Updates
By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
HAART and Ribavirin: Mitochondrial Toxicity
Source: Reiberger T, et al. Mitochondrial toxicity is associated with virologic response in patients with HIV and hepatitis C virus coinfection treated with ribavirin and highly active antiretroviral therapy. J Infect Dis. 2010;202:156-160.
This subset analysis from a larger prospective, multicenter HIV-HCV coinfection treatment trial found that patients receiving highly active antiretroviral therapy (HAART) in combination with pegylated interferon alfa and ribavirin for HCV were at greater risk for lactic acidosis and hyperlactatemia than those receiving HCV treatment alone. Patients received PEG-IFN 180 micrograms weekly and ribavirin 800 mg/day (for genotypes 1 and 4) or 1000-1200 mg/day (for genotypes 2 and 3), with their usual HAART regimen or with no HIV treatment. The use of d4T, ddI, or AZT was not allowed during study. Venous lactate levels were measured at baseline and at regular intervals during the study.
The subgroup of 64 HIV-HCV coinfected patients was followed for up to 12 months during HCV therapy. Forty-eight of these were also receiving HAART. Lactate levels were increased in both HAART and non-HAART users during HCV treatment, compared with baseline, although mean lactate levels were significantly higher at weeks 4 and 12 in HAART users than those receiving HCV therapy alone. By six months of HCV therapy, lactate levels appeared to stabilize and were similar between HAART and non-HAART users.
Thirteen of 14 patients with significant elevations in lactic acid (> 2 mmol/L) were receiving HAART, as was the single patient who developed lactic acidosis with lactate levels (> 5 mmol/L). Nine patients also had severe weight loss (> 10% body weight), all of whom were receiving higher-dose RBV and seven of whom were receiving concurrent HAART. Elevations in pancreatic enzymes were significantly more frequent in patients receiving HAART vs. those who were not (32% vs. 12%). Six patients developed symptomatic pancreatitis, necessitating discontinuation of therapy. A trend toward reduction of hepatic steatosis was observed in patients receiving HAART and lower-dose RBV (possibly because many of these patients were infected with genotype 3).
A trend toward improved response to HCV therapy was observed in patients with evidence of hyperlactatemia and mitochondrial toxicity (a sustained response occurred in 56% of patients receiving HAART vs. 31% non-HAART users, p = .088). The authors suggest this may be the result of higher intracellular ribavirin levels, with greater anti-HCV suppression but a consequent increased risk of mitochondrial toxicity.
ED Drugs and Unsafe Sex
Source: Jena AB, et al. Sexually transmitted diseases among users of erectile dysfunction drugs: Analysis of claims data. Ann Intern Med. 2010;153:1-7.
This large-scale population study, sponsored by the BING Center for Health Economics and the RAND Roybal Center for Health Policy, examined whether rates of STDs and HIV infection were affected by the use of drugs for erectile dysfunction. A large database of users was created from pharmacy and medical claims between 1997 and 2006 for 44 states. Men over the age of 40 years (who were more likely to have ED) who had filled at least one or more prescriptions for an ED drug for any quarter were identified, and all claims for STDs, HIV, or other comorbid conditions likely associated with ED were reviewed.
From 1997 to 2006, 33,968 men filled at least one prescription for an ED drug, while 1,376,838 remained non-ED drug users. In the year before the first ED drug was filled, rates of all newly diagnosed STDs were significantly higher in ED drug-users compared with non-users (adjusted OR 2.80, p < .001), including higher rates of HIV, Chlamydia, syphilis, and gonorrhea (although only those figures for HIV and Chlamydia were statistically significant). In the year after the first ED drug was filled, the risk of STD was also significantly higher in ED drug-users compared with non-users (adjusted OR 2.65, p < .001), although these figures were largely driven by cases of new HIV infection.
A surprising finding from this data was the rates of HIV infection and STDs in ED-drug users were similar both in the year before and in the year after the first prescription for an ED drug was filled. Thus, there was no apparent change in the rates of HIV and STDs in men who began using sildenafil or another similar agent but the use of an ED agent appears to be a marker for riskier sexual behavior, at least in some men. The authors suggest that earlier studies focusing on the use of these agents did not adequately capture baseline STD rates, resulting in the impression that increased rates of STDs were the result of (or facilitated by) the use of an ED agent.
Requests for an ED agent should prompt discussion regarding safer sex behavior and STDs even in those over the age of 40.
Update on Brucellosis: The Latest STD?
Brucellosis is the most common zoonosis world-wide, resulting in an estimated half million cases annually. Infection usually occurs from ingestion of contaminated dairy, aerosolization, or mucocutaneous contact with conjunctiva, abraded skin, or open infected tissues. Sexual transmission has seldom been documented in humans, although it is common in farm animals, and the organism has been found in both semen and vaginal fluids. One can imagine that disseminated infection could result in infection in genital secretions, which is indirectly supported by the fact that genital infection does occur, and infection within families is common (up to 50%).
The first article describes the apparent sexual transmission of Brucella spp. between two married couples.1The first patient was a 55-year-old man who had traveled to Israel, where he consumed unpasteurized goat milk. About two weeks later, he developed fever and rigors, and blood cultures yielded B. melitensis biovar 1. He received a combination of rifampin and doxycycline for two weeks and quickly recovered. Four weeks following the man's diagnosis, his wife, who had not traveled, presented with fever and rigors, and blood cultures yielded the same organism. Semen samples, obtained from the husband at that time (towards the end of his treatment course), failed to yield an organism, but PCR was positive for Brucella spp. Despite the same treatment regimen, and initial response, the wife relapsed with recurrent infection four weeks later. Culture of semen was negative, but PCR remained positive.
The second case described a 65-year-old man who presented with fever, chills, cervical discitis and osteomyelitis, and epididymo-orchitis. Blood cultures grew B. melitensis. He responded well to treatment. He recalled eating unpasteurized cheese purchased in a small village in Israel. About four weeks later, his wife, who had not traveled with him and had no history of exposure to unpasteurized dairy, developed fever and chills. Blood cultures grew B. melitensis.
Both cases are highly suggestive of sexual transmission from husband to wife. The persistence of the organism in semen in the first case, at least as demonstrated by persistently positive PCR, raises concern that persistence of the organism in genital secretions may present an ongoing risk to sexual partners, despite apparent response to treatment. Persistence of infection is, in part, what makes certain species of brucella particularly difficult to treat.
At least 10 different species of Brucella have been identified, each with apparent differences in host specificity, virulence, and in the ability to cause persistent infection, including more commonly B. melitensis (in goats), B. abortus (in cattle), and B. suis (in pigs). Increasing number of cases are being reported from Israel, Iraq, Iran, Kyrgyzstan, and Mongolia, as well as the U.S.-Mexican border. Two newer species have been identified within the past decade, including B. microti, which was first described in an outbreak in the Czech Republic in 2001. The reservoir for this organism in the wild appears to be the common vole.
Laboratory work with B. microti indicates that it may be more virulent than other species of Brucella, but may lack the ability to persist in tissues as other species.2 Jimenez de Bagues and colleagues infected human and murine macrophages with both B. microti and B. suis. At 24 hours of cell culture, B. microti demonstrated a significantly increased capacity for intracellular replication compared with B. suis. In vivo inoculation of different mice strains showed that the bacterial load in liver and spleen peaked at day 3 for B. microti, compared with day 7 for B. suis. Intraperitoneal inoculation of 105 B. microti resulted in death in 82% of Babl/c mice within 4-7 days. However, sublethal doses of B. microti resulted in total protection from subsequent lethal doses of organism suggesting that naturally occurring immunity in the wild may be important in preventing spread of the organism. Furthermore, B. microti had a lower residual capacity for persistence of infection in spleen tissue.
Interestingly, genetic sequencing studies suggest that all of the brucella species share a high degree of homology and, specifically, B. microti appears to be nearly identical to B. suis enough so that it has been proposed that all of these organisms should be grouped into one species (tentatively named B. melitensis). However, genetic analyses do not seem to adequately explain the observed differences in host specificity and possibly virulence between the various organisms.
References
- Meltzer E, et al. Sexually transmitted brucellosis in humans. Clin Infect Dis. 2010:51:e12-15.
- Jimenez de Bagues MP, et al. The new special of Brucella microtireplicates in macrophages and causes death in murine models of infection. J Infect Dis. 2010;202:3-10.
- Accompanying editorial by J. Glenn Morris, Jr., and F.S. Southwick. Brucella, voles, and emerging pathogens. J Infect Dis. 2010;202:1-2.
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