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House of Mirrors in the Virtual ICAAC

November/December 2001

Every year the American Society for Microbiology sponsors the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), a large conference linking the latest therapeutic advances from the laboratory with clinical practice. This year's event, originally scheduled for late September in Chicago, was postponed until mid-December due to the attack on New York. Last month we offered a preview of ICAAC presentations pertaining to the newly approved HIV drug, tenofovir (Viread). This month we continue with a selection of other HIV-related abstracts. Keep in mind that abstracts are submitted many months in advance of the conference and often report preliminary or partial data compared to the final poster presentation. For up-to-the-minute reporting on the latest from ICAAC, visit www.natap.org.

Drug Interactions

Interactions among HIV drugs are rife. Ritonavir, one of the nastier AIDS therapeutics on the shelf in terms of its side-effects at full dose, found new life due to its ability, at tolerable doses, to plug up a drain that can flush other, less toxic protease inhibitors (PI) from the body. Ritonavir "boosting" has since become a strategy to beat drug resistance by keeping the blood levels of these other PIs higher, longer. Its maker, Abbott Pharmaceuticals, rescued both ritonavir and their new, not exceptionally potent PI, lopinavir, by packaging the two together as Kaletra, a product that achieves therapeutic drug levels without intolerable toxicity.

(Abstract titles and authors are listed at the end of this article.)

A-494

Push-me, pull-you drug interactions can be tricky. A poster originally scheduled for presentation at ICAAC (but missing from the revised program) by investigators from Agouron Pharmaceuticals reported new details on pharmacokinetic interactions between ritonavir and their company's non-nucleoside reverse transcriptase inhibitor (NNRTI), delavirdine. It had previously been reported that delavirdine actually increased blood levels of ritonavir, while remaining unaffected in turn. In the new study, two groups of HIV-negative people (ten per group, randomized) received either 100 mg of ritonavir or 600 mg of delavirdine twice daily for 10 days. Following 14 days off drugs as a washout period, all twenty individuals then received combined doses of ritonavir and delavirdine twice daily for another 10 days. Continuous blood level monitoring of drug concentrations was performed on the last day of each 10-day dosing period.

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The investigators reported that mean minimum inter-dose levels of ritonavir were more than doubled by adding delavirdine; the maximum ritonavir dose was increased by 50 percent; and the total exposure to ritonavir (area under the curve) had increased by about 80 percent. Headache and rash were most commonly reported as side effects. The authors suggest that if delavirdine can boost ritonavir levels, then, in a kind of chain reaction, therapeutic blood levels of other concomitant PIs may also be improvable.

On a more practical note, these results suggest the need for care when using delavirdine to avoid unexpected ritonavir toxicity. This may be of particular concern when constructing regimens to treat multiple-drug resistant HIV. Although to date, delavirdine has been one of the least-prescribed HIV drugs, a quirk in how HIV resistance develops may have opened a new niche for its use. Workers at Virologic, Inc. after analyzing thousands of phenotypic drug resistance test results, observed an anomaly described as delavirdine hyper-susceptibility. They noted that some individuals who had formerly developed resistance to virtually every nucleoside and non-nucleoside RT inhibitor, began to show paradoxical renewed susceptibility to delavirdine. For people with few options, this is a slender thread of good news provided they are willing to bear the initial rash and itching that usually accompanies starting delavirdine. If this strategy is employed, however, the report on PK interactions with delavirdine should reinforce the importance of closely monitoring complex regimens containing multiple drug classes or multiple protease inhibitors, especially ritonavir.

Pass, Fail or Incomplete?

There has been much discussion about when to start antiretroviral therapy, but evidence about what happens after treatment has begun can be contradictory. HAART was quickly recognized as a miraculous gift for many people with very low CD4 counts and AIDS symptoms when they were pulled back from the brink of death. But not everyone had such a dramatic experience.

The hoped-for result of starting HIV treatment is for the virus to disappear and the immune system to come bouncing back. But there are other scenarios. The virus can go away but the CD4 count may languish. If the immune system is in the basement to start with, then the risk of getting sick remains even after actively replicating HIV is out of the picture. Much has been written about treatment failure as defined by renewed viral replication and subsequent decline in CD4 count. Another situation, though less common, is when virus levels come back and hover around a middling level while the CD4 count remains stable.

I-1906

An NIH study looked at the rate of viral decay in 38 previously untreated patients who started HAART. At baseline, most had uncontrolled viral loads above 10,000 copies/mL, however their CD4 counts varied widely, ranging from 6 to 784 cells/mm3. HIV RNA was quantified daily during the first week on treatment and then at fixed time points thereafter. Initial viral decay rates ranged from .15 to .35 log copies per day, which correlated with viral load results observed at weeks 4, 8 and 12. There was no association between the rate of viral decay and baseline viral load, CD4 count or CD8 count. The authors concluded that the initial clearance of plasma virus is due to drug therapy with no assistance from immune control. This means, they say, that ARV should work as well for those with advanced disease as for those with healthier immune systems.

But reducing viral load is not the whole story: To avoid AIDS symptoms and time in the hospital, CD4 counts need to go up as well. Researchers from the Ramon y Cajal Hospital in Madrid, Spain offered two studies that examined the clinical outcomes for previously untreated individuals who failed to have CD4 counts rise despite excellent viral control after initiating therapy.

I-1911

This observational cohort study looked at 288 patients who started HAART after March 1996 and subsequently maintained viral suppression for at least 24 months. The median CD4 count in this group was 186 cells/mm3. After one year of viral suppression below 50 copies/mL, 40 individuals (14%) had CD4 counts that declined or did not rise by more than 50 cells/mm3 despite successful control of virus. After two years of viral suppression, 25 individuals (10%) remained discordant, with CD4 counts failing to rise by more than 50 cells/mm3. During this period, 52 clinical events were recorded, primarily among patients who failed to have absolute CD4 counts rise above 200 cells/mm3. Non-significant associations were found between discordance and pretreatment viral load and age. The authors caution that complete viral suppression may not guarantee adequate immune recovery for a significant proportion of newly treated individuals with low baseline CD4 counts who remain at risk for disease and death.

I-1912

These investigators also reported on a two-year follow up study of 187 previously untreated patients from the hospital cohort who initiated HAART with CD4 counts below 200 cells/mm3. The main endpoint of this study was defined as the persistence of severe immunosupression (PSI), or CD4 counts remaining under 200 cells/mm3 despite control of HIV RNA below 200 copies/mL. The median baseline CD4 count was 87 cells/mm3 (ranging from 2-200).

Remarkably, 83% of the individuals achieved successful control of plasma HIV RNA after one year. The proportion of individuals with PSI dropped to 45% at 12 months; 21% at 24 months; and to 8% at 36 months. Having PSI was associated with lower baseline CD4 counts and male gender. The rates of hospital admissions, clinical events and death were not statistically significant between the PSI and non-PSI groups. However, the number of admissions per patient, the number of out-patient visits, and the time to the first hospital admission were significantly greater for those with PSI. These data support concerns about slower recovery for those who begin ART with advanced immune suppression. The authors also find that, although clinical outcomes were not greatly different during the study period, resource utilization was higher for PSI patients.

If the greater utilization among PSI patients is responsible for the lack of increase in death, this reinforces the continuing importance of attentive clinical management of AIDS-associated disease. Worldwide, an increasing number of individuals receiving treatment for the first time may be encountered in this danger zone of very low CD4 cell counts. While HAART may work its miraculous benefits on most people at this advanced stage of disease, these reports anticipate a need to support potentially large numbers of patients with complex clinical management during a long, slow recovery to functional immune competence.

The decision to offer antiretroviral treatment in low-resource settings may of necessity be governed by syndromic management if access to expensive assays is limited. Too-early initiation of treatment will also be discouraged to minimize toxicity and expense. The development and widespread deployment of a low-cost CD4 assay may become critical if timely treatment decisions are to be made before immune suppression is signaled by symptoms.

Finally, it seems that increased resource utilization is masking the appearance of clinical events that would occur otherwise. Can these measures serve as a stand-in for disease and death in clinical trials? The potential of resource utilization as a surrogate marker of clinical disease should continue to be investigated to determine its usefulness as an endpoint in long-term effectiveness studies of treatment interventions and strategies.

These papers looked at people who failed to have CD4 cell counts rise despite admirable control of viremia. Another study from the very large Eurosida cohort examined people on stable HAART regimens who have not completely controlled their virus yet haven't suffered dramatic declines in CD4 counts either.

I-1915

The investigators selected 471 patients from the Eurosida cohort who had been on HAART for more than six months; had been on the same regimen for at least 3 months; and who had a confirmatory viral load between 1000 and 10,000 copies at the baseline visit. Those selected were followed-up for one year or while they remained on their baseline drug regimen (median duration, 8 months). The median change in viral load during the year was +0.2 log copies/mL. The median change in CD4 count during the year was +13 cells/mm3. The authors commented that whereas the increase in viral load is consistent with natural history observations, the stability of CD4 counts during this period is notable.

These findings awaken interest in theories about the possibility of achieving equilibrium between therapeutic control and immune control of an evolved virus with impaired drug susceptibility but also impaired replication fitness. The authors suggest that genotypic analysis of these patients' isolates is a next step.

Abstracts Cited

  • I-1494
    J. Q. Tran, Delavirdine (DLV) Significantly Increases Exposure of Low Dose Ritonavir in Healthy Volunteers

  • I-1906
    M. Polis, Plasma HIV-1 Decay Rate Constant During Initial Therapy Is Independent of Baseline CD4+ and CD8+ Lymphocyte Counts and Baseline Viral Load

  • I-1911
    F. Dronda, Long-Term Outcome of Naive HIV-Infected Patients (pts) with Small Increases in CD4+ Cells After Successful Virological Suppression: A Study of Discordant Responses with HAART

  • I-1912
    A. Moreno, Clinical and Immunological Outcomes in Severely Immunosuppressed Naive Patients on Effective Protease Inhibitor-Based HAART

  • I-1915
    J. D. Lundgren, The Stability of the Viral Load in Subjects with Virological Failure Who Remain on the Same HAART Regimen: The EuroSIDA Study



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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