Median Baseline CD4 Research Articles

Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.

Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV.

The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial

Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.

Clinical Outcomes in Children With Human Immunodeficiency Virus Treated for Nonsevere Tuberculosis in the SHINE Trial.

Children with human immunodeficiency virus (HIV, CWH) are at high risk of tuberculosis (TB) and face poor outcomes, despite antiretroviral therapy (ART). We evaluated outcomes in CWH and children not living with HIV treated for nonsevere TB in the SHINE trial. SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, nonsevere TB who were randomized to receive 4 versus 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CWH. Of 1204 children enrolled, 127 (11%) were CWH, of similar age (median, 3.6 years; interquartile range, 1.2, 10.3 versus 3.5 years; 1.5, 6.9; P = .07) but more underweight (weight-for-age z score, -2.3; (3.3, -0.8 versus -1.0; -1.8, -0.2; P < .01) and anemic (hemoglobin, 9.5 g/dL; 8.7, 10.9 versus 11.5 g/dL; 10.4, 12.3; P < .01) compared with children without HIV. A total of 68 (54%) CWH were ART-naive; baseline median CD4 count was 719 cells/mm3 (241-1134), and CD4% was 16% (10-26). CWH were more likely to be hospitalized (adjusted odds ratio, 2.4; 1.3-4.6) and to die (adjusted hazard ratio [aHR], 2.6; 95% confidence interval [CI], 1.2 to 5.8). HIV status, age <3 years (aHR, 6.3; 1.5, 27.3), malnutrition (aHR, 6.2; 2.4, 15.9), and hemoglobin <7 g/dL (aHR, 3.8; 1.3,11.5) independently predicted mortality. Among children with available viral load (VL), 45% and 61% CWH had VL <1000 copies/mL at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 versus 6 months) on TB treatment outcomes by HIV status (P for interaction = 0.42). We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CWH treated for nonsevere TB. Irrespective of TB treatment duration, CWH had higher rates of mortality and hospitalization than their counterparts without HIV. Clinical Trials Registration. ISRCTN63579542.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States

BackgroundDespite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). Patients/MethodsWe retrospectively identified patients with HIV-cHL from the “Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)” database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. ResultsWe identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). ConclusionOur findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

IJCM_425A: Outcomes of Second Line Anti-Retroviral Therapy Among a cohort of people living with HIV/AIDS attending an ART Centre in Mangalore

Background: Anti-Retroviral therapy for HIV/AIDS has been effective, but the mortality rate remains to be high, resulting in the use of second line of ART treatment for better results. Objectives: 1) To estimate the number of deaths among PLHIV between the years 2011 and 2017. 2) To assess the clinical immunological and virological outcomes among these patients. 3) To find out the association of outcomes with the socio demographic characteristics. Methods: In this record-based study, medical records of PLHIV seeking treatment from an ART center associated with KMC, Attavar. between the years 2011 and 2017 were reviewed. The data was extracted using a data extraction sheet consisting of sections on demographic, clinical and treatment details of the patient. Results: The baseline median CD4 count before starting ARTs was found to be 253 (IQR 150-351). After starting second line ARTs it was found to be 461 (IQR 326-651). The correlation of CD4 count after initiation of second line ART with viral load among 34 patients measured was found to be -0.371 (P&lt;0.05). Conclusion: The study concludes that the outcomes of second line ARTs in the present study were found to be satisfactory. The average CD4 count after the initiation of ARTs was significantly high as compared to the CD4 count before the ARTs, implying that second line ARTs had a good, long-term and positive immunological outcome on PLHIV and attending a second-line ART clinic.

Outcomes of severely ill patients with AIDS treated with efavirenz or dolutegravir: a multicenter, observational study.

Currently, integrase inhibitors (INIs)-based ART regimens are the preferred initial therapy for AIDS patients. There is scarce information on the use of dolutegravir (DTG) among late-presenter people living with HIV (PLHIV). To compare the effect of DTG- or efavirenz (EFV)-based regimens on the outcomes of patients with advanced AIDS. We compared two cohorts of consecutive symptomatic AIDS patients (WHO stage 4, CD4 count<50 cells/mL) starting therapy with DTG-based (2018-2021, prospective cohort) or EFV-based regimens (2013-2016, retrospective cohort) from five Brazilian cities. The main endpoints were early (all-cause) mortality, viral suppression at 24 and 48 weeks, changes in CD4 count, and changes in initial therapy (for any reason). We included all eligible patients in a consecutive way (in both groups) until we reached 92 individuals per arm. The median baseline CD4 count (20 vs. 21 cells/mL) and the median HIV plasma viral load (5.5 copies/mL log10) were identical across the groups. Viral suppression rates were higher in the DTG group than in the EFV group at 24 (67.4% vs. 42.4%,) and 48 weeks (65.2% vs. 45.7%, p < 0.001 for both comparisons). More patients in the DTG group presented with CD4 > 200 cells/mL compared to the EFV group at 48 weeks (45% vs. 29%, p = 0.03). Treatment changes (ITT, M = F) were significantly more frequent in the EFV group (1% vs. 17%, p < 0.0001). The relative mortality rate was 25% lower in the DTG group, but without statistical significance. We detected a higher rate of virological suppression and greater treatment durability in patients with advanced AIDS treated with DTG than in those treated with EFV.

Chronic High-Level Parasitemia in HIV-Infected Individuals With or Without Visceral Leishmaniasis in an Endemic Area in Northwest Ethiopia: Potential Superspreaders?

People with human immunodeficiency virus (PWH) with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness. This study is nested within the Predicting Visceral Leishmaniasis in HIV-InfectedPatients (PreLeisH) prospective cohort study, following 490 PWH free of VL at enrollment for up to 24-37 months in northwest Ethiopia. Blood Leishmania polymerase chain reaction (PCR) was done systematically. This case series reports on 10 PWH with chronic VL (≥3 VL episodes during follow-up) for up to 37 months, and 3 individuals with asymptomatic Leishmania infection for up to 24 months. All 10 chronic VL cases were male, on antiretroviral treatment, with 0-11 relapses before enrollment. Median baseline CD4 count was 82 cells/µL. They displayed 3-6 VL treatment episodes over a period up to 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up (median cycle threshold value, 26 [interquartile range, 23-30]), including during periods between VL treatment. Additionally, we describe 3 PWH with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of up to 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL. These are the first data on chronic parasitemia in PWH from Leishmania donovani-endemic areas. PWH with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Hodgkin Lymphoma across the United States

Background: Despite a 5 to 20-fold higher risk of Hodgkin lymphoma (HL) in people with HIV (PWH) than the general population, PWH were excluded from clinical trials that led to the approval of anti-PD-1 agents (PD-1) in HL. PD-1 have overall response rates (ORR) of 65-70% in the general population and are used in all lines of HL therapy. Several prospective and retrospective studies have shown PD-1 are safe in PWH, but they remain underutilized in HIV-associated HL (HIV-HL) where data are limited. Methods: Patients (pts) with HIV-HL were identified from the retrospective, international database, “Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT)” consortium, that is maintained at the Dana-Farber Cancer Institute (DFCI) and approved by DFCI and local institutional review boards. Pts who received either nivolumab or pembrolizumab, alone or in combination with other agents were included. Records were reviewed for demographics, HL and HIV characteristics, and treatment data. Safety was evaluated by the occurrence of immune-related adverse events (irAEs) per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response to treatment was evaluated using descriptive statistics, and immune reconstitution was measured by changes in CD4 + T cell counts (CD4) from prior to end of PD-1 therapy via paired t-tests. ORR was defined as the proportion of pts with partial or complete response (PR/CR) per the 2014 Lugano classification for HL. Duration of response (DOR) was defined as the time from the date of the first CR or PR to the date of progressive disease (PD) or death. Progression-free survival (PFS) was defined as the time from PD-1 initiation to disease progression, death, or censored on the date of the last follow-up. Overall survival (OS) was defined as the time from PD-1 initiation to death or censored at the last follow-up. DOR, PFS, and OS were evaluated by Kaplan-Meier methodology. Results: We identified 23 pts with HIV-HL from 12 institutions in the United States: 20 cisgender men, 3 cisgender women; 10 Black,10 White, and 10 Hispanic; median age 48 years [interquartile range (IQR): 36-58]. At HL diagnosis, 19 (83%) pts had advanced stage disease, and in 20 pts where EBV status of the tumor was known, all were positive. Nine (39%) pts had primary refractory disease. The median number of prior systemic therapies was 2 (IQR: 1-3). One pt had PD-1 as 1 st-line therapy, 6 had PD-1 as 2 nd-line therapy, and 16 had PD-1 as ≥3 rd-line therapy. Fourteen (61%) pts received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as 1 st-line therapy. Two pts had prior autologous stem cell transplant (ASCT). At the time of PD-1 initiation, 22 pts (96%) had advanced stage disease, 17 (46%) had extranodal disease, and the median ECOG performance status was 1 (IQR: 0-2). Seventeen (74%) pts received PD-1 monotherapy, 5 (22%) received nivolumab + brentuximab vedotin, and 1 received nivolumab + ifosfamide, carboplatin, and etoposide. Four pts had uncontrolled HIV at the time of PD-1 initiation (HIV viral load range=10,000-2,000,000 copies/mL). All pts received antiretroviral therapy during treatment. Median baseline CD4 was 155 cells/µL (IQR: 66-297) and CD8 was 429 cells/µL (IQR: 158-716). Median CD4 and CD8 increased to 310 and 653 cells/µL at the end of PD-1 treatment (P=0.0084, P=0.32). The median number of PD-1 cycles was 6 (IQR: 4-21). Three (13%) pts had irAEs (all grade 3): hypothyroidism, autoimmune pancreatitis, and pneumonitis. None required PD-1 discontinuation. The ORR was 83% in the overall cohort. Sixteen pts (70%) had CR, 3 (13%) PR, and 4 (17%) PD as best response. Among the 19 pts with CR or PR, the median DOR was 19.7 months; 8 had PD after initial response and 11 had ongoing CR at data cut-off. Ten pts received consolidation with ASCT after PD-1, 6 of whom had received PD-1 at ≥3 rd line treatment. All pts who received ASCT had ongoing CR at data cut-off. Median PFS was 21.2 months in the overall cohort. Among pts with CD4 &amp;lt;200 and &amp;gt;200 cells/µL, PFS was not statistically different (17.3 vs 29 months; P=0.95). At data cut-off, 17 pts (74%) were alive and 6 (26%) had died due to HIV-HL. Median OS was 23.6 months in the overall cohort. Conclusion: In HIV-HL, PD-1 blockade was safe, had a high ORR and CR rate, and allowed for immune reconstitution in pts across a wide range of CD4 counts and HIV viral loads. These data add to the evidence that anti-PD-1 agents are effective in PWH and should be used in HIV-HL.

Impact of Head and Neck Cancer Treatment on CD4 T Cell Decline and Recovery in People with HIV

The effect of cancer treatment on immunologic decline and recovery in people with HIV (PWH) is not well-described. This study aims to describe the trajectory of treatment-related immunosuppression in PWH treated for HNC predominantly with radiotherapy with or without chemotherapy and/or surgery. We performed a retrospective chart review of 23 PWH diagnosed with nonmetastatic HNC at our institution between 2002 and 2020. Baseline and longitudinal changes in CD4 count from the time of cancer treatment initiation were investigated. Patients were followed for 3 years after treatment completion. Nonparametric Mann-Whitney tests were used to compare median baseline CD4 count, post-treatment nadir CD4 count within 1 year after start of treatment, and peak recovery CD4 count within 3 years. Nonparametric Kruskal-Wallis and Mann-Whitney tests were used to compare median baseline, nadir, and peak recovery CD4 counts stratified by treatment. The majority of patients were male (20 [87%]), were white (13 [57%]), had a smoking history (21 [91%]), and had stage III-IV disease (17 [74%]). The median age was 58 (IQR 55-62). Primary subsites included oropharynx (11 [48%]), larynx (5 [22%]), oral cavity (4 [17%]), hypopharynx (2 [9%]) and nasal sinus (1 [4%]). Treatment comprised of surgery alone (S, n = 2), radiotherapy +/- surgery (RT, n = 6), and chemoradiotherapy +/- surgery (CRT, n = 15), thereby involving radiotherapy in 21 (91%) patients. All patients were on antiretroviral therapy at the time of diagnosis, and baseline HIV load was <200 copies/ml in 20 (87%) patients. Median baseline CD4 count prior to diagnosis was 592 cells/mm3 (IQR 329 to 834). The median nadir CD4 count was 201 cells/mm3 (IQR 104-282) or 34% of baseline (IQR 23-52%) (p<0.0001 compared to baseline), occurring at a median of 3.8 months (IQR 2.5-6.0). The median CD4 counts at 6 months and 1-year post-treatment were 236 cells/mm3 (IQR 135-337) and 274 cells/mm3 (IQR 150-334), respectively, representing 39% (IQR 31-58%) and 50% (IQR 40-63%) of baseline, respectively. The median peak recovery CD4 count was 431 cells/mm3 (IQR 371-561), or 68% of baseline (IQR 59-102%) (p<0.0001 compared to nadir), occurring at a median of 31 months (IQR 22-34). Stratified by treatment, the median nadir CD4 count as a percentage of baseline was 53% (S), 41% (RT), and 34% (CRT) (p = 0.32) and the peak recovery CD4 count as a percentage of baseline was 82% (S), 88% (RT), and 63% (CRT) (p = 0.45). Among PWH with HNC, CD4 count nadirs to a 1/3 of baseline but gradually rebounds to 2/3 of baseline over the subsequent 2-3 years. While this data supports continuing to treat HNC in PWH with standard-of-care management, CD4 count should be monitored closely for several years following HNC radiotherapy.

Switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat in heavily antiretroviral-experienced, virologically suppressed HIV-infected adults receiving complex regimens.

To evaluate the efficacy and safety of the two-pill regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat as a switching strategy in heavily treatment-experienced people living with HIV (PLWH). Multicentre, prospective, single-arm pilot clinical trial. Participants were virologically suppressed adults receiving a stable antiretroviral regimen of at least three pills from at least three drug families due to previous virological failures and/or toxicities with no documented resistance to integrase strand transfer inhibitors or darunavir (≥15 points, Stanford). Clinical and laboratory assessments were performed at 0, 4, 12, 24, 36 and 48 weeks. HIV-1 proviral DNA was amplified and sequenced by Illumina at baseline. Plasma bictegravir concentrations were determined in 22 patients using UHPLC-MS/MS. The primary study endpoint was viral load (VL)< 50 copies/mL at Week 48 (ITT). We enrolled 63 participants (92% men) with median baseline CD4 count of 515 cells/mm3 (IQR: 334.5-734.5), 24 years on ART (IQR: 15.9-27.8). The median number of pills was 4 (range: 3-10). At baseline, proviral DNA was amplified in 39 participants: 33/39 had resistance mutations. Three participants discontinued owing to toxicity. At 48 weeks, 95% had VL < 50 copies/mL by ITT and 100% by PP analysis. A modest increase was observed in the bictegravir plasma concentration, and a significant decrease in estimated glomerular filtration rate was observed only at Week 4, probably related to interaction with renal transporters. Our data suggest that BIC/FTC/TAF + darunavir/cobicistat is an effective, well-tolerated regimen that may improve convenience and, potentially, long-term success in stable heavily pre-treated PLWH.

Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial

The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588. Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. Wellcome Trust.

Effects of Gender and Baseline CD4 Count on Post-Treatment CD4 Count Recovery and Outcomes in Patients with Advanced HIV Disease: A Retrospective Cohort Study.

Presentation to care with advanced HIV disease (AHD) is a significant problem in sub-Saharan Africa. We evaluated factors associated with immune recovery among individuals presenting to care with AHD in Zimbabwe. We conducted a retrospective evaluation of outcomes among adult (>18 years old) individuals with AHD (CD4 count ≤200 cells/mm3) receiving care at 18 outpatient primary care clinics in Harare, Zimbabwe. Baseline and 12-month CD4 count data were extracted from medical records. CD4 count recovery (defined as CD4 count >200 cells/mm3) after 12 months on non-nucleotide reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) regimen was determined and factors associated with CD4 count recovery were established using logistic regression. All statistical analysis was performed on SPSS v23. A total of 1,338 participant records were included in the analysis. The median interquartile range (IQR) age was 37 (30-43) years and 52% were females. The baseline median (IQR) CD4 count was 50 (28-75) cells/mm3 and was significantly lower among patients with history of cryptococcal meningitis compared to those without [25 (10-52) vs. 52 (32-77), respectively; p = .0009]. The median (IQR) CD4 count at 12 months after ART initiation increased from 50 (28-75) at baseline to 180 (92-290) cells/mm3. Immune recovery with a CD4 count >200 cells/mm3 was observed in 181/417 (43%). Male gender and low baseline CD4 count were strong predictors of poor immunological recovery on ART. Immunological recovery following ART initiation was 43% among individuals with AHD. Male patients are most vulnerable to persistent immunological failure. Clinical Trial Registration number: NCT02434172.

(5R)-5-hydroxytriptolide for HIV immunological non-responders receiving ART: a randomized, double-blinded, placebo-controlled phase II study

Therapeutic approaches to HIV-suppressed immunological non-responders (INRs) remain unsettled. We previously reported efficacy of Chinese herbal Tripterygium wilfordii Hook F in INRs. Its derivative (5R)-5-hydroxytriptolide (LLDT-8) on CD4 T cell recovery was assessed. The phase II, double-blind, randomized, placebo-controlled trial was conducted in adults patients with long-term suppressed HIV infection and suboptimal CD4 recovery, at nine hospitals in China. The patients were 1:1:1 assigned to receive oral LLDT-8 0.5mg or 1mg daily, or placebo combined with antiretroviral therapy for 48 weeks. All study staff and participants were masked. The primary endpoints include change of CD4 T cell counts and inflammatory markers at week 48. This study is registered on ClinicalTrials.gov (NCT04084444) and Chinese Clinical Trial Register (CTR20191397). A total of 149 patients were enrolled from Aug 30, 2019 and randomly allocated to receiving LLDT-8 0.5mg daily (LT8, n=51), 1mg daily (HT8, n=46), or placebo (PL, n=52). The median baseline CD4 count was 248cells/mm3, comparable among three groups. LLDT-8 was well-tolerated in all participants. At 48 weeks, change of CD4 counts was 49cells/mm3 in LT8 group (95% confidence interval [CI]: 30, 68), 63cells/mm3 in HT8 group (95% CI: 41, 85), compared to 32cells/mm3 in placebo group (95% CI: 13, 51). LLDT-8 1mg daily significantly increased CD4 count compared to placebo (p=0.036), especially in participants over 45 years. The mean change of serum interferon-γ-induced protein 10 was-72.1mg/L (95% CI -97.7,-46.5) in HT8 group at 48 weeks, markedly decreased compared to-22.8mg/L (95% CI -47.1, 1.5, p=0.007) in placebo group. Treatment-emergent adverse events (TEAEs) were reported in 41 of 46 (89.1%) participants in HT8 group, 43 of 51 (84.3%) in LT8, and 42 of 52 (80.7%) in PL group. No drug-related SAEs were reported. LLDT-8 enhanced CD4 recovery and alleviated inflammation in long-term suppressed INRs, providing them a potential therapeutic option. Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, Shanghai Pharmaceuticals Holding Co., Ltd., and the National key technologies R&D program for the 13th five-year plan.

Predictors of delayed Anti-Retroviral Therapy initiation among adults referred for HIV treatment in Uganda: a cross-sectional study

BackgroundUganda’s current guidelines recommend immediate initiation of Anti-Retroviral Therapy (ART) for persons living with HIV in order to reduce HIV/AIDS related morbidity and mortality. However, not all eligible PLHIV initiate ART within the recommended time following HIV diagnosis. We assessed the prevalence and factors associated with delayed ART initiation among PLHIV referred for ART initiation, five years since rolling out the test and treat guidelines.MethodsIn this cross-sectional study, we enrolled adult patients referred to Mulago Immune Suppressive Syndrome (Mulago ISS) clinic for ART initiation from January 2017 to May 2021. We collected data on socio-demographics, HIV diagnosis and referral circumstances, and time to ART initiation using a questionnaire. The outcome of interest was proportion of patients that delayed ART, defined as spending more than 30 days from HIV diagnosis to ART initiation. We performed multivariable logistic regression and identified significant factors.ResultsA total of 312 patients were enrolled of which 62.2% were female. The median (inter-quartile range [IQR]) age and baseline CD4 count of the patients were 35 (28–42) years and 315 (118.8–580.5) cells/μL respectively. Forty-eight (15.4%) patients delayed ART initiation and had a median (IQR) time to ART of 92 (49.0–273.5) days. The factors associated with delayed ART initiation were; 1) having had the HIV diagnosis made from a private health facility versus public, (adjusted odds ratio [aOR] = 2.4 (95% confidence interval [CI] 1.1–5.5); 2) initial denial of positive HIV test results, aOR = 5.4 (95% CI: 2.0–15.0); and, 3) having not received a follow up phone call from the place of HIV diagnosis, aOR = 2.8 (95% CI: 1.2–6.8).ConclusionThere was significant delay of ART initiation among referred PLHIV within 5 years after the rollout of test and treat guidelines in Uganda. Health system challenges in the continuity of HIV care services negatively affects timely ART initiation among referred PLHIV in Uganda.

Cutaneous Adverse Drug Reaction Among HIV-Infected Patients Starting Antituberculosis Treatment

Introduction. Treatment of tuberculosis (TB) in HIV patients is complicated due to numerous comorbidities and possible adverse effects. One of which is cutaneous adverse drug reaction (CADR). This adverse event is often difficult to manage because of multiple medications the patients get. The objective of this study was to know the prevalence and risk factors of CADR among HIV-infected patients starting anti-TB treatment. Methods. This retrospective study reviewed data from medical records of new patients at Working Group on AIDS outpatient clinic at Cipto Mangunkusumo Hospital, Indonesia in January 2008-December 2010 that had started anti-TB treatment. Risk factors of CADR among HIV patients treated with antituberculosis drugs evaluated were sex, age, route of HIV transmission, TB manifestation, and baseline CD4+ cell count. Numeric data were analyzed using independent T-test if normally distributed, otherwise Mann Whitney U test were used. Chi-square or Fisher’s exact test were used for categorical data. p-value was considered significant if below 0.05. Results. Of 454 HIV-infected patients that started anti-TB treatment, median age was 30 years. Most patients were male and intravenous drug users/IDU. Median baseline CD4+ cell count was 61 cells/ μL. There were 10.6% subjects that developed CADR. Most common manifestations were maculopapular rashes (66.7%), followed by erythema multiforme (14.6%), and Stevens Johnson Syndrome (8.3%). Anti-TB drugs were stopped and then re-challenge was conducted in 54.2% patients. Anti-TB drugs were continued and only the suspected drug was stopped in 29.2% patients. The offending drugs were cotrimoxazole (41.7%), rifampicine (41.7%), ethambutol (16.7%), pyrazinamide (14.6%), pyrimethamine (12.5%), isoniazide (10.4%), streptomycin (8.3%), efavirenz (8.3%), fixed dose combination of antituberculosis drugs (8.3%), and nevirapine (4.2%). The proportion of CADR was higher in woman than man (12% vs. 10.3%, p=0.66), non-IDU than IDU (13% vs. 9.2%, p=0.20), without extrapulmonary TB than extrapulmonary TB (11.1% vs. 9.4%, p=0.29), but the associations weren’t statistically significant. Median age was higher (31 vs. 30 years, p=0.32) and CD4 cell count (59.5 vs. 62 sel/μL, p=0.96) was lower in CADR group than non CADR group. Conclusion. The prevalence of CADR among HIV-infected patients starting anti-TB treatment was 10.6%. Sex, age, route of HIV transmission, TB manifestation, and baseline CD4+ did not have statistically significant association with CADR.

Immune Profiles Associated with Clinical Outcomes of Cervical Cancer Patients with and without HIV Infection in Botswana

<h3>Purpose/Objective(s)</h3> Cervical cancer (CC) remains a significant disease burden for women in low- and middle-income countries (LMICs) where HIV infections remain highly prevalent, even in settings with widely available antiretroviral therapy (ART). This study investigates immune profiles of CC patients with and without HIV infection to identify immune correlates of survival and treatment response. <h3>Materials/Methods</h3> Women with CC undergoing chemoradiation (CRT) with curative intent were enrolled in Gaborone Private Hospital, Botswana under the "Ipabablele" protocol (Grant #1U54 CA190158-01). Patient demographics, clinical characteristics, treatment characteristics, and blood samples were collected after informed consent was obtained. Multiparameter flow cytometry (FC) was performed on longitudinal peripheral blood mononuclear cell (PBMC) samples. Frequency of T cell subtypes and cytokine markers were analyzed at distinct points during CRT including prior to initiation (IT), at the completion (EOT), and three months after (M3) CRT. Logistic regression analysis identified immune markers that differed by HIV status and correlated with survival or treatment response (TS), defined as squamous cell carcinoma antigen below 2.2 ng/mL. <h3>Results</h3> This study analyzed samples from 131 women (HIV+ n=89, HIV- n=42). On laboratory blood tests done at the time of enrollment, the HIV+ patients had a median baseline CD4 count of 454 cells/μL (n=88, IQR=275-590 cells/μL). On FC analysis of PBMCs, HIV+ women had significantly lower CD4 frequency at IT than HIV- women (52.5% vs 72.0%, p<0.001). Between IT and M3, there were no significant changes in CD4 frequency (52.5% to 50.9%) or CD8 frequency (39.9% to 41.4%) in HIV+ women. However, HIV- women demonstrated a significant decrease in CD4 frequency (72% to 60.55%, p<0.001) and increase in CD8 frequency (20.9% to 31.5%, p<0.001) by M3. Both cohorts underwent similar T cell activation during CRT marked by loss of CCR7 and increases in CD57 and IFN<b>γ</b> expression. Significant (p<0.05) findings on logistic regression analyses demonstrated that survival in HIV+ women was associated with the presence of CD8 subsets lacking CD57 and CD28 at IT and EOT. In HIV- women, poor survival was associated with IL-2 and IFN<b>γ</b> expression on CD4 and CD8 cells at IT and positive treatment response correlated with IL-2 expressing CD4 T cells and proinflammatory CD8 T cells at M3. <h3>Conclusion</h3> This study demonstrates that CRT induces peripheral T cell differentiation and activation as well as a distinctive cytokine profile in all CC patients. However, a subset of these changes in the immune repertoire differs by HIV status. Patients with HIV also do not experience significant reduction in CD4 frequency while on treatment as compared to uninfected women. These results suggest that in women with well-managed disease, HIV infection may differentially impact immune response to CRT and in turn may reflect broader clinical outcomes including treatment response and survival.

Long-term outcome of lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients

BackgroundThe use of DTG-containing two-drug regimens is one of the most promising solutions to the need to ease the management of HIV treatment without harming its efficacy and safety. We report long- term results in patients switched, while virologically suppressed, to the combination of dolutegravir (DTG) plus lamivudine (3TC).MethodsThis is a prospective, clinical, uncontrolled cohort enrolling ART-experienced people living with HIV (PLWH) with HIV-RNA < 50 copies/ml for 6 months or longer, negative hepatitis B virus surface antigen, and without known M184V/I mutations. Kaplan-Meiers curves are used to describe persistency of virological suppression on therapy and a Cox regression model to evaluate baseline characteristics and the risk of stopping therapy.Results218 individuals switched their regimen since 2015. The mean estimated follow-up was of 64.3 months (95% CI 61.3–67.3) for approximately 1000 patient/years. After 5 years of follow-up, 77.1% were still on the DTG-3TC combination. No virologic failure was detected throughout the whole study period, and only 15 subjects presented single isolated viral blips above 50 copies/ml. Most patients stopped therapy because of reasons unrelated to study drugs (lost to follow-up; patients’ decision; moved to other Centers), but due to the unselected nature of the casuistry; 11 subjects died in the 5 years of follow-up mostly because of pre-existing co-morbidities (6 neoplastic diseases and 2 end-stage liver disease). The median baseline CD4 count was 669 cells/mcl (IQR 483–927). After 5 years it raised to 899 cells/mcl (IQR 646–1160) (P < 0.001) without a significant change of CD8 counts that lowered from 767 cells/mcl (IQR 532–1034) to 683 cells/mcl (IQR 538–988). Consequently, the CD4/CD8 ratio varied from 0.93 (IQR 0.60–1.30) to 1.15 (IQR 0.77–1.45) (P < 0.0001). A non-significant (P = 0.320) increment of mean creatinine, 0.06 mg/dl in magnitude, was observed over the whole follow-up.ConclusionThese long-term results over 5 years reinforce the durability and good tolerability of DTG-3TC. Our results continue to support the recommended switch use of this 2DR as a well-accepted treatment option for ART-experienced PLWH.

Performance of Creatinine- and Cystatin C-Based Equations for Glomerular Filtration Rate Estimation in HIV-1-Infected Individuals Receiving Dolutegravir + Tenofovir Disoproxil Fumarate + Lamivudine as Initial Antiretroviral Therapy: A Retrospective Observational Study.

Dolutegravir (DTG) may inhibit organic cation transporter-2 in renal tubules and elevate serum creatinine levels without true renal function deterioration. There are scarce data on the glomerular filtration rate (GFR) equations in Chinese HIV patients with DTG/TDF/3 TC. This retrospective study was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values among Chinese adult HIV patients with initial highly active antiretroviral therapy (HAART) with DTG/TDF/3 TC for 48 weeks. Retrospective analysis of Chinese adult HIV patients who received initial HAART with DTG/TDF/3 TC between January 2016 and May 2021. We compared the changes in creatinine-based and cystatin C-based estimated GFR before and 48 weeks after HAART to determine the optimal tool for renal function estimation. Ninety-five patients [91.58% men; median age, 34 years (interquartile range, 29-44 years)] were enrolled. The median baseline CD4+ cell count was 185 cells/µL [interquartile range, 53-303 cells/µL] and the median baseline viral load was 148,000 copies/mL [interquartile range, 26,800-596,000 copies/mL]. The estimated GFR at 4, 12, and 24 weeks was significantly different than at baseline (P < 0.05) using all 4 equations. Only the GFR estimated using the CKD-EPIcreat and CKD-EPIcys equations was significantly different at 48 weeks of treatment (P < 0.05). The modification of diet in renal disease-based decline of GFR incidence at 4, 12, 24, and 48 weeks of treatment (21.5%, 24.21%, 33.68% and 38.95%, respectively) was higher than that calculated using the other 3 GFR equations. The modification of diet in renal disease equation may not be optimal for Chinese HIV-1-infected adults receiving DTG + TDF + 3 TC as the initial antiviral therapy. Clinicians must carefully choose the GFR equation for patients with HIV/hepatitis B virus coinfection.

Use of Tenofovir Alafenamide/Emtricitabine/Elvitegravir-Cobicistat in HIV-Naive Patients with Advanced Disease: GENIS Study.

Objective: The primary endpoint of the study was to determine the proportion of patients with HIV RNA < 50 copies/mL at 48 weeks. Design: Phase IV, multicentric, open-label, single-arm clinical trial of participants recruited in 2018–2019 to evaluate the efficacy and safety of tenofovir alafenamide/emtricitabine/elvitegravir-cobicistat (TAF/FTC/EVG-c) as first-line treatment in HIV-1 infected naïve participants with advanced disease. Methods: Adverse events were graded according to the Division of AIDS scale version 2.0. Quantitative variables were recorded as median and interquartile range, and qualitative variables as absolute number and percentage. T-Student or Wilcoxon tests were used to analyze intragroup differences of the continuous variables. Results: Fifty participants were recruited with a baseline median CD4 lymphocyte count of 116 cells/µL and a viral load of 218,938 copies/mL. The proportion of patients with viral load <50 copies/mL at week 48 was 94% in the per-protocol analysis, with a median time of 1.9 months to achieve it. Three adverse events attributed to the study drug caused trial discontinuation. Conclusions: the use of TAF/FTC/EVG-c in patients with advanced HIV disease in our study demonstrated efficacy comparable to data from pivotal clinical trials with a good safety profile.