NATAP: HAART Interruptions-serious risky complications occur

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Risks of HAART Interruptions, serious complications observed

In previous studies it has been observed that HIV drug resistance can occur as a result of taking an interruption. The various classes of HIV drugs are eliminated from the body at different rates. NNRTIs such as efavirenz can take as long as 2 weeks or longer to be eliminated from the body and over this time the drug levels in the body go down slowly. This is a setup for potentially developing drug resistance. 3TC & FTC also leave the body slowly. There are other untested theoretical risks to interruptions. One is regarding inflammation. HIV causes inflammation which HAART suppresses. One affect of inflammation is that when starting HAART side effects of the drugs occur as a result of the inflammation, in theory. After HAART subsides the inflammation these side effects & toxicities subside. But if HAART is interrupted & stopped, inflammation due to HIV re-starts. When restarting HAART the side effects & toxicities of HAART drugs re-emerge. Thus, each time you re-start HAART this process occurs. A poster at CROI found that early HAART prevents emergence of certain toxicities. In addition, the SMART Study, a study examining CD4-guided interruptions found more complications and adverse events associated with interruptions than with continuous therapy even when patients had higher CD4 counts of 400 and did not have a low CD4 nadir.

Jules Levin

Early HIV Therapy Yields Better Outcomes and Fewer Toxicities

DENVER (Reuters Health) Feb 08 - HIV-infected patients may need to start highly active antiretroviral therapy (HAART) earlier than current US treatment guidelines suggest.

Treatment guidelines currently recommend delaying HAART until patients reach CD4 cell counts lower than 250 cells per microliter to avoid treatment toxicities. However, the results of a large study reported at the 13th annual Conference on Retroviruses and Opportunistic Infections found that patients who start treatment earlier and do not interrupt treatment actually have fewer toxicities and better outcomes.

"The intuitive thinking is the longer you are on a drug, the more the exposure to the drug, the greater the risk of developing toxicity will be," lead investigator Dr. Lichtenstein of the University of Colorado Health Center, Denver told Reuters Health.

"What we have found is that it's the exact opposite. If you're going to develop toxicity, you develop it early, and it usually is associated with more advanced disease. If you don't develop it in the first year, your risk of developing it in the second year is lower and the risk continues to go down over time."

Dr. Liechtenstein and colleagues at the Centers for Disease Control and Prevention in Atlanta and Cerner Corp in Vienna, Virginia, evaluated 2222 patients in the HIV Outpatient study cohort who were seen at least twice between 1996 and 2005.

The subjects were stratified by pretreatment CD4 cell count, time of HAART initiation, and the development of three major toxicities.

Overall, 113 patients developed renal insufficiency, 301 developed peripheral neuropathy and 176 had lipoatrophy.

Compared with patients who started HAART when CD4 counts were 200 cells per microliter or lower, patients with CD4 counts higher than 350 cells per microliter when they began treatment were at least 60% less likely to develop renal insufficiency. They were also at least 60% less likely to develop lipoatrophy and 30% less likely to develop peripheral neuropathy.

Adherence to treatment also affected outcomes. CD4 counts were higher over an 8-year period in patients who took HAART 95% of the time or more than patients who took their drugs less frequently -- regardless of pre-HAART CD4 level. Similarly, compared with less compliant patients, more patients who took HAART at least 95% of the time had viral loads below 50 copies/mL (57% vs 36%; p < 0.01).

Patients who stayed on treatment 95% of the time or more had a lower incidence of HIV-related mortality and morbidity and appeared to have a lower risk of developing some toxicities, compared with patients who were less compliant, regardless of when HAART began. Less consistent use of therapy was also associated with an increased risk of renal insufficiency and peripheral neuropathy, but the risk of lipoatrophy was decreased.

Dr. Lichtenstein believes the committee that advises Health and Human Services on HIV treatment guidelines should consider the results of this study, along with those of other studies with similar findings.

"I wouldn't change the guidelines based on this study alone," he said. He also stressed that this was an epidemiological study, not a randomized, controlled trial. However, "a lot of the same kinds of things were seen in large structured treatment interruption studies that were randomized, controlled trials."

As a clinician, Dr. Lichtenstein starts his patients on HAART early. "I have very few patients hospitalized and very few complications. Although this is anecdotal," he commented, "it's consistent with the data."

CD4 Count-Guided Therapy May Increase Risk of HIV Disease Progression

Beth Nierengarten

www.medscape.org

Feb. 8, 2006 (Denver) — With increasing concern over treatment-related morbidities in HIV-infected patients receiving long-term antiretroviral therapy (ART), different strategies to reduce morbidities while maintaining treatment efficacy continue to be investigated. New results from a large trial that looked at one of these strategies — interrupting and initiating treatment based on CD4 cell counts — show just how difficult and complex a problem this balancing act is, and how much more work needs to be done.

Presenting the latest data from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, Wafaa El-Sadr, MD, MPH, MPA, from the Harlem Hospital Center and Columbia University in New York City, highlighted that what one may expect may not be born out by the evidence. He discussed the findings here at the 13th Conference on Retroviruses and Opportunistic Infections.

"We thought that those [patients] using less drugs would have fewer complications," Dr. El-Sadr said in a press briefing, "but the surprising thing in SMART is that patients treated on the interruption arm still did have more side effects."

In the SMART trials, patients with a CD4 count higher than 350 cells/mm3 were randomized to continuous ART aimed at viral suppression (VS) or to an experimental group of CD4 count–guided drug conservation (DC). For patients in the DC group, treatment was only initiated when CD4 count decreased to less than 250 cells/mm3 and stopped when the count rose above 350 cells/mm3.

Patient characteristics were comparable between the 2 groups, with a median age of 46 years, 27% were women, and 30% were black. The primary end point of the study was HIV disease progression or death, with secondary end points of death and severe treatment-related complications.

Although the trial was designed to enroll 6000 participants, it was stopped on January 11, 2006, after a review by the trial's data and safety monitoring board found that patients in the DC arm had twice the risk of disease progression or death than the VS arm (3.7/100 person-years vs 1.5/100 person-years), with a relative risk (RR) of 2.5 (P < .0001). The DC group was also associated with a significantly increased risk of serious AIDS-related events (0.5/100 person-years vs 0.1/100 person-years; RR, 82; P = .01), kidney, liver, and cardiovascular disease (2.0/100 person-years vs 1.2/100 person-years; RR, 1.62; P = .02) as well as death (1.5/100 person-years vs 0.9/100 person-years; RR, 1.63; P = .04). At the time it was stopped, the study had enrolled 5472 patients from 318 sites in 33 countries.

Of the patients who died, "most of the deaths were not AIDS-related," said Dr. El-Sadr, "so something else is going on.... It is more complicated than we thought."

According to Dr. El-Sadr, a key take-home message of the trial is that a lot has yet to be learned about strategies based on starting and stopping ART and that large trials are needed for accurate assessment of the outcomes. "There have been smaller studies that show these strategies were safe," she said. "This highlights the importance of conducting larger studies."

Calvin Cohen, MD, a clinical instructor at Harvard Medical School and research director of the Community Research Initiative of New England, both in Boston, Massachusetts, agreed that more studies are needed to evaluate treatment interruption strategies, such as "ongoing small studies testing approaches of 'short-cycle' treatment interruptions that allow a few days off before restarting in order to avoid what may be the consequences of viremia in people with successful viral suppression."

For Dr. Cohen, the practical application of these results is that "we can now say that if someone wants to stop treatment, we can explain that there is a real risk of serious complications that is greater than what we saw in those who stayed on meds."

But, he emphasized, patients may decide that the risk of complications is worth stopping treatment. "It is not at all a surprise that some will still choose to take this risk to gain some perceived or anticipated benefit — people still smoke, for example. But if someone is asking for guidance, these data suggest that current treatment is safer than stopping. I think now that we understand the risk versus benefit equation is now better informed," he said.

13th CROI: Abstract 106LB. Presented February 6, 2006.