icon-folder.gif   Conference Reports for NATAP  
 
  12th Conference on Retroviruses and Opportunistic Infections (CROI)
Feb 22-25, 2005
Boston, MA
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Nevirapine MTCT--Drug resistance at the 12th CROI
 
 
  1st Report Written by Nancy Shulman, Instructor of Medicine, Stanford University School of Medicine
 
Of Moms and Babies:
 
A single dose of nevirapine (NVP) given to a pregnant HIV+ woman when she presents in labor and a dose to the infant reduces the rate of transmission to her infant by greater than 50%. This strategy is currently being used in many resource-poor settings. One problem is the development of NVP resistance (and efavirenz cross resistance) in the mothers and in the babies who do get infected. In one large Thai study, the mothers also had a decreased virologic response to combination therapy with two nucleosides and an NNRTI compared to those who never were exposed to single dose NVP (Lallemand, et al, 11th CROI). The other unanswered question is whether the infants of subsequent pregnancies in the same women will be adequately prophylaxed with another single dose of NVP. In prior reports we have seen rates of resistance in mothers exposed to NVP measured by conventional sequencing methods on the order of 20-40% 6-12 weeks post-partum and follow ups have generally decreased to near 0% by 1 year. Given how fast NNRTI resistance develops in HIV, particularly as monotherapy, these numbers are lower than we would expect. Well in fact, at this conference several abstracts used more sensitive methods of detecting specific resistance mutations; they found detected much more resistance in these women. In addition there was the first presentation about the efficacy of 2nd time around of single dose nevirapine to prevent mother to child transmission.
 
Johnson et al from the CDC used a real-time PCR method to detect K103N and Y181C in 50 South African women who received single dose NVP. This method detects mutations down to about 0.1%-1% vs. conventional sequencing which requires the mutant population to be about 20% or more. Ten of these 50 (20%) had detectable K103N 6-36 weeks after delivery by conventional sequencing methods. An additional 16 had detectable K103N by the real-time PCR method. Y181C was seen in 5 women, only one of which was detected by conventional methods. This pushes the prevalence of detectable resistance in this cohort up to 65%. A second cohort from S. Africa presented by Loubser used real-time methods at regular intervals beginning at 6 weeks up to a year. At 6 weeks post-dose, 16 of 18 women had detectable K103N which persisted to a year in 4 of 16 sampled. Lower rates were seen in when PBMC DNA was assayed, although that is likely an assay limitation rather than evidence that resistance not archived in these women as the author inferred.
 
Sarah Palmer of the NCI used the same type of assay to look at 15 women who had K103N or Y181C detected with conventional sequencing at 1-4 months after single dose NVP. 8 women were also detectable at a second sampling at month 5-9, while the other 7 were "undetectable" conventional sequencing. Most of the women who were "undetectable" at 6 months by conventional methods were detectable with real time PCR assay, as were many of the 12 month samples overall.
 
Overall conclusions: not too surprisingly, we miss a lot of resistance with conventional sequencing. Does the absence of mutations by these more sensitive methods ultimately mean anything more than the absence by conventional methods? Does any of this equate to better outcomes for these moms? Unfortunately we have no data that suggests having below a certain level of minority drug resistant mutant correlates with a better response to NNRTI therapy. All that we know is in adults in the US who have had NNRTIs in the past respond poorly to subsequent NNRTI therapy, even if no resistance NNRTI was detected at baseline (Mellors, 10th CROI and other smaller studies).
 
How effective will NVP be for subsequent pregnancies? One of the more interesting studies in the conference was a case control study of reported from S. Africa designed to ask this question. Unfortunately, it was probably underpowered (not a large enough sample size) to be conclusive. Mothers were prospectively recruited in 1:2 ratio of previous single-dose NVP (cases) vs. naive (controls) from 13 different clinics in Soweto. Women were controlled for clinic, parity, age, viral load, and CD4. They had recruited 106 cases and 212 controls at the time of the presentation. 77 and 140 had data on transmission. In the women who received single-dose NVP for the second time, 8 of 77 (10.8%) transmitted HIV to their infants, vs. 5 of 140 (3.8%), which was not statistically different. The author noted that 3.8% transmission is quite low and similar studies in naive patients have often been higher, including studies of women in Soweto (10% or so). In addition, only 75% of their data was analyzed and we await the final report. But 10.8% looks much better than 20-25% transmission rates observed in the absence of any prophylaxis, even if turns out to be higher than the naive patients who receive single-dose NVP.
 
How do we prevent NVP resistance in the setting of mother to child transmission? One potential solution is to give additional antiretrovirals for a long enough time to suppress the virus to low levels to cover the "NVP tail" or the duration of NVP exposure after a single dose (detectable up to 3 weeks in some women). In a late breaker from the ANRS DITRAME cohort 329 pregnant women in Abidjan were given ZDV+3TC starting at 32+ weeks of gestation, women also received a dose of ZDV, 3TC and NVP at labor, and continued the ZDV+3TC for 3 days post-partum. The transmission rate at 6 weeks was 4.7%. Using conventional sequencing, the resistance at 4 weeks was in the 16 mothers who transmitted as well as a random sampling of 80 non-transmitting mothers revealed low rates of resistance: 1.1% K103N/Y181C and 8.3% M184V, much lower than the 20-40% using single dose NVP only.
 
References:
 
1. Johnson J, et al. Resistance emerges in the majority of women provided intrapartum single-dose nevirapine. Abstract 100.
 
2. Loubser, S et al. Sensitive real-time PCR quantification of K103N resistance mutations following single-dose treatment with nevirapine. Abstract 102.
 
3. Palmer S, et al. Persistance of NNRTI-resistant variants after single-dose nevirapine in HIV-1 subtype C-infected women. Abstract 101.
 
4. Martinson N, et al. Effectiveness of single-dose nevirapine in a second pregnancy. Abstract 103.
 
5. Chaix ML, et al. Addition of 3 days of ZDV+3TC postpartum to a short course of ZDV+3TC and single-dose NVP provides low rate of NVP resistance mutation and high efficacy in preventing peri-partum HIV-1 transmission: ANRS DITRAME Plus, Abidjan, Cote d’Ivoire. Abstract 72LB.