Bulletin of Experimental Treatments for AIDS, No. 30; September, 1996
Ronald Baker, PhD

This commentary outlines 5 important subjects addressed by researchers and clinicians at the Vancouver meeting: HIV viral load testing, treatment during early HIV infection, treatment of asymptomatic individuals, possible eradication of HIV from the body, and HIV suppression. For a comprehensive report on these and other treatment developments presented by AIDS researchers and clinicians in Vancouver, see "Highlights from the XI International Conference on AIDS" in this issue.

HIV Viral Load Testing

* Increased baseline HIV viral load predicts increased risk for disease progression and death.

* A decrease in HIV viral load from drug treatment correlates with decreased disease progression.

* Each 1 log copies/mL reduction in HIV RNA correlates with a 66% reduction in the risk of AIDS and death.

* A baseline HIV viral load of 30,000 copies/mL or greater suggests a 13-fold increased risk of progression to AIDS and an 18-fold increased risk of death over a 10-year period, compared to a baseline value of less than 500 copies/mL.

* A baseline HIV viral load between 500-3,000 copies/mL suggests only a 2.5-fold increased risk of progression to AIDS or death over 10 years compared to a baseline HIV viral load less than 500 copies/mL.

* Higher baseline HIV RNA values predict a greater annual decline in CD4 cells.

* Higher HIV viral load among pregnant women at the time of delivery correlates with an increased likelihood of HIV transmission to infants.

* HIV viral load testing is probably the quickest way to diagnose HIV infection among infants and seroconverters.

Treatment During Early HIV Infection

* The time from initial exposure to HIV until primary HIV infection (PHI) typically ranges from 2 to 4 weeks, although longer periods have been reported. During PHI, people often experience mild to severe flu-like symptoms that may include rash, fever, sore throat, muscle aches and swollen lymph glands. When present, these symptoms indicate the newly-infected individual is experiencing acute retroviral syndrome (ARS). Clinical illness usually lasts from 1 to 2 weeks. Not all newly-infected individuals experience ARS.

* Treatment during PHI can decrease HIV in the blood to undetectable levels. Successful regimens include AZT plus ddI, AZT plus 3TC and AZT plus 3TC plus indinavir; interestingly, the use of protease inhibitors is not always needed to reach undetectable HIV levels.

* Treatment of 2 infants (twins) with AZT plus ddI plus nevirapine for 11 months led to undetectable HIV levels, HIV negative blood cultures and negative antibody tests; however, the twins tested positive for HIV DNA using an experimental PCR test.

* Triple therapy with AZT plus 3TC plus ritonavir begun 65 days after PHI led to undetectable viral load after 12 weeks among 12 men (mean viral load of 91,389 copies/mL); in this ongoing study, new subjects are using indinavir rather than ritonavir.

* Use of 4- and 5-drug therapy (AZT plus ddI plus ddC plus alpha interferon with or without 3TC) by 6 patients during PHI led to a maximum decrease in HIV viral load of 4.5 log copies/mL, which was sustained over a mean of 30 weeks. When treatment was s topped in the longest-treated patient (over 2 years), viral load rebounded to 10,000 copies/mL.

* 6-drug therapy with AZT plus ddI plus ddC plus 3TC plus alpha interferon plus saquinavir in patients HIV positive for greater than 6 months also produced "extreme suppression" of HIV.

* Among men treated during PHI, very large decreases in HIV viral load may occur without the use of protease inhibitor or non-nucleoside reverse transcriptase inhibitor drugs.

* Combination treatment with AZT plus 3TC plus d4T plus saquinavir (7,200 mg/day) during PHI (started 26 days after exposure) may resolve severe PHI symptoms. In one 35-year-old Australian man, HIV RNA decreased from 3 million copies/mL to undetectable from week 10 to week 17; this 6 log HIV viral load decrease is the largest ever reported.

* Treatment during early HIV infection may significantly reduce HIV infection of the lymph nodes.

* Treatment for HIV during early infection likely will become the standard of care.

Treatment of Asymptomatic Individuals

* The question of when to initiate anti-HIV therapy among asymptomatic individuals remains the subject of debate among researchers and clinicians.

* Recent guidelines from San Francisco General Hospital call for consideration of starting therapy among asymptomatic individuals if (1) HIV viral load is greater than 5,000 - 10,000 copies/mL, regardless of CD4 cell count, or (2) if the CD4 cell count is less than 350 cells/mm3, regardless of viral load.

* Some researchers and clinicians recommend initiation of therapy if the HIV viral load is at all detectable by one of the currently-used assays (e.g., greater than 200-500 copies/mL).

* Treatment of 151 treatment-naive, asymptomatic individuals with the triple combination of AZT plus ddI plus nevirapine in the Boehringer Ingelheim 1046 trial showed impressive results: 60% of participants had undetectable viral load and a mean increase of 120 CD4 cells/mm3 after 12 months on this regimen. Nevirapine has the advantage over protease inhibitors and most reverse transcriptase inhibitors of readily crossing the blood-brain barrier and the placenta (to the fetus). Nevirapine is now FDA-approved for use in combination regimens; monotherapy leads to the rapid development of high level resistance.

Is Eradication of HIV Possible?

* For eradication of HIV to be possible, combination treatment must reduce HIV replication to zero and keep it there for an extended period. Using a mathematical model, David Ho, MD, of the Aaron Diamond AIDS Research Center, theorizes that combination therapy would be necessary for about 1.5 to 3 years, during which time all infected cells would die and be replaced by new, uninfected cells. These calculations do not account for the possibility that HIV might remain hidden in the body in "sanctuaries" such as the brain, lymph nodes and spleen.

* The earlier combination treatment is started, the higher the chances for eradication of HIV. The best chance for success may be to treat with a combination of drugs very soon (within the first few hours) after exposure to HIV, before the virus has the opportunity to "seed" the lymph organs (lymph nodes and spleen) or the brain.

* The U.S. Centers for Disease Control and Prevention (CDC) in June 1996 issued new recommendations for post-exposure prophylaxis (PEP) following occupational exposure to HIV using the triple combination of AZT plus 3TC plus indinavir. Presumably, treatment with the same or a similar regimen would be appropriate very soon after known sexual exposure to HIV.

Complete Suppression of HIV

* Complete suppression of HIV replication is not the same as eradication of the virus. Eradication means that all HIV is cleared from the body, and the possibility of renewed replication is removed.

* Complete suppression implies that HIV still is present, but viral replication is halted by the successful action of drug therapy (or perhaps through the body's own anti-HIV defenses). If the suppressive effect of a drug regimen diminishes over time (due to drug resistance) or if therapy is halted, it is likely that HIV replication will resume and viral load will rebound to high levels.

* A few available combination drug regimens (with and without protease inhibitors) appear to have produced complete suppression of HIV, reducing the virus to undetectable levels for up to 2 years; only time and further study can tell us how long the suppressive effects of these regimens will endure.

* It is unlikely that currently available drug regimens can eradicate HIV from the bodies of individuals who have been HIV positive for over one year. However, complete suppression of HIV for an extended period may be possible among these individuals, especially if they are "treatment naive" (no previous use of anti-HIV drugs) and thus less susceptible to developing drug resistance.

* Among HIV positive individuals with extensive previous use of anti-HIV drugs, successful long-term suppression of HIV will likely depend on their ability to find drug combinations to which their viral pool is not already resistant.

* Even partial suppression of HIV can lead to slower disease progression, improved quality of life and prolonged survival among treatment-experienced individuals.

* If HIV viral load can be reduced to below 10,000 copies/mL, there is significantly less likelihood of progression to AIDS and death over a 10-year period (see BETA. June 1996, pages 9 -11).

Ronald Baker is Editor-in-Chief of BETA and Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation.

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Copyright © 1996 - San Francisco AIDS Foundation. Reproduced by permission. Reproduction of this article (other than one copy for personal reference) must be cleared through BETA: PO Box 426182, San Francisco, CA 94142-6182. Tel: 415 487 8060 Fax: 415 487 8069 URL: http://www.sfaf.org/beta E-mail: beta@sfaf.org

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