Effectiveness

Efavirenz (Sustiva) is a powerful anti-HIV drug that must be taken in combination with other antiretroviral drugs. It has been proven to reduce HIV-1 viral load to below 400 copies/ml within six months in 60 to 80% of people who have not previously taken any HIV treatments. Efavirenz is not active against HIV-2.

Efavirenz’s potency was demonstrated in study 006, in which efavirenz was found to be superior to indinavir (Crixivan), when either drug was combined with AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir). After three years, more patients taking efavirenz maintained viral suppression, even in patients with viral loads above 300,000 copies/ml before treatment began.1 Researchers have estimated that the average time to virological failure on efavirenz, AZT, and 3TC is six years, based on long-term follow-up of this study.2

Efavirenz-based treatment is also effective in patients starting therapy with CD4 cell counts below 100 cells/mm3. 3 However, its efficacy has not been assessed in patients starting with CD4 cell counts below 50 cells/mm3 or after failure of protease inhibitor-containing regimens.

A large-scale, comparative study called ACTG 384, was completed in 2002. It found that efavirenz, AZT and 3TC was the preferred first-line therapy in terms of antiviral efficacy and toxicity after 144 weeks of follow-up.4 5 In addition, two observational studies have suggested that people taking efavirenz are more likely to achieve and sustain undetectable viral load than those taking a protease inhibitor.6 7 Similarly, a retrospective study based in San Francisco has shown that first-line anti-HIV drug regimens containing efavirenz give better survival outcomes than any other combinations available prior to 2002.8 Another randomised study, which compared efavirenz with d4T (stavudine, Zerit) and ritonavir (Norvir)-boosted amprenavir (Agenerase) when taken in combination with AZT and 3TC, has also favoured efavirenz as first-line treatment.9 Similarly, efavirenz is more likely to suppress viral load than the protease inhibitor nelfinavir (Viracept) when combined with d4T and ddI (didanosine, Videx), although the two drugs have similar immunological outcomes.10

There is some dispute about the comparative efficacy of the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine (Viramune). The randomised 2NN study showed that nevirapine was not inferior to efavirenz, although the participants taking efavirenz experienced fewer side-effects.11 Quality of life was also similar in patients taking nevirapine and efavirenz.12 Despite this, based on several large cohort studies that have found efavirenz to be superior to nevirapine in terms of efficacy and rebound rates, United States treatment guidelines recommend efavirenz as the preferred NNRTI in first-line treatment.6 13 14 15 British guidelines do not endorse efavirenz as the superior NNRTI, and suggest that drug choices should be individualised.

There is a growing body of research indicating that switching to efavirenz from a protease inhibitor is an effective strategy. For example, one large, randomised study found that the likelihood of adhering to the drug regimen and maintaining viral suppression after one year was greater among people who substituted efavirenz for a protease inhibitor than those who continued on protease inhibitor therapy.16 Results from the Swiss HIV Cohort also indicate that people who switch from a protease inhibitor to efavirenz are more likely to maintain virological control one year after switching, although a recent study has suggested that this may be due to better adherence associated with an regimen that is easier to take.17 18

Further information on this came from results of ACTG 5142.19 This is a multicentre open-label randomised 96-week study of 753 treatment-naive patients with viral load over 2000 copies/ml and any CD4 count. At the start of the study, the median viral load was approximately 100,000 copies/ml and the median CD4 cell count was 182 cells/mm3, suggesting that the study population had relatively advanced HIV disease, and was starting treatment somewhat later than current guidelines recommend.

Patients received one of three regimens: efavirenz + 2 NRTIs, Kaletra (LPV/r) + 2 NRTIs, or an NRTI-sparing combination of efavirenz and Kaletra. The NRTI options were 3TC or FTC combined with stavudine (d4T), TDF, or zidovudine (ZDV).

By intent-to-treat analysis, 89% of the participants receiving efavirenz-based triple therapy had viral loads below 50 copies/ml after 96 weeks, as compared with 77% receiving Kaletra-based triple therapy.

The researchers were unclear why fewer participants on Kaletra-based triple therapy achieved viral loads below 50 copies/ml at week 96, compared with those on efavirenz-based triple therapy, since they found that the time to treatment-limiting toxicity was similar for all arms, and the proportion of grade 3 or 4 clinical adverse events was similar in each arm, at around 20%.

There is evidence to suggest that efavirenz penetrates the cerebrospinal fluid that surrounds the brain and the spinal cord, and that it may be effective against HIV in the brain. One small study found that efavirenz-containing drug combinations reduced the amount of HIV in the cerebrospinal fluid to below 400 copies/ml in nine people over 26 weeks.20 There is also evidence that a combination containing efavirenz can reduce HIV in the lymph tissue to very low levels.21

HIV-positive African Americans taking efavirenz are less likely to experience immunological failure than Caucasians, which may be due to a high prevalence of a genetic variant that slows down clearance of the drug.22 23 This variant also means that patients stopping efavirenz treatment who have this variant are at risk of developing efavirenz resistance for an extended period, while drug levels fall.24

References

  1. Staszewski S et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 341: 1865-1873, 1999
  2. Tashima K et al. Durable viral suppression on EFV-based HAART: 168 weeks of follow-up. 15th International AIDS Conference, Bangkok, abstract TuPeB4547, 2004
  3. Arribas JR et al. High effectiveness of efavirenz-based highly active antiretroviral therapy in HIV-1-infected patients with fewer than 100 CD4 cells/ul and opportunistic diseases: the EfaVIP study (efavirenz in very immunosuppressed patients). AIDS 16: 1554-1556, 2002
  4. Schafer R et al. Antiretroviral strategies in naive HIV+ subjects: comparison of 4-drug versus sequential 3-drug regimens (ACTG 384). 14th International AIDS Conference, Barcelona, abstract LbOr20B, 2002
  5. Robbins G et al. Antiretroviral strategies in naive HIV+ subjects: comparisons of sequential 3-drug regimens (ACTG 384). 14th International Conference on AIDS, Barcelona, abstract LbOr20A, 2002
  6. Matthews GV et al. Does the choice between NNRTI or PI based initial HAART predict virological suppression at 24 weeks in a clinical setting? AIDS 14: S33, 2000
  7. Friedl AC et al. Response to first protease inhibitor- and efavirenz-containing antiretroviral combination therapy. The Swiss HIV Cohort Study. AIDS 15: 1793-1800, 2001
  8. Chen SY et al. Which antiretroviral regimens yield the best odds of survival in San Francisco? 15th International AIDS Conference, Bangkok, abstract MoOrC1082, 2004
  9. Bartlett JA et al. Abacavir / lamivudine (ABC / 3TC) in combination with efavirenz (NNRTI), amprenavir/ritonavir (PI) or stavudine (NRTI): CLASS preliminary 48 week results. 14th International AIDS Conference, Barcelona, abstract TuOrB1189, 2002
  10. INITIO Trial Coordinating Committee et al. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitors, protease inhibitor, or both in INITIO: open-label randomised trial. Lancet 368: 287-298, 2006
  11. 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: 1253-1263, 2004
  12. van Leth F et al. Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine and / or efavirenz. Antivir Ther 9: 721-728, 2004
  13. Nunez M et al. The SENC trial: Spanish efavirenz vs nevirapine comparison trial. Preliminary results of a prospective, randomized, controlled, open-label study in HIV+ naive individuals. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 472, 2000
  14. Phillips AN et al. Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression. AIDS 18: 1795-1804, 2004
  15. Yeni PG et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA panel. JAMA 292: 251-265, 2004
  16. Becker S et al. Successful substitution of protease inhibitors with efavirenz in patients with undetectable viral loads - a prospective, randomized, multicenter, open-label study (DMP-049). Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 20, 2001
  17. Hirschel B et al. Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case-control study from the Swiss HIV Cohort. AIDS 16: 381-385, 2002
  18. Knobel H et al. Impact of simplification to a lower pill burden HAART in adherence and risk factors for non-adherence. 15th International AIDS Conference, Bangkok, abstract WePeB5773, 2004
  19. Riddler SA et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358(20):2095-2106, 2008
  20. Tashima K et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J Infect Dis 180: 862-864, 1999
  21. Dybul M et al. Evaluation of lymph node viral burden in HIV-infected individuals receiving an efavirenz-based protease-inhibitor sparing HAART regimen. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract LB15, 1999
  22. Burger D et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 61: 148-154, 2006
  23. Wang J et al. Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics 16: 191-198, 2006
  24. Sadiq ST et al. Efavirenz detectable in plasma 8 weeks after stopping therapy and subsequent development of non-nucleoside reverse transcriptase inhibitior-associated resistance. AIDS 19: 1716-1717, 2005
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