Covering the nevirapine tail
Polly Clayden, HIV i-Base
Two oral late breakers presented by researchers working in Thailand showed strategies to reduce risk of NVP resistance following receipt of single dose nevirapine (NVP). [1, 2]
Previous studies have demonstrated reduction in resistance using short courses of antiretrovirals as tail coverage. Currently 7 days of AZT and 3TC are recommended in the WHO pregnancy guidelines. [3, 4, 5, 6]
First presenting author, Russel Van Dyke, was from IMPAACT P1032. This group hypothesised that longer duration or a more potent regimen may further reduce incidence of resistance.
P1032 was a 3 arm randomised, open label, phase 2 study conducted in Thailand between June 2006 and June 2008 (and used historic controls). Pregnant women with CD4 >250 cells/mm3 were enrolled at 28-38 weeks gestation. All women received intrapartum single dose NVP (and were stratified according to whether or not they received an additional short course of antepartum AZT). Women were randomised to: Arm A, 7 days AZT+ddI+LPV/r; Arm B, 30 days AZT+ddI or Arm C, 30 days AZT+ddI+LPV/r. This trial was conducted in non-breastfeeding women.
Resistance testing was performed at 2, 3, 4, 5, 6 and 8 weeks post partum. Consensus sequencing was used and if negative by sequencing, oligonucleoside ligation assay (OLA), an ultra sensitive single point assay that can detect K103N, Y181C and G190A >2-5% of viral population.
The controls were women with CD4 >250 cells/mm3 from the PHPT-2 trial, in which women received single dose NVP or short course AZT and single dose NVP, and for whom matched samples were available at 2 and 6 weeks. The primary end point was a new NVP resistance mutation within 8 weeks post partum.
P1032 included 169 women in the analysis and 119 women from PHPT-2 were selected for the control group. Women in P1032 were slightly older than those in PHPT-2, median 28 vs 26 years, p=0.03 and a greater proportion received AZT during pregnancy, 78% vs 19%, p<0.001. Additionally they had higher median CD4, 456 vs 414 cells/mm3; lower median viral load 3.5 vs 4.0 log10 copies/mL, p<0.001; and a greater proportion were </=500 copies/mL, 25% vs 8%, p<0.001.
Intent to treat analyses found significantly lower incidence of NVP-resistance mutations in P1032 vs PHPT-2 at 2 or 6 weeks post partum (see table 1). In Arm A, one woman lost to follow up was missing 6 and week samples and assumed to have resistance.
Table 1: Incidence of NVP-resistance mutations at 2 or 6 weeks post partum
|Arm A AZT + ddI + LPVr; 7days||Arm B AZT + ddI; 30 days||Arm C AZT + ddI + LPV/r; 30 days||PHPT-2|
|Week 2 or 6 post partum||2 (3.6%)||4 (7.1%)||3 (5.3%)||37 (31.1%)|
|95% CI for difference P103 vs PHPT-2||13-43%||8.6-40%||11-42%||NA|
|Sequencing only||1 (1.8%)||0||0||15/112 (13.4%)|
Combined incidence at weeks 2, 3, 4, 5, 6 or 8 weeks post partum in P1032 were: Arm A, 4 (7.1% [95% CI, 2-17%]); Arm B, 7 (12.5% [95% CI, 5.2-24%]) and Arm C, 3 (5.3% [1.1-15%]).
Maternal and infant adverse events were uncommon and similar in the three arms.
In summary, the investigators found P1032 Arms A and C had <10% incidence of NVP resistance mutations, with confidence intervals excluding >17%. All three arms were significantly lower than the control group but the study was not powered to show equivalence between the arms.
Seven days of HAART following single-dose nevirapine prevents the selection of most nevirapine resistance mutations, they concluded.
Second presenting author, Gonzague Jourdain, reported findings from PHPT-4. This study evaluated a tail of one month AZT+ddI. Dr Jourdain noted that these antiretrovirals were selected for their potency and low risk for selection of NRTI mutations. This study avoided 3TC, FTC and tenofovir as Hepatitis B is common among Thai women.
The primary endpoint was selection of new NVP mutations at any timepoint post partum. This study also used consensus sequencing and OLA performed at baseline, 7-10, 37-45 and 120 days.
Pregnant women with CD4 cell count >250 cells /mm3 and haemoglobin >8.0 mg/dl were enrolled and matched to case controls from PHPT-2. The women were well matched between the two groups but women in PHPT-4 were slightly older, 27.8 vs 25.9 years, p=0.009. 229 women were exposed to single dose NVP, of these 222 had 7 days visit (14 samples missing); 219 had 37 days visit (5 samples missing) and 194 had 120 days visit (2 samples missing).
Dr Jourdain reported that at one month post partum there were no NVP mutations detected in PHPT-4 vs10.4 in PHPT-2 using consensus sequencing; 1.8 vs 19.2 using OLA and 1.8 vs 20.7 overall, p<10 to 10.
He noted that 5 (2.3%) of cases and 2 (0.9%) of controls had NRTI mutations, p=0.45. And at one month median haematocrit was 35.3% in cases vs 37.6% in controls. Serious adverse events were uncommon and similar across both groups.
He concluded: One month of ZDV/ddI postpartum prevented the selection of virtually all NNRTI resistance mutations detectable using consensus sequencing. He added that the resistance mutations detected in 2% of patients by OLA were no longer observed at four months. He suggested that AZT+ddI tail coverage for one month post partum may be a reasonable option for women receiving single dose NVP.
These two studies add to the existing data demonstrating that covering the nevirapine works. Additionally a poster at this conference showed findings from the BAN study, Malawi in which women with CD4 >250 celllls/mm3 receiving single dose nevirapine plus 7 days’ AZT/3TC tail coverage post partum were compared to women receiving single dose nevirapine alone. 
This study also showed a significant reduction (62%-9%) in nevirapine resistance among the women receiving tail cover.
Although the PHPT-4 presentation showed this, head to head comparisons between regimens are difficult, as the original tail cover study (TOPS) took all comers and the subsequent studies exclude women who meet eligibility criteria for treatment. Choice of regimen should depend on local situation and access.
It is unequivocal that women needing treatment for their own health should receive it,but until the question of universal HAART for all pregnant women vs AZT plus single dose nevirapine prophylaxis for healthier women is answered, women receiving prophylaxis need to be protected from acquisition of resistance, and in turn from the increased risk of virologic failure with subsequent NNRTI containing HAART.
- van Dyke R et al. A phase II study of the incidence of nevirapine resistance mutations in HIV-infected Thai women receiving a single intrapartum dose of NVP followed by a postpartum tail of ZDV/ddI or ZDV/ddI/LPV/r: IMPAACT P1032. 16th CROI, Montreal, 2009. Abstract 95aLB.
- Jourdain G et al. Efficacy and Safety of 1-Month Post-partum zidovudine and didanosine to prevent HIV-1 nevirapine resistance mutations following intrapartum single-dose nevirapine. 16th CROI, Montreal, 2009. Abstract 95bLB.
- McIntyre JA 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.
- Chi B et al. Single dose tenofovir and FTC for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. Lancet. Vol 370:1698-705.
- Arrive E et al. The TEmAA ANRS 12109 phase II trial, step 1: Tolerance and viral resistance after single-dose nevirapine and short-course of tenofovir disoproxil fumarate and emtricitabine to prevent mother-to-child transmission of HIV-1. 15th CROI, Boston, 2009. Abstract 45b.
- Farr S et al. Addition of 7 Days of zidovudine + lamivudine to peripartum single-dose nevirapine effectively reduces nevirapine resistance at 2 and 6 eeks post-partum in HIV-infected mothers: Lilongwe, Malawi. 16th CROI, Montreal, 2009. Abstract 958b.