NATAP: Detectable Viral Load Reduces Survival

[Guest guest]

Detectable Viral Load Reduces Survival

Undetectable Viral Load (<50 copies/ml) is Goal of Therapy

This past year we have seen the emergence of several new drugs (and some are New Classes of HIV drugs) that prompted the International AIDS Society to change their recommendation for patients with extensive drug resistance to a Goal of Therapy-to achieve <50 copies/ml. During the Summer TMC114 became available. In the last 2 years, tipranavir and Fuzeon (new class) became available. In the Fall TMC125 & Merck's integrase inhibitor (MK-518, a New Class) became available through Expanded Access Programs. Another New Class, a CCR5 entry inhibitor called Maraviroc is about to become available through an Expanded Access Program approximately sometime between December and the end of January, pending FDA approval. The phase III data for Maraviroc should be publicly presented at the February Retrovirus Conference. This will mark the first phase III data to become available for a new class of drugs since Fuzeon several years ago. These are tremendous advances in treatment. We can take these advances and say everyone should be tested for HIV, put into care, and be provided therapy when timing is appropriate, because HIV has become a chronic manageable disease. That does not mean that HIV is easy to manage, it is not, but you can turn this disease into a chronic manageable disease not different than diabetes. That means, that if a patient takes proper care of their heath and takes treatment properly, there is a very good chance they can have a normal lifespan or close to it. That means achieve and suatin viral load to <50 copies/ml.

In the early days after HAART was available it was uniformly accepted and it still is that a patient must achieve <50 cp/ml to retain sustained viral suppression, prevent drug resistance, and this will lead to being able to stay on the same regimen. There were modeling studies following patients for up to 10 years that showed if a patient achieves <50 c/ml & sustains that for the first two years this predicted they could stay <50 c/ml for 10 yrs, of course adherence would have to be maintained. Then there were questions about if a patient had 'viral blips' above 50 should they intensify therapy to immediately get below 50. Diane Havlir's study found patients who 'blipped' between 50 to 200 did not appear to experience viral failure after 4.5 yrs followup. I think further studies may have found that blips to 400 were acceptable in that they did not predict viral failure.

Firstly, the study below from the Danish HIV Cohort found that patients who maintained viral load <400 have much better survivial. Second, this study found that patients with a 2-week treatment interruption had worse survival. Third, I think the evidence that blips up to 400 after having achieved <50 is spotty and not very convincing. The Havlir study found that patients with blips between 50 to 200 did not rebound, and I think this finding has more merit. However, I think the best way to monitor patients who achieve <50 c/ml is with the most sensitive assay, <50 copies/ml. Using the 400 copy assay is not adequate. I think it's important to identify blips above 50. These blips may or may not develop into further increases in viral load, but will draw appropriate attention to the possibility. At the very least you can be aware of possible rebound. I realize that cost consideration plays a role in monitoring HIV RNA, but this is not relevant to the best care. Jules Levin Opinion.

Tight control for first 18 months means fewer deaths

Written for NATAP: A report from the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dec 2005

Mark Mascolini

Tight viral control during the first 18 months of antiretroviral therapy means lower mortality 90 months after treatment begins [10]. And a drug break for any reason during the first 18 months of therapyâ€â€by people with a sometimes-detectable viral loadâ€â€raises the risk of death down the road.

Those findings emerged from the Danish HIV Cohort Study, which includes everyone in the country who began a potent antiretroviral regimen since January 1995. Not only is this a comprehensive database, it is also one that loses few members. Nicolai Lohse from Odense University Hospital reported that only 67 people in his multiyear analysis (3.2%) stopped coming back for follow-up visits.

Lohse's study involved 2046 people who started potent therapy between January 1995 and January 2002 and did not die for at least 18 months after beginning treatment. He divided them into three groups, depending on how often during treatment months 6 through 18 they had a viral load above 400 copies/mL:

- Group 1: Never had a load above 400 copies/mL

- Group 2: Above 400 copies/mL 1% to 99% of the time

- Group 3: Always above 400 copies/mL

People in group 1 tended to start potent therapy in a later year than those in the other groups, and they started a strong combination much more often as their first regimen (Table). Group 1 members also tended to start before their CD4 sank below 200 cells/mm3, although the three groups began treatment with similar viral loads. Whereas 1% in group 1 interrupted treatment for 2 weeks or more during the first 18 months of therapy, 17% in groups 2 and 3 took a drug holiday in that time.

Pretreatment traits and outcomes in 2046 Danes

Outcomes 90 months after beginning therapy

Significantly more people in group 1 than in the other groups had a viral load below 400 copies/mL 90 months after starting potent therapy (Table). Group 1 also gained significantly more CD4 cells from month 18 through month 90. These advantages translated into 92.7% survival 90 months after group 1 began a strong combination, compared with 85.6% and 76.1% survival in groups 2 and 3. Compared with group 1, group 2 had a 2.63 times higher risk of death and group 3 a 4.53 higher risk in an analysis adjusted for relevant risk factors.

Perhaps most notably, a treatment break of at least 2 weeks during the first 18 months of treatment proved a strong predictor of death in group 2, the people with intermittent viral control. The 92 people who took drug breaks in that period had a death rate of 6.87 per 100 person-years. These people usually interrupted therapy because of poor adherence (30%), drug intolerance (27%), or "patient's wish" (27%), and rarely because their physician proposed a holiday (6%).

Lohse and coworkers noted that treatment interruptions may reflect other mortality risk factors, such as end-stage AIDS, antiretroviral toxicity, or non-HIV conditions that may affect antiretroviral adherence. But the higher death rate in people who took drug breaks remained high throughout follow-up. That consistency, the Danish group argues, makes it unlikely that end-stage AIDS or toxicity explains the high death rate in this group. Also, fewer people who interrupted therapy died of non-HIV causes than did people who never suspended therapy. That suggests non-HIV mortality does not account for the high death rate among treatment interrupters.

Danish clinicians have always regarded planned treatment breaks with a skeptical eye, and findings like these bolster that belief. Lohse and colleagues conclude that "physicians should focus on improving adherence through intensive patient coaching, individualizing drug regimens, and treatment of underlying comorbidity in order to avoid virological failure and these [treatment] interruptions."