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Nevirapine Resistance Develops in Therapy to Prevent Mother-To-Child Transmission
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Written by David Margolis, MD, University of Texas Southwestern Medical Center
Several reports at the 11th Retrovirus Conference in San Francisco (feb 8-11, 2004) presented study data showing that when nevirapine (Viramune) is used in a single dose for the pregnant woman and as a single dose after birth in the baby, as it was used in studies in developing countries to prevent mother-to-child transmission, nevirapine resistance can develop. These findings also have significant implications for the use of NNRTIs such as nevirapine (NVP), in prevention of mother-to-child transmission (PMTCT). Martinson (Abstract 38) found that in 623 HIV-infected mothers at 2 tertiary hospitals in South Africa given NVP for PMTCT (mother-to-child transmission), NNRTI resistance was detected in 24% of mothers 10 to 36 weeks after delivery.
Similarly, Jordain (abstract 41LB) found that single-dose nevirapine used for PMTCT has a significant negative impact on the success of subsequent antiviral therapy for the mother. After a single dose of NVP, plasma levels of the drug were detectable for up to a staggering 24 days. NNRTI-resistance mutations were detectable in 18% of a random sample of women by standard genotyping techniques (of far less sensitivity than those used by Palmer and colleagues at the NIH).
At 6 months of ART 75% of women who had not been exposed to NVP had achieved a viral load <50 copies/ml, 53% of women who had been exposed to NVP but had no NNRTI mutations detected achieved a viral load <50 copies/ml, but only 34% of women who had been exposed to NVP and had NNRTI mutations detected achieved a viral load <50 copies/ml. It will be necessary to develop new synergistic strategies for PMTCT to maximize benefit of subsequent antiretroviral therapy for the mother while preserving the benefits of PMTCT.
There are Risks When Stopping NNRTI Therapy
ed note from Jules Levin: Together these findings pose rather tricky questions for management of NNRTI-containing therapy in the developed world, such as in the USA. Patients sometimes stop the HAART therapy they are prescribed by their doctors. We know sometimes patients stop therapy vwith their doctor's knowledge and without their doctor knowing about it. The problem related to this issue of NNRTI resistsnce developing is that nevirapine and efavirenz both have long half lifes. This means they stay in the blood for days after you stop taking these drugs. After the NRTIs you are taking leave your body the NNRTIs are still present but at incrementally decreasing levels. These levels may not be adequate in preventing replication of HIV and can lead to drug resistance to NNRTIs.
Can NNRTIs ever be trusted if they have ever been stopped? If NNRTIs are to be stopped, how should it be done? Until further studies are done, all that can be offered are guidelines and best guesses. As it takes a few days for viral replication to re-initiate and as NNRTI levels decline slowly, if viral load is undetectable and NNRTIs are only stopped for a few days, it is likely that NNRTI therapy can be successfully restarted. 2003 UK HIV guidelines suggest that if NNRTIs are to be stopped that NRTIs be continued for 7 days, or that PI therapy be given for 1-2 weeks.
Given the persistence of NNRTI levels as presented at this meeting, and the interpatient variation in these levels, it might be prudent to “protect” waning NNRTI levels with other drugs for even longer. However, prolonged dual nuceloside therapy is obviously undesirable. Measuring NNRTI levels would give guidance in this situation, but is likely impractical, so clinical judgement (known as “guessing” to non-clinicians) may be required. If one is presented with a patient that stopped successful NNRTI-containing therapy some time ago without these precautions, one is left with the options of avoiding NNRTIs altogether, or carefully monitoring therapy when it is reinitiated so that if failure occurs unprotected NRTIs are not administered for a prolonged period of time.
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