Stopping nevirapine five days prior to nucleosides may avoid resistance

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Stopping the nevirapine component of nevirapine-based HAART five days prior to the nucleoside backbone when stopping or interrupting treatment appears to be a “reasonable strategy” and is not associated with evidence of resistance mutations to either nevirapine or 3TC, according to the results of a nine-patient study published in the May edition of HIV Medicine.

Nevirapine, like the other European-approved non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz, has a long half-life as well as a low genetic barrier to the selection of resistance (only one mutation in the virus is needed to cause high-level resistance).

If the drug is stopped at the same time as the nucleoside analogue backbone, diminishing effects of the NNRTI may persist for much longer than effects of the nucleoside analogues. This could lead to the emergence of NNRTI resistant HIV mutations.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

half-life

The amount of time it takes for a concentration in blood to be reduced by 50%. After one half-life, the concentration of a drug in the body amounts to half the starting dose of any drug to be eliminated from the body.

wild-type virus

The naturally occurring, non-mutated strain of a virus. When exposed to antiretroviral (ARV) drugs, wild-type HIV can develop mutations that make the virus resistant to specific HIV drugs. 

 

plasma

The fluid portion of the blood.

rash

A rash is an area of irritated or swollen skin, affecting its colour, appearance, or texture. It may be localised in one part of the body or affect all the skin. Rashes are usually caused by inflammation of the skin, which can have many causes, including an allergic reaction to a medicine.

On the other hand, even when allowing for nevirapine's half-life, it is possible that stopping the NNRTI before the nucleoside analogues could lead to the emergence of resistance to 3TC, which is one of the most common components of HAART, because 3TC also has a low genetic barrier to resistance.

Guidelines have not yet been produced regarding the ideal scenario for stopping NNRTIs, despite the fact that treatment interruptions for reasons of toxicity, individual choice, or after a course of nevirapine in order to avoid mother-to-child transmission are relatively common in clinical practice.

Investigators at Imperial College, London hypothesised that five to seven further days of the nucleoside backbone after stopping nevirapine should be long enough to prevent the single key mutation (K103N) that can result in resistance across the entire NNRTI class, and short enough to prevent the emergence of 3TC resistance.

The plasma of six men and three women (no ethnicity was reported) who were attending either the HIV or GUM clinic at St. Mary’s Hospital in London was assessed for pharmocokinetics, viral load and resistance data before and after stopping nevirapine-based HAART. All nine followed instructions to continue their nucleoside backbone for five days after stopping nevirapine.

All had been on nevirapine for at least two weeks (range 2-71 weeks) and were taking nevirapine for a variety of reasons. Five were taking short-course nevirapine as part of a primary HIV infection study, two were taking short-course nevirapine to prevent mother-to-child transmission, one experienced rash two weeks after starting nevirapine-based HAART, and one individual on nevirapine-based HAART for 71 weeks chose to interrupt treatment.

Four to twelve hours after the final 200mg dose of nevirapine, the mean plasma nevirapine concentration was 4199ng/ml, although it ranged from 2404 ng/ml to 6741 ng/ml in the nine individuals. The mean nevirapine half-life was 24.3 hours, although again this ranged from 16.2 hours to 31.6 hours amongst the nine individuals. The investigators predicted that it would take an average of 168 hours (seven days) for nevirapine concentrations to fall to 10ng/ml – the lowest level at which activity against wild-type virus has been reported – although this ranged from 108 hours to 264 hours (four-and-a-half to eleven days) in the nine individuals.

On stopping therapy, eight of the nine individuals had a viral load below 50 copies/ml. It was found that all had wild-type virus prior to stopping therapy, and again at viral rebound, with no mutations seen. The individual stopping therapy due to rash had a viral load of 143 copies/ml at the time of stopping, but switched immediately to a new regimen which caused his viral load to become undetectable, so no genotypic resistance measurement was possible.

The investigators do not detail the exact nucleoside backbones of the nine individuals, but comment that 3TC resistance (M184V) was not seen.

The authors also describe the previous case of a man who simultaneously stopped all the components of his nevirapine-, and then his efavirenz-based, HAART due to side-effects, and who acquired the K103N mutation after taking and stopping both NNRTIs (resistance testing was not done between the two NNRTI-based regimes). Five months later, however, K103N-mutated HIV was already archived, and no longer detected through genotypic resistance tests. In his case, viral load was detectable at the time of both treatment interruptions. The investigators comment that the risk of acquiring the K103N mutation is unknown when stopping all therapy at once, but suggest it is likely to be more common when viral load is uncontrolled.

The investigators therefore recommend that if nevirapine-based therapy is to be stopped it should be done when viral load is undetectable and the nucleoside backbone continued for five days. An alternate strategy suggested by Dr Martin Fisher and pharmacist Heather Leake Date of Brighton and Sussex University Hospitals in ATU 123 (although one not examined by the authors and one that would not be possible when stopping due to unexpected adverse events), would be to replace nevirapine (or efavirenz) with a potent antiretroviral with a short half-life (they use Kaletra) two weeks prior to ceasing HAART.

Further information on this website

Gene most commonly seen in Africans greatly increases efavirenz levels - news story

Nevirapine for mums compromises their future treatment options - news story

Use drug holidays cautiously in NNRTI-treated patients

- news story

Structured treatment interruption - overview of key research

Treatment interruptions - factsheet

AIDS Treatment Update - Issue 123: HAART interrupted

References

Mackie NE et al. Clinical implications of stopping nevirapine-based antiretroviral therapy: relative pharmacokinetics and avoidance of drug resistance. HIV Medicine 5, 180-184, 2004.