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WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.Janssen.

Background Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. Methods This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. Discussion This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. Trial registration ClinicalTrials.gov NCT04385719. Registered 13 May 2020.

Background In sub-Saharan Africa, artemisinin-containing therapies for malaria treatment are regularly co-administered with ART. Currently, dolutegravir-based regimens are recommended as first-line therapy for HIV across most of Africa. Objectives To investigate the population pharmacokinetics of dolutegravir during co-administration with artemether/lumefantrine or artesunate/amodiaquine, two commonly used antimalarial therapies. Methods We developed a population pharmacokinetic model of dolutegravir with data from 26 healthy volunteers in two Phase 2 studies with a total of 403 dolutegravir plasma concentrations at steady state. Volunteers received 50 mg of dolutegravir once daily alone or in combination with standard treatment doses of artemether/lumefantrine (80/480 mg) or artesunate/amodiaquine (200/540 mg). Results A two-compartment model with first-order elimination and transit compartment absorption best described the concentration–time data of dolutegravir. Typical population estimates for clearance, absorption rate constant, central volume, peripheral volume and mean absorption transit time were 0.713 L/h, 1.68 h−1, 13.2 L, 5.73 L and 1.18 h, respectively. Co-administration of artemether/lumefantrine or artesunate/amodiaquine increased dolutegravir clearance by 10.6% (95% CI 4.09%–34.5%) and 26.4% (95% CI 14.3%–51.4%), respectively. Simulations showed that simulated trough concentrations of dolutegravir alone or in combination with artemether/lumefantrine or artesunate/amodiaquine are maintained above the dolutegravir protein-adjusted IC90 of 0.064 mg/L for more than 99% of the individuals. Conclusions Dolutegravir dose adjustments are not necessary for patients who are taking standard 3 day treatment doses of artemether/lumefantrine or artesunate/amodiaquine.

Aim: To evaluate the genetic factors influencing tuberculosis (TB) clinical outcomes in HIV-infected Black African patients. Materials & methods: We systematically searched and identified eligible publications from >550 databases indexed through February 2021. Results: Eighteen studies were included in the qualitative synthesis. Only two cohorts from one study were included in quantitative synthesis of which the low expression MIF−794 CATT5,6 ( 5/5 + 5/6 + 6/6) genotypes were not associated with TB infectivity in HIV-infected patients (OR: 1.31, 95% CI: 0.46–3.79). Other TB clinical outcomes observed in HIV/TB co-infected patients included: drug-induced liver injury, peripheral neuropathy, mortality, lung function and TB cure. Conclusion: This review finds inconclusive evidence that genetic factors are associated with TB clinical outcomes among HIV-infected patients in sub-Saharan Africa.

The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine.In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points).We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers)., Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir., Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.)

BACKGROUND: Early diagnosis of HIV associated lymphoma is challenging because the definitive diagnostic procedure of biopsy, requires skills and equipment that are not readily available. As a consequence, diagnosis may be delayed increasing the risk of mortality. We set out to determine the frequency and risk factors associated with the misdiagnosis of HIV associated lymphoma as tuberculosis (TB) among patients attending the Uganda Cancer Institute (UCI). METHODS: A retrospective cohort study design was used among HIV patients with associated lymphoma patients attending the UCI, Kampala, Uganda between February and March 2015. Eligible patient charts were reviewed for information on TB treatment, socio-demographics, laboratory parameters (Hemoglobin, CD4cells count and lactate dehydrogenase) and clinical presentation using a semi structured data extraction form. RESULTS: A total of 183 charts were reviewed; 106/183 were males (57.9%), the median age was 35 (IQR, 28-45). Fifty six (30.6%) patients had a possible misdiagnosis as TB and their median time on TB treatment was 3.5 (1-5.3) months. In multivariate analysis the presence of chest pain had an odd ratio (OR) of 4.4 (95% CI 1.89-10.58, p

Objectives To investigate the effect of food on the steady-state pharmacokinetics of rilpivirine when administered as a fixed-dose combination tablet containing tenofovir disoproxil fumarate, emtricitabine plus rilpivirine (TDF/FTC/RPV) in HIV-1-infected Ugandan patients. Methods This was an open-label, three-period, longitudinal pharmacokinetic study with patients serving as their own controls. Fifteen consenting and virologically suppressed HIV-1-infected adults were switched from an efavirenz-based regimen to TDF/FTC/RPV for 56 days. Enrolled patients underwent 24 h blood sampling with TDF/FTC/RPV dosing in the fasted state (day 42), with a low-fat meal (11 g of fat/353 kcal, day 49) and with a moderate-fat meal (19 g of fat/589 kcal, day 56; reference). A viral load assessment was performed on day 56. Results Rilpivirine AUC0–24 was significantly decreased by 16% (geometric mean ratio, 90% CI: 0.84, 0.73–0.96) during administration in the fasted state when compared with AUC0–24 during administration with a moderate-fat meal. Similarly, rilpivirine C24 was significantly decreased by 21% (0.79, 0.65–0.97) in the fasted state compared with a moderate-fat meal. Pharmacokinetic parameters were unchanged during administration with a low-fat meal, except for C24, which was significantly increased by 15% (1.15, 1.01–1.31) when compared with the moderate-fat meal. Rilpivirine Cmax was similar under the three meal conditions. Virological suppression was unchanged at the end of the study. Conclusions A food effect was observed for steady-state pharmacokinetic parameters of rilpivirine (AUC0–24 and C24) when TDF/FTC/RPV was administered in the fasted state compared with the moderate-fat meal. The TDF/FTC/RPV formulation can be administered with either a low-fat or moderate-fat meal.