was also similar.
Although these preliminary data report a similar response following nevirapine exposure and non-exposure, these findings were hard to interpret. There were no viral load or resistance data and it was unclear whether the results were due as Dr McIntyre suggested – to more complex MTCT interventions than single dose nevirapine alone.
Comment
In the Abidjan study, the mothers who had received AZT/3TC antenatally also has 3 days postpartum AZT/3TC; it may be that this postpartum tail cover is reducing resistance, and therefore it is difficult to see how generalisable these data are. The same group reported just over 1% NNRTI resistance in the AZT/3TC plus single dose nevirapine treated women at CROI [6], compared to 28% in their historical comparison in women who received antenatal AZT plus IP/PP nevirapine with no AZT/3TC postpartum cover.
Good news is that the draft WHO MTCT guidelines include a seven day regimen of AZT/3TC postpartum to be considered in appropriate circumstances to reduce the emergence of nevirapine resistance in mothers.
References:
- McIntyre JA, Martinson N, Gray GE et al. Addition of short course Combivir to single dose Viramune for the prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and paediatric NNRTI-resistant virus. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract TuFoO2O4.
http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2176901 - Clayden P. Adding Combivir to single dose nevirapine for reduction of MTCT significantly reduces resistance. HTB. Volume 5. August/September 2004. Number 7/8. Pp12-14.
https://i-base.info/htb/8996 - Clayden P. Resistance during MTCT strategies: new data on protective benefit of Combivir added to single dose nevirapine, and impact of treatment and breastfeeding on the infant. HTB Volume 6. July 2005. Number 7. Pp 5-8.
https://i-base.info/htb/7240 - Gray G, McIntyre J, Hopely M et al. NNRTI-resistant mutations in HIV-1 infected infants following single dose nevirapine are reduced by the addition of short course zidovudine and 3TC. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract TuPe54P01.
http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2177421 - Bedikou G, Viho I, Towne-Gold B et al. Six month immunological response with HAART containing nevirapine in HIV-infected women post exposure to single dose of nevirapine for PMTCT. The MTCT Plus Initiative in Abidjan, Cote DIvoire (2003-2005). 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract MoOa0203.
http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2177559 - Chaix ML, Dabis F, Ekouevi D et al. Addition of 3 days of ZDV/3TC postpartum to a short dose of ZDV+3TC and single dose nevirapine provides low rate of NVP resistance mutations and high efficacy in preventing peri-partum HIV-1 transmission: ANRS DITRAME Plus Abidjan, Cote DIvoire. 12th CROI, Boston, 2005. Abstract 72LB.
http://www.aegis.com/conferences/croi/2005/72LB.html