Resistance: What You Don't Know -- Can It Hurt You?

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Resistance: What You Don’t Know — Can It Hurt You?

Two experts weigh in on whether to switch regimens in a patient with evidence of triple-class resistance.

A 50-year-old man with long-standing HIV infection was admitted to the hospital with gallstone-related pancreatitis. Despite extensive prior treatment with multiple agents in all three major drug classes, he had maintained clinical stability on a regimen of tenofovir/FTC and ritonavir-boosted fosamprenavir for the previous 3 years, with his CD4 count stable at 300 to 500 cells/mm³ and his viral load measuring either <50 copies/mL or 50 to 500 copies/mL. At this level of viremia, no resistance test had been performed. In the days preceding his admission and during much of his hospital stay, however, the man was unable to take anything by mouth, including his antiretrovirals. His viral load rebounded to 15,000 copies/mL, and a genotypic resistance test was ordered. After recovery, the man resumed the same antiretroviral regimen, and his viral load quickly fell again to <50 copies/mL. The resistance test ordered during admission demonstrated the following mutations:

NRTI: 20wt/R, 35I, 41wt/L, 67N, 74V, 115F, 181C, 184V, 214F, 215Y, 219R, 221Y

NNRTI: 135T, 181C, 221Y

PI: 10I, 13V, 20R, 35D, 36I, 37D, 48V, 54T, 63P, 71V, 73S, 82A, 89V, 90M, 93L

The interpretation of this genotype was that the virus was resistant to all NRTIs (partial resistance to tenofovir) and NNRTIs (the report did not include etravirine) and had preserved susceptibility only to the PIs darunavir and tipranavir.

He is tolerating the current regimen well, with no drug-related side effects. Self-reported adherence to medications is excellent.

Would you change his regimen? If so, to what?

Response 1

— Joseph C. Gathe, Jr., MD, FACP, FIDSA

Based on the scenario presented, I would not change this patient’s regimen. His viral load was <50 copies/mL at the latest evaluation and was consistently undetectable before his hospitalization. The problem comes in trying to interpret the results of his genotypic resistance test, especially given the episodes of low-level viremia. At face value, the data would suggest that his viral load fell from 15,000 copies/mL to <50 copies/mL with only one partially active agent (tenofovir). However, such a decline is extremely unlikely, even if one assumes some activity from fosamprenavir.

One interpretation is that the genotypic test results are inaccurate. Ample data suggest that quality-control issues occur with genotypic and phenotypic testing — and that individual test results should be placed in the context of treatment history and clinical presentation. In my own practice, it is not unusual to receive resistance test reports that make no clinical sense.

An alternative interpretation is that this genotypic test is accurate. Several studies have shown that, even with low-level viremia for as little as 6 to 12 months, patients can accumulate additional mutations (including those associated with drugs they have never received) that would jeopardize their future treatment options (Abstract 615, 13th Retrovirus Conference, 2006; Abstract 874, 15th Retrovirus Conference, 2008; AIDS 2007; 21:721). Still, I would not have expected this patient to respond so well to a regimen to which the virus has limited genotypic susceptibility.

Although I would not change this patient’s regimen now, I would remain vigilant for further clinically significant episodes of low-level viremia. Should such episodes occur, I would consider switching the patient to a regimen that includes two new active agents. Possibilities include the integrase inhibitor raltegravir, the fusion inhibitor enfuvirtide, the PI darunavir, and the second-generation NNRTI etravirine. I would not suggest a CCR5 inhibitor because of the difficulty in my clinic of accessing tropism assays and because I doubt this patient has CCR5-tropic virus, given his triple-class resistance (Abstracts 655 and 233, 13th Retrovirus Conference, 2006).

In summary, clinicians should treat the patient, not the chart or the lab reports. Thus, I would keep this patient on his current regimen and follow him closely. Should low-level viremia recur, I would consider switching him to another regimen to prevent the development of further resistance.

Response 2

— Richard Elion, MD

Although this patient has maintained long-term virologic suppression on his current regimen, the viral genotype indicates the presence of substantial resistance, which presumably developed during some period of nonadherence. This resistance poses a serious threat to his virologic suppression and, consequently, to his long-term treatment options. If he were to become viremic, he would likely develop additional resistance to PIs and lose susceptibility to that drug class entirely. I would therefore recommend changing his regimen to one that positions him for more-durable suppression over time. This approach might seem counterintuitive because he is doing well now, but not switching would be akin to not wearing a seatbelt just because one hasn’t hit any major bumps in the road yet.

For this patient’s next regimen, I would avoid nucleosides because of the risk for future toxicity, coupled with the diminished likelihood of effectiveness and limited potency due to resistance. Instead, I would recommend a combination of raltegravir, etravirine, and ritonavir-boosted darunavir, with raltegravir being the key component. This drug focuses on a new target; the patient’s virus is not resistant to it; and it is potent, tolerable, and administered twice daily, placing it in harmony with the other agents in the regimen. In the BENCHMRK trials, patients who received two active agents in addition to raltegravir had greater rates of virologic suppression than did those who received only one active agent beyond raltegravir (Abstracts 105aLB and 105bLB, 14th Retrovirus Conference, 2007). Etravirine is a reasonable option because the patient’s virus has only one associated mutation (181C), and, according to DUET data, at least three such mutations are required to diminish response (Abstract 32, XVI International HIV Drug Resistance Workshop, 2007). Darunavir would also be expected to have excellent activity, given this patient’s viral genotype and the results of the POWER studies (Abstract 157, 13th Retrovirus Conference, 2006). If the patient was tested for and found to have CCR5-tropic virus (which seems likely, given his high CD4-cell count over time), maraviroc could be substituted for any of the drugs that I’ve recommended.

In summary, one should not settle for virologic suppression in a patient with a known viral genotype that predicts long-term problems. The availability of active and tolerable regimens for this patient argues for a proactive switch to ensure long-term immunologic stability and virologic suppression.