Over the past three years, there has been a great interest in the use of nonnucleoside reverse transcriptase inhibitors (NNRTI) in clinical practice. Although new agents in this class are under development (capravarine, calanolide A and the DuPont series of compounds to name but a few), we are left with the "big three" (delavirdine [DLV], efavirenz [EFV] and nevirapine [NVP], in alphabetical order) for the foreseeable future.

First-Line Therapy
An interesting application of NNRTI therapy has been the use of a single dose of NVP given to the mother during labour (with an additional dose to the infant in the first week of life) to prevent maternal-fetal transmission of infection, especially in women receiving no pre-natal care. Although additional doses of NVP may need to be given to infants born to mothers previously on NVP (due to accelerated drug clearance, Abstracts 716, 717), this approach has proven highly successful from a public health perspective. However, in 14 Ugandan women given a single dose of NVP at the time of labour, drug resistance developed in 3 cases (Abstract 658). Fortunately, primary drug resistance remains quite uncommon outside of this setting at the present time (4% in one Canadian study of 87 patients, Abstract 567). As this regimen is used more widely in women presenting in this manner in other parts of the world, we will have to be mindful of the risk of transmission of resistant isolates. This being said, the major application of NRTI in drug-naive individuals will be as part of a HAART regimen. In one study undertaken in Spain and Argentina, the efficacy of Combivir with either nelfinavir (NFV) or NVP was compared (n=143, baseline CD4 count 364 cells/mm3, plasma viral load 63,000 copies/mL). After 12 weeks, 56-57% patients (ITT analysis) had plasma viral load values below 200 copies/mL, suggesting that, in this preliminary analysis, the two approaches are virologically equivalent (Abstract 510). The longer term efficacy of NNRTI-based regimens is now becoming understood. In a group of 62 patients on the combination of AZT/3TC/NVP, 28 (45%) had maximal plasma viral load suppression (<50 copies/mL) after 48 weeks, with no influence of the baseline plasma viral load (Abstract 517). In a group of 42 patients treated with indinavir (IDV) and EFV, 38 (91%) had plasma viral load measures below 400 copies/mL after 132 weeks (Abstract 513).

NVP and EFV have been considered for more widespread use in IVDU, as they can be administered once daily and constitute a low pill burden. However, a negative drug interaction with methadone may limit our ability to use these agents productively in this population. Although both agents reduce methadone levels by 50%, a formal evaluation has demonstrated that withdrawal symptoms are not universally present (Abstract 88). If they occur, they are delayed 8-10 days, and require an increase in methadone dose of 15-30 mg, a manageable change in therapy in the vast majority of cases.

Drug-Associated Toxicity
It has been proposed by many that the use of PI-sparing approaches may reduce the risk of long-term drug-associated toxicities, including metabolic changes, morphologic changes and the risk of cardiovascular disease. The absence of clear case definitions has prevented us from determining the true prevalence of these conditions, but a number of observational studies have been completed. In a large Australian study of 1350 patients, the prevalence of body habitus changes consistent with lipodystrophy was 81% in PI-treated patients, 33% in PI-naive individuals, and only 5% in those never having received any therapy (Abstract 201). The risk of peripheral wasting may decrease by 5%/month when comparing its prevalence in NVP vs. PI-based therapy (David Cooper, personal communication). In a French review of 646 patients (Abstract 17), patients receiving PI (76.9%) were compared to those receiving other regimens (23.1%). Over 3.5 years, the prevalence of lipodystrophy was higher in PI-treated individuals (63.4% vs. 39.6%, p=0.001). In addition, cholesterol and triglyceride levels were lower in the absence of PI therapy. Additional studies suggest that EFV may be an independent risk factor for dyslipidemia (relative hazard 1.9; Abstract 21), supporting animal experiments showing an increase in serum triglycerides, fatty acids and cholesterol in EFV-treated mice (Abstract 41). Further, in a clinical study of 33 patients changed from a PI to EFV, no improvement in weight, fat redistribution patterns and metabolic abnormalities was observed over 10 months (Abstract 46). Two other studies of 39 and 43 patients suggest only a slight, subjective improvement in fat redistribution, and even a slight increase in triglyceride levels (Abstracts 48, 49). To be fair, a 31% decrease in triglyceride levels was reported in one study of 20 patients (Abstract 50). A switch to NVP under similar circumstances led to a decrease in triglycerides and HDL cholesterol in 40 patients (Abstract 45). Significant decreases in plasma triglyceride levels have been confirmed by two other "NVP switch" studies (80 and 60 patients, respectively), but improvement in body habitus is less clear (Abstracts 205, 206).

The most serious possible complication of therapy would be, without a doubt, an increase in cardiovascular morbidity as a result of blood lipid abnormalities. With this in mind, large American and international groups (including over 25,000 subjects to be evaluated over two years or more) with academic and corporate participation have been established to address this issue. Assuming 100 clinical endpoints, this study will be appropriately powered ( =0.90, =0.05) to address the issue of linking specific therapies with cardiac morbidity.

A number of studies have been done to evaluate the relative benefits and risks of switching from a PI to an NNRTI-based regimen in the face of maximal virologic suppression. In one such study, 40 patients were changed from a PI (IDV in 60%) to NVP and followed for 24 weeks (Abstract 45). Although 7 patients developed a rash and were changed from NVP to EFV, only a single individual experienced a virologic breakthrough over the period of observation. In a study of 80 patients randomized to continue PI-based therapy vs. a change to a complex regimen of abacavir (ABC), NVP, adefovir (ADV) and hydroxyurea (HU) showed no difference in maintenance of virologic suppression (81% vs. 94% respectively) over 24 weeks (Abstract 205). In 60 patients randomized to continue d4T/3TC/PI or d4T/ddI/NVP, 87% vs. 90%, respectively, maintained suppression (Abstract 206). Finally, in a study of 138 patients (104 switched to NVP and 24 maintained on their PI-based regimen), viral rebound occurred in 11%, vs. 29% in the other group. The risk of virologic breakthrough appears similarly small if the PI is switched to EFV, as evaluated in three studies totalling over 100 patients (Abstracts 48, 49, 50.

Salvage Therapy
NNRTI will play a key role in the design of salvage therapy regimens. In many cases, the regimens will include combinations of drugs from all three classes, and it is important to understand the pharmacokinetic interactions that may be present. Some have advocated the use of two NNRTI, an approach that will be evaluated in clinical trials. The first rigorous data show that NVP lowers EFV trough concentrations by 36% (Abstract 80). This suggests that if the two agents are used together, EFV dosing should be increased to 800 mg /day. EFV itself has been shown to decrease the blood levels of many PI, an interaction that may limit our therapeutic options. The addition of ritonavir (RTV) to the combination of EFV/amprenavir (APV) (Abstract 78) or EFV/saquinavir (SQV) (Abstract 79) largely overcomes this effect, and may even allow us to consider once daily administration of EFV/APV/RTV, given the appropriate model. In contrast, DLV has a more positive pharmacokinetic interaction with PI. It has now been shown that the combination of DLV 600 mg/SQV (soft gel capsule) 1400 mg bid produces adequate drug levels of both agents (Abstract 82). Similarly, the combination of DLV with reduced-dose IDV (600 mg tid) produces adequate drug levels while preserving virologic efficacy (Abstract 535).

With respect to clinical trials, it is quite instructive to review the results of ACTG 359 (Abstract 235), a study conducted in NRTI/PI-experienced, NNRTI-naive individuals (n=277, baseline CD4 count 229 cells/mm³, plasma viral load 31,746 copies/mL). Among the six study groups, all patients received SQV (soft gel capsule), with half also receiving RTV and half also receiving NFV. For each double-PI combination, subjects were assigned to receive DLV, ADV, or both. At 16 weeks, 30% had maximal virologic suppression (<500 copies/mL), with 59% of this group maintaining suppression to week 48. There was no difference in response rates according to the PI component of the regimen, nor did the addition of ADV play a significant role. However, the use of DLV was predictive of success (p=0.003). In ACTG 364 (Abstract 531), NRTI-experienced individuals were randomized to receive two new NRTI with NFV, EFV or both (n=195, baseline CD4 count 389 cells/mm³, plasma viral load 7,776 copies/mL). The NFV/EFV combination produced superior virologic suppression (<50 copies/mL at 40-48 weeks) with 67% success, as compared to 22% and 44% in the NFV and EFV groups, respectively. In the randomized portion of ACTG 370 (Abstract 525), patients having previously received two NRTI (including 3TC) were randomly assigned to receive ZDV/3TC/IDV or ZDV/DLV/IDV (n=64, baseline CD4 count 461-528 cells/mm³, plasma viral load 3,300-3,500 copies/mL). Although prior 3TC exposure limits our ability to evaluate these results, 70% patients receiving DLV had plasma viral loads below 50 copies/mL after 48 weeks, as compared to only 40% in the other group. In ACTG 373 (Abstract 526), the combination of d4T/3TC/NVP/IDV was given to APV-experienced patients (n=56, baseline CD4 count 346 cells/mm³, plasma viral load 15,488 copies/mL). It is quite heartening that on this triple-class regimen, 33 (59%) individuals had plasma viral loads below 500 copies/mL. In CNA2007, the combination of ADV/ABC/EFV was used as a focused approach to salvage therapy in patients naive to all three agents (n=101, baseline CD4 count 160 cells/mm³, plasma viral load 122,000 copies/mL). Overall, 39% NNRTI-naive patients with baseline plasma viral load levels below 40,000 copies/mL had maximal virologic responses (<500 copies/mL at 48 weeks), as compared to only 3% individuals who were previously exposed to NNRTI and had higher viral loads. Interestingly, intermediate response rates (28-33%) were observed in patients who had lower viral loads at entry or were NNRTI-naive, emphasizing the importance of both factors in determining the response to therapy. Overall, the enhanced efficacy of NNRTI in salvage therapy has been repeatedly demonstrated. It has now been suggested that up to 30% of viral isolates may be "hyper-susceptible" to the NNRTI (>2.5-fold decrease in IC50) as a result of prior exposure to NRTI's, and as a function of the number of NRTI resistance mutations that have developed (Abstract 526). The clinical significance of this phenomenon remains to be conclusively demonstrated.

In children, the combination of NRTI's/EFV/NFV has been administered to 19 NRTI-experienced children (baseline CD4 count 706 cells/mm³, plasma viral load 40,000 copies/mL). The liquid suspension of EFV was quite well tolerated, and 11 patients had plasma viral load levels below 50 copies/mL after 48 weeks.

Conclusion

The role of NNRTI in clinical practice continues to expand. They are clearly useful in first line therapy, especially in populations such as IVDU. The risk of primary drug resistance due to wider use of these agents is a real possibility, and monitoring must be in place to detect it. It has now been identified that long-term use of PI may be associated with specific metabolic and morphologic changes, and that these seem to occur less frequently when non-PI-based regimens are used, especially if these include NVP. It is possible that EFV may itself be associated with such toxicities, and this will be clarified over the next year. Further, in patients who have an optimal virologic response to PI-based therapies and who do experience these changes, the substitution of the PI for NVP (and, to a lesser extent, EFV) may reverse some of the metabolic changes without significant likelihood of virologic breakthrough. Finally, NNRTI will play a key role in salvage therapy in adults and children. All clinical trials completed to date show a clear added value of the NNRTI in any regimen, such that it should always be included unless there is a specific reason to avoid it. Among the NNRTI, DLV may have a special role, due to its positive pharmacokinetic interactions with the PI, especially SQV and IDV.

In conclusion, NNRTI represent an exciting class of drugs that have a clear role to play at all stages of antiretroviral therapy. Further research will help refine their use in clinical practice.