Planning HIV therapy to prevent future comorbidities: patient years for tenofovir alafenamide.

Since the introduction of suppressive antiretroviral therapy (ART), HIV has become a chronic disease, with infected people in high-income countries approaching similar life expectancy to the general population. As this population ages, an increasing number of people with HIV are living with age-, treatment-, and disease-related comorbidities. Lifestyle factors such as smoking, alcohol abuse, and substance misuse have a role in age-related comorbidity. Some degree of immune dysfunction is suggested by the presence of markers of immune activation/inflammation despite effective suppression of HIV replication. Cumulative exposure to some antiretroviral drugs contributes to HIV-associated comorbidities, with risk increasing with age. Specifically, tenofovir disoproxil fumarate (TDF), ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir are associated with renal impairment, and TDF is known to cause loss of bone mineral density. Tenofovir alafenamide (TAF) was developed to improve on the safety profile of TDF, while maintaining its efficacy. TAF has better stability in plasma, and higher intracellular accumulation of tenofovir diphosphate in target cells, which has resulted in improved antiviral activity at lower doses with improved renal and bone safety. TAF has been studied extensively in randomized clinical trials and real-world studies. TAF-based regimens are recommended over TDF-containing regimens for the improved safety profile.

Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III).

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.

Live attenuated herpes zoster vaccine for HIV-infected adults.

OBJECTIVES: Multiple guidelines exist for the use of live viral vaccines for measles-mumps-rubella (MMR), varicella and yellow fever in people with HIV infections, but these guidelines do not make recommendations regarding live attenuated herpes zoster vaccine (LAHZV), which is approved for people over 50 years in the general population. LAHZV is made with the same virus used in varicella vaccine. The incidence of herpes zoster remains increased in people with HIV infection, even when on suppressive antiretroviral therapy, and a growing proportion of HIV-infected patients are over 50 years of age. The purpose of this article is to review the use of varicella vaccine and LAHZV in people with HIV infection and to make recommendations about the use of LAHZV in adults with HIV infection. METHODS: A PubMed search was undertaken using the terms 'herpes zoster AND HIV' and 'varicella AND HIV'. Reference lists were also reviewed for pertinent citations. RESULTS: Varicella vaccine is recommended in varicella-susceptible adults, as long as they have a CD4 count > 200 cells/µL, the same CD4 threshold used for MMR and yellow fever vaccines. No transmission of vaccine strain Varicella zoster virus has been documented in people with HIV infections with a CD4 count above this threshold. LAHZV was administered to 295 HIV-infected adults with a CD4 count > 200 cells/µL, and was safe and immunogenic with no cases of vaccine strain infection. CONCLUSIONS: It is recommended that LAHZV be administered to HIV-infected adults with a CD4 count above 200 cells/µL, the same CD4 threshold used for other live attenuated viral vaccines.

Predictors of survival and eradication of Mycobacterium avium complex bacteremia (MAC) in AIDS patients in the Canadian randomized MAC treatment trial. Canadian HIV Trials Network Protocol 010 Study Group.

OBJECTIVE: To assess the importance of baseline characteristics including medical history, indicators of current disease status, therapeutic drug use, in vitro drug susceptibility, immune status and mycobacterial load on bacteriologic response and survival in HIV-positive patients with Mycobacterium avium complex (MAC) bacteremia. DESIGN: An observational substudy of an open-label randomized controlled trial of two alternative therapeutic regimens for MAC. SETTING: Twenty-four hospital-based HIV clinics in 16 Canadian cities. MAIN OUTCOME MEASURES: The main outcome measures were survival and bacteriologic response, defined by consecutive negative blood cultures for MAC at least 2 weeks apart within 16 weeks of study entry. RESULTS: Prior AIDS diagnosis, low Karnofsky score, active unstable AIDS-related conditions, absence of antiretroviral therapy and absence of Pneumocystis carinii pneumonia prophylaxis were associated with shorter survival by univariate regression using the proportional hazards model. On multivariate analysis, antiretroviral therapy was not an independent predictor of mortality, and previous rifabutin prophylaxis was independently associated with poor survival outcomes, a result consistent across study treatment. Using a logistic regression model, baseline quantitative mycobacterial load [relative odds of clearing, 1.97 for a decrease of 1 log10 colony forming count; 95% confidence interval (CI), 1.36-2.87; P < 0.001] and Karnofsky score were the only statistically significant univariate predictors of clearance, although previous prophylaxis with rifabutin was also a significant predictor in a multivariate model (relative odds of clearing, 0.39; 95% CI, 0.17-0.88; P < 0.05). CONCLUSIONS: This study indicates that although the level of MAC bacteremia is an important predictor of clearance, it is not associated with survival.

Acute bacterial meningitis in adults. A 12-year review.

One hundred three episodes of acute bacterial meningitis in adults hospitalized in Edmonton's 2 largest hospitals from 1985 to 1996 were reviewed. Cases complicating neurosurgery were excluded. Most cases were community-acquired (87%). Twenty-three cases remained culture-negative, and there was no statistical relation between culture negativity and antibiotic pretreatment. Streptococcus pneumoniae was the predominant pathogen (52.5%), but Listeria monocytogenes was the second most common isolate, accounting for 12.5% of culture-positive cases. Compared to non-listerial meningitis, those with listeriosis were more likely to have negative cerebrospinal fluid (CSF) Gram stains (p = 0.07), CSF leukocyte counts < 1,000 cells/mm3 (p < 0.003), and normal CSF glucose (p = 0.006). Bacterial antigen detection was found to be of low sensitivity: 33% in all patients, but only 9% in cases with negative CSF Gram stains. The overall mortality was 18%, with 15 deaths directly attributable to acute meningitis; the case-fatality rates for S. pneumoniae and L. monocytogenes were 24% and 40%, respectively. Mortality was significantly higher among those with seizures (34% versus 7%, respectively; p < 0.001; OR = 17.6). Despite the urgency of acute bacterial meningitis, there were considerable delays in the institution of empiric antibiotics; mortality rates were slightly higher in those who experienced such a delay (16% versus 7% respectively; p = 0.18).

The chronic fatigue syndrome.

The chronic fatigue syndrome (CFS) was formally defined in 1988 to describe disabling fatigue of at least 6 months' duration of uncertain etiology. Reports of CFS have emerged from the United States, Canada, the United Kingdom, Australia, New Zealand, Israel, Spain, and France. The disease primarily affects individuals between 20 and 50 years of age, and there is a preponderance of females. Although a triggering infectious illness is reported by most patients with CFS, there is no convincing evidence causally linking any currently recognized infectious agent to CFS. Multiple minor immunologic aberrations are frequent but inconsistent and of uncertain significance. There is no consistent evidence for myopathy or physical deconditioning. Depression is found in approximately 50% of CFS patients, with depression preceding the physical symptoms in half of the cases. No therapy has been proved effective in controlled clinical trials with prolonged follow-up, although antidepressants have not been formally evaluated. The long-term prognosis of patients with CFS has not been well studied, but CFS appears to be a disease of prolonged duration with considerable morbidity but no mortality. Further research into the pathogenesis and treatment of CFS is necessary.

Treatment of the chronic fatigue syndrome. A review and practical guide.

The chronic fatigue syndrome (CFS) was formally defined in 1988 to describe a syndrome of severe and disabling fatigue of uncertain aetiology associated with a variable number of somatic and/or psychological symptoms. CFS has been reported in most industrialised countries and is most prevalent in women aged between 20 and 50 years. Despite occasional claims to the contrary, the aetiology of CFS remains elusive. Although abnormalities in tests of immune function and cerebral imaging have been described in variable numbers of CFS patients, such findings have been inconsistent and cannot be relied upon, either to establish or exclude the diagnosis. Thus, diagnosis rests on fulfillment of the Centers for Disease Control case definition which was revised in 1992. This case definition remains somewhat controversial, largely due to its subjectiveness. The mainstay of treatment is establishing the diagnosis and educating the patient about the illness. An empathetic clinician can stop further consultations elsewhere ('doctor shopping') and subsequent excessive investigations, which frequently occur in such patients. Most patients should undertake a trial of antidepressant therapy, even if major depression is not present. The choice of antidepressant drug should tailor the tolerability profile to relief of particular CFS symptoms, such as insomnia or hypersomnia. Failure to improve within 12 weeks warrants an alternative antidepressant agent of another class. Many other drugs have been reported anecdotally to be beneficial, but no therapy has been demonstrated to be reproducibly useful in double-blind, placebo-controlled clinical trials with an adequate duration of follow-up.

Pharmacology and clinical experience with amprenavir.

Amprenavir (APV, Agenerase) is the fifth protease inhibitor (PI) available for clinical use. It is highly active and its pharmacokinetics allow convenient twice-daily administration. It is metabolised by the cytochrome P450 system, leading to a number of drug interactions that have been well defined. Mutations at codons 50 (along with additional changes at codons 46 and 47) lead to the development of resistance, both in vitro and in vivo. In over 200 drug-naive patients, APV-based combination therapy has led to maximal suppression of plasma viral load (generally below 50 copies/ml) in over 50% patients participating in clinical trials lasting 24 - 48 weeks. Benefit has also been demonstrated in over 500 previously treated patients, especially if they are naive to PIs as a therapy. APV-based therapy also appears to be effective in children. Major adverse effects observed in clinical usage have been gastrointestinal (GI) intolerance, skin rash and peri-oral paresthesias. At the present time, it is unclear whether APV offers any advantage over similar types of drugs. Overall, it may be easier to take than some other PIs, but the cost in terms of pill burden is quite high. The toxicity profile (especially the risk of serious skin rashes) may also be an issue. It may be also important in the treatment of isolates that are resistant to other PIs. Its specific role in therapy can only be clarified once the results of ongoing trials (particularly comparative trials of its use in previously treated patients) are available.

A multicenter, open comparative study of parenteral cefotaxime and ceftriaxone in the treatment of nosocomial lower respiratory tract infections.

A multicenter Canadian study enrolled 74 persons to compare low-dose cefotaxime at 1 g every 8 hr to ceftriaxone 1 g every 12 hr in patients with nosocomial pneumonia. Of 57 evaluable patients (30 cefotaxime and 27 ceftriaxone) in this preliminary report, 93% responded to therapy in both groups. Ceftriaxone patients tended to have more side effects (14.2%). This study is continuing to accrue patients to achieve 100 evaluable patients. Interim data, however, support the continued use of low-dose cefotaxime as an appropriate alternative for clinically effective and cost-effective management of nosocomially acquired pneumonia.

Branhamella catarrhalis bronchopulmonary isolates in PICU patients.

Branhamella catarrhalis is commonly considered a respiratory commensal but has recently been implicated as a pathogen, particularly in adults. Over a 28 month period, B. catarrhalis was isolated from bronchopulmonary secretions of 14 PICU patients with acute respiratory infections. Twelve patients had pneumonia and two had tracheitis. The mean age was 3.5 years. Seven patients had chronic cardiopulmonary disease including two who were immunosuppressed. Three had an acute underlying condition and four had no complicating medical problem. Polymorphs and Gram-negative diplococci on Gram stain were found in respiratory secretions of all patients. Twelve of 14 isolates produced beta-lactamase, and six patients had a second potentially pathogenic bronchopulmonary isolate. All patients were treated for B. catarrhalis infection and none died. When isolated in pure culture from bronchopulmonary secretions in symptomatic patients, B. catarrhalis should be considered a pathogen. When isolated in mixed culture, its pathogenic role is uncertain. We conclude that B. catarrhalis can be a bronchopulmonary pathogen in critically ill children with otherwise normal cardiopulmonary function as well as in those with chronic cardiopulmonary dysfunction. When administering antibiotics the high frequency of beta-lactamase-producing strains must be taken into consideration.

Prevention and treatment of disseminated Mycobacterium avium complex infection in human immunodeficiency virus-infected individuals.

Disseminated Mycobacterium avium complex (DMAC) infection is a common complication of advanced HIV disease, and is an independent predictor of mortality. The clinical features of DMAC infection are fever, weight loss, abdominal pain, anemia, elevated serum alkaline phosphatase, and elevated serum lactate dehydrogenase. The diagnosis is made by blood cultures; clinical diagnosis is unreliable. Chemoprophylaxis of DMAC infection with azithromycin is recommended when the CD4 lymphocyte count is below 50 cells/mm3. Established DMAC infection is treated with clarithromycin plus ethambutol, unless the isolate is macrolide-resistant, in which case the optimal therapy is uncertain. Highly active antiretroviral therapy is important in both prevention and treatment of DMAC infection.

Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.

Isolated native tricuspid valve endocarditis caused by viridans streptococcus.

The present report describes a case of native tricuspid valve endocarditis caused by viridans group streptococcus in a 43-year-old man who had recently undergone dental extraction. The patient had no history of intravenous drug use, heart disease or right heart catheterization. Although there have been scattered reports of unusual organisms, to the authors' knowledge, this is the first case of viridans group streptococcal endocarditis involving only the tricuspid valve after dental manipulation.

The cost of health care for AIDS patients in Saskatchewan.

The medical records of 19 patients with acquired immune deficiency syndrome (aids) were reviewed in an attempt to estimate their health care costs. The patients were all male, members of high risk groups and diagnosed between April 1985 and February 1988. Twelve of the patients died; they lived a mean of 240 days (range 0 to 580) after diagnosis, were admitted three times (range one to six) to hospital for 65 total days (range one to 148) for a cost per patient of $33,721 (range $2,768 to $64,981) for inpatient care. They made five (range zero to 25) office visits per patient costing $196 per patient (range $0 to $4,999) for outpatient care. The seven survivors (one was lost to follow-up) have lived 375 days (range 186 to 551) since diagnosis, have been admitted to hospital two times (range zero to seven) for 30 total days (range zero to 86) for a total cost per patient of $14,223 (range $0 to $39,410) for inpatient care. They have made 11 office/emergency room visits (range zero to 46) costing in total $4322 (range $0 to $13,605) for outpatient care. The total expenditure was $546,332 ($28,754 per patient), of which total fees to physicians were $37,210 (6.8%), and estimated costs of laboratory tests $117,917 (21.6%), drugs $36,930 (6.7%), and medical imaging $20,794 (3.8%). Patients now deceased cost $416,445 (mean $34,704 per patient), accounting for 76.2% of overall expenditures. The average medical/surgical and drug costs per patient day in hospital were greater for aids patients than for the average medical/surgical patient in the authors' institution.

Seroprevalence of HSV-1 and HSV-2 antibodies in Canadian women screened for enrolment in a herpes simplex virus vaccine trial.

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) infections continue to be among the most common and unrecognized sexually transmitted infections in the world. Although treatable, HSV-1 and HSV-2 infections remain incurable. Hence, there is interest in the development of a vaccine to prevent genital herpes. As part of a multicentre, randomized, placebo-controlled trial to test such a vaccine, healthy women 18-30 years were enrolled as volunteers in several Canadian centres between 2005 and 2007. This study reports the seroprevalence of HSV-1 and HSV-2 antibodies in this group. A total of 2694 adult female volunteers in Canada with no known history of herpes simplex were screened for HSV antibodies using Western blot assay (the gold standard for diagnosis of HSV) for potential participation in a randomized, double-blind efficacy field trial of a herpes simplex vaccine. This trial provides a unique opportunity to examine the prevalence of antibodies to HSV-1 and of antibodies to HSV-2 in women with no known history of herpes simplex infection. The prevalence of antibodies to HSV-1 and to HSV-2 is compared with that found in previous Canadian studies that focused on a more general population. The overall seroprevalence of antibody to HSV-1 was 43%; that of HSV-2 was 2.5% and seropositivity to both was 2%. The prevalence of antibody to both HSV-1 and to HSV-2 increased with age. Seronegativity to both HSV-1 and HSV-2 was 56% in participating centres with populations under 250,000 and 46% in participating centres with populations over 250,000. Significant racial differences in seropositivity to HSV-1 and to HSV-2 were noted. The likelihood of participants being seropositive to HSV-1 and to HSV-2 was found to increase with age and to positively correlate with the population of the city in which they resided. Hypotheses are proposed to account for differences in racial seropositivity to HSV-1 and to HSV-2.