Important note: Information in this article was accurate in November 2002. The state of the art may have changed since the publication date.
This pre-conference workshop, directed by John Mellors and Julio Montagner, took place September 26 and 27 in San Diego. A summary of the presentations addressing the state-of-the-art for treatment experienced patients follows.
Sam Bozette reviewed the experience of the HIV Costs and Services Utilization Study (HCSUS), which is the $30 million RAND analysis of HIV care in the U.S., and presented the following conclusions:
In 1995, approximately 200,000 patients in the U.S. were receiving antiretroviral therapy.
About 94% of patients who had received HIV care had been treated with antiretroviral drugs.
A major challenge in HIV care is delayed detection of disease. Specifically, 35% of HIV-related deaths in 2000 occurred in patients who were diagnosed within 6 months of their death. About 50% of those who died had never been treated with antiretroviral drugs. Fifty-six percent of patients with an AIDS-defining diagnosis were "late testers," and 44% developed AIDS while in care.
Among patients currently in care, 24% had viral loads <50 c/mL, 51% <5,000 c/mL, and 65% <20,000 c/mL.
Resistance data, which have been summarized previously by Doug Richman, demonstrate that approximately 100,000 of 135,000 (74%) patients on treatment with a viral load >500 c/mL have at least one major resistance mutation.
Bozette concluded that a major challenge for HIV care is to find those who are infected and, in terms of total numbers, this may be substantially more important than dealing with salvage therapy.
Robert Hogg reported his experience at the University of British Columbia with 1,219 patients. He noted that >95% adherence is often cited as the requirement for virologic suppression; however, his analysis concluded that adherence of =75% of prescribed doses contributes substantially to survival, as reported in his prior study [AIDS 2002 Oct 18;16(15):2065-72]. Low socioeconomic status contributed to reduced survival, but there was no increased risk in a subset analysis restricted to low income patients who were given HAART. The conclusion was that there is a need to establish therapeutic guidelines to insure equitable access. Another major factor emphasized by the author was the role of physician experience, which validates the reports from others [J Acquir Immune Defic Syndr 2000 Jun 1;24(2):106-14].
Amy Justice reported her experience with a three-site study in the VA (VACS-3), which includes 881 adults. Common medical co-morbidities were hepatitis (53%), hypertension (24%), and hyperlipidemia (17%). Also, 46% had significant symptoms of depression (CES-D test), and 21% were at risk for excessive alcohol use (AUDIT test). These co-morbid conditions were considered more important than AIDS for both survival and poor quality of life. In patients with advanced HIV (CD4 count <200 cells/mm3), the major indicators of poor prognosis were increased transaminase, anemia, peripheral neuropathy, renal failure, and pancreatitis. For those with earlier stage HIV infection (CD4 count >200 cells/mm3), the major indicators for decreased survival and quality of life were hypertension, coronary artery disease, and hyperlipidemia. Both AST and hemoglobin showed an "astonishing interaction" with other factors in survival. The author concluded that non-HIV-related co-morbidities, including general medical and psychiatric diagnoses, are critical factors that must be addressed in the management of HIV infected patients.
Michael Lederman discussed the possibilities for a therapeutic vaccine. The challenge is enormous: 1) There is no precedent (e.g. no therapeutic vaccine for any disease). 2) HIV is characterized by immune deficiency which obviously hampers this approach to therapy. 3) There is substantial strain variability and mutational escape. 4) There are no good assays for measuring immune response. Despite these obstacles, the author concluded that HIV infection is unique, we now have better vaccines and adjuvants, and that prior tests of this approach to treatment may have been too demanding.
Veronica Miller summarized several points, as follows:
Resistance testing in untreated patients with acute HIV infection has shown at least one major resistance mutation in 6.7-12%, according to studies performed from 1999-2002. Some have reported somewhat sequential results that have not clearly progressed over time, including Little and colleagues, who showed resistant mutations in 3.4% of HIV strains from 264 patients studied in 1995-98, 12% of 113 patients studied in 1999-2000, and 6.7% of 122 patients studied from 2000-2002.
Clinical implications of baseline resistance in untreated patients seem unclear due to variations in reports. Some show no association between baseline resistance and treatment results [Abstract 167], and others show a significantly greater reduction in the viral load response for those without baseline resistance.
Measurement of resistance off treatment is problematic because of re-emergence of wild-type virus at 8-11 weeks after treatment is discontinued.
The author concluded that the association between resistance and outcome depends on the method of measuring outcome. The association with viral load is more clear than the association with CD4 cell count changes, and clinical outcome has not been well addressed.
Courtney Fletcher presented the following possibly important observations as examples of the utility of pharmacology studies:
Concentrations of saquinavir are higher in women.
There is substantial penetration of EFV into the CNS.
Both trough levels and AUC seem to correlate with viral suppression.
The author also presented his concept of a "composite concentration index," which includes intracellular measurements of triphosphate concentrations of nucleosides. His conclusion was that there is a pressing need to merge virology and pharmacology.
Roy Gulick summarized multiple studies indicating that a first regimen failure can usually be managed successfully with a second regimen, including Merck 035, Merck 039, DuPont 020, ACTG 388, ACTG 364, and Abbott 462. Some studies have shown that failure with PI monotherapy can be managed by simply adding nucleosides; examples included Merck 035, in which AZT/3TC was added to indinavir monotherapy, and ACTG 378, in which amprenavir monotherapy was later supplemented with d4T/3TC. Gulick also emphasized the changing philosophy of managing virologic failure. In 1998, the recommendation was for an entirely new regimen. However, GART and other studies showed that viral breakthrough is usually not associated with resistance to all drugs, making selection based on resistance testing feasible. Nevertheless, he emphasized that a change in therapy should occur early in the course of virologic failure. Gulick concluded by reiterating his strong impression that "failure begets failure" is an erroneous concept when applied to failure following the first regimen.
Julio Montagner presented his experience with "mega-HAART." His work has shown that at 24 weeks, 50% achieved a viral load of <400 c/mL and 40% achieved a viral load of <50 c/mL. He cautioned about the complexities of mega-HAART with the following examples: The combination of lopinavir/ritonavir (LPV/r) 3-4 caps bid plus amprenavir (APV) 750 mg bid shows a complex pharmacokinetic interaction; LPV/r 3-4 caps bid plus indinavir (IDV) 600 mg bid requires monitoring for renal toxicity; when prescribing the combination of LPV/r 3-4 caps bid plus saquinavir (SQV) 1,000 mg bid, clinicians should use the Invirase rather than the Fortovase formulation of SQV to decrease toxicity. Some of these combinations will require therapeutic drug monitoring due to these complex interactions.
He finished by claiming the availability of new drugs will magnify the options.
Joe Eron presented the results of two phase III studies of the new peptide fusion inhibitor, enfuvirtide (T-20). TORO-1 included 491 patients in North America and Brazil who had failed multiple antiretroviral regimens. This group had a median baseline viral load of 5.2 log10 c/mL, a mean of 12 prior antiretroviral agents, and 80% had =5 resistance mutations. Results at 24 weeks showed that T-20 recipients had a mean reduction in viral load of 1.7 log10 c/mL compared to 0.76 log10 in the control group. TORO-2 was similar in design and involved 504 patients in Europe and Australia. In this group the mean reduction in viral load at week 24 was 1.3 log10 c/mL in T-20 recipients compared to 0.65 log10 c/mL in control. The most common side effect was reaction at the injection site, but only 3% of participants in both studies discontinued treatment because of adverse reactions.
James Harrigan presented the following observations regarding resistance testing:
The latest resistance test underestimates cumulative drug resistance, especially NRTIs.
Studies in British Columbia in treatment-experienced patients found that NRTI resistance decreased from 1996 to 2002, PI resistance mutations have leveled at 20%, and the rate with NNRTIs is about 50%.
The most common PI mutations are 90M, 10I and 71V; the most common NRTI mutations are 41L, 215Y and 184V.
Many mutations are selected that have not been characterized for clinical significance.
Harrigan concluded that interpretation of resistance test results is complex.
John Urquhart noted that the main problems are under-dosing and intermittent or delayed use. Many patients have good "taking" compliance but poor "timing" compliance.
Diane Havlir observed that long-term viral suppression is best predicted by baseline VL and post-treatment nadir. "Blips" do not predict failure, but "bumps" (sustained VL >500 c/mL) do. CD4 count predicts symptoms, so should the goal be VL suppression or CD4 count increase? Switching based on VL is most appropriate at earlier stages of disease, due to the need to preserve options at this stage.
Alan Landry noted that virologic failure is associated with or predicted by the following:
Baseline CD4 <125/mm3 (ACTG 890)
Increased CD8 activation (ACTG 315)
Absent lymphocyte proliferation assay response to p24
Decreased thymic output
Absent naïve CD4 cell response
Reduced memory CD4 cell response
Despite the interest in immunologic monitoring, the tests reported here other than a simple CD4 count are generally available only in research labs.
The workshop provided a good review of HIV treatment failure with relatively sparse information that could be used by experienced care providers in their clinics the next Monday. However, there were some points worth emphasizing:
The biggest challenge is to find people with HIV infection who haven't been diagnosed.
HIV-infected patients under treatment have complex psychiatric and general medical conditions that require multidisciplinary non-ID resources.
Adherence is accepted as a critical factor in outcome, but the "95% rule" may oversimplify the issue since lower levels of adherence may still lead to clinical benefit, and timing is an under-appreciated determinant.
Rescue treatment after one regimen failure is often easy. It gets tougher with subsequent treatment failure.
Therapeutic drug monitoring is topical, but specific recommendations that result in better clinical outcomes have not been established.
Genomics are presumably important, but we don't have any useful applications yet.
Resistance testing is now the standard of care for virologic failure, but it seems best for defining which drugs shouldn't be used. Old tests and drug history are critical, and the previous rule stressing the need to change all drugs is obsolete.
Immunologic monitoring includes multiple studies that measure CMI response and competency of new CD4 cells, but the only test available to most clinicians is a CD4 cell count.
Virologic control is the goal, but CD4 counts predict morbidity, and "failing" therapy still benefits patients who have no other options.
The most important rule for achieving virologic success is to change early in the course of failure.
There are several new drugs in development, but the most exciting, most potent, most expensive, and most near to FDA approval is T-20.
20021101
JH20021102
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