CD4 Cell Count and AIDS-Defining Malignancies (ADM)

CD4 cell count is strongly associated with the risk of death from both AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM). Non-AIDS events have become an important cause of mortality as individuals with HIV infection survive to older ages and have started to suffer from similar age-related diseases to the HIV-uninfected population.
Rate of death of nADM is higher than from ADM in all patients other than those with very low CD4 cell counts. Lung cancer is the most common fatal nADM, concordance with the high prevalence of smoking among the HIV-infected population.
Age is also a strong predictor of death from malignancies, suggesting that, at similar CD4 cell counts, older patients are at greater risk of dying from malignancy. This may be a consequence of the higher incidence of cancers in older individuals, as well as an increased likelihood of death in older individuals, irrespective of the cause. However, this may also reflect reduced immune system activity in the elderly. Interestingly, the HIV RNA level was only weakly associated with ADM mortality and was not independently associated with nADM mortality.
Non-AIDS-defining malignancies was related to combination antiretroviral (cART) exposure. The individuals taking effective cART are less likely to die from ADM and, as a result, may be more likely to die from nADM. In contrast, patients dying from ADM may be more likely to have stopped or never received cART.
(AIDS. 2008;22(16):2143-2153)

Treatment of Patients Infected with both HIV and HCV

There are many individuals with both HIV and HCV infection. A total of 130 million people around the world estimated to be infected with HCV and 40 million with HIV. Shared routes of transmission mean that coinfection is common affecting an estimated 4-5 million individuals around the world. In the developing world, infection with HCV is frequently associated with unsafe injection practices and unscreened blood transfusions. An increased incidence of sexual transmission of HCV in HIV positive patients has been reported in heterosexual couples and in MSM.
Following the advent of highly active antiretroviral therapy (HAART) for the treatment of HIV, liver disease is emerging as a major cause of death and has overtaken AIDS defining illnesses in some patient populations. More rapid progression of HCV-related liver disease is seen in HIV positive individuals, HCV treatment success rates are lower in patients with HIV infection and there are complex issues with interactions of antiviral medication, interferon (IFN) and ribavirin.
Many ARV agents are potentially hepatotoxic and there have been concerns that there may be an increased risk of hepatotoxic reactions in those with hepatitis C.
HIV positive patients with acute hepatitis C may wish to elect for prompt treatment with IFN and ribavirin in view of a higher likelihood of response during early infection. Patients who are considered eligible for treatment may require HAART or antidepressant medication prior to starting IFN and this may result in a longer diagnosis treatment time period. Depression is a significant concern when treating such patients as it reaches a high prevalence in patients with dual infection (up to 42%). Treatment of HIV positive individuals superinfected acutely with HCV may achieve higher SVR rates with PEG IFN and ribavirin than those with chronic infection. However, a significant proportion of patients does not respond or qualify for treatment.

(J Viral Hepat. 2008;15(11):773-781)

The Immunologic Cascade of Kawasaki Syndrom Trigerred by An Infectious Agent?

Kawasaki syndrome (KS) is the most common cause of acquired heart disease in children. This acute, self-limited vasculitis results in permanent coronary artery damage in up to 25% of untreated children. High dose intravenous gamma globulin reduces the risk of coronary artery aneurysm to 3-5% if administered early in the course of disease. However, without a specific diagnostic test, affected children may be difficult to recognize, and delayed diagnosis and treatment continue to result in potentially preventable morbidity and mortality. The etiology of Kawasaki syndrome (KS) remains unknown despite 30 years of intensive search for an agent.
Associations have been observed between antecedent respiratory illness and KS. It is proposed that an agent causing KS could first infect the upper respiratory tract before triggering a systemic immunologic response. Researchers found an increased IgA plasma cell infiltration of the upper respiratory tract and coronary arteries in KS patients, therefore, further support the respiratory route as a potential portal of entry for the causative agent. The presence of IgA-secreting plasma cells in the upper respiratory tract mimics the response seen in autopsies of children who died of known viral respiratory infection such as respiratory syncytial virus.
(Pediatr Infect Dis J. 2008;27(11):981-985)

Maraviroc, The CCR5 antagonists

Maraviroc (Celsentri or Selzentry; Pfizer Ltd., Sandwich, UK) belongs to a new class of anti-HIV drugs named CCR5 antagonists, which block HIV entry into cells. Viral entry is an attractive step for the development of new agents against HIV variants resistant to current antiretroviral drugs. HIV gains entry into CD4-expressing cells through a series of sequential interactions between the envelope glycoprotein gp120 and the CD4 receptor and one of two coreceptor molecules, chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4), which are expressed on the surface of target cells. Maraviroc specifically inhibits the replication of R5-tropic HIV variants by an allosteric mechanism after binding to the transmembrane CCR5 coreceptor cavity. Because of its exclusive activity against CCR5 tropic strains, viral tropism testing is mandatory before using CCR5 antagonists in the clinic.

Maraviroc is a substrate for the P-glycoprotein and the cytochrome P450 (3A4), both of which are involved in the metabolism of multiple other agents, including several antiretroviral drugs. Therefore, drug interactions using maraviroc should be kept in mind. Briefly, the standard 300 mg twice daily dose of maraviroc does not require changes when the drug is given concomitantly with methadone, statins, nevirapine, cotrimoxazole, etinilestradiol nor pegylated interferon and ribavirin. However, dose adjustments have to be made when maraviroc is used along with some potent inhibitors or inducers of CYP3A4.
(AIDS. 2008;22(17):2231-2240).

New Recommendation of Childhood and Adolescent Immunization Schedules

The American Academy of Pediatrics, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, and the American Academy of Family Physicians approved new recommendations of childhood and adolescent immunization schedules. For children 6 months through 18 years of age it is recommended to have annual influenza vaccine administration. All eligible close contacts of children 0 through 59 months of age should also receive influenza vaccine, as should contacts of children 5 through 18 years of age who have an underlying medical condition predisposing them to complications of influenza.

Another new recommendation is a harmonization of the dosing schedules for the 2 licensed rotavirus vaccines. The first dose of either vaccine should be administered at 6 weeks through 14 weeks 6 days of age, and the final dose by 8 months 0 days of age. Immunization should not be started for infants 15 weeks 0 days of age or older.

(Pediatrics. 2009;123;189–190)

Beware for Prolonged Initial Antibiotic Therapy for Extremely-Low-Birth-Weight Infants

In extremely-low-birth-weight (ELBW, birth weight of <1000 g) infants, prolonged initial empiric antibiotic therapy should be used with caution. It could cause an increased risk for necrotizing enterocolitis (NEC) or death. Although cultures from normally sterile sites usually do not yield any bacterial agents and the incidence of culture-proven bacterial sepsis is low in this population, ELBW infants admitted to intensive care nurseries usually receive empirical antibiotic treatment in the first postnatal days. A study suggested that cefotaxime for the first 3 postnatal days is associated with higher mortality risk, even for the most preterm infants.
(Pediatrics. 2009;123;58-66).

Acquired Vancomycin Resistance Pathogens

Acquired vancomycin resistance appears to be a serious and growing therapeutic challenge among various Gram-positive pathogens worldwide. In Enterococcus, different types of gene clusters encoding vancomycin (and teicoplanin) resistance have been identified; the vanA and, to a lesser extent, the vanB types are the most prevalent. Occasionally, the vanA cluster spread to S. aureus, constituting the first seven cases of VRSA (vancomycin-resistant S. aureus) that all emerged independently. Vancomycin treatment failure can be associated with van-independent mechanisms of (intermediate) resistance to vancomycin and seems to be an increasing problem in S. aureus and the CNS (coagulase-negative staphylococci).
(Future Microbiol. 2008;3(5):547-562)

Drug-drug Interactions (DDI)

It is a difficult task to find the most appropriate medication regimen for our patients. Patients sometime require multiple medications placing them at risk for drug-drug interactions (DDIs). DDI is a situation that occurs when 1 of a combination of drugs alters the effect of another drug. Drug-drug interactions may result in decreased therapeutic benefit, adverse effects, or patient harm. Non-prescription medications, herbal preparations, and complementary medications also contribute to patient polypharmacy and the potential for DDIs.

DDIs contribute to patient morbidity and may cause emergency department visits, hospitalizations, and re-admissions. Examples of patient morbidity caused by DDIs include gastrointestinal (GI) bleeding, renal dysfunction, electrolyte imbalance, hypertension, hypotension, bradycardia, arrhythmia, drug toxicity, and decreased drug effect.

Well known examples of mortality associated with DDIs include fatal outcome from a warwarin and nonsteroidal anti-inflammatory drug (NSAID) interaction, ciprofloxacin in fatal seizures, and moclobemide-clomipramine overdose in fatal serotonin syndrome. Other examples are fatal interactions between tranylcypromine and imipramine and also between methotrexate and trimethoprim.
Polypharmacy, narrow therapeutic range of the medication (eg, digoxin, cyclosporine, warfarin), decreased renal and or hepatic function of the patient each may increase the risk for DDIs and should be identified prior to coadministration. One should consider the potential for DDIs at all steps of the drug-delivery process. Furthermore, an increasing number of medications administered further increased the risk for adverse effects. Literatures said patients taking 2, 5, and 7 medications had a 13%, 38%, and 82%, respectively, for developing adverse drug interactions.
Advanced age is an additional risk factor for DDIs. The need for multiple medications often arises with advancing age that may further the risk for DDIs. Other patient-related risks for DDIs include very young age, female sex, genetics, decreased organ function, major organ impairment, metabolic or endocrine risk conditions (eg, hypothyroidism, hypoproteinemia), and acute medical issues (eg, dehydration).

Amlodipine Plus Benazepril Combination For Hypertension Therapy

Although the optimal pharmacotherapy regimen for hypertension is not yet determined, current guidelines recommend inclusion of a diuretic. The guidelines prefer to use diuretics as monotherapy or to use diuretics and an ACE inhibitor in combination therapy. However, recommendation of thiazide-type diuretics as initial therapy for most patients with hypertension needs to be reexamined. Combination therapy is probably a good initial strategy for high-risk patients, rather than starting with one drug and going slow.

Treatment with antihypertensive combination therapy (the angiotensin-converting enzyme (ACE) inhibitor benazepril plus the calcium-channel blocker amlodipine) is more effective than treatment with the ACE inhibitor and diuretic. Studies suggest that the calcium-channel blocker amlodipine effectively increases the availability of vascular endothelial nitric oxide and that the combined effects of amlodipine and an ACE inhibitor on nitric oxide are greater vs the effect with either drug alone.

In patients with hypertension who were at high risk for cardiovascular events, the benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing the primary composite outcome of cardiovascular events and death. The single-tablet benazepril-amlodipine combination reduced the risk of morbidity and mortality by 20% compared with conventional therapy. Putting patients on either combination doubled their control rate, so combination therapy is something clinicians need to think about, even if they want to keep the diuretic. But the drug that gives superior cardiovascular outcomes is the calcium-channel blocker and ACE inhibitor.

The cardiovascular benefits of specific classes of antihypertensive drugs may go beyond their effect on blood pressure. The combination of amlodipine and benazepril appears to synergistically reduce left ventricular hypertrophy and arterial stiffness, suggesting that they may protect target organs independently of the drugs' antihypertensive effects.

References:

Jamerson K, Weber MA, Bakris GL, et al. 2008. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 359: 2417-2428.

Chobanian AV. 2008. Does it matter how hypertension is controlled? N Engl J Med. 359:2485-2488.

New Guidelines for HIV Treatment

In AIDS 2008-XVII International AIDS Conference, the International AIDS Society–USA recommends new guidelines for HIV treatment. This recommendation is simplified and strengthened. One change in the recommendations is a greater emphasis on full virologic suppression. In this recommendation, deciding whether to start treatment in patients with a CD4 cell count of 350 cells/μL or more should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient willingness to begin treatment. Individuals with incomplete virologic suppression have greater morbidity and mortality than those who more completely suppress it.
The guidelines move aggressively toward earlier initiation of antiretroviral therapy. Treatment should be started before CD4 cell count decreases to less than 350/μL if there are correlates of faster HIV disease progression such as high plasma viral load (>100,000 copies/mL), rapidly decreasing CD4 cell count (>100/μL per year), active hepatitis B or C virus coinfection (resulting in faster progression of liver disease), cardiovascular disease risk, and HIV-associated nephropathy. Initiation of therapy in patients within the 200 to 350/μL CD4 cell count range should be strongly considered and individualized. The recommendations to start therapy in any patient with symptomatic HIV disease, regardless of CD4 count or viral load, and asymptomatic patients with less than 200/μL CD4 cell count.
Clinicians are encouraged to evaluate the whole patient, not just the status of HIV disease, but all coexisting conditions. Resistance testing should be conducted in all patients as part of their baseline workup. There is a little change in recommendations for an initial regimen in patients who are not infected with resistant virus. The first-line choice is a backbone of either an NNRTI or a ritonavir-boosted protease inhibitor (PI), combined with a dual nucleoside reverse transcriptase inhibitor (NRTI) component. The initial treatment regimen for HIV infection must be individualized, particularly in patients with comorbid conditions, but typically includes efavirenz or a ritonavir-boosted PI plus 2 NRTIs (tenofovir or emtricitabine or abacavir or lamivudine). Better not using darunavir as part of an initial regimen but holding it in reserve to use with patients who develop resistance to other PIs. Current first-line regimens are good and simple to use, and there is still concern about holding some drugs in reserve for patients who develop resistance to existing drugs. Even in heavily pretreated patients, the goal of treatment is an HIV-1 RNA level below assay detection limits. Treatment failure should be promptly identified and managed.

Depending on the NRTI mutations present, one might want to consider use of etravirine. Failure of a PI-based regimen can be more complicated, depending upon the genetic barriers. If caught early, changing the NRTI component to 2 active drugs might be sufficient to save the regimen. But as resistance points accumulate, one should consider use of darunavir or tipranavir.

The 3 drugs approved since the last version of the guidelines in 2006 are maraviroc, the first drug to target the CCR5 co-receptor on the surface of the cell; raltegravir, the first drug in the integrase inhibitor class; and etravirine, a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with clear activity against some NNRTI-resistant viruses. Enfurvitide remains an important option for the heavily treatment experienced population, but problems associated with daily injections and the emergence of other therapeutic alternatives such as raltegravir or maraviroc have reduced its use.

(AIDS 2008: XVII International AIDS Conference. Antiretroviral Treatment of Adult HIV Infection, 2008 Recommendations of the International AIDS Society–USA Panel. Presented August 3, 2008. JAMA. 2008;300:555-570)

UTI (Urinary Tract Infection) in Nonpregnant Woman

More than one half of women will have at least 1 urinary tract infection (UTI) during her lifetime, and 3% to 5% of all women will have multiple recurrences. Acute bacterial cystitis usually presents with dysuria, urinary frequency and urgency, sometimes with suprapubic pain or pressure, and rarely with hematuria or fever. Upper UTI or acute pyelonephritis often presents with fever, chills, flank pain, and varying degrees of dysuria, urgency, and frequency.

Screening for and treatment of asymptomatic bacteriuria is not recommended in nonpregnant, premenopausal women. Women with uncomplicated acute bacterial cystitis, including women 65 years or older, should receive antibiotics for 3 days. For initial treatment of symptomatic lower UTI with pyuria, bacteriuria, or both, urine culture is not required. For uncomplicated acute bacterial cystitis, recommended treatment regimens are as follows:

• The preferred therapy is Trimethoprim–sulfamethoxazole (1 tablet (160 mg trimethoprim–800 mg sulfamethoxazole) twice daily for 3 days), or Trimethoprim 100 mg twice daily for 3 days. When resistance rates are more than 15% to 20%, antibiotic class should be changed.
• Ciprofloxacin 250 mg twice daily for 3 days, levofloxacin 250 mg once daily for 3 days, norfloxacin 400 mg twice daily for 3 days, or gatifloxacin 200 mg once daily for 3 days.
• Nitrofurantoin macrocrystals 50 to 100 mg 4 times daily for 7 days.
• Nitrofurantoin monohydrate 100 mg twice daily for 7 days.
• Fosfomycin tromethamine 3-g dose (powder) single dose.

For women with frequent recurrences of lower UTI, continuous prophylaxis decreases recurrence risk by 95%. The need for continued prophylaxis can be re-evaluated after 6 to 12 months. For women with frequent recurrences of lower UTI, continuous prophylaxis has been shown to decrease the risk for recurrence by 95%. Suitable prophylactic regimens include once-daily treatment with nitrofurantoin, norfloxacin, ciprofloxacin, trimethoprim, trimethoprim–sulfamethoxazole, or another agent listed in this article.

Women with infections that do not respond to appropriate antimicrobial therapy or in whom the clinical status worsens require further evaluation. Renal ultrasonography is the best noninvasive method to evaluate renal collecting system obstruction.

(References: Obstet Gynecol. 2008;111:785-794).

Clostridium difficile-associated disease (CDAD)

Clostridium difficile-associated disease (CDAD) is an important nosocomial infection associated with healthcare, and it may recur in 15% to 30% of patients. The agent, Clostridium difficile, is a Gram-positive, anaerobic spore-forming bacillus. C. difficile was first identified as an aetiological agent of antibiotic-associated pseudomembranous colitis in the late 1970s. Approximately 15% to 20% of antibiotic-associated cases of diarrhea and nearly all cases of pseudomembranous colitis have been attributed to this bacteri. The incidence of CDAD has steadily climbed in the past decade, and it is an important cause of morbidity both in North America and in Europe.

Rapid diagnosis of CDAD further allows implementation of infection control measures and timely treatment. Stool assays is not a good strategy for rapid diagnostic since the false-negative rates is very significant. The best methods for rapid identification of C. difficile–associated pseudomembranous colitis is sigmoidoscopy.
Control of C difficile infection requires prudent use of antimicrobial agents, prevention of cross-infection, and ongoing surveillance. For patients with mild CDAD, discontinuation of the causative antibiotics without further treatment may be sufficient. Many guidelines recommend the use of metronidazole, an imidazole derivative, in patients thought to need antibiotic treatment, however it has a high failure rates and and resistance to metronidazole has been reported. Controlled clinical trials have shown efficacy for CDAD treatment with vancomycin, a glycopeptide. The mean duration of symptoms was also significantly shorter with vancomycin comparing with that of metronidazole. For patients with severe CDAD, intensive care unit (ICU) admission may be needed. A combined medical and surgical approach is recommended, with surgical resection of the inflamed colon as a therapeutic option.

The Health Risks Associated with Noncoital Sexual Activity

Noncoital sexual behaviors, which include mutual masturbation, oral sex, and anal sex, are common expressions of human sexuality. Couples may engage in noncoital sexual activity instead of penile-vagina intercourse hoping to reduce the risk of sexually transmitted diseases and unintended pregnancy. Although these behaviors carry little or no risk of pregnancy, women engaging in noncoital behaviors may be at risk of acquiring sexually transmitted diseases.

Most individuals engaging in oral sex are unlikely to use barrier protection. However, sexually transmitted diseases (STDs) may be spread through saliva, blood, vaginal secretions, semen, and fecal matter, especially in the presence of preexisting infections, open sores, or other lesions.

Hepatitis B virus is commonly spread through noncoital sexual activities, as it is found in semen, saliva, and feces. Hepatitis A is transmitted via fecal contamination of the oral cavity and is more common in men practicing oral-anal contact. Although sexual transmission of hepatitis C virus is uncommon, it may occur with preexisting hepatitis B virus and HIV infection and with oral-genital contact.

The Tendon Rupture in Fluoroquinolone-treated Patients

Fluoroquinolone products (ciprofloxacin [Cipro, Bayer; and generics] extended-release ciprofloxacin [Cipro XR, Bayer; Proquin XR, Depomed], gemifloxacin [Factive, Oscient) levofloxacin [Levaquin, Ortho McNeil], moxifloxacin [Avelox, Bayer], norfloxacin [Noroxin, Merck], and ofloxacin [Floxin, Ortho McNeil; and generic]), increase the risk for tendon rupture.

Universal Screening at Hospital Admission to Reduce Nosocomial Methicillin-resistant Staphylococcus aureus (MRSA) Infection?

A study reported in the March 12 issue of the Journal of the American Medical Association (JAMA. 2008;299:1149-1157, 1190-1192.) concluded that universal screening on hospital admission for methicillin-resistant Staphylococcus aureus (MRSA) infection may not reduce the rate of hospital-acquired infections in surgical patients.