This case raises several important issues. Enfuvirtide has proven to be an extremely valuable drug for treatment-experienced patients after the TORO trials demonstrated superior viral suppression in those who received this drug as part of an optimized regimen.^[1,2] Since those without prior enfuvirtide exposure are likely to have susceptible virus, this drug is increasingly being used as part of optimized background therapy with other new agents, such as boosted tipranavir and boosted darunavir (Capsule Summary).^[3-5]

Additional information regarding enfuvirtide has emerged from studying those who do not achieve full suppression on this agent. In particular, data have shown that resistance to enfuvirtide can occur quickly if full virologic suppression is not achieved (Capsule Summary).^[6,7] Moreover, it has been seen in those patients with persistent viremia and enfuvirtide resistance that this drug only contributes a modest amount of additional viral suppression; viral loads in patients with detectable viremia on an enfuvirtide-containing regimen increased by a mean of only 0.2 log₁₀ copies/mL after enfuvirtide alone was discontinued.^[8] By contrast, those who achieve full viral suppression while taking a regimen that includes enfuvirtide are likely to be deriving significant benefit. In fact, Bonjoch and colleagues^[9] reported that 5 of 8 highly treatment–experienced individuals with virologic suppression on an enfuvirtide-containing regimen who then stopped this drug experienced virologic rebound compared with 0 of 10 patients in a similar group who continued enfuvirtide.

How can these pieces of information be extrapolated to the patient in question, who has achieved virologic suppression and now requests to discontinue enfuvirtide? Although the limited data reported by Bonjoch and colleagues would suggest that stopping enfuvirtide may be risky, it is important to note that the patient in this case had been on enfuvirtide for a prolonged period of time with detectable viremia prior to achieving undetectable viral load on his current regimen. This fact, combined with the knowledge that enfuvirtide resistance emerges rapidly during nonsuppressive therapy, suggests that it is unlikely that enfuvirtide is contributing much antiviral activity to the current regimen. Consequently, although there is always some risk of modifying treatment, the likelihood of virologic rebound after stopping enfuvirtide should be relatively low and perhaps acceptable in this particular patient.

For the remainder of this discussion, it is worth considering whether this decision might differ had the patient received enfuvirtide for the first time as part of his current virologically suppressive regimen. This hypothetical case would be more analogous to those patients studied by Bonjoch and colleagues in whom there might be considerable risk associated with discontinuing enfuvirtide. Therefore, although stopping enfuvirtide in this scenario may not be wise, options for such a patient may be expanding with the availability of new drugs with activity against drug-resistant virus, such as the new NNRTI etravirine, the integrase inhibitor raltegravir, and the CCR5 inhibitor maraviroc, all currently available through Expanded Access Programs. The availability of these drugs raises the possibility of replacing enfuvirtide with another active (but orally administered) agent; however, it is important to recognize that there are no empirical data to support this strategy. Therefore, one would need to proceed with great care and with full disclosure to the patient. Therefore, in the proposed case, it may be reasonable to consider switching enfuvirtide to etravirine, which is active against many viruses resistant to first-generation NNRTIs. Since this patient has already used efavirenz, such variants are certain to exist as part of his viral population. Nevertheless, predicting which NNRTI-resistant viruses are most likely to respond to this second-generation NNRTI is not yet fully known.

Replacing enfuvirtide with a novel drug from a new class is another option. It is assumed that CCR5 inhibitors will be active in patients with CCR5-tropic virus who have no previous exposure to this class of drugs (Capsule Summary).^[10,11] However, this hypothetical patient’s viral load is currently undetectable. Therefore, there is no way to determine his viral tropism. In fact, based upon existing data his history of advanced HIV disease would suggest that there is a reasonable chance he might harbor X4 or dual/mixed tropic virus.^[12] a setting where virologic response may be attenuated (Capsule Summary).^[13]

Switching enfuvirtide to an integrase inhibitor is potentially more straightforward since it is expected that all subjects without integrase inhibitor experience are likely to have fully susceptible virus (Capsule Summary).^[14,15] Before such a change could be made, the patient must be informed of the lack of data supporting this strategy along with the risks of viral rebound, including that with integrase inhibitor–resistant virus.

This case illustrates an excellent example of how decisions often need to be made to accommodate a given patient’s needs in the absence of complete data. Nevertheless, it is possible to extrapolate from existing studies to inform the patient of the potential risks and benefits even when data about switching therapies are not available. It is important in a situation such as this to advise the patient what is and is not supported by data and the potential risks involved so that the patient is able to make a fully informed decision about his or her future treatment options.

1. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med. 2003;348:2175-2185.

2. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003;348:2186-2195.

3. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475. (Capsule Summary)

4. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER. AIDS. 2007;21:395-402.

5. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369:1169-1178.

6. Lu J, Deeks SG, Hoh R, et al. Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis. J Acquir Immune Defic Syndr. 2006;43:60-64. (Capsule Summary)

7. Poveda E, Rodes B, Lebel-Binay S, Faudon JL, Jimenez V, Soriano V. Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol. 2005;34:295-301.

8. Deeks SG, Lu J, Hoh R, et al. Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen. J Infect Dis. 2007;195:387-391.

9. Bonjoch A, Negredo E, Puig J, et al. Viral failure in HIV-infected patients with long-lasting viral suppression who discontinued enfuvirtide. AIDS. 2006;20:1896-1898.

10. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104aLB. (Capsule Summary)

11. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104bLB. (Capsule Summary)

12. Brumme ZL, Goodrich J, Mayer HB, et al.  Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals.
J Infect Dis. 2005;192:466-474.

13. Mayer H, van Dder Ryst E, Saag M, et al. Safety and efficacy of MARAVIROC (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1:  24-week results of a phase 2b exploratory trial. rogram and abstracts of the 16th International AIDS Conference; August 13-18 2006; Toronto, Canada. Abstract THLB0215. (Capsule Summary)

14. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 105bLB. (Capsule Summary)

15. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 105aLB. (Capsule Summary)