The controversial topic of When to Start Treatment was addressed at several points during the Conference. One aspect of this, starting during or shortly after primary HIV infection versus during chronic infection was addressed by Bruce Walker, MD during his State-of-the-Art discussion on Treatment Interruptions. The issue was also mentioned at several times during oral presentations in reference to the newly updated US DHHS Treatment Guidelines (see report by Graeme Moyle, MBBS). The new Guidelines reflect a more conservative approach in waiting until the CD4 count reached below 350 cells per microliter before therapy should be offered, at any HIV RNA viral load level (www.hivatis.org).

Studies on when to begin therapy have flaws, and perhaps the biggest is they have been following patients for relatively short periods of time of 2-4 years. Some differences in HIV progression may not be detectable within a few years. There also were 3 posters that specifically addressed the When to Start issue. Dr. Ray Y Chen of the University of Alabama concluded from their HIV population of 715 patients that the 4-year survival after starting HAART when the CD4 count was at least 200 CD4 cells per microliter was 85% and no different for those with starting counts of 200-350 or those with greater than 350 cells (abstract 341). Whereas, the 4-year survival rate was only 65% for those who started when the CD4 count was less than 200 cells. HIV viral load was not found to be a significant factor in the statistical analysis. Quite similar conclusions were reported by Dr. Robert S. Hogg of the University of British Columbia in Vancouver, Canada in their cohort of 1,219 persons with HIV receiving HAART (abstract 342). He concluded that the effectiveness of HAART on survival is decreased among patients who initiate it after the CD4 count is less than 200 cells per microliter, and is independent of viral load. On the other hand, several studies show that individuals who start therapy when cd4s are 350-500 respond better to therapy which in theory (if person remains adherent) should lead to more durability in response. At Glasgow, Andrew Phillips reported retrospective data from large European databases and found that CD4 and viral load response was the same to HAART whether a patient started therapy at 200-350 CD4s or >350 CD4s. Other studies have found differently including studies discussed below. At last year's Retrovirus Conference, data from Merck and Johns Hopkins found that starting therapy when CD4s are higher is more likely to result in better CD4 and viral load responses when using HAART.

Starting Therapy When Cd4s are Higher May Slow Progression
In a 2-3 year follow-up of efavirenz+AZT/3TC in the "006" study, DuPont researchers reported data suggesting that baseline CD4 count does predict response to therapy. The results suggest that if a person starts therapy when CD4s are >350 with a potent regimen that is capable of fully suppressing viral load to <50 copies/ml the person is more likely to have undetectable viral load 2 years out than if they started with cd4s <350. This data is preliminary but suggests that the higher the CD4 count when starting therapy the more likely a person will sustain viral load <50 copies/ml. Of course, this assumes the patient is fully adherent. Milos Opravil reported data on 358 treated & untreated patients from the Swiss HIV Cohort Study in an oral Late Breaker (abstract LB6). Patients who started therapy with median 480 CD4s and who were followed for 4 years had less AIDS defining events (3 vs 16 events) and less progression to death (5.3% vs 1.4%) compared to patients who deferred therapy. However, there appeared to be a number of flaws in the study design including preselection bias of patients who deferred therapy. Patients had difficulty staying on therapy: 29% changed treatment due to adverse events; 20% were not on ART any more by the end of the follow-up. If untreated, there was a relatively low risk of severe clinical events (4.5% for AIDS, 5.3% for death). Patients lost to follow-up were 14% in the treated arm and 28% in the untreated arm.

John Kaplan from the CDC assessed the risk for death in 5000 patients followed in the CDC Adult and Adolescent Spectrum of Disease Project. Kaplan admitted there were many limitations of this analysis: patients were not randomized but this was an observational analysis; they don't know for sure whether patients were ART naïve before starting therapy; adherence was not followed; other outcomes like toxicity, development of resistance and quality of life were not followed; and including patients on 2 drug regimens (to increase sample size) dilutes the analysis but the 3-drug analysis helps. Kaplan compared the risk of death as a function of CD4 level at which ART was started (lowest CD4 count within 12 months prior to starting HAART). Follow-up was only 2 years and the data was not statistically significant but suggests that the higher the CD4 count when starting therapy the less risk for death. The hazard ratio when starting HAART at 450-499 was 1.0 compared to 3.1 when starting therapy at 300-349. Kaplan said that 300 CD4s appears to be a level where survival slightly changes and much more so at 200 CD4s. At 50-99 CD4s the hazard ratio was 5.1. However, these data are not statistically significant perhaps due to short follow-up time. Two-year survival was only significantly reduced when starting HAART at 150 CD4 or lower.

CD4 More Important Than Viral Load? Tim Sterling from Johns Hopkins (abstract 519) studied 1000 patients in the HIV Clinic and follow-up was only 2 years. He found CD4 was a better predictor of response to HAART than viral load as Julio Montaner has previously reported finding. The essence of his data suggests you can defer therapy til 200 cd4s. Using a multivariate proportional hazards model of and after adjusting for age, sex, race, IVDU, prior OI and CD4, viral load before starting HAART of above or below 100,000 copies/ml was not associated with disease progression. The relative hazard for disease progression was slightly higher when starting therapy if CD4s are 201-350 compared to >350, but this is not statistically significant. These data suggest treating with HAART when CD4s are 200 - 350 is not associated with disease progression compared to treating with HAART when CD4s are >350. But that treating when CD4s are <200 is associated with disease progression. But I think there may be some flaws in the study, when considering that adherence is not monitored, that this study compares HAART vs no ART or only dual nuke use (combined in group 2), and the short follow-up of only 2 years.

Considerations in the decision to start therapy should ultimately be individualized, based upon discussions between the patient and provider. Does HIV replication unchecked by therapy create more risk than starting therapy early? Relevant issues include potential benefits and potential risks including known drug side effects and toxicities (and unknown ones that might surface in the future).. Discussions must also consider the concept of viral reservoirs in the compartments of blood, immune organs, brain, "GI" (stomach, intestines), genitals, and other "mucosal" (moist linings) tissues. Early initiation of therapy when adherence is not adequate can lead to drug resistance, and less sensitivity to other HIV drugs. Long-term adherence to dosing is difficult. Additional considerations include concurrent medical conditions (hepatitis virus co-infection, high cholesterol, diabetes, high blood pressure, illicit drug habit, others). Higher viral load and lower CD4 counts may increase the risk for developing neuropathy. Data has shown that viral load over 10,000 increases risk for peripheral neuropathy by 25% over a 10-year period. In general, when HAART is started the immune system stops the decline caused by HIV: CD4s increase, the cd4/cd8 ratio improves, etc. Deferring therapy & letting cd4 count decline permits continual decline in the immune system. Even if starting HAART when CD4s are 200 or more, It appears as though most patients are able to increase their CD4s to levels protective against major opportunistic infections. Still, we don't know what cd4 count is the cut-off for increased risks for other complications or for depletion of CD4 repertoires. Over the course of many years cancers may be more likely to develop if CD4s go too low before starting therapy. We don't have data proving this, but this is a concern. It could take many more years before we see cancers starting to pop up. Allowing viral load to replicate unchecked permits a patient's virus to mutate & become genetically diverse. This may have the effect of reducing the response to therapy.

The controversial issue of When to Change Therapy also was addressed in a few posters. It appears that many patients experiencing "virologic failure" with their current anti-HIV regimen may continue to derive clinical benefit if the viral load is lower than the previous viral set-point (stable level) and/or if the CD4 count is still higher than the nadir (lowest) CD4 count (assumes multi-drug resistant HIV). The lead authors of two reports were Steven G. Deeks, MD of San Francisco General Hospital (abstract 428) and Richard Chaisson, MD of Johns Hopkins University (abstract 429), respectively. Such benefits may relate to decreased viral "fitness" of the dominant HIV species, as presented by Robert Grant, MD, PhD in a Late Breaker presentation. Further refinements about When to Start and When to Change treatment will continue to emerge with future research.