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Is That "One Pill" Treatment Enough?

Two experts describe how they would manage a patient with isolated resistance to 3TC/FTC who has requested the "one-pill" HIV treatment.

A 61-year-old woman is seen to discuss antiretroviral options. She acquired HIV infection from her husband (who has since died of AIDS) in the early 1990s, if not before. In 1996, with a CD4 count of 550 cells/mm³ and a viral load of 43,000 copies/mL, she started d4T and 3TC. She tolerated the drugs well but experienced mild thinning of the face and extremities. She continued on the regimen until 2002, when it became clear, in retrospect, that she did not meet current criteria for starting therapy. At the time of treatment cessation, she had a viral load of 5000 copies/mL and a CD4 count of 680 cells/mm³; a resistance genotype showed the M184V mutation.

Since this patient stopped treatment, the mild thinning she experienced on therapy has improved slightly. Her viral load has consistently been between 30,000 and 100,000 copies/mL, and her CD4-cell count has declined gradually. At the present visit, her CD4 count is 290 cells/mm³, and she agrees to resume therapy. The only medications she currently takes are hydrochlorothiazide and lisinopril for hypertension. She specifically requests the "one-pill" treatment she has heard about.

Would you prescribe coformulated tenofovir/FTC/efavirenz (Atripla) for her? Why or why not? If not, what treatment would you recommend? Would you request a viral tropism test?

Response 1

— Joel E. Gallant, MD, MPH

I would not prescribe tenofovir/FTC/efavirenz for this woman, because she has documented resistance to FTC, one of the three components of the regimen. In this setting, the combination would essentially be a two-drug regimen in which both active drugs have a low genetic barrier to resistance.

Combining a ritonavir-boosted PI with tenofovir/FTC would be the easiest option, allowing her to take a once-daily regimen with a low pill burden. Although one could argue that this is still a two-drug regimen because of FTC resistance, boosted PIs are known to have higher barriers to resistance than do NNRTIs. Furthermore, although M184V is archived in this patient’s latent reservoir, FTC is likely to be active against her circulating virus. Finally, should M184V be reselected, the mutation would increase the activity of tenofovir.

In the past, when treating patients who had known 3TC/FTC resistance, I often prescribed three NRTIs (tenofovir/FTC + AZT) plus either a boosted PI or efavirenz, to take advantage of M184V-induced hypersusceptibility to both tenofovir and AZT. However, I’m less inclined to use AZT now that other agents are available that are safer, more potent, and better tolerated — and it would be an especially poor choice in this patient, who already has lipoatrophy from prior use of d4T. When AZT is being used for resistance reasons, I sometimes replace it with raltegravir. For example, I would expect the combination of raltegravir plus tenofovir/FTC/efavirenz to be effective in this patient, although it would require twice-daily dosing. Another option would be to turn the combination of tenofovir/FTC plus a boosted PI into a solid three-drug regimen by adding raltegravir, but this might be unnecessary for the reasons discussed above.

I wouldn’t order a tropism test in this patient because I have no immediate plans to treat her with maraviroc. A patient who has only the M184V mutation has many effective treatment options that don’t require extra testing.

In this patient, the provider had the foresight to order a genotype before stopping treatment with d4T and 3TC. The more common case is the patient with prior use of nonsuppressive dual-NRTI therapy who does not have resistance data available. If that had been the case here, I would have assumed the worst: that a patient treated for 6 years with two NRTIs has not only M184V but also multiple thymidine analogue mutations that could result in cross-resistance to tenofovir and other NRTIs. In that case, I would have no confidence in NRTIs and would consider using a boosted PI plus an NNRTI, a boosted PI plus an integrase inhibitor (raltegravir), or possibly a regimen containing all three of those classes.

Response 2

— José R. Arribas, MD

Before making any treatment recommendations, I would first order a new genotypic resistance test to rule out recent superinfection with resistant HIV and to demonstrate the loss of M184V after 6 years of antiretroviral treatment interruption. I would also order a tropism test, which I consider to be a routine part of resistance testing. Most likely, resistance genotyping would show wild-type HIV, because M184V tends to disappear within weeks after pharmacologic pressure is withdrawn (Clin Infect Dis 2005; 41:236).

The safest approach for this patient would be to assume that her HIV is already resistant to 3TC/FTC and might have some hidden resistance to thymidine analogues. Theoretically, coformulated tenofovir/FTC/efavirenz has only a very small chance of being effective and so should not be recommended. As an alternative, I would use a boosted PI plus a second fully active drug, such as efavirenz, raltegravir, or maraviroc (if the virus is found to be CCR5 tropic). No clinical trial data are available to support one option versus the others in the context of isolated resistance to 3TC/FTC. Dual therapy is very likely to be enough, but some clinicians would still add a third drug, such as tenofovir, to complete an "orthodox" triple-drug regimen.

What if the patient really wants to take tenofovir/FTC/efavirenz? If genotyping shows wild-type HIV, as I would expect, then we should have time to test such an "unorthodox" approach, given her latest CD4-cell count. Efavirenz would be fully active, tenofovir would likely have substantial activity, and FTC should retain some activity against the majority wild-type population, at least for a period of time. I’m not aware of any study that shows how long recycled FTC or 3TC is "active" after such a prolonged interruption and reversion of 3TC/FTC resistance. We know that in women who have received single-dose nevirapine, a new nevirapine-containing regimen can be effective, at least in the short term (6 months), if reversion of nevirapine mutations occurs (N Engl J Med 2007; 356:135). This scenario might somewhat resemble what we could expect in our patient. We can be almost sure that this patient harbors a minority population of viruses with M184V that is not going to be detected by population genotyping. Will this minority population be enough to guarantee failure of tenofovir/FTC/efavirenz? Interestingly, a recent analysis from the ACTG 5095 trial showed that 29% of patients without virologic failure on AZT/3TC plus efavirenz had detectable Y181C (Abstract 83, 15th Retrovirus Conference, 2008). Could treatment with tenofovir/FTC/efavirenz also be successful occasionally in patients who harbor minority populations with M184V?

In summary, I would explain to the patient that other options are preferable, but if she is determined to use tenofovir/FTC/efavirenz, I do not think we would lose a lot by trying. If the virus develops M184V and K103N, and the regimen subsequently fails, we could still design a regimen that is very likely to be active. Boosted PIs are an option for this patient, as is etravirine, which is active in the presence of K103N.

Tell us what you would do

How would you manage this patient? Send your thoughts to arcase@mms.org, and we’ll publish a selection of responses in an upcoming issue.

Dr. Gallant is Professor of Medicine and Epidemiology, Division of Infectious Diseases, at Johns Hopkins School of Medicine in Baltimore.

Dr. Arribas is Associate Professor of Medicine at the Autónoma University School of Medicine and an attending physician in the HIV Unit at Hospital La Paz in Madrid, Spain.

Published in Journal Watch HIV/AIDS Clinical Care June 9, 2008

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