EACS: Nevirapine studies highlight new first-line uses

Despite a recent decline in the popularity of nevirapine as a first-line NNRTI, researchers are still investigating ways of using it in first-line treatment. Several studies reported at last week's Eleventh European AIDS Conference (EACS) in Madrid highlighted ways in which it might continue to be used - and one way it shouldn't be used.

Once-daily nevirapine

Quite apart from the prescribing restraints on nevirapine that confine its use to women with baseline CD4 cell counts below 250 cells/mm³ and men with CD4 counts below 400 cells/mm³, nevirapine (Viramune) has always suffered in comparison with efavirenz (Sustiva) because it must be taken twice daily. The 2NN study showed a trend towards a higher rate of grade 3 and 4 liver toxicity in the once-daily group, and this has limited once-daily use despite the drug's long half-life.

A recent study found that starting patients on nevirapine once-daily as opposed to the licensed twice-daily dose led to an increased risk of treatment failure – see this report. Another recent study reported found that adherence rates did not improve in patients taking nevirapine once a day and that the number of drug-free days increased by 70 per cent.

However a retrospective analysis of a UK patient cohort presented at the European AIDS Conference suggests that patients who switch from twice-daily to once-daily nevirapine do not risk failure, and in fact no patient failed treatment on once-daily nevirapine. Another found that switching from a conventional Kaletra plus two NRTIs regimen to nevirapine plus atazanavir (though the nevirapine was twice-daily) resulted in improved virological control.

However a report of a third trial of once-daily tenofovir/FTC/nevirapine, which was terminated early after very high failure rates, suggests that nevirapine may be a ‘fragile’ drug to start patients with.

The cohort study was an analysis of patents at St Mary’s Hospital in west London of all patients who started HIV therapy on nevirapine plus two nucleosides, one of which had to be 3TC (lamivudine, Epivir) or FTC (emtricitabine, Emtriva), between January 2002 and January 2006.

One hundred and seventy-nine patients started therapy with nevirapine-based regimes during this period. They all started on nevirapine twice-daily, but during the four years of the study over one in four – 49 patients or 27.7% - switched to taking it once a day. The average time taken to switch to the once-daily drug was 576 days (19 months).

The patient group had a wide range of CD4 counts when starting, ranging from 10 to 540 cells/mm³– the latter being way beyond the maximum CD4 count of 250 in women and 400 in men recommended by the ‘black box’ warning for the drug. Nearly half (46%) of the patients were women.

The average viral load on starting was 96,000, again with a wide range from 80 to six million.

The NRTIs they used comprised AZT/3TC (68%), tenofovir/FTC (14%), tenofovir/3TC (10%), abacavir/3TC (6%) and d4T/3TC and ddI/3TC 1% each.

Over four years, three-quarters of patients remained on nevirapine one- or twice-daily. Of the 24% who stopped, a quarter did so because of virological failure and the rest for ‘other’ reasons, largely toxicity. Those who stopped nevirapine largely did so early on - the average time to stopping nevirapine was 252 days (eight months). This, plus the fact that 56% of patients who stopped nevirapine remained on the same NRTIs, suggesting that many discontinuations were due to early toxicity.

An analysis was done of the viral load of patients 48 weeks after starting their nevirapine-based regimen, at which point 85% of patients had viral loads under 50 copies/ml, and the average CD4 rise was 204. There was no significant association between treatment failure and baseline CD4 count or the NRTIs taken while baseline viral load may have had some influence, but was not statistically significant (p=0.07).

By this time 23 patients (13%) had switched to once-daily nevirapine. None of these patients failed – in short, 100% of patients on once-daily nevirapine once a day had viral loads under 100 copes/ml compared with 85% on twice-daily nevirapine. This fell just short of statistical significance (p=0.051).

Because this is a retrospective cohort study the causation for the apparently greater success of patients on once-daily nevirapine cannot be established, and numbers were small. However it does appear to show that switching to taking the drug once-daily may be safe.

Nevirapine/atazanavir

Switching to an atazanavir/nevirapine NRTI-sparing regimen also showed some promising results in a small Italian study, and appeared superior to remaining on a conventional Kaletra plus two NRTIs regimen.

In the NEVATA study 60 patients who had maintained a viral load below 40 copies/ml for over six months were randomised either to stay on Kaletra plus NRTIs or switch to atazanavir plus nevirapine.

Forty-eight weeks after the switch, 27/28 patients on ATZ/NVP maintained viral undetectability (96%) compared with 20/27 (71%) on Kaletra/NRTIs. This was statistically significant (p = 0.025). There was a trend towards higher CD4 counts on Kaletra (540 versus 495) but this was not significant. Total and LDL-cholesterol fell in patients on ATZ/NVP, though not significantly, while triglycerides fell significantly and HDL (‘good’) cholesterol rose significantly. Glucose and insulin levels were also significantly higher in patients on Kaletra/NRTIs. ‘A Quality of Life’ questionnaire administered at weeks 12, 24 and 48 revealed significant increases in patients’ perception of overall health and their role function (ability to do things).

One patient on Kaletra/NRTIs discontinued to drug-related toxicity (unspecified) while two patients on nevirapine/atazanavir had severe nevirapine drug reactions, though these were both managed and neither discontinued the drug.

In contrast, an Italian study intending to compare nevirapine plus tenofovir/FTC (Truvada) with tenofovir, FTC and atazanavir/ritonavir was stopped very early when high failure rates were seen in patients on the Truvada arm. The findings underline those of the DAUFIN study reported earlier this year, which found a similar high failure rate using the same combination in French patients.

Patients in this study took nevirapine twice daily, not once daily, so this is not the explanation for the failure rates. Truvada plus nevirapine is used as an alternative initial regimen in the UK and high failure rates have not been noted, so the cause remains mysterious.

The intention had been to recruit 60 patients for each arm but it was stopped at twelve weeks after only 16, seven taking Truvada and nine atazanavir, had been enrolled, because three out of the seven on Truvada experienced viral rebound at 12 weeks.

Two patients on Truvada/nevirapine discontinued, one after eleven days because of fever and severe rash, and one after four weeks because of liver toxicity, meaning that only two out of seven patients on Truvada/nevirapine maintained undetectability.

All three of the patients who failed on Truvada had baseline viral loads over 100,000. In contrast the two patients on atazanavir who had viral loads over 100,000 did not fail. Of the three that failed, none had viral loads below 1,000 copies/ml at week four, and by week twelve these had rebounded in all cases to 25,000-30,000 copes/ml. All three patients developed resistance mutations to nevirapine, one developed the M184V 3TC/FTC resistance mutation and one the K65R tenofovir/abacavir resistance mutation.