Project Inform - March, 1997

Viral Load in Plasma and Other Reservoirs

A recent study showed that HIV RNA levels in semen strongly correlate with RNA levels in plasma (blood). Semen viral load was not necessarily higher in people with lower CD4+ counts. This study found that there was no relationship between viral load in semen and disease progression. Both semen and plasma viral load decreased dramatically after starting antiretroviral therapy.

Another study looked at viral load in vaginal secretions and found that HIV RNA levels in vaginal secretions fell in 13 of 14 women who started therapy. Five women who did not take antiretroviral therapies had no reductions in RNA levels in their vaginal secretions. When three of the women stopped their therapies, the RNA levels promptly increased.

Confirming earlier European results, a study at the University of Minnesota showed a correlation in viral load changes in the plasma and lymphoid tissue. Lymphoid tissue was obtained from the tonsils of people who were treated with AZT + 3TC + ritonavir. Participants had a 2.5 to 2.8 log drop in plasma viral load after 24 weeks of therapy. The 10 lymph tissue samples studied so far had an average 3.4 log drop in HIV RNA levels after 24 weeks. Generally, lymphoid tissue has about 2 logs more RNA than plasma.

Another study looking at lymphoid tissue, but from a layer of cells (mucosa) in the rectum, showed similar results. This study found that the number of HIV RNA copies in this kind of lymphoid tissue fell dramatically after one week of potent 3-drug combination therapy. Perhaps most importantly, this study opened a new and perhaps less invasive way to study lymphoid tissue.

Resistance

A retrospective study of people with HIV in Iowa reported that the HIV protease enzyme can develop mutations associated with drug resistance, even prior to the administration of protease inhibiting drugs. The study tested blood samples taken between 1993 and 1996 before any of the participants had used protease inhibitors. Nevertheless, 30% had naturally occurring mutations in the protease enzyme. More significantly, 26% had mutations associated with resistance to the protease inhibitors and 23% harbored virus that had multiple mutations in the protease enzyme. This may partially explain why some people get a less durable or no response at all when they start protease inhibitor therapy. Somewhat surprisingly, 10 people who had these naturally occurring mutations in the protease enzyme still had good results on a 3-drug therapy (2 reverse transcriptase inhibitors and one protease inhibitor). Most of the participants had undetectable viral loads after 6 months of therapy.

Another study looked at 23 samples from people who had failed indinavir (Crixivan), saquinavir (Invirase) or ritonavir (Norvir) to determine if they would be resistant to nelfinavir (Viracept). Generally, people who had developed only one mutation in the protease enzyme remained sensitive to nelfinavir; but people who had multiple mutations were resistant and did not benefit from the drug. The data, however, suggest that some of the people "failed" the other drugs for reasons other than true resistance, as resistance to ritonavir and indinavir takes more than one mutation (a single mutation, though, may produce resistance to saquinavir). It is uncertain whether people who develop true high-level resistance to ritonavir or indinavir will respond to nelfinavir.

Duration of Therapy Effects

A critical question for most people is how long the effects of protease inhibitors will last. Preliminary results were presented from a study to determine whether viral load can predict the duration of viral suppression during protease inhibitor therapy. The durability of treatment response was defined as the time from starting therapy to the time HIV RNA levels increased by 0.3 log. Surprisingly, the durability of response was not predicted by baseline viral load, baseline CD4+ cell counts, magnitude of viral load drop or magnitude of CD4+ cell increase. Instead, only the lowest HIV RNA value (nadir) achieved on therapy could predict the length of response. This study also found that viral levels must be undetectable (less than 200 copies of HIV RNA) to prevent indefinitely or significantly delay the emergence of resistant virus. The specific results showed that people whose viral load did not fall below 1,000 copies of HIV RNA had a response of only 60 (+/- 26) days. People with a lowest level of 200-1,000 copies of HIV RNA had a 102 (+/- 25) day response and people with a lowest level of fewer than 200 copies of HIV RNA had a response of 207 (+/- 81) days. These data answer a critical question faced by patients and physicians who wondered if it was sufficient to simply lower the viral load, or whether it was necessary to suppress it below the limits of detection. The data demonstrate that the effect of treatment will be short lived when therapy fails to fully suppress viral replication. The implication is that therapy should be aggressively applied to whatever degree is necessary for full suppression (within the limits of tolerability). This would require more routine monitoring of HIV RNA levels, especially for people just starting or switching antiretroviral therapy, so that modifications in their treatment regimens can be made, if necessary. These new results suggest that for some people, four- and possibly five-drug regimens will be necessary to suppress HIV RNA levels below the limit of detection in order to get the maximum benefit from therapy.

These data also suggest that recent guidelines issued on viral load use by the International AIDS Society USA may already be outdated. Those widely cited guidelines suggest that a treatment has failed when viral load returns to or is within 0.3 to 0.5 log of pretreatment levels. This study demonstrates that waiting for ‘treatment failure’ to occur is too late and modifying or changing treatment regimen should be considered when HIV RNA levels increase by 0.3 log from the lowest level.

A study of 1330 people from seven different ACTG (AIDS Clinical Trials Group) studies show that both HIV RNA levels and CD4+ cell counts are important variables in determining disease progression. Additionally, this study found that HIV RNA level changes and CD4+ cell count changes taken together are a better indication of therapy success than either measure alone. A particularly interesting finding was that the benefit of reductions in HIV RNA levels does not depend on the baseline HIV RNA level. Rather, the benefit of a therapy depends on the amount of reduction, regardless of baseline HIV RNA levels. For example, a one log reduction from 150,000 copies of HIV RNA to 15,000 copies reduces the relative risk of disease progression by the same amount as a one log reduction from 50,000 copies of RNA to 5,000 copies.

970301
PI970303

©1997. This document is copyrighted by Project Inform, 205 13th Street, #2001, San Francisco, CA 94103. Treatment Hotline: 800-822-7422 (toll-free) or 415-558-9051 (in the San Francisco Bay Area and internationally) All Project Inform materials may be reprinted and/or distributed without prior permission. However, reprints may not be edited and must include the following text: "From Project Inform, for more information contact the Project Inform National HIV/AIDS Treatment Hotline, 800-822-7422." For permission to edit any Project Inform material for further publication, contact David Evans at the Project Inform office.

Project Inform, established in 1985 as a national, non profit, community-based HIV/AIDS treatment information and advocacy organization, serves HIV-infected individuals, their care-givers, and their healthcare and service providers through its national, toll-free treatment hotline, the PI Perspective and other information publications, educational Town Meetings, on-line services and research and drug access advocacy programs. All information is available free of charge; donations are strongly encouraged. For more information, contact the Project Inform National HIV/AIDS Treatment Hotline. Email: web@projinf.org; Website: http://www.projinf.org.

The original of this article can be found at http://www.projinf.org/pub/21/ViralLoad.html