Four years of immunization with OM-85 BV to prevent respiratory infections in HIV+ patients

Abstract

We report an interventional, non-randomized experience of OM-85 BV immunization in a group of 104 HIV-infected subjects presenting recurrent seasonal respiratory bacterial infections. We compared the number of respiratory events, the use of antibiotics and the cost related to antibiotics before (2005–2006) and after (2008–2011) the introduction of such intervention. The year 2007 was excluded from the analysis since half of the patients were immunized in that year in an exploratory approach. Respiratory infections dropped in all groups but in subjects with recurrent otitis, leading to a reduction in the use of antibiotics. This is the first report of the effect of OM-85 BV in vivo in HIV-infected subjects.

Keywords: :

• OM-85 BV
• seasonal respiratory infections
• COPD
• four years
• recurrent sinusitis

Letter

Highly effective antiretroviral therapy has changed life expectancy and quality of life of HIV-infected individuals, but persistent inflammation still accelerates aging and organ damage.¹ Every effort should be done to prevent infectious events, and recently attention is growing toward respiratory infections, whose prevalence in this population is high,² partly due to the unhealthy lifestyle of many of our patients. Chronic obstructive pulmonary disease (COPD) age-adjusted prevalence is higher and the evolution is worse among HIV-infected patients than in the general population.³ Recurrent rhinosinusitis and otitis media are not more frequent, but add drug burden and inflammation in this delicate population.⁴

OM-85 BV is an immunostimulant preparation containing lysates of Hemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Klebsiella ozaenae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, Neisseria catarrhalis, whose efficacy in reducing infectious events in COPD patients, although demonstrated in some randomized clinical trials⁵ has not yet been clearly defined due to the heterogeneity of trials conducted up to date.⁶ Moreover, recent data confirm the drug’s efficacy in a population of immunodeficient subjects.⁷ An in vitro and ex vivo study of the adherence of Staphylococcus aureus, Klebsiella pneumoniae, and Candida albicans to the buccal epithelial cells of HIV-infected and uninfected subjects showed significant and comparable reduction in adhesion of the tested strains after immunization with OM-85 BV.⁸

A subgroup of 386 HIV-infected patients followed at the “Luigi Sacco” outpatients’clinic were proposed to participate to an observational study on respiratory tract infections since July, 2005.

During autumn 2007, 65 subjects affected by recurrent or chronic respiratory infections underwent three courses of OM-85 BV from September to December, achieving a high index of satisfaction and a dramatic drop in respiratory events.

Therefore, in summer 2008 and 2009 all patients at risk of developing seasonal respiratory tract infections were prescribed OM-85 BV, to be assumed daily, for the initial ten days of September, October and November. One sample t-test was used to determine the significance in events’ reduction compared with the baseline values (events occurred before the introduction of the immunization, years 2005–2006).

Data were recorded on the electronic database of the clinic, analyzed on February 2010 and brought as a poster to the XVIII IAS Conference held in Vienna in July of the same year.⁹ Since then this intervention entered in the routine practice. One hundred 53 additional patients with risk of developing respiratory infections joined the cohort but have been excluded from the present analysis for homogeneity of data.

Within the subgroup of 386 HIV-infected patients observed since 2005, 228 were smokers, 36 were affected by COPD (11 harbouring bronchiectasis), 21 by recurrent sinusitis not requiring surgical intervention, 5 by recurrent otitis media and 6 presented COPD + sinusitis. Moreover, 62 smokers not presenting with full clinical criteria for COPD in the previous 5 y developed every year at least one episode of acute bronchitis requiring antibiotic treatment. During the course of the study 82/228 patients stopped smoking (33/62 high-risk smokers). Two of the COPD patients died of end-stage liver disease, one in 2010 and one in 2011. One subject discontinued the drug after the first cycle, reporting fatigue, malaise and nausea. Respiratory infections in the overall high-risk population (n = 130) were considered for three biennia, pre-immunization (2005–2006), experimental immunization (2008–2009), and confirmed routine practice (2010–2011). Year 2007, in which only part of the population had been immunized, was excluded from the analysis. All subjects were on antiretroviral therapy, 62 being on 2 nucleoside analogs + boosted protease inhibitors (PIs), 44 on 2 nucleoside analogs + non-nucleosides and 24 on more complex rescue regimens. All maintained HIV-1 RNA suppression in plasma with the exception of 18 isolated ‘blips’ for the whole observation period. There have been 15 intra-class or cross-class switches related to toxicity or simplification issues. Infections declined steeply after immunization in all subgroups, with the highest effect in high-risk smokers. Furthermore, antibiotic cycles decreased from 259 to 54 and then to 50, with 7.615 € direct savings between the first and the second biennium, and a 91 € further reduction in the confirmed routine practice period, possibly reflecting the effect of continued immunologic gain given the simple maintenance of the previous strategy (Table 1). Subjects with recurrent otitis media had the smallest clinical and economic gain. Otitis was predominantly treated with amoxicillin/clavulanate, while the most used drugs in COPD subjects and high-risk smokers were levofloxacin (45%), followed by azythromicin (40%) and ceftibuten (25%) often in association with azythromicin. Trimetoprim-sulphametoxazole and amoxicillin were also used, though at lower rates. Smoke cessation had some impact only in the high-risk smokers’ subgroup (93% events’ reduction vs 75% in persistent smokers).

Table 1. Demographic characteristics of the cohort and clinical and economic impact of the immunization

	COPD+/− sinusitis (n = 42)	Recurrent sinusitis (n = 21)	Recurrent otitis (n = 5)	High-risk smokers (n = 62)
					Median age, years (range)	49 (35 - 72)	47 (42 – 57)	47 (45 – 49)	48 (27 – 77)
Sex, n (males, females)	29, 13	15, 6	2, 3	38, 24
Risk factor, n (IDU, MSM, HS, O)*	22, 12, 7, 1	9, 6, 6, 0	1, 1, 3, 0	39, 15, 8
Median time on antiretrovirals, years (range) at September, 2008	16 (5 - 19)	10 (6 - 13)	13 (9 - 16)	14 (3 - 19)
Median baseline CD4/mm^3 (range) at September, 2008	302 (133 – 502)	331 (201 – 589)	257 (97 – 347)	326 (125 – 559)
Median CD4 increase (2008–2011)	+ 138	+ 197	+ 204	+ 231
CDC stage C (%)	36,1	36,4	20	37,1
P (one sample t-test)	0,0041	0,0182	0,0635	0,0028
Respiratory infectious events per biennia (n)
2005 - 2006	92	47	15	134
2008 - 2009	14	13	6	21
2010 - 2011	13	11	4	22
Antibiotic expenditure per biennia (€)
2005 - 2006	3.320	1.776	342	4.218
2008 - 2009	664	330	72	975
2010 - 2011	625	287	56	982

*IDU, intravenous drug users; MSM, males having sex with males; HS, heterosexuals, O, other or unknown source of infection.

Overall, the stability of the cohort, confirming each year the willingness to spend their own money to buy OM-85 BV (not subsidised by the Italian National Health System) and to prolong the observation period, underlined the clear benefit that the patients derived from this experiment. These results lead to consider also other advantages which could not be quantified in our study, such as less days lost from work, and reduced family epidemics (reported by some patients, but not thoroughly recorded to allow interpretation). Moreover, the reduction in antibiotics’ consumption has the potential of reducing the generation of resistant strains. However, there are several evident limitations in this study. First of all this is an observational study and not a randomized controlled trial. Second, the impact of the immunologic gain from antiretroviral therapy and from the continued exposure to risk factors, such as smoking, could not be quantified. Finally, the different weather conditions across the years might have influenced the rate of seasonal respiratory infections. However, given the evident effects observed, and durably maintained over four years, we can state that in this observational cohort OM-85 BV reduced the frequency of respiratory events requiring antibiotic therapy in all subgroups, particularly in high-risk smokers and in COPD patients.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.