Among people on combinations containing non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistance readily emerges to the NNRTIs if HIV is not quickly and fully suppressed to very low levels. This is because a single mutation can confer high level resistance to an NNRTI. Consequently, NNRTIs should only be used as part of powerful combinations containing at least three anti-HIV drugs which can reduce HIV levels below the limits of detection.

Cross-resistance to all NNRTIs usually occurs after resistance to one NNRTI has developed. There is no clinical evidence that people with resistance to one NNRTI will benefit from second-line NNRTI treatment. The mutation K103N is most associated with NNRTI cross-resistance. All the NNRTIs - efavirenz (Sustiva), nevirapine (Viramune), delavirdine (Rescriptor) and the experimental NNRTI emivirine select for the K103N mutation.

Efavirenz, often used as a first-line NNRTI, strongly selects this mutation. The single K103N mutation is associated with high level resistance to efavirenz. Subsequent mutations increase resistance (Bachelor 2000). Occasionally mutations such as K103S/T/H occur and these also confer NNRTI resistance (Harrigan 2005).

The other key mutation associated with the NNRTIs is the Y181C mutation. This appears during early virologic failure with nevirapine. 106A and 190A also commonly appear. One study of people who stayed on nevirapine for over 16 weeks despite viral rebound found that the 181C and 190A mutations were most common, with the K103N mutation rarely seen (Hanna 2000).

The initial mutation associated with resistance to nevirapine and delavirdine may be influenced by which nucleoside reverse transcriptase inhibitors (NRTIs) a person is also taking. For example, when nevirapine is taken with AZT, the K103N mutation is more likely to emerge than the Y181C mutation (MacArthur 2000). The ACTG 241 study found that nevirapine resistance mutations were less likely to emerge in patients who had no AZT mutations on entry to the study.

Similarly, treatment with 3TC and an NNRTI in the presence of viral rebound is likely to promote NNRTI resistance, and treatment with 3TC after NNRTI treatment ceases is also likely to preserve NNRTI resistance mutations. This pattern was not observed with any other NRTI (Winston 2002).

The use of NNRTIs in drug sequencing is a high-risk strategy, because of the risk of cross-resistance with currently available drugs. Although genotypic resistance testing may help to determine whether people who have previously failed one NNRTI can benefit from another one later on, it is unclear how long NNRTI-related resistance might persist after the drug has been stopped, and whether a very small population of NNRTI-resistant viruses, undetectable by current assays, could swiftly become dominant if a new NNRTI were to be introduced. A number of clinical studies have demonstrated high rates of failure in patients treated with an NNRTI after the failure of a previous NNRTI-based regimen (Ait-Khaled 2003; Bachelor 1999; Briones 2000; Gonzalez de Requena 2003). In addition, the rates at which NNRTI resistance mutations disappear after treatment is stopped is highly variable between patients, with one study that used ultra-sensitive resistance testing revealing that K103N can persist for between six months and over six years (Palmer 2006).

Natural polymorphisms or genetic variations in the NNRTI binding region account for variation in susceptibility to the NNRTI class of drugs. People who experience NNRTI failure with only low-level resistance are likely to have some of these natural polymorphisms (Brown 2000).

Other rare mutations at codons V106M and V179D also confer high level resistance to NNRTIs (Palmer 2003).

There is no residual effect of NNRTIs on viral load once high level resistance emerges, unlike the effect of several NRTIs such as 3TC (lamivudine, Epivir). An analysis of patients in the Puzzle salvage therapy study found that 19 patients with median viral load of 79,400 copies/ml who discontinued efavirenz or nevirapine two weeks before randomisation to a new regimen experienced no evidence of viral rebound, suggesting no residual NNRTI effect in the presence of drug resistance (Piketty 2004).

Risk of resistance when stopping

The NNRTIs have a long half-life, which means that the body clears these drugs from the body slowly. This means that if a patient stops taking all anti-HIV drugs at the same time, low levels of the NNRTIs may remain in the blood after the other drugs have gone. This may put the patient at increased risk of NNRTI resistance.

If a patient is considering stopping a treatment regimen which includes an NNRTI, staggering the discontinuation of the drugs may be beneficial. One expert has recommended that efavirenz and nevirapine be stopped five or six days before NRTIs are stopped. However, there is considerable variability in the rates at which efavirenz is cleared from the body, which is controlled by human genetics in part, making it difficult to provide clear guidelines for all patients.

See Risks of treatment interruption and Specific drug issues in treatment interruption in Anti-HIV therapy: Structured treatment interruption for further details.

The long half-life of nevirapine also means resistance is a risk when women are treated with nevirapine monotherapy during labour. Although this strategy is known to reduce the risk of mother-to-child HIV transmission in resource-poor settings, resistance can develop. See Short treatment courses in Anti-HIV therapy: Options during pregnancy for further details.

Hypersusceptibility

The presence of certain NRTI mutations may lead to a slight increase in the susceptibility of HIV to NNRTIs, according to several studies. Hypersusceptibility to NNRTIs has been associated with superior treatment outcomes (Albrecht 2002; Hammer 2002; Haubrich 2002; Shulman 2001; Tozzi 2004; Whitcomb 2002).

In patients failing their first protease inhibitor (PI)-containing regimen, one study reported that response to second-line therapy with efavirenz was significantly better after six and twelve months in those patients with virus that was judged hypersusceptible to NNRTIs by a phenotypic resistance test (Haubrich 2002). People with NNRTI-hypersusceptible virus had, on average, a significantly greater reduction in viral load than people with non-susceptible virus.

Results from ACTG 398 have also confirmed that efavirenz hypersusceptibility produces superior virological responses in people who have taken PI-containing regimens (Hammer 2002).

A study of over 350 people who had previously taken NRTI treatment and undergone resistance testing was conducted to investigate response to subsequent PI- or NNRTI-based treatment. Despite the similar NRTI resistance profiles of the two groups, 63% of the people taking efavirenz suppressed HIV to below 50 copies/ml compared to only 33% of the PI group. Factors associated with viral suppression in the efavirenz group were the presence of the M41L, M184V, L210W or T215Y mutations. Some combinations of these mutations were associated with an even higher rate of viral suppression.

Research to date suggests that particular patterns of mutations in reverse transcriptase are the key to hypersusceptibility. In particular, hypersusceptibility is associated with several NRTI mutations:

• K65R (associated with resistance to tenofovir) (Chappey 2005).

• M184V (associated with resistance to 3TC).

• K65R plus M184V.

• T215Y plus two other thymidine analogue mutations (TAMs associated with resistance to AZT [zidovudine, Retrovir] and d4T [stavudine, Zerit]) such as 41, 201, 208 and 118 (Shulman 2002; Coakley 2005).

• 70R plus two other TAMs and the mutation at 69X (Coakley 2005; Chappey 2005).

The more TAMs that are present (e.g. M41L, D67N, K70R, L210W, T215Y/F, and K219Q), the more susceptible virus is likely to be to the NNRTIs (Whitcomb 2002). In the absence of the M184V mutation, mutations M41L and T215Y may confer hypersusceptibility to delavirdine and efavirenz but not to nevirapine. Q151M does not lead to hypersusceptibility. NNRTI-associated mutations at codons 103, 181, and 190 may play a role in enhancing hypersusceptibility associated with T215Y.

Not surprisingly, hypersusceptibility is more common among people who have previously taken NRTIs. A study of over 700 people found that 29% of patients in the NRTI-experienced group versus 11% in the NRTI-naive group had hypersusceptibility to at least 1 of the NNRTIs (Whitcomb 2002). One study found that hypersusceptible virus had an average of 4.3 NRTI-associated mutations.

These findings have led some to suggest that NNRTIs should be reserved for second-line or salvage therapy. However, many experts continue to prefer to recommend the use of NNRTIs as a component of first-line therapy, given the well established evidence regarding their efficacy, tolerability and convenient dosing regimens.

There is no evidence to date that combining NNRTIs, which select for mutations which reverse some NRTI resistance, with AZT or d4T, which select for mutations (e.g. 215, 208, and 118) which drive NNRTI hypersusceptibility, produces better treatment outcomes (Gallant 2004).

Experimental non-nucleoside reverse transcriptase inhibitors

The experimental NNRTI called emivirine has been associated with the K103N mutation as well as K101E, V108I, G190A and the E138K mutation. The clinical implications of this resistance profile remain unclear although only 45% of individuals in one study who developed emivirine resistance had cross-resistance to efavirenz (McCreedy 1999; Sereni 2000).

Interest is now developing in a range of compounds called S-DABO non-nucleoside reverse transcriptase inhibitors which are due to enter human studies shortly. Test tube studies have shown that these compounds are highly active against HIV and that one compound (MC-848) is effective against viruses with codon changes at 100, 103, 106, 179, 181 and 188. These are the mutations which commonly confer resistance to the currently available NNRTIs, and to all other NNRTIs in development.

DPC 083 is a new NNRTI under development by Bristol-Myers Squibb that may be active against HIV that is resistant to nevirapine and efavirenz. In a group of 48 people with NNRTI resistance, 57% achieved undetectable viral load after eight weeks of DPC 083 plus NRTI therapy (Ruiz 2002).

Another new NNRTI called etravirine is being developed by Tibotec-Virco. There is encouraging data that it may have some efficacy against HIV which is resistant to other NNRTIs (Andries 2005).

GlaxoSmithKline is developing a new generation NNRTI called GW695634 for use in people with common NNRTI resistance mutations. GW695634 has been tested over 7 days in 46 people with NNRTI resistance (55% with the K103N and 30% with Y181I/C). Viral load fell by between 1.1 log₁₀ and 1.6 log₁₀ among people taking GW695634 compared with no significant response among people on placebo (Becker 2005). This study provides sufficient evidence of GW695634s efficacy against NNRTI-resistant virus to support clinical development.

See the individual drug entries in Drugs used by people with HIV: Non-nucleoside reverse transcriptase inhibitors for full summaries of research on resistance and references to studies discussed in this section.

Non-nucleoside reverse transcriptase inhibitor resistance and non-B subtypes

The V106M mutation causes resistance to the NNRTIs in people with non-B subtypes of HIV, particularly subtype C. People with subtype C may have a greater risk of 'natural' resistance to the NNRTIs than people with other subtypes. See Resistance in non-B HIV sub-types in Anti-HIV therapy: Resistance for further details.

Key research

Haubrich (2002) studies 177 patients who had been treated for an average of 41 months. NNRTI-hypersusceptibility (HS) was present in around one in five patients (efavirenz [EFV]HS=24%, delavirdine [DLV]HS=17.5%, and nevirapine [NVP]HS=20%). EFV-HS was associated with duration of previous NRTI use (p<0.001), number of nucleoside agents (p=0.002), use of AZT (p=0.04), and reduced susceptibility to AZT and abacavir (fold change in IC50>5.0 compared to control, p<0.005). The mean change in viral load 6 months after starting a new NNRTI-containing regimen was greater in the 21 patients with NNRTI-hypersusceptible virus than in the 77 patients without HS (-1.2 versus -0.8 log reduction; p=0.016). The difference persisted at month 12 (p=0.023). Multiple linear regression analysis showed that NNRTI hypersusceptibility was a significant independent predictor of the magnitude of early HIV RNA reduction (up to month 4), after accounting for the baseline HIV RNA and the number of newly prescribed drugs to which the patient's virus was susceptible (p<0.02). CD4 cell increases were also greater for patients with NNRTI hypersusceptibility. Between months 4 to 12, the average additional CD4 gain in those with NNRTI hypersusceptibility was 28-60 cells/mm³, differences that trended toward significance at months 4, 6, and 10.

Shulman (2001) studied response to an efavirenz and adefovir-containing regimen in 30 treatment-experienced patients. Isolates were classified as hypersusceptible if they halved the amount of drug needed to halve viral load of wild-type virus. A total of 11 isolates without detectable NNRTI resistance mutations displayed hypersusceptibility to efavirenz, 10 to delavirdine, and 8 to nevirapine. Overall, 9 of 12 hypersusceptible isolates contained mutations associated with NRTI treatment: M184V (associated with resistance to lamivudine), and M41L, L210W and T215Y (AZT), and 11 of the 12 contained M184V, T215Y, and M41L. However, a multivariate linear regression analysis revealed that the mutations most strongly associated with hypersusceptibility were the NNRTI-associated mutations at codons 103, 181, and 190, with an AZT-associated mutation at T215Y also enhancing susceptibility.

Hammer (2002) reported that efavirenz hypersusceptibility was associated with a better virologic response in protease inhibitor-experienced patients (odds ration 0.16 at week 48, p<0.001). The correlates of NNRTI hypersusceptibility were analysed in 17,000 isolates submitted for phenotypic resistance testing. Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7%, 10.8% and 8% of samples. Hypersusceptibility was significantly more common in patients previously exposed to nucleoside analogues (29%, 26% and 21% respectively), and was inversely correlated with NRTI resistance. An analysis of 2050 isolates showed that NNRTI hypersusceptibility was associated with a significantly higher frequency of mutations associated with nucleoside analogue treatment (M41, D67, T69, K70, L74, V75, M184, L210, T215 and K219), with a mean of 4.3 mutations from this group in hypersusceptible isolates. Using genetically engineered viruses, the group was also able to show that a virus with the nucleoside-associated mutations M41L, T215Y and M184V mutations was hypersusceptible to all three NNRTIs, whilst the absence of the M184V mutation conferred hypersusceptibility to delavirdine and efavirenz but not to nevirapine. Conflicting results were seen when multi-nucleoside resistance mutations were compared: whilst the T69SS insertion mutation was associated with hypersusceptibility when linked to the M41L, A62V and T215Y mutations, Q151M did not lead to hypersusceptibility.

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