Maximal Viral Suppression Research Articles

Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Structurally modified nucleotide/nucleoside analogues can exert potent inhibitory effect on HBV polymerase activities. Some of these agents have been approved for the treatment of chronic hepatitis B. Because of a high risk of reactivation upon drug withdrawal, continuous long-term therapy is recommended to maintain maximal viral suppression. Consequently, drug resistance has developed in a significant proportion of patients. During long-term therapy, mutations occur not only in the polymerase gene but also in the S gene, resulting in the emergence of surface protein mutants. Two types of surface protein mutants are recognized. The first type arises as a result of amino acid substitutions caused by primary and compensatory resistance mutations in the polymerase gene, which concomitantly generate S gene mutations owing to overlapping S and polymerase genes. The second type occurs because of prolonged viral suppression leading to seroclearance of HBV surface antigen, where vaccine-escape-like mutants might be selected. The second type of mutants does not possess primary resistance mutations in the polymerase gene. Some drug-related S gene mutations are nonsense mutations, leading to truncation of the surface proteins. Among them, the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential. The clinical consequences of infection by these S gene mutants demand further clarification. Judicious selection of the antiviral agents and vigilant monitoring of viral mutants during the course of therapy are advised.

Effect of Suppressing HIV Viremia on the HIV Progression of Patients Undergoing a Genotype Resistance Test after Treatment Failure

Treatment guidelines for multi-experienced HIV patients have recently evolved from aiming to preserve immunity to achieving virological success, largely due to the availability of new antiretroviral drugs and drug classes. To assess the role of viral suppression on clinical progression following a genotypic resistance test (GRT), we have examined a database on patients failing to respond to combined antiretroviral therapy (cART). Patients undergoing a GRT after failure to respond to cART between January 1999 and May 2006 were followed up to December 2006. Time-to-death or a new AIDS event/death were considered to be analysis end-points. Viral suppression (< 50 copies/ml [c/ml]) after GRT, a time-dependent covariate, was tested as predictor of disease progression. Overall, 1,389 patients were included in this observational study. After the GRT, patients were followed up to 72 months (median 28 months, IQ range 13-51 months). During the follow-up, 124 patients (9%) died, and 86 (6%) experienced a new AIDS event. 774 patients (56%) achieved < 50 c/ml HIV-RNA. The results of an adjusted Cox model showed that undetectable HIV-RNA after the GRT was significantly associated with a lower risk of death (hazard ration [HR] 0.46, 95% confidence interval [CI] 0.27-0.76) and AIDS/death (HR 0.43, 95% CI 0.28-0.65). The adjusted hazard ratios suggested a twofold risk reduction. A threefold risk reduction of death related to achieved undetectable viral load was found in patients with resistance to more than one drug class and with CDC-C diagnosis; a fourfold reduction was found in patients with < 200 CD4+/mm(3). Maximal viral suppression has a large impact on HIV progression, particularly in heavily pre-treated individuals. Our findings support the latest treatment guidelines, which have rapidly evolved from an initial lack of indication to suggestions, and finally to strong recommendations for achieving the goal of suppressing viremia.

Hepatitis B en pacientes con infección por el virus de la inmunodeficiencia humana

Chronic hepatitis B virus infection affects approximately 10% of HIV-infected patients. There are an estimated 4 million patients with HIV/HBV coinfection. HIV infection has a deleterious effect on the natural history of chronic hepatitis B and increases the risk of progression to cirrhosis and terminal liver disease. Since the widespread use of highly active antiviral therapy (HAART), liver disease has emerged as one of the main causes of morbidity and mortality in HIV-positive patients. Therefore, all patients with HIV/HBV coinfection should be evaluated for treatment of hepatitis B, independently of the CD4 lymphocyte count. Six drugs are currently authorized for the treatment of chronic hepatitis B: standard interferon-alpha (2a and 2b), pegylated interferon alpha-2a, lamivudine, adefovir, entecavir and telbivudine. Other drugs with activity against HBV, such as tenofovir and emtricitabine, are used for the treatment of HIV infection. In patients not requiring HAART, treatment of hepatitis B should preferably consist of drugs without activity against HIV, such as pegylated interferon or adefovir. In contrast, in patients requiring HAART, a combination of drugs with activity against both viruses should be used, such as lamivudine, emtricitabine and tenofovir, with the aim of achieving maximal viral suppression and avoiding the development of resistance. Patients with HIV/HBV coinfection require periodic clinical and virological monitoring. Patients with cirrhosis should undergo ultrasonography and alphafetoprotein determination every 6 months for the early detection of hepatocellular carcinoma.

Recommendations and potential future options in the treatment of hepatitis B

The natural history of chronic hepatitis B should be clearly defined before appropriate recommendations for treatment can be advocated. In patients who acquire the disease in early life, the complications of chronic hepatitis B continue to occur as a result of prolonged insidious damage to the liver, even in the low viraemic phase. Treatment that ends with hepatitis B e antigen seroconversion with hepatitis B virus DNA levels just below 105 copies/ml may not be sufficient. Patients with mild elevation of alanine aminotransferase levels are already at considerable risk of developing complications. Treatment strategy should aim at maximal and prolonged viral suppression to the lowest possible hepatitis B virus DNA levels. Nucleotide/nucleoside analogues will become the mainstay of treatment. Future treatment strategic plans should target maximising antiviral potency and minimising the chance of drug resistance.

Response to Waters et al. ‘Successful use of genotypic resistance testing in HIV-1-infected individuals with detectable viraemia …’

Waters et al. [1] recently reported their success of 69.4–92.9% in HIV genotypic resistance antiretroviral testing for clinical samples with low viremia (between 50 and 1000 copies/ml) using the ABI 3730XL sequencer and Virco BVBA proprietary primer mixers (Mechelen, Belgium). Their lowest rate of amplification and sequencing was at the HIV-RNA range of 50–200 copies/ml. We had also obtained credible genotypic resistance results from low viral loads and performed validation of the commercial HIV genotypic resistance kit, TruGene (Bayer HealthCare, Tarrytown, New York, USA), in our laboratory. In a comparison of original clinical plasma specimens with samples diluted to approximately 100 copies/ml, we found that resistance interpretations were 97.1% concordant, and our testing performance was not significantly affected, as measured by multiple assay parameters [2]. Subsequently, our laboratory accepted clinical samples from untreated patients whose viral loads were 400 copies/ml or greater, patients whose HIV RNA did not achieve less than 400 copies/ml by 24 weeks or less than 75 copies/ml by 48 weeks of treatment, or treated patients whose viral loads rebounded above those levels on two occasions. Using these criteria, 39 out of 389 of our genotypic resistance testing samples (10%) were less than 1000 copies/ml. A rate of 92.3% for successful amplification and sequencing was identical for both HIV-RNA ranges of 75–399 copies/ml (12/13) and 400–999 copies/ml (24/26). By comparison, the remaining 350 clinical samples with HIV RNA of 1000 copies/ml or greater had successful amplification and sequencing at a rate of 98.6%. The clinical goal of antiretroviral therapy is durable and maximal viral suppression [3], as circulating viremia has been shown to be a compelling prognosticator of HIV progression [4]. Therefore, the importance of detecting drug resistance with low HIV viremia is paramount, because a timely therapeutic change would spare the continuation of a failing regimen and prevent the development of untoward drug interactions and toxicities. We agree with Waters et al. [1] that laboratories should explore genotypic resistance testing on clinical samples with HIV RNA of less than 1000 copies/ml. However, we caution that each laboratory should establish the performance characteristics of its method before routine genotypic resistance testing for samples with low viremia. Disclaimer: The views expressed in this letter are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.

Antiretroviral therapy: Need for a long-term view

a s ite ho ste d b y M ed kn ow P ub lic ati on s therapy in the CD4 stratum between 200-350 cells/ organization and UNAIDS are aiming for “universal mm in an asymptomatic patient is a controversial access to ART for all by 2010”. The dramatic decline issue. ART should probably be started within this range in annual AIDS-related mortality has largely been depending on the symptoms, viral load, CD4 slope, attributed to the use of highly active antiretroviral patient preference, and associated co-morbidities. therapy (HAART). Several effective antiretroviral agents are available and many more are in the pipeline The pretreatment evaluation should include a [Table 1]. However, injudicious use of ART may be complete history and physical examination, fundus harmful to patients as well as society at large. It is examination, complete blood count, biochemistry therefore essential that the treating physician has a profile, lipid profile, CD4/CD8 T cell count/ratio, clear set of goals to guide him/her. This includes plasma HIV-1 RNA measurement (viral load) and achieving not just maximal viral load suppression or supplementary tests including VDRL, Mantoux test, qualitative and quantitative immune reconstitution chest X-ray and serology for hepatitis C and B. In .m ed kn ow .co ).

439 Improving antiviral therapy in chronic hepatitis B: Maximal viral suppression at week 24 correlates with better clinical efficacy at one year

439 Improving antiviral therapy in chronic hepatitis B: Maximal viral suppression at week 24 correlates with better clinical efficacy at one year

ADVANCES IN HIV TREATMENT AND TREATMENT TOXICITIES

Among the different classes and complexities of antiretroviral regimens, maximal viral suppression, sustained durability, increased CD4 count, decreased evolving resistance, and fewer side effects combined with increased compliance resulting in decreased morbidity and mortality remain the goals of therapy. Serial viral load measurements help best guide the direction of therapy. According to the CDC 20% fewer people died of HIV in 1998 compared to 1997 in the United States. HAART, although expensive (sometimes exceeding $20,000 per year), is not readily available to 95% of the estimated 36 million HIV-infected people in the world. HAART therapy commonly consists of two NRTIs and a protease inhibitor, but other combination regimens exist. The disadvantage of HAART therapy is that antiretroviral agents are not virucidal, thus eradication with these drug cocktails cannot be achieved. When HAART therapy is stopped, viral loads return to pre-treatment levels. New drug classes under investigation may completely prevent fusion between the HIV virus and healthy cells. For now, the epidemic can only be controlled with good public awareness, such as education, condom use, or abstinence. Because a cure does not seem immediately foreseeable, an effective prophylactic vaccine may afford protection. Defined treatment regimens exist for occupational postexposure prophylaxis. Ultimately, an expert in the field should be involved in manipulating drug regimens; however, dermatologists remain an integral part of the health care team because most HIV patients experience cutaneous manifestations related either to their HIV or to their drug therapy.

T cell receptor excision circle (TREC) content following maximum HIV suppression is equivalent in HIV-infected and HIV-uninfected individuals.

The adult human thymus contributes to de novo T cell synthesis; such synthesis can be assessed by analyzing T cell receptor excision circles (TREC). TREC levels were measured in total peripheral blood mononuclear cells (PBMC) and CD4- and CD8-enriched cells of 29 HIV-positive patients with maximal viral suppression. The expression of CD45RA+CD45RO-, CD45RA+CD62L+, CD45RO-CD27+CD95low and HLA-DR+CD38+ was assessed using three-color flow cytometric analysis of whole blood. Thymic index score was based on computed tomographic scans of the thymus. The relationship of TREC with thymic index and the expression of the naive phenotypes was evaluated. TREC expression was not statistically different in these HIV-positive patients from that in age-matched HIV-negative controls. Among HIV-positive patients with CD4 cell count of > 500 x 10(6) cells/l after antiretroviral therapy (n = 15), PBMC TREC levels correlated with the expression of CD45RA+CD45RO- and CD45RA+CD62L+ naive phenotypes, and inversely correlated with the expression of HLA-DR+CD38+. The change between pre- and post-therapy CD4 cell counts for these 15 patients significantly correlated with both thymic index and expression of the CD45RA+CD45RO- phenotype. The finding that TREC expression was equivalent between HIV-positive patients after therapy and HIV-negative donors suggests that there is no reduction in thymic output among HIV-positive individuals after therapy. Given that TREC is inversely correlated with HLA-DR/CD38 expression, its analysis in studies of thymopoiesis should be evaluated in the context of maximum viral suppression to reduce HIV-mediated immune activation and/or by normalizing for cell turnover.

Worsening Pneumonia Caused by Endobronchial Obstruction with Mycobacterium avium Complex as a Paradoxical Response to Highly Active Antiretroviral Therapy in AIDS

A 36-year-old man was diagnosed with AIDS when he presented with Pneumocystis carinii pneumonia. HIV viral load was 196,000 copies/ml with a CD4 lymphocyte count of 3 μL −1 . After completion of trimethoprim-sulfamethoxazole therapy, highly active antiretroviral therapy with zidovudine, lamivudine, and nelfinavir was begun. Maximal viral suppression occurred after 9 weeks of therapy. Two months after the episode of P. carinii pneumonia, he developed recurrent fever and dyspnea due to a new left upper lobe pneumonia caused by Mycobacterium avium complex (MAC). Therapy with ethambutol and clarithromycin was initiated with improvement of symptoms. Two weeks into treatment, fever and pleuritic chest pain developed with progression of the infiltrates. Bronchoscopy showed a polypoid lesion occluding the associated segmental bronchus that, on biopsy, revealed poorly formed granulomas. Paradoxical worsening of pulmonary MAC disease may occur after initiation of HAART therapy. The pathogenesis, presentation, evaluation, and management of this entity will be reviewed.

Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study.

Predictors of virological response to highly active antiretroviral therapy (HAART) have never been systematically evaluated in a large continental multicenter cohort of unselected human immunodeficiency virus (HIV)-infected people. To determine the factors related to achieving and maintaining undetectable plasma HIV-1 RNA levels among HIV-1-infected patients first starting protease inhibitor- or nonnucleoside retrotranscriptase inhibitor-containing HAART in Europe. Prospective multicenter cohort study. Fifty-two clinical centers in 17 European countries included in the EuroSIDA Study Group, from August 1996 to April 1999. A total of 1469 HIV-positive patients first starting HAART recruited from an unselected cohort of more than 7300 HIV-positive patients. Detection of factors related to virological success after first starting HAART (baseline) and ensuing failure by standard survival techniques, including Kaplan-Meier techniques and Cox proportional hazards models. All analyses were intention to treat. Most patients (80%) achieved plasma HIV-1 RNA levels of less than 500 copies/mL during follow-up (60.4% at 6 months from the onset of HAART). Patients with higher baseline HIV-1 RNA levels (relative hazard [RH], 0.76 per log higher; 95% confidence interval [CI], 0.69-0.84; P<.001) and those taking saquinavir mesylate hard gel as a single protease inhibitor (RH, 0.62; 95% CI, 0.47-0.82; P<.001) were less likely to reach undetectable HIV-1 RNA levels. Conversely, higher CD4+ lymphocyte counts (RH per 50% higher, 1.09; 95% CI, 1.02-1.16; P = .008) and the initiation of 3 or more new antiretroviral drugs (RH, 1.29; 95% CI, 1.03-1.61; P = .02) were independent predictors of higher success. Once success was achieved, HIV-1 RNA levels rebounded in more than one third of all patients during follow-up (24% at 6 months). Antiretroviral-naive patients (RH, 0.50; 95% CI, 0.29-0.87; P = .01), older patients (RH, 0.86 per year older; 95% CI, 0.75-0.99; P = .04), and those starting a protease inhibitor other than saquinavir hard gel (RH, 0.66; 95% CI, 0.44-0.98; P = .04) were at decreased hazard for virological failure. Higher baseline HIV-1 RNA level (RH, 1.18 per log higher; 95% CI, 0.99-1.40; P = .06) and a longer time to achieve virological success (RH per 12 months, 1.53; 95% CI, 0.99-2.38; P = .06) were marginally significant predictors of a decreased hazard of ensuing virological failure. HAART is associated with a favorable virological response if started when the baseline HIV-1 RNA level is low, if at least 2 new nucleoside retrotranscriptase inhibitors are added, and if standard doses of saquinavir hard gel capsule are avoided as a single protease inhibitor. Older patients are more likely to achieve virological success. Thereafter, the higher durability of virological response is predicted by an antiretroviral-naive status and by the use of specific regimens. Lower baseline HIV-1 RNA levels and rapid maximal viral suppression seem to be other important factors in the durability of virological response.