A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

BACKGROUND: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. METHODS: Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. FINDINGS: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. INTERPRETATION: In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. FUNDING: USAID and Janssen Research & Development.

The lived experiences of tuberculosis survivors during the COVID-19 pandemic and government lockdown in South Africa: a qualitative analysis.

BACKGROUND: Tuberculosis (TB) is a major health concern in South Africa, where prior to COVID-19 it was associated with more deaths than any other infectious disease. The COVID-19 pandemic disrupted gains made in the global response to TB, having a serious impact on the most vulnerable. COVID-19 and TB are both severe respiratory infections, where infection with one places individuals at increased risk for negative health outcomes for the other. Even after completing TB treatment, TB survivors remain economically vulnerable and continue to be negatively affected by TB. METHODS: This cross-sectional qualitative study, which was part of a larger longitudinal study in South Africa, explored how TB survivors' experienced the COVID-19 pandemic and government restrictions. Participants were identified through purposive sampling and were recruited and interviewed at a large public hospital in Gauteng. Data were analyzed thematically, using a constructivist research paradigm and both inductive and deductive codebook development. RESULTS: Participants (n = 11) were adults (24-74 years of age; more than half male or foreign nationals) who had successfully completed treatment for pulmonary TB in the past two years. Participants were generally found to be physically, socioeconomically, and emotionally vulnerable, with the COVID-19 pandemic exacerbating or causing a recurrence of many of the same stressors they had faced with TB. Coping strategies during COVID similarly mirrored those used during TB diagnosis and treatment, including social support, financial resources, distraction, spirituality, and inner strength. CONCLUSIONS: Implications and suggestions for future directions include fostering and maintaining a strong network of social support for TB survivors.

A Randomized Clinical Trial of Human Papillomavirus Test-and-Treat as Compared to Cytology-Based Screening for Prevention of Cervical Cancer Among Women With Human Immunodeficiency Virus: AIDS Clinical Trials Group Protocol A5282.

BACKGROUND: Cytology-based cervical cancer screening followed by confirmation and treatment of biopsy-proven high-grade squamous intraepithelial lesions (bHSIL) is difficult to implement in resource-constrained settings. We hypothesized that high-risk human papillomavirus (hrHPV) testing followed by immediate cryotherapy of women with hrHPV (HPV screen-and-treat) may improve outcomes. METHODS: Randomized, open-label, phase 2, multinational clinical trial enrolling women with human immunodeficiency virus (HIV) age 18 or older with cervical hrHPV and having no cervical lesions or lesions appropriate for cryotherapy. Women were randomized to immediate cryotherapy (Arm A) or cytology-based screening (Arm B). For Arm A, cervical biopsies were obtained followed by cervical cryotherapy, and in Arm B, women with abnormal cytology underwent colposcopy followed by loop electroexcision procedure (LEEP) if bHSIL was detected. Women were followed through 30 months. The primary outcome was time to bHSIL detected from Month 6 through study completion. RESULTS: In total, 288 women (145 in Arm A, 143 in Arm B) were randomized: median age 35 years, 84% on antiretroviral therapy, median CD4 501 cells/mm3. In Arm A, 39 (27%) of women had bHSIL at entry, and in Arm B, 88 (62%) had abnormal cytology, 22 (15%) were diagnosed with bHSIL, 12 (8%) underwent LEEP. In follow-up, 30 (21%) and 31 (22%) developed bHSIL; time to bHSIL was similar between arms (P=.94). The prevalence of hrHPV at Month 6 was similar between arms (61% and 70%, P=.13). CONCLUSIONS: HPV test-and-treat was not associated with improved bHSIL outcomes as compared to cytology-based screening. More effective treatment options are required to improve outcomes from screen-and-treat programs. CLINICAL TRIALS REGISTRATION: NCT01315363.

Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial.

BACKGROUND: Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS: Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS: In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS: In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION: NCT00084136.

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial.

BACKGROUND: Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis. METHODS: This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete. FINDINGS: Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related. INTERPRETATION: The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis. FUNDING: Médecins Sans Frontières.

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.

The lived experiences of Tuberculosis survivors during the COVID-19 pandemic and government lockdown in South Africa: a qualitative analysis.

Background Tuberculosis (TB) is a major health concern in South Africa, where prior to COVID-19 it was associated with more deaths than any other infectious disease. The COVID-19 pandemic disrupted gains made in the global response to TB, having a serious impact on the most vulnerable. COVID-19 and TB are both severe respiratory infections, where infection with the one place individuals at increased risk for negative health outcomes for the other. Even after completing TB treatment, TB survivors remain economically vulnerable and continue to be negatively affected by TB. Methods This cross-sectional qualitative study, which was part of a larger longitudinal study in South Africa, explored how TB survivors' experienced the COVID-19 pandemic and government restrictions. Participants were identified through purposive sampling and were recruited and interviewed at a large public hospital in Gauteng. Data were analyzed thematically, using a constructivist research paradigm and both inductive and deductive codebook development. Results Participants (n = 11) were adults (24-74 years of age; more than half male or foreign nationals) who had successfully completed treatment for pulmonary TB in the past two years. Participants were generally found to be physically, socioeconomically, and emotionally vulnerable, with the COVID-19 pandemic exacerbating or causing a recurrence of many of the same stressors they had faced with TB. Coping strategies during COVID similarly mirrored those used during TB diagnosis and treatment, including social support, financial resources, distraction, spirituality, and inner strength. Conclusions Implications and suggestions for future directions include fostering and maintaining a strong network of social support for TB survivors.

Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial.

BACKGROUND: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. METHODS AND FINDINGS: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. CONCLUSIONS: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3). TRIAL REGISTRATION: ClinicalTrials.gov NCT00089505.

Prevalence of peripheral neuropathy in antiretroviral therapy naïve HIV-positive patients and the impact on treatment outcomes--a retrospective study from a large urban cohort in Johannesburg, South Africa.

Peripheral neuropathy (PN) is associated with advanced HIV disease and may be a complication of antiretroviral therapy (ART) or anti-tuberculosis (TB) drugs, specifically isoniazid (INH). The effect of non-ART-drug-related PN on treatment outcomes is yet to be determined. We analysed prospectively collected cohort data for HIV-infected ART-naive adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa from June 2004 to June 2009. Patients who presented with signs and symptoms of numbness or dysesthesia prior to initiation of ART were defined as having PN. Cox proportional hazard models were used to estimate the effect of PN alone (HIV-related PN) or PN with a history of INH use (TB-related PN) on mortality, lost to follow-up (LTFU), persistent and recurrent PN by 12 months of follow-up. Of the 9,399 patients initiating ART, 3.9 % had HIV-related PN while a further 1.8 % had TB-related PN. Patients with PN did not have a significantly higher risk of mortality compared to those without PN (hazard ratio (HR) 1.17 95 % CI 0.92-1.49). Patients with TB-related PN were less likely to be LTFU by 12 months (HR 0.65 95 % CI 0.44-0.97) compared to those without PN. Patients with HIV-related PN were at increased risk of persistent PN at 3 months post-ART initiation. Patients with HIV-related PN had a similar risk of recurrent PN compared to those with TB-related PN (HR 1.28 95 % CI 0.72-2.27). We demonstrate that patients with PN at initiation of ART present with advanced HIV disease. Completion of TB treatment may reduce the risk of persistent PN in patients with TB-related PN. Use of HIV drugs, even neurotoxic ones, may overall limit neuropathy.

Tuberculosis and Sexual and Reproductive Health of Women in Four African Countries.

Tuberculosis (TB) is a major reason of maternal mortality in low-income countries, and it increases the probability of adverse sexual and reproductive health (SRH) outcomes, including ectopic pregnancy and perinatal mortality. The data presented here is from the TB Sequel observational cohort conducted in four African countries. For this sub-study, we selected only female participants, who were diagnosed with drug susceptible TB and followed-up until the end of anti-TB treatment. The data collection included questionnaires, clinical examination and laboratory tests at TB diagnosis, day 14, month 2, 4 and 6. A total of 486 women, with 88.3% being 18-49 years old, were included in the analysis. Around 54.7% were HIV positive. Most of the participants (416/486; 85.6%) in our cohort were considered cured at month 6. Only 40.4% of non-pregnant women of reproductive age used contraception at TB diagnosis. A total of 31 out of 486 women experienced pregnancy during TB treatment. Pregnancy outcomes varied between live birth (16/31; 51.6%), induced abortion (6/31; 19.4%), miscarriage (4/31; 12.9%) and stillbirth (3/31; 9.6%). Integration and linking of SRH services with TB programmes are vital to increase contraception use and protect women from obstetric risks associated with pregnancy during TB treatment.

Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial.

BACKGROUND: Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs. METHODS: Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in ex vivo whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points. RESULTS: All PET/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in ex-vivo culture was enhanced by auranofin compared to controls, but not by other HDTs. CONCLUSIONS: None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.

Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial.

BACKGROUND: Expanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients. METHODS: This randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per microL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1.40. This study is registered with ClinicalTrials.gov, number NCT00255840. FINDINGS: 408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1.09 (95% CI 0.89-1.33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60-144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively. INTERPRETATION: Nurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART. FUNDING: National Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases.

Efficacy, safety and central nervous system effects after switch from efavirenz/tenofovir/emtricitabine to doravirine/tenofovir/lamivudine.

OBJECTIVE: Doravirine is an alternative treatment option for individuals who do not tolerate efavirenz. We assessed efficacy, safety, and CNS effects in adults with HIV-1 and CNS complaints who switched from an efavirenz-based regimen to a doravirine-based regimen. DESIGN: Multicenter, double-blind, randomized trial (NCT02652260). METHODS: Virologically suppressed adults receiving efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF), or its components, with ongoing EFV-associated CNS toxicity grade 2 or higher (DAIDS criteria) were switched to doravirine/lamivudine/tenofovir (DOR/3TC/TDF) on day 1 (Immediate Switch Group [ISG]) or after 12 weeks (Deferred Switch Group [DSG]). CNS toxicity data were collected by self-administered questionnaire. The primary endpoint was the proportion of participants with any grade 2 or higher CNS toxicity at week 12. Secondary endpoints included virologic response and effect on fasting lipids. RESULTS: Eighty-six participants (58% men, 56% black, median age 41 years, median 4 years on prior EFV regimen) were enrolled (43 ISG, 43 DSG) and included in the analyses. At week 12, 42% of ISG and 37% of DSG had at least 1 grade 2 or higher CNS toxicity [difference 4.7%, 95% CI (-16 to 25%); P = 0.33]. At 24 weeks postswitch, HIV-1 RNA less than 50 copies/ml was maintained in 95.3% of participants, and fasting lipids were significantly decreased (LDL-cholesterol -11.0, non-HDL-cholesterol -13.2, HDL-cholesterol -7.7, total cholesterol -20.9, and triglycerides -13.0 mg/dl). CONCLUSION: In participants who had CNS complaints while receiving EFV/FTC/TDF, improvement in CNS toxicities attributable to EFV was not significantly different after switching to DOR/3TC/TDF compared with remaining on EFV/FTC/TDF. Virologic efficacy was maintained and lipid profiles improved after switching to DOR/3TC/TDF.

Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial.

BACKGROUND: Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis. METHODS: In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV1 and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020. FINDINGS: Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV1 in the control group was 61·7% of predicted (95% CI 56·3-67·1) at baseline and 69·1% (62·3-75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV1 at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06-12·54; p=0·048; and 6·56%, 0·18-12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study. INTERPRETATION: CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV1, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted. FUNDING: The Bill & Melinda Gates Foundation and the South African Medical Research Council.

Cost-effectiveness of new MDR-TB regimens: study protocol for the TB-PRACTECAL economic evaluation substudy.

INTRODUCTION: Current treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial. METHODS AND ANALYSIS: Primary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04207112); Pre-results.

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial.

BACKGROUND: New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis. METHODS: In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1-14 then 200 mg three times per week (BloadPaZ) or oral bedaquiline 200 mg daily (B200PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B200PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0-56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log10 (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up. FINDINGS: Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to BloadPaZ, 60 to B200PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the BloadPaZ group, 56 in the B200PaZ group, and 59 in the HRZE group were included in the primary analysis. B200PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61-5·77]), followed by BloadPaZ (4·87% [4·31-5·47]) and HRZE group (4·04% [3·67-4·42]). The bactericidal activity in B200PaZ and BloadPaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the BloadPaZ (six [10%] of 59) and B200PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the BloadPaZ group, three [5%] in the B200PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the BloadPaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment. INTERPRETATION: B200PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B200PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes. FUNDING: TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

Raltegravir 1200 mg Once Daily vs 400 mg Twice Daily, With Emtricitabine and Tenofovir Disoproxil Fumarate, for Previously Untreated HIV-1 Infection: Week 96 Results From ONCEMRK, a Randomized, Double-Blind, Noninferiority Trial.

BACKGROUND: Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study. METHODS: ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1-infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA <40 copies per milliliter (Food and Drug Administration Snapshot approach); the noninferiority margin was 10 percentage points. RESULTS: Of the 797 participants who received study therapy (84.6% were men, 59.3% were white, and mean age was 35.9 years), 694 completed 96 weeks of treatment (87.6% QD; 84.4% BID), with few discontinuations because of lack of efficacy (1.1% for both groups) or adverse events (1.3% QD; 2.3% BID). At week 96, 81.5% (433/531) of QD recipients and 80.1% (213/266) of BID recipients achieved HIV-1 RNA <40 copies per milliliter (difference 1.4%, 95% confidence interval: -4.4 to 7.3). CD4 T-cell counts increased >260 cells/mm from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens. CONCLUSIONS: In HIV-1-infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.

Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial.

The impact of early ART initiation (versus deferring) on kidney function has not been studied. START was a randomised comparison of immediate versus deferred ART initiation among HIV-positive persons with CD4+ (cells/mm3) counts >500. Serum creatinine and urine dipstick protein were measured at Months 0, 1, 4, 8 and 12, and annually thereafter. The two arms were compared for changes in eGFR (mL/min/1.73 m2, calculated by CKD-EPI equation), over time using longitudinal mixed models. Of 4685 START participants, 4629 (2294 in immediate and 2335 deferred arm) were included. Median baseline CD4+ and eGFR were 651 and 111.5, respectively. ART was initiated in 2271 participants (99.0%) in the immediate and 1127 (48.3%) in the deferred arm, accounting for >94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 0.56 (95% CI 0.003-1.11) higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or bPI use (1.85, 95% CI 1.21-2.50) and in Black participants (30.1% overall) (3.90, 95% CI 2.84-4.97) versus non-Blacks (1.05, 95% CI 0.33-1.77) (P < 0.001 for interaction). Relative risk for proteinuria in the immediate versus deferred arm was 0.74 (95% CI 0.55-1.00) (P = 0.049). In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower proteinuria risk versus deferring ART (more pronounced in Black participants). Whether this early benefit translates into a lower risk of CKD requires further follow-up.