Phase IIb randomized trial of adjunct immunotherapy in patients with first-diagnosed tuberculosis, relapsed and multi-drug-resistant (MDR) TB.

Placebo-controlled, randomized, phase 2b trial was conducted in 34 adults comprising 18 first-diagnosed (52.9%), 6 relapsed (17.6%), and 10 MDR-TB (29.4%) cases to investigate the safety and efficacy of an oral immune adjunct (V5). The immunotherapy (N = 24) and placebo (N = 10) arms received once-daily tablet of V5 or placebo for one month in addition to conventional anti-TB therapy (ATT) administered under directly observed therapy (DOT).The enlarged liver, total bilirubin, erythrocyte sedimentation rate, lymphocyte and leukocyte counts improved significantly in V5 recipients (P = 0.002; 0.03; 8.3E-007; 2.8E-005; and 0.002) but remained statistically unchanged in the placebo group (P = 0.68; 0.96; 0.61; 0.91; and 0.43 respectively). The changes in hemoglobin and ALT levels in both treatment arms were not significant. The body weight increased in all V5-treated patients by an average 3.5 ± 1.8 kg (P = 2.3E-009), while 6 out of 10 patients on placebo gained mean 0.9 ± 0.9 kg (P = 0.01). Mycobacterial clearance in sputum smears was observed in 78.3% and 0% of patients on V5 and placebo (P = 0.009). The conversion rate in V5-receiving subjects with MDR-TB (87.5%) seemed to be higher than in first-diagnosed TB (61.5%) but the difference was not significant (P = 0.62). Scoring of sputum bacillary load (range 3-0) at baseline and post-treatment revealed score reduction in 23 out of 24 (95.8%) V5 recipients (from mean/median 2.2/3 to 0.3/0; P = 6E-010) but only in 1 out of 10 (10%) patients on placebo (1.9/1.5 vs. 1.8/1; P = 0.34). No adverse effects or TB reactivation were seen at any time during follow-up. V5 is safe as an immune adjunct to chemotherapeutic management of TB and can shorten substantially the duration of treatment.

Adjunct oral immunotherapy in patients with re-treated, multidrug-resistant or HIV-coinfected TB.

This Phase IIb, placebo-controlled study involved 55 TB patients treated with anti-TB therapy. They were divided into two groups, matched by age, gender, baseline bodyweight and clinical manifestations: one group (n = 27) received a once-daily V-5 Immunitor (V5) immunotherapy pill and the other (n = 28) received placebo. Only one (3.7%) and three (10.7%) subjects in V5 and placebo arms, respectively had first-diagnosed, drug-sensitive TB; the remaining patients had re-treated TB, multidrug-resistant TB or HIV-TB coinfection. After 1 month, 26 out of 27 patients (96.3%) became sputum smear negative in the V5 group (p < 0.0000001), whereas seven out of 28 (25%) in the placebo group had converted (p = 0.005). V5 contributed to the downregulation of TB-associated inflammation, as shown by normalization of high leukocyte counts, erythrocyte sedimentation rate and faster defervescence than controls. Patients in both arms experienced an increase in the levels of hemoglobin corresponding to 128.9 ± 17.6 versus 133.1 ± 14.7 g/l (p = 0.03) and 112.6 ± 14 versus 117 ± 11.7 g/l (p = 0.03) in V5 and placebo arms, respectively. In total, 19 out of 28 placebo patients (67.9%) gained, on average, 1.07 kg (59.1 ± 10 vs 60.1 ± 10.4 kg; p = 0.003). By contrast, all patients in the V5 group gained weight with mean 3.4 kg (59.7 ± 8 vs 63.1 ± 9 kg; p = 5.7E-007). Clinical symptoms improved among all patients in V5 arm, while 28.6% of patients on placebo reported satisfactory results (p = 0.007). No adverse or side effects attributable to V5 were seen at any time. Further studies are needed to gauge the extent of the benefits of V5 as safe and effective adjunct immunotherapy for TB.

Clinical experience with therapeutic vaccines designed for patients with hepatitis.

Franciscan missionary Giovanni Di Plano Carpini traveled in 1245 to a country named Yeke Tartar, to visit a certain man called Genghis Khan. His journey's report narrated peculiar dietary habits of the locals: "they eat anything, even lice". Little that Carpini knew, he had actually documented the earliest known to us record of oral vaccination against blood-borne infections - an approach that is still used occasionally in the present-day Mongolia for therapy of hepatitis. Currently, efforts aimed at developing therapeutic hepatitis vaccines have switched to more palatable path, but we may still benefit from the insight of medieval Mongols. This review provides an update on development of hepatitis B and C vaccines as related to immunotherapy of hepatitis. Immune therapy is a fast-moving field but the results so far failed to pitch woo. Current trends in research on therapeutic vaccine candidates and liver immunology are discussed. We subscribe to the idea that viral hepatitis is essentially an autoimmune disease generating immune-mediated liver damage. Therapeutic vaccines need to be designed in such a way that self-destructive immunity of the host is targeted not the virus, which is not cytopathic.

Open-label trial of therapeutic immunization with oral V-5 Immunitor (V5) vaccine in patients with chronic hepatitis C.

We evaluated whether V-5 Immunitor (V5)--tableted therapeutic bivalent vaccine comprising heat-inactivated HCV antigens from pooled blood of HBV- and HCV-infected donors - may produce clinical benefit through induction of oral tolerance and reduction of immune-mediated liver injury. Once daily dose of V5 was administered per os to 10 patients with chronic hepatitis C in an open-label study that lasted 1 month. Every patient who entered the study had elevated liver enzyme levels, which at the end of study have decreased in 100% of analyzed patients. The reduction was highly significant, from 157.7+/-73.4 to 49.9+/-43.8 U/L (P=0.0013) and 147.0+/-79.2 to 58.7+/-56.6 U/L (P=0.0132), for ALT and AST, respectively. The AST/ALT ratio has improved from 0.93 to 1.18 (P=0.00058) indicating the reversion of progression to cirrhosis. None of intent-to-treat patients who were anti-HCV antibody positive at study entry, became negative after 1 month on V5 (P=0.998). All patients, except one, reported complete recuperation from hepatitis C-associated clinical symptoms present at baseline (P=0.0016) with Mantel Haenszel's odds ratio 9.4 (P=0.0021) at 95% confidence interval: 2.7