Christopher H. Sherlock

Diagnosis and treatment approaches of CMV infections in adult patients

BACKGROUND Cytomegalovirus (CMV) infections are very common in the general population. Clinical CMV disease, particularly CMV pneumonitis, greatly impacts the morbidity and mortality of immunosuppressed patients. OBJECTIVE To present an overview of the basic aspects of the biology, epidemiology, and clinical features of CMV in relation to the available diagnostic and therapeutic approaches in adult patients. METHODS Review of the medical literature on cytomegalovirus infection and disease in adult hosts, with a focus on approaches to diagnosis and treatment of CMV respiratory disease in immunosuppressed hosts. CONCLUSIONS Cytomegalovirus infections are likely to remain a significant cause of morbidity and mortality among immunosuppressed patients. Important aspects of the biological events underlying the transition from infection to clinical disease remain unclear. Despite that, considerable progress has been made in the design of improved diagnostic techniques and the development of antiviral agents. Preventive and particularly preemptive therapeutic approaches demand further technical improvements in diagnostic testing. At present, the emphasis in the search for improved diagnostic testing rests on the development of quantitative methods for early detection of the increased viral replicative activity that presumably precedes the onset of CMV disease in infected individuals.

Antiviral effect of double and triple drug combinations amongst HIV-infected adults : lessons from the implementation of viral load-driven antiretroviral therapy

Objective:To study the antiviral effect and predictors of response to two- and three-drug regimens amongst antiretroviral-naive individuals using an intent-to-treat analysis. Main outcome measure:Suppression of plasma viral load to <500 copies/ml. Patients:A total of 420 (264 double drug, 156 triple drug) individuals in a province-wide treatment programme were studied. Results:A decrease in plasma viral load to < 500 copies/ml was documented in 197 (47%) subjects. This was independently associated with a lower baseline plasma viral load (odds ratio, 3.67; 95% confidence interval, 2.13–6.30) and initiation onto a three-drug regimen (odds ratio, 3.86; 95% confidence interval, 2.24–6.66). Median plasma viral load failed to reach < 500 copies/ml and in fact rebounded in the two-drug group. In contrast, 91 (58%) subjects receiving three drugs reached <500 copies/ml during the study period. Conclusion:These results support the use of powerful triple drug regimens as initial therapy in HIV-infected individuals.

Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy

ObjectiveTo characterize the relationship between plasma viral load (pVL) suppression and triple drug antiretroviral therapy, and the accompanying changes in CD4 cell counts. MethodRetrospective study of 465 participants in a HIV/AIDS Treatment Program who initiated triple drug therapy between August 1996 and May 1998. Participants were divided into three groups according to their pVL response: (i) non-responders (NR; n = 112) exhibited pVL persistently > 500 copies/ml over the study period; (ii) partial responders (PR; n = 100) achieved a pVL < 100 copies/ml at least once and subsequently rebounded to > 500 copies/ml; and (iii) full responders (FR; n = 253) achieved a pVL < 500 copies/ml and sustained this level for the remainder of the study period. For each group, the accompanying changes in absolute and fractional CD4 cell counts were evaluated. ResultsThe median net change in pVL per person from baseline to the end of the observation period was −0.37, −2.27, and −2.56 log10 copies/ml for NR, PR and FR, respectively. During weeks 68–83, the median CD4 cell count (× 106 cells/l) was 150 [interquartile range (IQR) 90–370], 380 (IQR 300–480) and 525 (IQR 305–705) for NR, PR and FR, respectively. Median changes in CD4 cells (× 106 cells/l) were −20 (IQR −90 to 40), 150 (IQR 30–250) and 240 (IQR 110–365) for NR, PR, and FR, respectively. The net percentage change in CD4 cells per person was 0% (IQR -34–31), 54% (IQR 6–160), and 83% (IQR 39–173) for NR, PR, and FR, respectively. By weeks 68–83, the median fractional CD4 cells was 0.16 (IQR 0.07–0.22), 0.22 (IQR 0.15–0.28), and 0.26 (IQR 0.17–0.34) for NR, PR and FR respectively. ConclusionsAn optimal CD4 cell count response appears to be coupled with continued pVL suppression. Our data indicate that maximal suppression of viral replication should remain the primary goal of therapy.

Transcription-mediated amplification is more sensitive than conventional PCR-based assays for detecting residual serum HCV RNA at end of treatment

OBJECTIVE:In patients chronically infected with hepatitis C virus (HCV) undergoing antiviral therapy, sustained virologic response is suggested by viral clearance by end of treatment (EOT). Viral clearance is defined by nondetection of serum HCV RNA, usually by qualitative PCR-based assays with limits of detection ranging from 100 to 1000 copies/ml. However, some individuals relapse after achieving apparent viral clearance by EOT. These individuals may have low levels of viremia not detected by current PCR methods. The aim of this retrospective study was to determine whether the Bayer HCV RNA Qualitative Assay, which employs Transcription Mediated Amplification (TMA) and detects 50 HCV RNA copies/ml, could detect residual serum HCV RNA in patients who achieved apparent viral clearance by EOT and subsequently relapsed.METHODS:Samples were obtained at EOT (wk 24 or 48) and follow-up (wk 24–26 posttreatment) from 97 patients treated for HCV (78 relapsing patients, 19 sustained responders). All samples in which HCV RNA was not detected by PCR were tested in a blinded manner for HCV RNA by the TMA-based assay.RESULTS:HCV RNA was detected by the TMA-based assay in 27 (34.6%) EOT and 76 (97.4%) follow-up samples from relapsing patients, but not in any of the EOT or follow-up samples from sustained responders.CONCLUSION:Residual serum HCV RNA was detected by the TMA-based assay in EOT samples from 34.6% of patients that had achieved apparent viral clearance by PCR. The detection of HCV RNA by the TMA-based assay could help redefine EOT response and assist in the antiviral management of HCV infection.

Multicenter Evaluation of the VERSANT Hepatitis B Virus DNA 3.0 Assay

ABSTRACT The VERSANT hepatitis B virus (HBV) 3.0 Assay (branched DNA [bDNA]) (referred to herein as VERSANT 3.0) was evaluated at four external sites for analytical sensitivity, specificity, reproducibility, linearity of quantification, and limits of detection. In addition, each of the test evaluation sites provided HBV DNA-positive clinical samples that were previously analyzed by one of three commercially available HBV DNA quantitative tests: Digene Hybrid Capture II HBV DNA Test (Digene); VERSANT HBV DNA 1.0 Assay (bDNA) (VERSANT 1.0); and COBAS AMPLICOR HBV Monitor Test (COBAS AMPLICOR). These samples were reexamined using VERSANT 3.0. The results from these studies showed that VERSANT 3.0 has high specificity (99.3%), excellent reproducibility (between-run coefficient of variation [CV] = 1.6 to 9.4%; within-run CV = 6.5 to 20.7%), and a broad linear range of quantification (2.0 × 103 to 1.0 × 108 HBV DNA copies/ml) that facilitate the monitoring of HBV DNA levels at diagnosis and throughout the course of treatment. In general, correlation was very good between results obtained from clinical samples analyzed by VERSANT 3.0 and the comparative HBV DNA quantitative assays (VERSANT 1.0, R2 = 0.900; Digene, R2 = 0.985; COBAS AMPLICOR, R2 = 0.771). The greatest differences in comparative quantitation occurred at HBV DNA levels approaching the limits of the dynamic ranges for the comparative assays. The performance characteristics of the new VERSANT 3.0 assay demonstrated that it provides a reliable and robust method for routinely monitoring serum HBV DNA levels in assessing disease activity and determining response to antiviral treatment.

The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study.

Objective:To characterize the antiviral effect and predictors of response to ritonavir and saquinavir-based antiretroviral combination therapy. Design:Intent-to-treat analysis with suppression of plasma viral load to levels below 2.7 log10 copies/ml as the main outcome measure. Patients:All adult HIV-positive individuals in the province of British Columbia who started taking ritonavir and saquinavir (each at 600 mg twice daily) in combination from 1 September 1996 to 28 February 1997, with a minimum of two plasma viral load measurements, one at baseline and one after the initiation of therapy. Results:A total of 58 participants were prescribed ritonavir and saquinavir. The median plasma viral load at entry was 4.80 log10 copies/ml (interquartile range, 4.51–5.15 log10 copies/ml). A total of 29 (50%) subjects demonstrated a decrease in plasma viral load to levels below 2.7 log10 copies/ml. This level of suppression was associated with higher baseline CD4 cell counts (P = 0.022) and no prior exposure to protease inhibitors (P = 0.001). After controlling for baseline CD4 cell count and plasma viral load, participants naive to protease inhibitors were almost seven times (odds ratio, 6.99; 95% confidence interval, 1.85–26.39; P = 0.004) more likely to suppress their plasma viral load to below 2.7 log10 copies/ml than those who had previously used protease inhibitors. Conclusion:Our analysis demonstrates that a ritonavir and saquinavir-based combination can produce a substantial decrease in plasma viral load with half of the participants decreasing their plasma viral load to below the limit of quantification of the assay. This response, however, is seriously compromised by prior exposure to protease inhibitors.

Suppression of Plasma Virus Load below the Detection Limit of a Human Immunodeficiency Virus Kit Is Associated with Longer Virologic Response than Suppression below the Limit of Quantitation

Suppression of human immunodeficiency virus type 1 plasma virus load (PVL) to <20 copies/mL is associated with a longer virologic response after initiation of antiretroviral therapy. The relationship between duration of virologic response and PVL nadir according to a less sensitive assay was explored. When compared with subjects with a PVL nadir >500 copies/mL, the relative risks of PVL rising above 1000 copies/mL for participants in the INCAS trial and the British Columbia Drug Treatment Program with a PVL nadir below the limit of detection (LOD) were 0.04 (95% confidence interval [CI], 0.02-0.09) and 0.06 (95% CI, 0.03-0.12), respectively. The corresponding relative risks for persons with a detectable but not quantifiable PVL nadir were 0.25 (95% CI, 0.13-0.50) and 0.54 (95% CI, 0.25-1.19). The relative risks of virologic failure associated with a PVL nadir detectable but not quantifiable and a PVL nadir below the LOD were statistically different (P<.0001) in both data sets.

Oral manifestations of cytomegalovirus infection

Disease caused by cytomegalovirus is reported with increasing frequency. Cytomegalovirus is an important pathogen in immunocompromised and immunosuppressed patients. The most common manifestation of cytomegalovirus infection of the gastrointestinal tract including the oral mucosa is ulceration. The role of cytomegalovirus in xerostomia, Sjögrens syndrome, and Kaposis sarcoma is continuing to be investigated. This article reviews the oral manifestations of cytomegalovirus, including recently reported oral manifestations.

Hairy leukoplakia-like lesions following bone-marrow transplantation

Hairy leukoplakia (HL) also occurs in immunosuppressed post-bone-marrow transplantation patients, and in the presence or absence of Epstein-Barr virus. It may not always be diagnostic of HIV positivity. However, HIV status should still be determined in patients with HL.

Clinical study of herpes simplex virus infection in leukemia

Twenty-nine patients with leukemia were observed for the development of and recovery from oral herpes simplex virus (HSV) lesions. In patients with seropositive test results, lymphocyte and monocyte counts may provide a guide to predict the onset of HSV infections and to indicate when to institute acyclovir prophylaxis. When HSV developed, acyclovir was effective in preventing progression of the lesions, which did not resolve until white cell counts had recovered.