There were several presentations at the CROI on the controversial issue of when to initiate highly active antiretroviral therapy (HAART) in asymptomatic HIV-infected patients. Although HAART significantly decreases clinical disease progression, currently available drugs are unlikely to eradicate HIV infection. In addition, HAART has been associated with substantial toxicity, such as hyperglycemia, hyperlipidemia, lipodystrophy, and lactic acidosis. Because there have been no prospective, randomized trials to determine the most appropriate time to initiate HAART, we must rely on data from observational cohort studies. A recently-published study by Hogg suggests that HAART could be initiated at CD4 counts substantially lower than 500 cells/mm³, but should be initiated before CD4 counts drop below 200 cells/mm³ [JAMA 2001 Nov 28;286(20):2568-77]. Two studies from the Johns Hopkins HIV Clinic database have demonstrated that HAART does not have a significant impact on clinical disease progression when initiated at CD4 counts >350 cells/mm³, but that HAART is associated with substantial rates of drug toxicity and non-durable virologic suppression [Sterling TR, et al. AIDS 2001 Nov 23;15(17):2251-7; Sterling TR, et al. Clin Infect Dis 2001: 33;1205]. Supporting the claim that HAART can be initiated at relatively low CD4 counts, Philips and colleagues have shown that virologic suppression is possible even among individuals with a low CD4 count and high viral load prior to starting therapy [JAMA 2001 Nov 28;286(20):2560-7]. Although several studies presented at this conference supported delaying initiation of therapy until the CD4 count is in the 200-350 cells/mm³ range, one study suggested that therapy should be initiated at CD4 counts >350 cells/mm³ [Palella, Abstract 13].

In a study from British Columbia, Wood and colleagues assessed the cumulative mortality rate among a cohort of 1,416 patients who initiated HAART between August 1996 and July 2000 [Abstract 465]. The overall crude mortality rate was 7.8%. The mortality rate was higher among persons with CD4 counts <200 cells/mm³ than among those with >200 cells/mm³ prior to initiating HAART. The mortality rate was also increased among non-adherent patients (defined as patients who received <75% of their medications during their first year of therapy). In addition, the risk of death was increased among patients treated by physicians with less experience in the management of HIV (defined as treating <5 HIV-infected patients). In a multivariate model that adjusted for AIDS at baseline, age, baseline viral load and baseline CD4 count, patients who received >75% of their prescribed medications were 70% less likely to die, and patients whose physicians were more experienced were 33% less likely to die.

This author reported on a study from the Johns Hopkins HIV Clinic, in which 1,130 patients received HAART between July 1996 and June 2001, and clinical disease progression (defined as development of a new opportunistic infection or death) was assessed in patients with durable vs non-durable virologic suppression [Abstract 469]. Durable suppression was defined as more undetectable (<400 c/mL) than detectable viral load measurements. There was no difference in clinical disease progression among patients with durable vs non-durable suppression among those who had baseline CD4 counts >350 cells/mm³, but among patients with baseline CD4 counts <350 cells/mm³, durable virologic suppression was associated with a lower rate of disease progression. However, among patients with baseline CD4 counts <350 cells/mm³ who achieved durable virologic suppression, there was no difference in disease progression among those with baseline CD4 counts <50, 51-200, or 201-350 cells/mm³. The authors concluded that after a relatively short period of follow-up (median 30 months), initiation of therapy at low CD4 counts did not have a negative impact on subsequent disease progression, as long as patients were able to achieve durable virologic suppression. Although this study did not include data on adherence to therapy, other studies have shown that adherence is extremely important for achieving durable virologic suppression. This underscores the importance of addressing issues that would improve adherence (e.g., substance abuse) prior to initiating therapy.

In a study from Abbott Laboratories, the impact of baseline CD4 count and viral load on durable virologic suppression was assessed among patients randomized to receive either lopinavir/ritonavir (LPV/RTV) + d4T + 3TC or nelfinavir + d4T + 3TC [King, et al. Abstract 470]. Patients were followed through 96 weeks. Low baseline CD4 count and high baseline viral load did not have a substantial impact on the durability of virologic response in persons in the LPV/RTV arm. However, in patients treated with the nelfinavir-based regimen, the durability of virologic response was diminished in persons with lower baseline CD4 counts and higher baseline viral loads. Of note, data on adherence to either regimen were not presented.

In a study from the Swiss HIV Cohort Study, clinical disease progression was assessed among persons who did not achieve virologic suppression while on HAART [Egger, Abstract 471]. They assessed the area under the viral load curve (AUC) as a measure of average viral burden, and assessed its value as a predictor of clinical disease progression on therapy. As one might expect, higher average viral load over time was associated with an increased risk of progression to a new AIDS event or death. The probabilities at 5 years were as follows:

In an HIV clinic-based study of trends in treatment use and virologic suppression, Lampe and colleagues demonstrated that between 1999 and 2001 there was a steady increase in the proportion of patients who were treated with HAART (increasing to 70% by 2001), as well as in the proportion of patients who achieved virologic suppression [Abstract 477]. The proportion of patients with viral load <400 c/mL increased from 71% to 85% among all treated patients, and from 79% to 88% among patients on HAART for >30 weeks.

In another study from the Johns Hopkins HIV Clinic, Perez and colleagues found that HAART had a greater impact on survival in persons >50 years old (n=253) than in those <50 years (n=535) [Abstract 472]. Among patients who did not receive HAART, older patients were significantly more likely to die than younger patients. However, among persons treated with HAART, there was no difference in survival between older vs younger groups. Stratification by CD4 count <350 cells/mm³ did not change the survival curves. These data emphasize the importance of treating HIV-infected patients >50 years old with HAART and the substantial survival benefit that such therapy provides.

A study presented by Palella suggested that initiation of antiretroviral therapy among patients with baseline CD4 counts >350 cells/mm³ was associated with improved survival [Abstract 13]. This is consistent with data presented at the 8th CROI by Opravil [Abstract LB6], but contradicts the majority of data published in peer-reviewed literature to date. Palella’s analysis assessed patients according to whether or not they initiated antiretroviral therapy (not limited to HAART) while within a specific CD4 stratum, or delayed therapy until entering a lower CD4 stratum. The CD4 strata were 501-750, 351-500, and 200-350 cells/mm³. In each of the three strata, more than two thirds of the delayers started therapy at the next lower stratum. For persons with CD4 501-750 cells/mm³, the mortality rate per 100 person-years was 7.5 among those who started in that stratum vs 3.1 in those who delayed (relative risk: 2.38). In the 351-500 cells/mm³ stratum, the rates were 9.6 (initial) and 18.3 (delayed) per 100 person-years (RR: 0.52). In the CD4 201-350 cells/mm³ group, the mortality rate was 18.3 per 100 person-years among those who started in that stratum vs 69.3 among those who delayed therapy (RR: 0.26). A sub-analysis of persons who initiated HAART (instead of just any antiretroviral therapy, as in the baseline analysis) yielded similar results, but there was decreased power due to smaller sample size. Similarly, results were comparable when they assessed AIDS deaths as an endpoint instead of all deaths. The authors concluded that for persons in the 351-500 and 201-350 cells/mm³ CD4 strata, mortality rates were lower among persons who initiated therapy when they first were in those strata vs delaying therapy until they were in a lower CD4 stratum, and therefore, early initiation of therapy is warranted.

Reisler presented data on the incidence of grade 4 toxicity events, AIDS-defining events, and mortality in a large multi-center cohort of patients who were treated with HAART in one of 5 Community Programs for Clinical Research on AIDS (CPCRA) HIV treatment studies [Abstract 36]. A total of 3,050 patients were enrolled in the 5 studies. In these five treatment trials there were 316 AIDS events and 663 grade 4 toxicity events. These rates varied according to CD4 count:

At 30 months of follow-up, the cumulative percentage of patients with any grade 4 event was 27%, while the rate of developing an AIDS-defining illness was 13.4%. The most common grade 4 events were liver toxicity, neutropenia, pancreatitis, and anemia. The authors concluded that in this cohort, surprisingly, the incidence rate of grade 4 toxicity was twice the rate of AIDS events. The risk of death associated with a grade 4 event was similar to the risk of death associated with AIDS; however, the grade 4 events were not found to be attributed to HAART or to any specific HAART regimen. Nonetheless, this report confirms that there is substantial toxicity associated with the treatment of HIV.

Conclusion

The majority of the published data, as well as the data presented at this meeting, support delaying the initiation of HAART until the CD4 count is in the 200-350 cells/mm³ range, though two studies suggest that it could be beneficial to initiate therapy at CD4 counts >350 cells/mm³. The optimal CD4 count between 200 and 350 at which to initiate HAART remains unknown. The risk of disease progression is lowest among persons who achieve virologic suppression, and suppression is more likely among persons who adhere to therapy. Persons who achieve durable virologic suppression do well, even if they initiate therapy at CD4 levels <200 cells/mm³. Clinician experience in the management of HIV infection also plays an important role in decreasing the risk of disease progression.

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