AIDS Treatment Update, Issue 55, July 1997
Keith Alcorn

There are four NNRTIs now available through various routes: nevirapine (Viramune), delavirdine (Rescriptor), loviride and DMP-266.

Nevirapine and delavirdine are already licensed in the United States, and licence applications are being considered for these drugs in Europe this year. Loviride and DMP-266 are still undergoing clinical trials; a trial of DMP-266 recently started in the UK, and an expanded access scheme will make the drug available to people with few treatment options later this year.

When should NNRTIs be used?

NNRTIs may give their best results when given in combination with at least two other drugs. They may also be more effective is used by people who are starting treatment for the first time, rather than as second- or third-line treatment. This view is based on a comparison of the effect of combinations which include nevirapine and delavirdine in separate studies among people who have taken treatments before and among those who have not.

In one study among previously untreated people, known as BI 1046 or the INCAS study, those treated with the triple combination of AZT/ddI/nevirapine had a good response. After 48 weeks the average CD4 count of those on the triple combination had risen by +148 from its baseline level of 376. 51% of people on this combination had viral load below 20 copies after 52 weeks of treatment, from an average baseline of about 26,000.

In a study among drug-experienced people, however, the effects of NNRTI treatment were less dramatic. In ACTG 241, people who had taken AZT were randomised to receive AZT/ddI or AZT/ddI/nevirapine. After 48 weeks of treatment even those on the triple combination had CD4 counts which had almost returned to the average level on entry to the study.

Everyone who joined ACTG 241 had taken AZT for at least six months. Two-thirds had taken either AZT/ddI or AZT/ddC prior to entering the study, and the average period of prior nucleoside treatment was 25 months. In other words, many people joined ACTG 241 because their current treatment regimen was failing, and added just one drug to a failing combination. This practice is now considered to be a sub-optimal form of treatment.

Some doctors believe that the most important factor that predicts the effectiveness of NNRTIs may be the number of new drugs you start, rather than whether you have taken any anti-HIV drugs before. For instance, even the previously untreated participants in the INCAS study had a disappointing response to the double combination of AZT/nevirapine.

Likewise, drug-experienced people may derive much greater benefits from switching to a combination that includes an NNRTI if they also start at least one other new drug at the same time. In ACTG 241, better and more sustained average viral load reductions were seen among AZT/ddI/nevirapine recipients who had never taken either ddI or nevirapine before, compared with the whole group of triple combination recipients, many of whom had already taken both AZT and ddI. Good results have also been seen in pilot studies in which NNRTIs were combined with protease inhibitors (see page 4).

Delavirdine doubts?

Doubts about the antiviral effects of delavirdine were expressed by expert advisers to the US licensing authorities when the drug was first considered for approval in late 1996, and licensing was delayed (see AIDS Treatment Update issue 48/49). But this had much to do with the design of the studies used to seek licensing approval, none of which tested delavirdine as part of a triple combination.

In contrast, nevirapine has been tested in several large trials of three drug versus two-drug combinations (see issue 43). While studies of triple combinations that include delavirdine are now under way, at present there are no data which would allow us to compare the long-term suppressive effect of delavirdine or nevirapine in three-drug combinations.

Side-effects

Rash is a side-effect common to all the NNRTIs, although it occurs with differing severity and frequency between drugs.

Many people taking loviride report gastrointestinal problems in the first few months of treatment, but these side-effects usually go away. Severe rash occurs in a small minority of people who take the drug, but it will disappear if treatment is discontinued.

Around 20% of people taking nevirapine are likely to develop a rash within two to four weeks of starting treatment. In many cases the rash can be treated with anti-histamines. However, in about 7% of people who take the drug a more a more serious form of the rash may develop, which may lead to fever and ulcers of the mouth and mucous membranes and requires the discontinuation of treatment. This form of severe reaction may indicate that you will be unable to tolerate delavirdine too.

Around one third of people who take delavirdine develop a rash within two to four weeks of starting treatment.

NNRTIs and resistance

Resistance to NNRTIs develops rapidly when a substantial level of viral replication is taking place. In the case of each drug, only one mutation is required for HIV to become much less sensitive. In some cases there is a high degree of cross-resistance between NNRTIs, meaning that if you develop resistance to one NNRTI, you may also be resistant to others.

Based on these concerns, some experts argue that it may be unwise to include NNRTIs in a first-line combination unless the aim of treatment is to achieve very low (i.e. below detectable) levels of viral replication, which may prevent or delay the emergence of resistance.

NNRTIs and the risk of cross-resistance

In the past, concern has been expressed that use of one NNRTI might lead to cross-resistance to all other NNRTIs in the future. Current evidence suggests that this may sometimes -- but not always -- be the case.

Resistance to delavirdine develops quickly when the drug is used alone. In test-tube studies, some of the HIV mutations that confer resistance to delavirdine also confer resistance to nevirapine and other NNRTIs. These mutations appear at specific positions in HIV's reverse transcriptase enzyme, known as codons 103 or 181. However, in some cases resistance to delavirdine develops due to a mutation at codon 236; in these cases, HIV remains sensitive to other NNRTIs. However, clinical studies show that the codon 103 and 181 mutations tend to emerge before the codon 236 mutation, suggesting that there is little prospect of benefiting from nevirapine once delavirdine resistance has emerged.

Nevirapine resistance also develops quickly when the drug is used alone or in combination with one nucleoside analogue. However, a sub-analysis of the INCAS study suggested that the emergence of resistance to nevirapine may be less likely among people taking AZT/ddI/nevirapine, compared with those taking AZT/nevirapine. Resistance emerged in the triple combination recipients mainly amongst those who had missed doses frequently.

If resistance to nevirapine develops through mutations at codons 103 or 181, cross-resistance with other NNRTIs will result, but if mutations occur at codons 188 or 190, HIV may remain sensitive to delavirdine. Resistance to loviride seems not to emerge quickly, but when it does develop, it appears to cause cross-resistance with all other NNRTIs.

The use of NNRTIs in drug sequencing is thus a high-risk strategy, because of the risk of cross-resistance with currently available drugs (although cross-resistance may be less of a problem with DMP-266).

Protease inhibitor combinations

Certain NNRTIs may prove attractive drugs to combine with some protease inhibitors. There are two arguments for doing this:

* the drugs target different stages of HIV's life-cycle, which may increase the anti-viral impact

* delavirdine boosts blood levels of certain protease inhibitors because they are metabolised by the same enzyme pathway in the liver (see issue 51)

Delavirdine reduces the rate at which indinavir and saquinavir are cleared from the body. This boosts saquinavir levels five-fold, which is desirable given the relatively poor absorption of saquinavir. Elevated liver enzymes were seen among some people who took this combination, so it may be problematic in people with existing liver problems.

Delavirdine increases indinavir levels by up to two-fold; this may not be desirable because it may increase the risk of indinavir-related kidney stones, so it may be advisable to reduce the dosage of indinavir to 600 mg three times daily. Delavirdine appears not to affect levels of ritonavir. No data is yet available on interactions between delavirdine and nelfinavir. There is no increase in delavirdine levels when it is co-administered with protease inhibitors.

Nevirapine may reduce blood levels of saquinavir, so it is not recommended to combine these drugs unless the saquinavir dose is increased. It also reduces levels of nelfinavir and indinavir, requiring the dose of the protease inhibitor to be increased to 1000 mg three times daily. Nevirapine reduces levels of ritonavir a little, but not enough to require any dose modification.

Combining NNRTIs and protease inhibitors may be a useful option for heavily drug-experienced people. In a small study in Vancouver, 21 nucleoside-experienced people whose average CD4 count was below 50 and average viral load was above 100,000 took nevirapine, indinavir and 3TC; all three drugs were new to them. After 20 weeks, their viral load had fallen by an average of -3.12 log, their CD4 counts had increased by an average of +75, and 56% had viral load below 400. Three people withdrew due to side-effects.

DMP-266 - a new NNRTI

A new NNRTI is now available through a clinical trial in the UK, and an expanded access scheme is planned for later this year. DMP-266 can be taken once a day and seems to be well tolerated, although side-effects of rash and dizziness have been reported.

DMP-266 has shown strong anti-viral effects when combined with indinavir in a pilot study. To date, 15 people have completed 42 weeks of treatment with indinavir and DMP-266; three-quarters of them had taken nucleoside analogues before, and at baseline their average CD4 count was 270 and their average viral load was about 100,000. At 42 weeks they showed an average increase in CD4 count of +140 and an average reduction in viral load of -2.5 log; 90% of participants' viral load had decreased to below 400. Information about resistance is limited, but nevirapine-resistant HIV is still sensitive to DMP-266 in the test-tube.

Key conclusions

* NNRTIs work best when used with at least one and ideally two other new drugs

* You may only be able to benefit from an NNRTI once due to the risk of cross-resistance

* It may therefore be best to use the drug as part of a regimen which aims for maximum viral suppression, and thus may reduce the chances of resistance

Trials of NNRTIs now recruiting

Drug Study arms Inclusion Centres criteria

Clinics in Belfast, Current therapy Birmingham, plus 3TC & Currently Brighton, Delavirdine delavirdine vs. taking Glasgow, current therapy AZT/ddI or London, plus 3TC & placebo AZT/ddC. Manchester and Nottingham

Current therapy plus 3TC & Currently Clinics in Nevirapine nevirapine vs. taking AZT Brighton, current therapy and/or ddI London and plus 3TC & placebo or ddC. Manchester

CD4 above 50. Viral DMP-266/indinavir load above vs. 10,000. No Kobler DMP-266 AZT/3TC/indinavir prior use Centre, vs. of NNRTIs, Royal Free AZT/3TC/DMP-266 protease and Brighton inhibitors or 3TC.

Current availability of NNRTIs outside clinical trials

Drug Availability Contact for Doctors criteria

Anyone failing on current Hugh Devine, Pharmacia & Delavirdine therapy. Must be Upjohn Medical Division. used in Tel. 01908 603068 combination.

Anyone suffering disease progression with CD4 below 350. Must be used in combination with John Drake, Nevirapine two other drugs. Boehringer-Ingelheim. Tel. If failing on 01344 741468 current therapy it is recommended you switch all drugs.

Only available for people who have received loviride in Loviride clinical trials Not applicable to continue treatment after the trial has ended

None. See trial DMP-266 details on page Not applicable 2.

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