The evolving role of antiretroviral drug resistance testing in HIV-infected individuals

Scientific advances have made HIV resistance testing routinely available to clinicians and other HIV caregivers. However, interpretation of HIV resistance results is complicated by the lack of knowledge of the clinical consequences of specific genotypic and phenotypic results for most antiretroviral agents. Limitations of viral genotype and phenotype HIV resistance testing include factors such as lack of uniform quality assurance, turn around time, cost, and insensitivity to those mutant strains present in less than 20% to 30% of the viral population. Since there are currently no multicenter prospective data that compare and support the use of one type of resistance testing over another, clinicians who are caring for HIV-infected individuals should become familiar with the pros and cons of the available assays. Clinicians will need to watch for new developments in HIV resistance testing that are on the horizon and will become available in years to come.     

Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing

BACKGROUND: Primary HIV drug resistance has been associated with poor treatment outcome of first-line highly active antiretroviral therapy (HAART) in several trials. The aim of the study was to assess the efficacy of first-line HAART guided by resistance testing. METHODS: In a prospective multicenter study in the state of Nordrhein-Westfalen, Germany, chronically HIV-infected patients underwent genotypic resistance testing and were monitored for 48 weeks after initiation of HAART. RESULTS: Primary drug resistance was found in 30 of 269 patients entering the study between January 2001 and December 2003 [11.2%; 95% confidence interval, 7.4-14.9]. In intent-to-treat analysis, the proportion of patients with viral load below 50 copies/mL after 24 and 48 weeks was 70.0% and 66.7%, respectively, in patients with resistance and 74.1% and 73.6%, respectively, in patients without (P = 0.66 and 0.51). In on-treatment analysis, the proportions were 80.8% and 83.3%, respectively, in patients with resistance and 81.9% and 85.0%, respectively, in patients without (P= 0.79 and 0.77). These results were also valid considering a detection limit of 400 copies/mL. CONCLUSIONS: The prevalence of primary drug resistance was 11.2% in chronically HIV-infected patients. HAART guided by resistance testing had similar efficacy in patients with primary drug resistance as compared with patients with wild-type virus. Based on these facts, resistance-adapted first-line HAART is suggested as routine practice.     

A physician's primer to antiretroviral drug resistance testing

Evaluating the genetic composition of HIV has evolved from a traditional epidemiologic research tool into a widely used clinical asset in the management of HIV infection. Genotypic and phenotypic testing is designed to identify drugs less likely to be therapeutically effective. Genotypic assays identify specific "gene mutations" or nucleotide substitutions known to confer drug resistance, whereas phenotypic assays measure the amount of drug necessary to inhibit viral replication in vitro. Prospective studies of antiretroviral drug resistance testing have shown its value as an independent predictor of optimal virologic response to drug therapy. Current guidelines recommend use of these tests following treatment failure and during pregnancy; considerations for testing include primary infection and treatment-naive patients. The identification of drug resistance can help the clinician individualize treatment regimens to attain maximal viral suppression and patient longevity.     

HIV antiretroviral drug resistance in Africa

Highly active antiretroviral therapy (HAART) has dramatically reduced mortality and morbidity in HIV-infected persons in developed countries. Although the use of HAART remains limited in Africa, there are global efforts to make available these drugs to several million HIV-infected persons on the continent. In this review we examine the impact of HIV genetic diversity on the occurrence of drug-resistance mutations among non-B subtypes, and discuss the implication of resistant strains in programs aimed at implementing antiretroviral treatment (ART) in Africa, with respect to factors that may favor the occurrence of treatment-acquired drug-resistant viruses, ways to monitor for drug resistance, and strategies to limit its occurrence. We assert that antiretroviral drug resistance is an inevitable consequence when providing long-term treatment, and should not be seen as a limitation of providing antiretrovirals to patients in resource-poor settings, but rather a necessary challenge to be incorporated into the rational design of programs that provide ART in Africa.     

Genotypic antiretroviral resistance testing for human immunodeficiency virus type 1 integrase inhibitors by use of the TruGene sequencing system

A sequencing assay for detection of mutations conferring resistance to human immunodeficiency virus type 1 (HIV-1) integrase inhibitors raltegravir and elvitegravir was developed using the automated TruGene sequencing system. The assay returned clear sequencing results for samples with ≥500 RNA copies/ml for mutation detection and HIV-1 subtyping across a spectrum of HIV-1 subtypes.     

Elevated phenotypic switching and drug resistance of Candida albicans from human immunodeficiency virus-positive individuals prior to first thrush episode

Strains of Candida albicans obtained from human immunodeficiency virus (HIV)-positive individuals prior to their first episode of oral thrush were already in a high-frequency mode of switching and were far more resistant to a number of antifungal drugs than commensal isolates from healthy individuals. Switching in these isolates also had profound effects both on susceptibility to antifungal drugs and on the levels of secreted proteinase activity. These results suggest that commensal strains colonizing HIV-positive individuals either undergo phenotypic alterations or are replaced prior to the first episode of oral thrush. They also support the suggestion that high-frequency phenotypic switching functions as a higher-order virulence trait, spontaneously generating in colonizing populations variants with alterations in a variety of specific virulence traits.     

Update on antiretroviral drug resistance testing: combining laboratory technology with patient care

HIV drug resistance testing has been considered an emerging asset to modernized HIV management. Despite the increased number of antiretroviral agents currently available, virologic failure remains a significant problem. Drug resistance testing is designed to identify gene mutations or viral growth characteristics that suggest reduced drug susceptibility. The widespread use and virologic benefits of resistance testing in some prospective clinical trials have prompted the development of formal guidelines by expert panels for clinical use. Despite technological advances in drug resistance testing, clarification of assay interpretation, assay standardization, and the results from validation studies are needed. This review discusses updated genotyping and phenotyping methodologies, assay utilities and limitations, clinical validation studies, and current recommendations.     

Antiretroviral drug resistance testing

While antiretroviral drugs, those approved for clinical use and others under evaluation, attempt in lowering viral load and boost the host immune system, antiretroviral drug resistance acts as a major impediment in the management of human immune deficiency virus type-1 (HIV-1) infection. Antiretroviral drug resistance testing has become an important tool in the therapeutic management protocol of HIV-1 infection. The reliability and clinical utilities of genotypic and phenotypic assays have been demonstrated. Understanding of complexities of interpretation of genotyping assay, along with updating of lists of mutation and algorithms and determination of clinically relevant cut-offs for phenotypic assays are of paramount importance. The assay results are to be interpreted and applied by experienced HIV practitioners, after taking into consideration the clinical profile of the patient. This review sums up the methods of assay currently available for measuring resistance to antiretroviral drugs and outlines the clinical utility and limitations of these assays.