The non-nucleoside reverse transcriptase inhibitors (NNRTIs) attack the same HIV enzyme as the nucleoside analogue drugs such as AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC), d4T (stavudine, Zerit), abacavir (Ziagen) and 3TC (lamivudine, Epivir), but in a different way, binding onto reverse transcriptase to prevent it from working.

There are three NNRTIs now available through various routes: nevirapine (trade name Viramune), efavirenz (Sustiva), and delavirdine (Rescriptor) . Nevirapine and efavirenz are licensed drugs, and delavirdine is available through expanded access schemes and clinical trials. Another NNRTI, loviride (Lotrine), was assessed in clinical trials but has now been abandoned.

Comparing efficacy

A large, international presented in early 2003 at the Tenth Conference on Retroviruses and Opportunistic Infections suggested that nevirapine-based regimens are not inferior to efavirenz-based regimens. The 2NN study found no significant difference in the antiviral efficacy of efavirenz and once and twice daily nevirapine when taken with d4T and 3TC after 48 weeks of treatment (Van Leth 2003). CD4 rises were also similar.

Another smaller study directly comparing efavirenz with nevirapine has been conducted. This study found no significant difference between the two treatment arms, with about 80% of both groups achieving viral loads below 50 copies/ml, although a small number of the nevirapine group had viral loads between 50-500 copies and there was a trend to a stronger CD4 response in the nevirapine group. However, the study does not shed any light on the relative potency of these drugs among those with high viral loads because individuals with baseline viral loads above 100,000 were excluded (Nunez 2002).

Two non-randomised studies have reported long-term comparative data on efavirenz and nevirapine. A meta-analysis of studies involving over 3000 people who started therapy with efavirenz or nevirapine plus two nucleoside analogues found the two NNRTIs to be equivalent after one year of therapy (Neuwelt 2003). However, data collected by the Chelsea and Westminster Hospital in London on 694 people who commenced treatment with efavirenz or nevirapine since 1996 has favoured efavirenz. Multivariate analysis showed nevirapine was a risk factor for virological failure or switch relative to efavirenz (risk hazard 1.6) (Matthews 2003).

Comparing side-effects

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

Around 16% 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, or perhaps with corticosteroids. However, in about 7% of people who take the drug 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 18% of people who take delavirdine develop a rash within two to four weeks of starting treatment, leading to discontinuation in less than 5%. The delavirdine rash is less severe and more people may be treated through this side-effect than with nevirapine.

The main side-effects of efavirenz are dizziness, rash and diarrhoea during the first few weeks of treatment. The latter two are each reported by 10-15% of people taking part in trials of the drug. Mental changes, feelings of sedation, bad dreams, and suicidal thoughts have been reported as part of a 'syndrome' of central nervous system effects, which affect up to half of those who take the drug. However, it is rare that these side-effects have caused people to stop treatment. Efavirenz may cause foetal abnormalities. These have been noted in animal experiments, and so the drug is not recommended for women unless you are using a form of contraception which will not interact with any of the HIV medications you are taking.

Rash is a side-effect that has been seen with all NNRTIs, and a recent UK study found no significant difference in the rate of rash between nevirapine and efavirenz-treated patients, although rash was more likely to lead to discontinuation of nevirapine than efavirenz.

The retrospective study included an analysis of the charts of 285 people treated with nevirapine between January 1997 and January 2000 and 52 people treated with efavirenz between June 1999 and January 2000. The sample included 103 women and 160 people of black ethnicity. The average CD4 count at the commencement of treatment was 215 cells/mm³, and viral load was on average 20,000 copies/ml.

A history of previous drug allergy was reported by a little under 7% of the study sample and rash by 19 people (5.6%).

The investigators found that nineteen people (6.7%) treated with nevirapine and three (5.8%) of those treated with efavirenz developed a rash. The nevirapine-associated rash tended to develop within six week of starting therapy, whilst all the efavirenz-associated rashes developed within two weeks of treatment being initiated. Treatment was discontinued by thirteen of those treated with nevirapine and by one of the those receiving efavirenz. Nine of the people who stopped taking nevirapine because of rash were able to switch to efavirenz without a recurrence of the allergic reaction.

Being a woman was found to be significantly associated with the development of an allergic rash, with an incidence of 14.6% compared to 3% of men. This difference was statistically significant. Initial analysis found that being black was also a predictor for the development of a rash, with 8.8% of people of black ethnicity experiencing the side-effect compared to 4.7% of white people. However, once the figures were adjusted for sex, the difference ceased to be statistically significant (Mazhude 2002).

The life-threatening (though very rare) Stevens Johnson Syndrome has been reported as a side-effect of all NNRTIs, most commonly with nevirapine (0.03% incidence).

A retrospective chart review of 288 people in Canada who commenced an NNRTI found the following rates of rash: 15% (27/184) efavirenz; 10% (9/91) nevirapine, and 46% (6/13) delavirdine. Only ten people were required to permanently stop NNRTI treatment due to rash (Tsoukas 2003).

Nevirapine is no more likely to cause liver toxicity than other antiretrovirals, according to a comparison of patients who received nevirapine versus other drugs conducted by manufacturer Boehringer Ingelheim (Stern 2002). Data from over 1700 nevirapine-treated patients and 1900 control patients who took part in Boehringer Ingelheim-sponsored clinical trials was analysed together with information from 814 people treated with nevirapine in other trials. In addition, over the records of over 5000 patients enrolled in observational cohorts were analysed for risk factors of hepatic side-effects.

Investigators found that asymptomatic hepatic side-effects, indicated by increases in ALT/AST levels occurred in between 0.5% and 9% of people participating on Boehringer trials, and were comparable to the levels observed in the control populations (up to 7.5%). A CD4 count above 400 cells/mm³ in men and 250 cells/mm³ in women was identified as a risk factor.

Symptomatic liver toxicities were rare in people treated with nevirapine (between 1% and 5% of people participating in Boehringer trials) and were not significantly higher than those observed in controls. Investigators also noted that hepatic toxicities ceased with the discontinuation of nevirapine treatment and were associated with a rash in 46% of people. There were insufficient data to determine if elevated ALT/AST levels at baseline or coinfection with hepatitis B or C increased the chances of liver toxicities or rash.

The large, prospective 2NN study found significantly more severe liver enzyme elevations in people taking once daily nevirapine (400mg) versus once daily efavirenz. However, the twice daily nevirapine regimen was not associated with a greater risk of serious liver toxicity when compared to efavirenz. Combining the two NNRTIs together produced an even higher rate of serious liver toxicity than once daily nevirapine, and this combination is not recommended (Van Leth 2003).

The other key side-effect finding of the 2NN study was the improved lipid profile among nevirapine versus efavirenz recipients after 48 weeks of treatment. HDL or 'good' cholesterol improved by a greater degree among people taking nevirapine and there was a significantly greater decrease in the total cholesterol to HDL cholesterol ratio (associated with risk of cardiovascular disease) in the nevirapine group.

Dosing comparisons

Efavirenz is taken once daily. Nevirapine is taken twice daily, but once daily dosing is being investigated. Once daily nevirapine seems to be as effective as the twice daily dose (Felipe 2000). In the 2NN study, the percentage of patients with undetectable viral load after 48 weeks of treatment was 56.4% among those taking once-daily nevirapine and 56.3% among those taking twice daily nevirapine (Van Leth 2003).

Delavirdine is currently recommended as a three times daily drug, but was being tested as a twice daily new formulation (to reduce the number of tablets which must be taken), but there is a question mark over the drug's further development. If you find the tablet difficult to take, you can dissolve delavirdine with water or cola. Delavirdine cannot be taken at the same time of day as ddI.

Resistance to non-nucleoside reverse transcriptase inhibitors

Resistance to NNRTIs develops rapidly when viral replication is detectable. 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.

The use of NNRTIs in drug sequencing is thus a high-risk strategy, because of the risk of cross-resistance with currently available drugs. Further information on this subject is discussed in Resistance to non-nucleoside reverse transcriptase inhibitors in Anti-HIV therapy: Resistance .

Combining non-nucleoside reverse transcriptase inhibitors

There has been little research into dual NNRTI combinations, primarily due concerns about an increased risk of rash and other side-effects.

The presentation of the 2NN study in early 2003 confirmed these fears. The study found that more people taking nevirapine and efavirenz together experienced severe liver toxicity compared with those taking either drug alone (Van Leth). It was hoped that taking two NNRTIs together would have a more powerful virological effect, but this was not borne out. Between 56-62% of patients who took either efavirenz or nevirapine achieved a viral load below 50 copies/ml compared with only 47% of the efavirenz/nevirapine group. The poorer outcomes were attributed to the higher rate of side-effects and the associated high drop-out rate. Leading researcher Professor Joep Lange of the University of Amsterdam Academic Medical Centre said that the study showed that nevirapine and efavirenz should not be used together.

Other dual NNRTI studies are preliminary test-tube studies or uncontrolled, multi-drug studies. One small, pilot study of nevirapine/efavirenz/ddI was reported at the 2000 International AIDS Conference (Jordan). Results were encouraging: 9/11 treatment-experienced individuals and 12/15 previously untreated individuals achieved viral loads below 400 copies HIV RNA after nine months. This was despite a drug interaction which reduced concentrations of efavirenz.

Combinations with protease inhibitors

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

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

• Favourable drug interactions: for example delavirdine boosts blood levels of certain protease inhibitors because they are metabolized by the same enzyme pathway in the liver.

• Such combinations may be particularly attractive to people with a lot of experience of NRTIs, and who may not expect to benefit fully from other drugs in this class.

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 hard gel 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 substantially, but increases nelfinavir levels by 100%. However, nelfinavir reduces delavirdine blood levels by 40%, so dose adjustment of delavirdine will be necessary. Recipients of the nelfinavir/delavirdine combination also seem to be at increased risk of neutropenia (shortage of neutrophils).

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.

As noted above, efavirenz has shown strong anti-viral effects when combined with indinavir (Staszewski), and it is known to boost blood levels of nelfinavir and decrease levels of saquinavir. A randomised, open-label study of indinavir/ritonavir/efavirenz with or without d4T has found equivalent efficacy after one year in 93 treatment-naive people. Intent-to-treat analysis showed 72% of each arm below 400 copies/ml at week 48, and 53% of the PI/efavirenz arm and 61% of the d4T arm below 50 copies/ml (Stek 2003).

References

Felipe G et al. An open randomized study comparing d4T + ddI + nevirapine (qd) vs dd4T + ddI + nevirapine (bid) in antiretroviral naive chronic HIV-1 infected patients in very early stages: Spanish scan study: final results. Thirteenth International AIDS Conference, Durban, abstract A1156, 2000.

Jordan WC et al. Nevirapine (NVP)+efavirenz (EFV)+didanosine (ddI): a very simple, safe, and effective once-daily regimen. Thirteenth International AIDS Conference, Durban, abstract B3207, 2000.

Matthews G et al. Durability of efavirenz compared to nevirapine with long term follow-up of an antiretroviral-naive patient cohort. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 561, 2003.

Mazhude C et al. Female sex but not ethnicity is a strong predictor of non-nucleoside reverse transcriptase induced rash. AIDS 16(11): 1566-1568, 2002.

Neuwelt MD et al. Systemic review of nevirapine-versus efavirenz-containing three-drug regimens for initial treatment of HIV infection. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 552, 2003.

Nunez M et al. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clinical Trials 3(3):186-194, 2002.

Stek M et al. Comparison of PI-boosted indinavir with efavirenz plus stavudine regimens in EASIER (European and South American Study of indinavir, efavirenz, and ritonavir). Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 39, 2003.

Stern JO et al. Hepatic safety of nevirapine: results of the Boehringer Ingelheim Viramune hepatic safety project. Abstract LBOr15, Fourteenth International AIDS Conference Barcelona, 2002.

Tsoukas C et al. The effect of cutaneous drug reactions to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on maintenance of NNRTI based therapies. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 695, 2003.

Van Leth F et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 363(9417):1253-63, 2004.