HIV Susceptibility Testing and Survival
HIV Susceptibility Testing and Survival
Abstract and Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Synopsis: In this study, 2,699 HIV-infected patients eligible for genotypic or phenotypic (GPT) susceptibility testing followed in the HIV Outpatient Study (HOPS) cohort from 1999-2005 were studied. The use of GPT was independently associated with improved survival among HAART-experienced patients.
Source: Palella FJ, et al. The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: A cohort study. Ann Int Med. 2009;151:73-85.
HOPS is an ongoing prospective, observational cohort study of HIV-infected patients at 10 participating HIV clinics in the United States. A total of 2,699 patients with HIV RNA > 1,000 copies/uL were seen from 1999-2005. Demographic characteristics, clinical factors, and GPT use were correlated with all-cause mortality. Crude and adjusted hazard ratios (HRs) for the association between GPT and survival were calculated. During the median 3.3 years of follow-up, 915 (34%) patients underwent GPT. Patients who had GPT had lower mortality rates (2.0 vs. 2.7 deaths/100 person-years) than those who did not. In Cox models, GPT was associated with improved survival (HR 0.69) when adjusted for demographic characteristics, CD4+ count, HIV RNA level, and intensity of clinical follow-up.
Commentary
In 1998, the landmark Marschner meta-analysis was published. This paper established HIV RNA (in addition to CD4+ count) as a continuous variable that correlated with progression to AIDS and death.1 Based on this overwhelming data set, the FDA formally established the policy that new antiretroviral agents could receive marketing clearance if the sponsors could demonstrate the activity in patients by effect on this surrogate marker, and no longer were required to show that antiretroviral agents actually reduced progression to AIDS and death.
In 1989, Richman2 and Larder3 demonstrated that virologic and clinical failure in patients treated with AZT was associated with development of HIV resistance, as demonstrated by phenotypic assays in cell culture and genotyping of the reverse transcriptase gene, respectively. By 1999, the clinical use of HIV susceptibility testing was becoming well-established in the United States and Canada. The clinical utility of HIV genotyping was demonstrated in two well-controlled, prospective, randomized clinical trials, which Viradapt4 conducted in Europe and GART5 conducted in the United States. The benefit of HIV genotyping in both of these studies was seen in patients who had failed one or multiple antiretroviral regimens. The mean incremental benefit of HIV genotyping over "standard of care" was approximately 0.5 log10 HIV RNA. Largely based on the strength of these two studies (and a retrospective reanalysis of archived plasma samples from GART and several analytical performance trials), the FDA's Center for Biologics granted marketing clearance for Visible Genetics' TRUGENE HIV genotyping system as an in vitro diagnostic device. Parenthetically, only one prospective, randomized trial, the Virco-sponsored VIRA 3001 study, has demonstrated the clinical utility of in vitro phenotyping, but inclusion in this study was restricted to patients who were failing their first ARV regimen. Prospective, randomized studies of HIV phenotyping in more treatment-experienced patients, as were studied in both the NARVAL and the CCTG 575 trials, have consistently failed to demonstrate any benefit over educated guessing, hence the infrequent use of in vitro phenotyping outside of the United States.
This HOPS cohort study followed patients long enough to demonstrate a benefit of GPT on survival when the data were analyzed using multivariate analysis. However, like all cohort studies, a number of sources of bias may be present despite the statistical efforts made to control for this. A perusal of the baseline study population characteristics showed a number of imbalances between the GPT vs. no GPT groups. This includes a higher percentage of racial and ethnic minority patients, injection drug users, lack of insurance, and HCV co-infection in patients who did not undergo GPT. All of these are probably good surrogate markers for patients who are likely to have excess mortality from a variety of causes. Despite these limitations, the implications of this study clearly support the clinical utility of GPT.
References
- Marschner IC, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis. 1998;177:40-47.
- Larder BA, et al. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989;243:1731-1734.
- Larder BA, et al. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989;246:1155-1158.
- Durant J, et al. Drug resistance genotyping in HIV-1 therapy: The VIRADAPT randomized controlled trial. Lancet. 1999;353:2195-2199.
- Baxter JD, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. AIDS. 2000;14:F83-F93.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.