Online Coverage from the 12th World AIDS Conference
June 29 - July 2, 1998
c Medscape, Inc.
Standards of Medical Therapy for HIV -- Lessons from the 12th World AIDS Conference
Speaker: Julio Montaner, MD, the University of British Columbia, Vancouver
Reporter: Bill Valenti, MD
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Introduction
Incomplete adherence represents the single most significant challenge to long-term effectiveness of the currently available HIV regimens, according to Dr. Julio Montaner of the University of British Columbia, Vancouver, who delivered a summary presentation on standards of care and treatment in 1998. In so saying, Montaner reaffirmed a message that was stated clearly all week: commitment to long-term treatment adherence will improve outcomes individually and reduce the transmission of resistant strains.
Long-term safety of currently available drugs is the second major threat to durably effective therapy. Protease inhibitors have been a cornerstone of highly active antiretroviral therapy (HAART), but associated metabolic complications of long-term use make therapeutic options other than protease inhibitor (PI)-containing regimens desirable.
Simplified HAART regimens are being developed and are gaining widespread acceptance. Compact regimens using existing therapies will make adherence less of a burden on patients. Daily didanosine (ddI), lamivudine (3TC), and nevirapine; fixed-combination zidovudine(AZT)/3TC; and twice-daily PI administration are examples. In addition, newer agents such as efavirenz (Sustiva, once-daily), abacavir, a nucleoside analogue; adefovir, a new class of nucleoside reverse transcriptase inhibitor (NRTI, also once-daily); and amprenavir, a new PI, all expand our armamentarium considerably and, if incorporated into HAART therapies, will also aid patients in compliance.
While suppression of plasma viral load (PVL) to <500 copies/mL was possible with two drugs, only triple combinations have been able to achieve long-term suppression of PVL to <500 copies (AIDS Clinical Trials Group (ACTG)-320). In 1997, this realization led to the reformulation of our therapeutic standard for HIV. Plasma viral load target levels became <500 copies/mL, and recommended therapy consisted of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) + a PI or, as an alternative, two NRTIs + one NNRTI. Data presented at this conference have definitively established the role of NNRTIs as an integral part of triple combination therapy.
The era of triple-drug therapy began with the AZT, 3TC, and indinavir combination, and now includes a variety of other drugs added to 2-drug combinations. All of these combination have had significant impact on morbidity and mortality, including improved outcome, fewer deaths and opportunistic infections, improved quality-of-life and fewer hospitalizations.
Viral Load: How Low Should You Go?
The duration of virologic effect of a given regimen increases proportionately as the PVL falls following the start of therapy, as established by both the INCAS (AZT, ddI, nevirapine) and AVANTI II (AZT, 3TC, indinavir) and III (AZT, 3TC, nelfinavir) protocols. Findings from these studies suggest that patients who achieved a viral load nadir below the lower limit of detection (<20 to 50 copies/mL) were most likely to have durable responses to highly active antiretroviral therapy (HAART). Interestingly, patients who have viral load nadirs between 50 and 500 and over 500 both have similar rates of virologic failure. Based upon these data, Dr. Montenar suggests that the target PVL level should be revised to less than 20 copies/mL.
Such a goal for PVL is clearly attainable, and prolonged suppression of viral replication with the drugs that are available today can forestall, if not prevent, the emergence of resistance. Unfortunately, a number of laboratories showed that replication-competent virus can be isolated from the blood of fully suppressed patients receiving HAART. Also, rapid rebound of HIV in vivo has been documented after prolonged apparent suppression with HAART. These facts and findings should encourage us all to devote resources to patient support and adherence.
Which Regimen is Best?
None of the regimens in Table I have proven substantially different from the others, when analyzed in terms of their ability to achieve a PVL level less than 500 or less than 50, at 16 weeks in antiretroviral-naive patients.
Table I - Summary of HAART Trials
Trial Drugs
AVANTI II AZT, 3TC, indinavir
AVANTI III AZT, 3TC, nelfinavir
INCAS AZT, ddI, nevirapine
NV15355 2 nucleosides + saquinavir soft gel capsules
DMP 00 AZT, 3TC, efavirenz
CNA 3003 AZT, 3TC, abacavir
The Future
Reducing viral load and eliminating latent reservoirs are the ultimate goals of effective antiretroviral therapy. Early initiation of therapy results in smaller reservoir size compared with late, thus increasing the possibility of eliminating all latently infected cells. In patients with advanced disease at the time of initial therapy, this goal seems even less likely. Regardless of time to first treatment, however, HIV therapeutics must overcome a number of obstacles, including pharmacokinetic interactions, prior resistance, adverse effects, and incomplete adherence, all of which will promote virologic failure over time.
Individualizing therapy, both to social factors (in order to promote adherence) and disease-specific factors, will help address many of the outstanding therapeutic issues. VIRCO and Virologic technologies allow phenotypic testing, which may eventually become an indispensable tool for clinical management. In a retrospective study, the phenotypic assay was able to predict virologic outcome. Prospective evaluation of phenotypic testing is necessary in order to move on to the next step: developing guidelines for the optimal use of this technology in clinical practice.
Conclusion
Therapy for HIV has made considerable progress over the last 10 years. Key issues for continued improvement in outcomes for patients, include establishing durable suppression of viral replication, simplified regimens, reduced long-term complications of therapy, and increased tolerability and adherence. In addition, to treat the disease in endemic developing countries, we must bridge the gap for those who cannot afford the high cost of therapy.
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