September 15, 2003
Dr. Trip Gulick moderated the first section and he concentrated on deciding when was the best time for a patient to start antiretroviral therapy (ART). He opened the discussion with a case study. He described a newly diagnosed young woman with a CD4 count of 372 cells/µL and an HIV RNA viral load (VL) of 37,000 copies/mL. The vast majority of responses -- via the interactive system that everyone in the audience had and could use to register their opinion -- was to defer treatment until the next visit. This is consistent with the 2003 DHHS Guidelines.
Dr. Gulick discussed the pros and cons of starting treatment early versus starting late. Reasons to start early include: 1. HIV is a progressive disease, so it's best to intervene early; 2. ART reduces HIV viral load and improves immune function; 3. With six years of follow-up data we now know that treatment response is durable; and 4. Suppressing viral load prevents or reduces HIV transmission, thereby assisting public health efforts.
The argument to delay therapy is that we know the risk of HIV progression is low early in disease, therefore we should wait until ART is absolutely necessary so that we can limit the side effects and long-term toxicities of ART. As an example, Dr. Gulick quoted Dr. Eggers and colleagues (reporting in Lancet from data of 12,574 patients): the risk of developing a clinical event is low when a patient's CD4 cell count is above 350 cells, but the risk progresses as the CD4 declines below 200 cells.
Dr. Gulick then presented a table comparing how the last three versions of the DHHS guidelines had changed. He talked about the most current guidelines released July 2003, which recommend that ART be offered to asymptomatic patients with CD4 counts between 200-350 cells, noting that controversy exists among experts. The guidelines state that one should consider ART if the HIV RNA viral load is more than 55,000 copies/mL in patients with higher CD4 counts.
Dr. Gulick continued on with the case he had first described: a young woman who had a CD4 count of 372 cells/µL. He noted that upon repeat labs, the same young woman had a CD4 count of 265 cells/µL and an HIV viral load of 128,000 copies/mL. All agreed via the interactive voting system that she needed ART but interestingly the audience was equally split on whether to obtain a genotype prior to starting therapy. Dr. Gulick gave several examples of resistance patterns among primary HIV infection including Susan Little's study (JAMA) and the CATCH study presented this past July in Paris. The IAS-USA resistance guidelines recommend resistance testing in all acute and recent infection, chronic HIV infection if regional prevalence is at least 5 percent, and in cases of drug failure or pregnancy. One of the criticisms of this recommendation is that most regions are unaware of their resistance pattern.
Dr. Gulick spent the rest of the time discussing treatment strategies and citing published studies to support the DHHS recommendations. He noted that the critical issues to consider when selecting a first regimen include the activity or potency of the therapy itself; the durability of the regimen; tolerability; convenience; preserving future options; and patient or host factors such as CD4, HIV viral load, co-morbidities, access to care/therapy and costs. In the interactive registration of opinions 71 percent of the audience chose two nucleosides and an NNRTI as the preferred initial regimen with 58 percent choosing AZT (zidovudine, Retrovir)/3TC (lamivudine, Epivir) and 20 percent choosing tenofovir (TDF, Viread)/3TC as the preferred initial nucleosides.
Although the DHHS guidelines prefer boosted lopinavir (LPV+RTV, Kaletra) as the preferred protease inhibitor (PI) and efavirenz (EFV, Sustiva) as the preferred NNRTI, Dr. Gulick was quick to point out that other factors play a role and regimens must be individualized.
The discussions following his presentation included the fact that atazanavir (ATV, Reyataz) received FDA approval after the guidelines were written, and that one may want to consider a favorable metabolic profile when choosing an initial PI.
Another discussion ensued regarding the use of nevirapine (NVP, Viramune), especially in women of child-bearing age given the teratogenicity of efavirenz in addition to the tolerability and similar virologic efficacy. Dr. Henry also questioned whether the data that was presented represented the "real world," especially those regarding the one- to two-year failure rate. Although 44 percent of the audience agreed with the 20-25 percent failure rate at one to two years, Dr. Henry reminded us that those are the patients in his clinic that agree to do a clinical trial. Dr. Gulick said that similar responses have been reported in observational cohort studies. Afterwards, Dr. Henry asked, "If a review of state Medicaid prescriptions show that 30 percent of patients are behind in their prescriptions, how can the failure rate only be 20 percent?"
We do acknowledge that certain sub-populations have a difficult time adhering to any regimen. But the bottom line is that there are now many different regimens that are potent and durable if taken according to directions. In addition to all the other factors that may affect the success rate, we still have to deal with the human factor and we must continue to assist patients with understanding adherence. And, as Dr. Gulick concluded, when to start treatment may be based on objective measures such as CD4 T-cell counts, HIV viral load and presence of clinical symptoms, but the ultimate decision is "when the patient is ready."
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