Effect of single dose nevirapine on subsequent nevirapine-containing HAART: long term outcomes
Polly Clayden, HIV i-Base
Two posters showed results of long term outcomes for women receiving nevirapine (NVP) containing HAART who had previously received single dose NVP for prevention of mother to child transmission (PMTCT). [1, 2]
Gonzague Jourdain and co-workers reported 4-year results for women in PHPT-2. In 2004 this group had reported an association with impaired treatment response at 6 months in women receiving single dose NVP vs placebo in addition to AZT from 28 weeks gestation. 
Women initiated NVP containing HAART postpartum at CD4 = 250 cells/mm3. Viral load and CD4 tests were performed 6 monthly. After 6 months, women with confirmed virologic failure or CD4 decrease were able to switch to a PI. Treatment failure was defined as: viral load >400 copies/mL after 4.5 months, or CD4 <50 cells/mm3 after 6 months, or switch to PI, or death.
The 221 NVP-exposed and the 48 -unexposed women (the same group that were included in the earlier analysis) were well matched, with median age 28.7 years (IQR 25.1 to 32.7), weight 50 kg (46 to 56), CD4 168 cells/mm3 (79 to 219), viral load 4.63 log10 copies/mL (4.00 to 5.09).
The investigators found, four years after initiation of treatment, 65% of the NVP-exposed and 73% of the -unexposed were still being followed, p=0.32. In the exposed and unexposed groups, 69 vs 6 women experienced virologic failure, 2 vs 0 immunological failure, 11 vs 5 switched to a PI, 6 vs 0 died, respectively.
Overall 41% of NVP-exposed women failed vs 23% of unexposed women, p=0.02). The majority failed within two years of treatment initiation. In multivariate analysis, single dose NVP (adjusted hazard ratio 2.0, p=0.04), pregnancy CD4 cell count (AHR 1.17 per 50-cell decrease, p=0.02), and viral load (AHR 1.47 per log10 copies/mL increase, p=0.01) were associated with failure.
When the investigators looked failure defined as viral load as >50 copies/mL, they found treatment initiation within 6 months of delivery to be associated after adjustment for age, CD4 and viral load during pregnancy and at initiation of treatment (AHR 2.23, p<0.001).
They also found that the risk of failure in NVP-exposed women decreased as the length of interval from delivery to treatment initiation increased (AOR 0.93 per month increase, p=0.001). However it remained independent in unexposed women. They noted that predicted risks of failure in both groups were similar only at 18 months.
They concluded that the consequences of single dose NVP exposure were, still significant after 4 years of therapy, justifying the development of strategies to prevent resistance mutations.
Shahin Lockman and co-workers showed similar results among women in long term follow up in the Botswana Mashi trial, in which all women (n=1200) received AZT from 34 weeks gestation and either single dose NVP or placebo.  Women initiated NVP containing HAART post partum when they met WHO criteria (CD4 <200 cells/mm3 or AIDS illness).
The follow up for women on HAART in this study was up to five years; the median duration was 42 months. The primary endpoint for the study was virologic failure (defined as viral load >400 copies/mL at 6 months or > 1 log drop at 3-months).
The investigators reported that 360/1200 women in Mashi initiated NVP-containing HAART post partum (182 had received single dose NVP vs178 placebo). Of these 61 (17%) initiated treatment within 6 months of delivery and 299 = 6 months of delivery. Excluding death, 16% of women were lost to follow up at 42 months and 19% by 60 months. Women initiated HAART at a median of19 months after delivery. Viral load results were available for 96% of women.
They found a difference in viral failure between NVP-exposed and placebo- women by timing of HAART initiation after an interval since delivery 6 months vs > 6 months (p=0.003 for interaction); at <12 months, p=0.0001. But they found no difference in viral failure in those starting HAART =12 months postpartum, p=0.7822 and late virologic failure was uncommon across all subgroups (see Table 1).
Table 1: Virologic failure rates in women initiating HAART after prior sdNVP vs placebo exposure by interval since delivery
|Months after HAART initiation||# (%) failling, placebo arm||# (%) failing, sdNVP arm||p-value|
|HAART started <6 months after placebo/sdNVP(n = 61)||n=37||n=24|
|6||0 (0%)||9 (37.5%)||0.0001|
|12||1 (2.9%)||11 (45.8%)||< 0.0001|
|24, 36||2 (5.4%)||11 (45.8%)||0.0002|
|48, 60||2 (5.4%)||12 (50.3%)||< 0.0001|
|HAART started >6 months after placebo/sdNVP(n=299)||n=141||n=158|
|6||7 (5.1%)||12 (7.7%)||0.36|
|12||13 (10.0%)||19 (12.9%)||0.46|
|24||18 (14.6%)||23 (16.1%)||0.74|
|36||19 (15.9%)||27 (20.2%)||0.39|
|48, 60||20 (17.7%)||27 (20.2%)||0.64|
They concluded: Women starting NVP-based HAART = 6 months after sdNVP exposure had similar long term rates of virologic failure as non-sd-exposed women.
The findings from these studies were unsurprising. They add to the growing evidence that prior use of single dose nevirapine contributes to virologic failure when HAART is initiated within six months (and maybe within 12 months) after sdNVP exposure.
- Jourdain G et al. 4-Year Clinical and therapeutic consequences of intra-partum single-dose nevirapine for the prevention of perinatal HIV in Women Who Subsequently Initiated a Nevirapine-based ART. 16th CROI, Montreal, 2009. Abstract 954.
- Lockman S et al. Long-term maternal and paediatric virologic outcomes on nevirapine-based HAART following receipt of peripartum single-dose nevirapine or placebo, Botswana. 16th CROI, Montreal, 2009. Abstract 955.
- Jourdain G et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med Volume 351, 15 July 2004.
- Lockman S et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Eng J Med Volume 356, January 11, 2007.