By Carol A. Kemper, MD, FACP

HBV Infection in the HAART Era

SOURCE: Falade-Nwulia O, Seaberg EC, Snider AE, et al. Incident hepatitis B virus infection in HIV-infected and HIV-uninfected men who have sex with men from pre-HAART to HAART periods: A cohort study. Ann Intern Med 2015;163:673-680.

Despite advances in anti-retroviral therapy and prevention strategies, men who have sex with men (MSM) remain at risk for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. I was reminded of this when a young man presented with acute infection with both HIV and HBV. While pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine may provide protection for MSM against HIV, it’s conceivable it also may provide protection against HBV. Studies suggest the administration of highly active antiretroviral therapy (HAART) to HIV-infected men may provide partial protection from HBV infection. While HBV vaccination remains the first line of prevention, many MSM have not received the vaccine, the vaccine may fail to induce adequate immunity, and immunity may wane with time. The need for booster doses of vaccine, even in HIV-infected MSM, has not been determined.

These authors examined the incident rate of HBV infection in MSM enrolled in the Multicenter AIDS Cohort Study (MACS) beginning in 1985, comparing the rates of HBV infection in those with or without HBV vaccination, with or without HAART therapy, and for those with HIV RNA viral loads 400 copies/mL or greater than 400 copies/mL. The MACS study began in 1984 in four large metropolitan areas in the United States (Baltimore, Pittsburgh, Chicago, and Los Angeles). Individuals were screened for HBV infection at entry to the study (anti-HBC and HBsAg). Incident HBV infection was defined as evidence of seroconversion at any time during study, or the results of serologic testing of samples collected at the last documented visit before December 2013.

Of the 2,375 HBV-uninfected men enrolled in study, 244 HBV infections occurred. During the 25,322 person-years of follow-up, the unadjusted incident rate was 9.6% per 1,000 person-years. In multifactorial analysis, a greater incidence of HBV infection was observed in those of younger age (< 40 years), or those reporting two or more sex partners within the preceding six months. HBV infection also was more common in HIV-infected MSM compared with HIV-uninfected MSM, with an incident rate of HBV infection of 14.9 for HIV-infected MSM compared with 7.8 per 1,000 person-years for HIV-uninfected MSM (incident rate ratio [IRR], 1.9; 95% confidence interval [CI], 1.5-2.4).

When the analysis was restricted to the HAART period (1996 or later) compared with the pre-HAART period, the incident rate dramatically decreased for both HIV-positive (IRR, 0.2) and HIV-negative MSM (IRR, 0.3). Further, a significant benefit was observed for the use of effective HAART therapy. In men with HIV RNA VL < 400 copies/mL, the incident rate of HBV infection was only 2.6 per 1,000 person-years. Compliance with effective HAART therapy, containing either lamivudine (3TC) or tenofovir disoproxil fumarate (TDV, Viread), appears protective against HBV infection.

Compared with unvaccinated participants, the reported receipt of one or more doses of HBV vaccine also was protective (IRR, 0.3). Only one-third of the men reported one or more doses of HBV at study entry, and 60% reported vaccination during follow-up. While these data were based on self-report, and may underestimate the use of HBV vaccine in this cohort, other studies have observed rates of HBV vaccination as low as 25% even among HIV-infected men in active care. Even in those who receive vaccine, impaired immunogenicity coupled with waning immunity to vaccination may leave individuals vulnerable to infection.

In our HIV clinic, a major obstacle to vaccine administration was getting patients back at regular intervals for the three-dose vaccination schedule. Even double doses of three separate doses of vaccine, administered over two months, resulted in only 60% seroconversion. And the need for booster doses of vaccine remains undetermined — the CDC suggests retesting of anti-HBSAb levels at various intervals in immunocompromised hosts, with revaccination of those with failing immunity (Ab levels < 10 IU/L) — although this seems impracticable. It has been our practice to verify antibody levels in response to vaccination, provide a second series of vaccine as needed, and, without verifying further antibody levels, provide booster HBV vaccine at approximately 10 years in all HIV-infected individuals.

While it is good to know that HAART therapy — as well as PrEP — may provide some protection for MSM, making sure individuals are properly vaccinated is the most important task.

Current Trends in Salmonella Resistance

SOURCE: A ProMED-mail post. Antibiotic resistance, Salmonella — USA: National Antimicrobial Resistance Monitoring System for enteric bacteria (NARMS), 2014. Sept. 8, 2015.

The National Antimicrobial Resistance Monitoring System for Enteric Bacteria, called NARMS, first began tracking antimicrobial susceptibility for certain enteric bacteria found in retail meats, food animals, and in humans with infection in 2003. This project involves collaboration between the CDC, U.S. Food and Drug Administration, and local and state public health departments throughout all 50 states and the District of Columbia. Annual reports are published, and a really nice, detailed interactive web report has been made available (wwwn.cdc.gov/narmsnow/). For the first time ever, whole genomic sequencing for individuals infected with drug-resistant Salmonella is available.1

The current report, which documents resistance for isolates collected in 2014, indicates the portion of Salmonella with multi-drug resistance is tracking at 9-11% throughout the United States. A total of 2,127 non-typhoidal isolates and 335 typhoid isolates were tested. Antimicrobial resistance was demonstrated for non-typhoidal isolates, in decreasing order of resistance, for trimethoprim-sulfamethoxazole (9.4%), ampicillin (9.1%), nalidixic acid (3.5%), ceftriaxone (2.4%), ciprofloxacin (0.4%), and azithromycin (0.04%). In comparison, antimicrobial resistance in typhoidal isolates, in decreasing order of resistance, was demonstrated for nalidixic acid (72.2%), trimethoprim-sulfamethoxazole (13.4%), ampicillin (12.8%), and ciprofloxacin (5.4%); none of the typhoidal isolates were resistant to azithromycin or ceftriaxone. (I was unable to determine the specific MIC breakpoints used on the CDC interactive website.)

Overall, current Salmonella resistance to ciprofloxacin is tracking at approximately 4%, and ceftriaxone resistance remains rare. While these figures are encouraging overall and relatively stable compared with 2011 data, there are some concerning trends. Of the 51 isolates with CFTX-resistance (all non-typhoidal isolates), six were found to carry the ESBL gene. Most of the ceftriaxone-resistant isolates were specific serovars (e.g., Dublin, Newport, Typhimurium). None of the strains exhibiting CFTX-resistance were also found to be insensitive to azithromycin.

However, for human bloodstream isolates, resistance to first-line antimicrobials was documented in 20% of cases which is higher than in 2011. And for one of the non-typhoidal strains commonly found in meat products and food animals, multi-drug resistance more than doubled to 43% in 2014 compared with 18% in 2011.

Increasingly frequent multidrug-resistant salmonella, especially non-typhoidal strains, represents an ever-present threat. It also is important to remember these figures may differ for individuals coming into this country with salmonella infection. For example, rates of multidrug resistance may be significantly greater in individuals in our area, with a large Asian Indian population in Silicon Valley. Estimates of resistance in Salmonella species found in India, reported in 2013, described 92% resistance to nalidixic acid, 52% intermediate sensitivity or resistance to azithromycin, and 14% resistance to ciprofloxacin.

Consideration should be given to the ciprofloxacin MICs when treating patients with Salmonella infections, and whether the isolate remains sensitive to nalidixic acid. While the initial CLSI breakpoint for ciprofloxacin was 4 mg/L, treatment failures occurred in both typhoid and non-typhoidal strains when the ciprofloxacin MIC was significantly less. As a result, in 2012, the CLSI breakpoint was revised downward to 1 mg/L, although some experts would define sensitive strains as less than 0.125 mg/L. Observations of comparative nalidixic acid and ciprofloxacin MICs found that none of the isolates with intermediate sensitivity to nalidixic acid had reduced susceptibility to ciprofloxacin (MIC values 0.008-0.015 mg/L). In contrast, isolates with resistance to nalidixic acid consistently demonstrated reduced susceptibility to ciprofloxacin with MICs 0.125- > 1.2

REFERENCES

  1. Pellegren J. CDC releases genome sequencing data on antibiotic-resistant Salmonella. Contagion Live, Sept. 8, 2016. Available at: www.contagionlive.com/news/cdc-releases-genome-sequencing-data-on-antibioticresistant-salmonella. Accessed Sept. 12, 2016.
  2. Ryan MP, Dillon C, Adley CC. Nalidixic acid-resistant strains of Salmonella showing decreased susceptibility to fluoroquinolones in the midwestern region of the Republic of Ireland due to mutations in the gyrA gene. J Clin Microbiol 2011;49:2077-2079.