Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

Antiretroviral drug summary: Nevirapine (NVP; Viramune)

Last updated on Sep 24, 2007
Key Mutations
Major
K103N/S/T
Y181C/I/V
G190A/S/E/Q
Y188L/H//C
V106A/M
Mutations at positions 103, 181, 190, 188, and 106 are the most common mutations in viruses from patients with virologic failure while receiving an NVP-containing treatment regimen or single-dose prophylaxis (Casado et al. 2000; Conway et al. 2001; Deshpande et al. 2007; Eshleman et al. 2001; Ferradini et al. 2006; Grossman et al. 2004; Hanna et al. 2000; Idigbe et al. 2007; Jackson et al. 2000; Jourdain et al. 2004; Kantor et al. 2005; Kassaye et al. 2007; Marconi et al. 2007; Seoighe et al. 2007).

K103N, Y181C, G190A/S, Y188L, and V106A/M each reduce NVP susceptibility >=50-fold with the precise reduction in susceptibility depending on other synergistically acting polymorphisms (Ceccherini-Silberstein et al. 2007; Rhee et al. 2006). Thymidine analog mutations increase NNRTI susceptibility but do not appear likely to restore virological efficacy in the presence of NNRTI resistance mutations (Shulman et al. 2000; Tozzi et al. 2004).

K103R is a polymorphism that is not selected by NNRTIs; but when present with V179D it reduces NVP susceptibility ~15 fold (Parkin et al. 2006). K103S/T/H are rare mutations that also cause high-level NVP resistance (Harrigan et al. 2005). Y181I/V and G190E/Q/C/T are rare mutations that reduce NVP susceptibility >100-fold. Y188H/C occur less commonly than Y188L and reduce NVP susceptibility 10-15-fold. V106A reduces NVP susceptibility >50-fold. V106M occurs commonly in subtype C viruses in patients receiving NVP and causes high-level NVP resistance (Brenner et al. 2003; Grossman et al. 2004; Loemba et al. 2002).
 
Accessory
L100I
K101E/P
A98G
V108I
V179D/E
P225H
F227L
M230L
K238T/N
N348I
L100I, K101P, P225H, and K238T/N usually occurs in combination with K103N and together reduce NVP susceptibility >100 fold (Bacheler et al. 2001; Parkin et al. 2006; Pelemans et al. 1998b; Rhee et al. 2006).

K101E reduces NVP susceptibility 5-10-fold (Bacheler et al. 2001; Rhee et al. 2003; Rhee et al. 2006). F227L usually occurs with V106A and synergistically reduces NVP susceptibility (Balzarini et al. 1998). M230L usually occurs with other NNRTI-resistance mutations; by itself it reduces NVP susceptibility about 40-fold (Huang et al. 2000).

A98G, V108I, and V179D/E each reduce NVP susceptibility about 2-fold. V179D occurs in 1%- 2% of untreated persons. A98G and V108I occur in about 0.5% of NNRTI-naive persons. The clinical significance of these mutations on the response to NVP-containing initial HAART regimens is not known.

N348I is a recently reported mutation that appears to be selected both by ZDV and NVP and reduces NVP and DLV susceptibility by 5-20-fold (Hachiya et al. 2007; Yap et al. 2007).
 
Potential Cross-Resistance
E138K
V179F
F227C
Y318F
E138K is a rare mutation selected in vitro by ETR that may cause low-level NVP resistance (Brillant et al. 2004; Su et al. 2007). V179F occurs almost exclusively in combination with Y181C and in this setting causes high-level resistance to NVP and DLV as well as ETR (Rhee et al. 2003; Vingerhoets et al. 2005; Vingerhoets et al. 2004). F227C is a rare ETR-associated mutation which based on preliminary data appears to also reduce NVP and EFV susceptibility (Andries et al. 2004; Su et al. 2007; Vingerhoets et al. 2004). Y318F is selected primarily by DLV but reduces NVP susceptibility 3-4 fold (Harrigan et al. 2002; Pelemans et al. 1998a).

P236L is a DLV-resistance mutation which increases NVP susceptibility in vitro (Dueweke et al. 1993).
 
Clinical Uses
Initial therapy
The DHHS and IAS-USA guidelines recommend NVP as an alternative to EFV for an initial NNRTI-containing regimen in patients who cannot tolerate EFV, are pregnant, or may become pregnant and have fewer than 250 CD4 cells/uL (Hammer et al. 2006; US DHHS Panel 2006).

NVP and a recommended dual-NRTI backbone is effective for treatment simplification in patients with complete virologic suppression for >6 months on a PI-based initial ARV regimen (Martinez et al. 2003; Ruiz et al. 2001).
 
Salvage therapy
In patients failing a PI-based regimen with viruses lacking NRTI-resistance mutations NVP and a recommended dual-NRTI combination may occasionally be effective at achieving and maintaining virologic suppression. However, EFV is preferred because of its greater potency and track record for its greater potency during initial and salvage therapy (Albrecht et al. 2001; Boyd et al. 2005; Falloon et al. 2002; Kempf et al. 2001; van Leth et al. 2004). Moreover, almost all NNRTI-resistance mutations cause higher levels of resistance to NVP than EFV (Rhee et al. 2003), therefore NVP is rarely the preferred NNRTI for salvage therapy in patients with NNRTI-resistant viruses.

In the presence of NRTI resistance, there will be a high risk of virologic failure with an NNRTI plus two NRTIs. If an NNRTI is used, it should be used with a triple-NRTI regimen and/or change in PIs.

In NNRTI-naïve patients with high-level resistance to multiple NRTIs and PIs, strong consideration should be given to delaying an NNRTI unless it is combined with a drug belonging to a new drug class and an optimized background regimen to reduce the risk of virologic failure and subsequent NNRTI resistance.

In NNRTI-experienced patients with virus containing a major NVP-resistance mutation, there appears to be little benefit of including NVP in a salvage regimen (Deeks et al. 2005).
 
References
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