Effectiveness of GenoType MTBDRsl in excluding TB drug resistance in a clinical trial.

OBJECTIVES: To assess the performance of the GenoType MTBDRsl v1, a line-probe assay (LPA), to exclude baseline resistance to fluoroquinolones (FQs) and second-line injectables (SLIs) in the Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB 1 (STREAM 1) trial.METHODS: Direct sputum MTBDRsl results in the site laboratories were compared to indirect phenotypic drug susceptibility testing (pDST) results in the central laboratory, with DNA sequencing as a reference standard.RESULTS: Of 413 multidrug-resistant TB (MDR-TB) patients tested using MTBDRsl and pDST, 389 (94.2%) were FQ-susceptible and 7 (1.7%) FQ-resistant, while 17 (4.1%) had an inconclusive MTBDRsl result. For SLI, 372 (90.1%) were susceptible, 5 (1.2%) resistant and 36 (8.7%) inconclusive. There were 9 (2.3%) FQ discordant pDST/MTBDRsl results, of which 3 revealed a mutation and 5 (1.3%) SLI discordant pDST/MTBDRsl results, none of which were mutants on sequencing. Among the 17 FQ- and SLI MTBDRsl-inconclusive samples, sequencing showed 1 FQ- and zero SLI-resistant results, similar to frequencies among the conclusive MTBDRsl. The majority of inconclusive MTBDRsl results were associated with low bacillary load samples (acid-fast bacilli smear-negative or scantily positive) compared to conclusive results (P < 0.001).CONCLUSION: MTBDRsl can facilitate the rapid exclusion of FQ and SLI resistances for enrolment in clinical trials.

Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

The activity of phosphate-dependent glutaminase from the rat small intestine is modulated by ADP and is dependent on integrity of mitochondria.

The effect of adenine nucleotides and phosphate on rat small intestine phosphate-dependent glutaminase (PDG) activity was investigated in intact mitochondria. Disruption of the integrity of mitochondria by sonication or freeze-thawing resulted in loss of enzyme activity. ADP was the strongest adenine nucleotide activator of the enzyme giving a V(max) that was over 5-fold of that for AMP or ATP. The sigmoid activation curve of PDG by ADP became hyperbolic in presence ATP. ADP also lowered the K(m) for glutamine and increased V(max) and these effects were further enhanced by the presence of ATP. Activation of PDG by phosphate and ADP was not completely additive suggesting some antagonism between the activators. There was no clear relationship between changing ATP/ADP ratios and PDG activity in presence of a constant concentration of phosphate. However, ratios of approximately 1:4 and 4:1 gave the highest and lowest activities, respectively. The pH dependence of PDG activity was affected by phosphate concentration and results suggest that the divalent ion is the activating species.

Messages about dual contraception in areas of high HIV prevalence are not heeded.

BACKGROUND: Dual protection is recommended for prevention of unwanted pregnancies and protection against sexually transmitted infections, including HIV. It is critical for HIV-negative women to prevent seroconversion and HIV transmission to their infants during pregnancy and breastfeeding. METHODS: Women were followed up after delivery, monthly for the first 9 months and then 3-monthly to 24 months, in a cohort study investigating postnatal HIV transmission. Study nurses discussed family planning, including condom use, at each visit. Contraceptive methods used since the last visit were recorded. All women knew their HIV status, and most women breastfed for a minimum of 6 months. RESULTS: Among 1,137 HIV-positive and 1 220 HIV-negative women the most common contraceptive method was the hormonal injectable; few women used condoms alone or as dual contraception (0-3 months 6.8%; 7-12 months 16.3%; 19-24 months 14.4%). Compared with uninfected women, HIV-positive women were more likely to use condoms in years 1 and 2 after delivery (adjusted odds ratio (AOR) 1.72, 95% confidence interval (CI) 1.38-2.14, p<0.001; AOR 1.61, 95% CI 1.15-2.25, p=0.006 respectively). Compared with women with a flush toilet, those with a pit latrine were less likely to use condoms in years 1 and 2 (AOR 0.22, 95% CI 01.7-0.28, p<0.001; AOR 0.27, 95% CI 0.19-0.39, p<0.001). Older women were more likely to use condoms in the first postpartum year (AOR 1.78, 95% CI 1.03-3.09, p=0.040). CONCLUSIONS: More creative ways of promoting condoms and dual contraception need to be found if new HIV infections, in women and children, are to be prevented.

Messages about Dual Contraception in Areas of High HIV Prevalence are not Heeded

Background : Dual protection is recommended for prevention of unwanted pregnancies and protection against sexually transmitted infections; including HIV. It is critical for HIV-negative women to prevent sero-conversion and HIV transmission to their infants during pregnancy and breastfeeding. Methods: Women were followed post-partum; monthly to 9 months and 3-monthly to 24 months; in a cohort study investigating postnatal HIV transmission. Study nurses discussed family planning; including condom use; at each visit. Contraceptive methods used since the last visit were recorded. All women knew their HIV status; most women breastfed for a minimum of six months.Results : of 1137 HIV-positive and 1220 HIV-negative women the most common contraceptive method was the hormonal injectable; few women used condoms alone or as dual contraception (0-3 months 6.8; 7-12 months 16.3; 19-24 months 14.4). HIV-positive women were more likely to use condoms in years one and two post-partum (AOR 1.72; 95CI 1.38-2.14; pp=0.040). Conclusions. More creative ways of promoting condoms and dual contraception need to be found if new HIV infections; in women and children; are to be prevented

AIDS awareness and sexual behaviour in a high HIV prevalence area in rural northern Kwazulu-Natal, South Africa.

The objective was to assess AIDS awareness and sexual behaviour in a rural South African community with a high HIV prevalence. One hundred clinic attenders underwent a structured interview using a standard questionnaire. Although the 64 female and 36 male patients, mean age 22 (range 13-45), had good knowledge of AIDS-related issues, only 50 perceived HIV/AIDS as a common problem. Of the 75 patients who were sexually active only 30 (40%) used condoms (men 16; 55% vs women 14; 30%, P=0.033) despite being better informed about the protective effect of condoms (active 61; 81% vs abstinent 14; 56%, P=0.011). More men than women admitted to multiple sexual partners (17; 47% vs 7; 11%, P<0.0001). In conclusion, despite a high level of awareness of HIV/AIDS issues, self-perceived risk was low, condom use was infrequent and especially men continued to have multiple sexual partners. Awareness has yet to translate into reduction of risk behaviour.