Protease inhibitors are currently the best option when it comes to treatment of pregnant HIV-infected women and preventing MTCT. Although all tested protease inhibitors generally showed good data, boosted saquinavir and atazanavir seemed to be less affected by pregnancy and can therefore be considered as the first choice to be used for preventing MTCT. However, it is essential to generate more data to support this recommendation. Because the observed lower exposure in some women, therapeutic drug monitoring is indicated during pregnancy.

No abstract

Background Many women in sub-Saharan Africa initiate antenatal care (ANC) late in pregnancy, undermining optimal prevention of mother-to-child-transmission (PMTCT) of HIV. Questions remain about whether and how late initiation of ANC in pregnancy is related to adherence to antiretroviral therapy (ART) in the era of national dolutegravir roll-out. Methods This study employed a qualitative design involving individual interviews and focus group discussions conducted between August 2018 and March 2019. We interviewed 37 pregnant and lactating women living with HIV selected purposively for early or late presentation to ANC from poor urban communities in South Africa and Uganda. Additionally, we carried out seven focused group discussions involving 67 participants in both countries. Data were analysed thematically in NVivo12. Results Women described common underlying factors influencing both late ANC initiation and poor ART adherence in South Africa and Uganda. These included poverty and time constraints; inadequate health knowledge; perceived low health risk; stigma of HIV in pregnancy; lack of disclosure; and negative provider attitudes. Most late ANC presenters reported relationship problems, lack of autonomy and the limited ability to dialogue with their partners to influence household decisions on health and resource allocation. Perception of poor privacy and confidentiality in maternity clinics was rife among women in both study settings and compounded risks associated with early disclosure of pregnancy and HIV. Women who initiated ANC late and were then diagnosed with HIV appeared to be more susceptible to poor ART adherence. They were often reprimanded by health workers for presenting late which hampered their participation in treatment counselling and festered provider mistrust and subsequent disengagement in care. Positive HIV diagnosis in late pregnancy complicated women’s ability to disclose their status to significant others which deprived them of essential social support for treatment adherence. Further, it appeared to adversely affect women’s mental health and treatment knowledge and self-efficacy. Conclusions We found clear links between late initiation of ANC and the potential for poor adherence to ART based on common structural barriers shaping both health seeking behaviours, and the adverse impact of late HIV diagnosis on women’s mental health and treatment knowledge and efficacy. Women who present late are a potential target group for better access to antiretrovirals that are easy to take and decrease viral load rapidly, and counselling support with adherence and partner disclosure. A combination of strengthened health literacy, economic empowerment, improved privacy and patient-provider relationships as well as community interventions that tackle inimical cultural practices on pregnancy and unfair gender norms may be required.

NCT00825929 and NCT000422890.

29 30 Running title: high dose rifampicin in tuberculous meningitis 31 Word count: running title: 46 characters; abstract: 199 words; main text: 3487 words 32 2 ABSTRACT 33 34 Background 35High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-36 pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg 37 orally (as previously studied) are warranted to maximize treatment response. 38 Methods 39In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in 40 Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined 41 with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival. 42 Results 43A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in 44 plasma in the critical early days (21) of treatment (AUC 0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, 45 p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 46 3/4 adverse events. Six-month mortality was 7/20 (35%), 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg 47 groups, respectively (p=0·12). 48 Conclusions 49Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. 50Survival benefit with this dose should now be evaluated in a larger phase III clinical trial. 51 52 53 54 55 In 2016, the WHO published data on 10.4 million new tuberculosis (TB) cases and 1·3 million deaths caused by 57 this disease worldwide, making it the leading single infectious disease killer.(1) In turn, tuberculous meningitis 58 (TBM) is the most devastating form of TB. It occurs in 1-6% of patients with TB,(2, 3) leading to death or 59 neurological disability in more than 30% of affected patients.(2, 4, 5) 60 Antimicrobial treatment for TBM follows the model for pulmonary TB, with intensive and continuation phases 61 of treatment. It adheres to the same first-line TB drugs and dosing guidelines,(6) although it is known that some 62 first-line TB drugs, including rifampicin, achieve suboptimal concentrations beyond the blood-brain and blood-63 cerebrospinal fluid (CSF) barriers. Rifampicin is a crucial TB drug, evidenced by the high mortality rate in TBM 64 patients with resistance to rifampicin.(7, 8) As it takes a long time to develop new drugs to treat TB and TBM, it 65is important to make the best possible use of existing drugs. We performed a series of studies to evaluate higher 66 doses of rifampicin in Indonesian patients with TBM. 67A first open-label, randomised phase II clinical trial showed that a 33% higher dose of rifampicin administered 68 intravenously (13 mg/kg iv) for two weeks led to a three-fold higher exposure to rifampicin in plasma and CSF 69 during the first critical days of treatment, and a strong reduction in mortality at six months after the treatment 70 started (adjust...