Response to nevirapine containing HAART following single dose nevirapine for PMTCT

5 February 2007. Related: Pregnancy.

Polly Clayden, HIV i-Base

A post hoc analysis from the Mashi study in Botswana [1,2] looked at response to nevirapine-containing antiretroviral treatment among women and infants who had previously been randomised to receive a single dose of nevirapine or placebo as part of a PMTCT strategy [3]. All women also received AZT from 34 weeks of gestation.

The primary end point for mothers and infants was virologic failure by 6-months from initiation of antiretroviral treatment.

A group of 218 women who had started antiretroviral treatment (112 had previously received a single dose of nevirapine and 106 had received placebo) were included in the analysis.

Sixty women began antiretroviral treatment within 6 months post partum and 158 women 6 months or more post partum. Viral load results at 12 months (limit of detection <400 copies/mm³) were available for 94 women in the nevirapine group (87.0%) and 88 women in the placebo group.

The investigators found that by the 6-month visit after the initiation of treatment, 5 (5.0%) of the women who had received placebo had virologic failure compared to 20 (18.4%) of those who had received a single dose of nevirapine (p= 0.002). Higher rates of failure were also observed: 9 (9.6%) vs 21 (19.7%) women, p=0.04 and 10 (11.3%) vs 25 (27.9%), p=0.008, receiving placebo vs nevirapine, at 12 and 24 months respectively.

They reported an interaction between exposure to single dose nevirapine or placebo and time to initiation of treatment. Of the 60 women initiating treatment within 6 months of receiving placebo (n=36) or a single dose of nevirapine (n=24), no women in the placebo group and 10 (41.7%) in the nevirapine group had virologic failure (p<0.001).

They found similar rates of virologic failure: 1.0 (2.9%) vs 11.0 (45.8%) in the placebo and nevirapine groups; both at 12 and 24 months after initiating treatment.

Among the 158 women initiating treatment 6 months or more after receiving placebo (n=70) or single dose nevirapine (n=88), they reported no significant differences in rates of virologic failure between the groups receiving placebo or nevirapine: 5 (7.8%) vs 10 (12%), p=0.39; 8 (13.8%) vs 10 (12%), p=0.76; 9 (17.1%) vs 14 (24.7%), p=0.38, at 6, 12 and 24 months respectively.

At 24 months viral load data were available for 26 women starting treatment <6 months and 23 women starting treatment at >6 months. For those who had received single dose nevirapine 19 women in the <6 months initiation group and 28 in the <6 months group had data available.

The authors noted that post hoc evaluation of their data suggested that it was logical to divide the women into subgroups according to a 6-month cut off point. They wrote that when a 12 month cut off point was used “the association between exposure to a single dose of nevirapine and virological failure was somewhat attenuated (but still significant)” in the women initiating treatment <12 months post partum (p=<0.001). They also noted no significant differences in virological failure among women starting 12 months or more post partum or between 6 and 12 months post partum.

Additionally, the investigators evaluated 30 infants who initiated antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group).

Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo 1 (9.1%) vs 10 (76.9%), p<0.001; 1 (9.1%) vs 10 (76.9%), p<0.001; 2 (18.2%) vs 10 (76.9%) <0.001 at 6,12 and 24 months respectively. The infants in the nevirapine group also had smaller CD4 increase (median CD4% 28.6% [5.2% increase] vs 37.1% [22% increase], p=0.01).

The investigators wrote: “We did not find that a previous single dose of nevirapine compromised the efficacy of subsequent nevirapine based antiretroviral treatment 6 months or more after delivery. Among the 30 HIV-infected infants, a single dose of nevirapine (one to each mother and infant) as compared with placebo was associated with significantly higher rates of virologic failure and smaller CD4 percentage increases to subsequent nevirapine-based antiretroviral treatment.”

Comment

The findings from this analysis are encouraging but also bad news.

This report downplays the other side of the finding, ie that women initiating nevirapine containing regimen less than six months after receiving single dose nevirapine did badly: 47.7% failure in the nevirapine group vs. none in the placebo group (p<0.001).

The authors also noted that although a 6 month cut off point was chosen in this post hoc evaluation, when a 12 month cut off point was used, the association between single dose nevirapine and virological failure was still significant (p=<0.001).

The “wait 6 months” news has provoked a somewhat conclusive response in some. In an article entitled “AIDS drug to protect fetus is safe for infected mothers, study finds” in the NY Times they write, despite previous “fears that any antiretroviral drug cocktail containing nevirapine would be useless”, “The Botswana study concludes that waiting six months after single dose nevirapine allows the nevirapine resistant strains to disappear from the body.”

And Flys et al, in the March edition of The Journal of Infectious Diseases say “recent clinical studies suggest that the response to NNRTI-based HAART is not compromised by prior SD NVP exposure if treatment initiation occurs at a time distant from the exposure”, citing these findings and those from Zijenah et al and Coovadia et al from last years CROI who reported 48 and 24 week data. In these two studies, early to medium term virological outcome did not appear to be compromised in these cohorts if NNRTI-containing HAART is commenced more than 1 year after single dose nevirapine for PMTCT.

The Botswana findings do raise important issues. It seems critical to find women who need treatment for their own health in pregnancy and to initiate treatment, rather than providing single dose nevirapine followed by HAART soon after delivery – which is happening in some programmes and may be the worst of all scenario. The authors write: “Every effort should be made to provide antepartum combination antiretroviral treatment to women who qualify for antiretroviral treatment for their own health, since these are the women at highest risk for AIDS-related complications or death, for transmitting HIV to their infants, and for the development of nevirapine resistance after a single dose of nevirapine” but this deserves more emphasis particularly for programmes who have the capacity to deliver HAART as well as PMTCT interventions. And this only adds to the argument for CD4 tests for women found to have positive HIV results in pregnancy.

It is also of concern that these findings may work against the move to provide cover for the nevirapine tail for women receiving single dose or preferably more complex AZT plus single dose nevirapine regimens, for women who who do not yet need treatment for their own HIV.

But hopefully these partly encouraging data are not the final word. There needs to be stronger evidence, both from trials and operational research, before “just wait 6 months” recommendations can be broadly made and all efforts should be made to provide pregnant women who need it, treatment for their own health.

References:

1. Shapiro R, Thior I, Gilbert P et al. Maternal single-dose nevirapine may not be needed to reduce mother-to-child HIV transmission in the setting of maternal and infant zidovudine and infant single-dose nevirapine: results of a randomised clinical trial in Botswana. 12th CROI, Boston, 2005. Abstract 74LB
2. Mashi Study : late breakers on breastfeeding. HIV Treatment Bulletin. April 2005.
3. Lockman S, Shapiro R, Smeaton L et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 356; 2 January 11, 2007.