Efficacy and safety of switching to bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed Asian adults living with HIV: A pooled analysis from three international phase III randomized trials.

OBJECTIVES: Data on switching to bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) in virologically suppressed Asian people living with HIV are limited. We performed a pooled analysis of virologically suppressed Asian participants from three international phase III trials to evaluate the efficacy and safety of switching to B/F/TAF. METHODS: Virologically suppressed people living with HIV were randomized to switch to B/F/TAF or to stay on baseline regimens. The primary endpoint was the proportion of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48. We analysed the incidence of adverse events (AEs), laboratory abnormalities, and changes in relevant tolerability parameters through 48 weeks. RESULTS: Overall, 136 Asian participants were included. The proportions of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48 were low in both arms (0% for B/F/TAF vs 1.4% for those who stayed on baseline regimens). Those who switched to B/F/TAF had virological suppression rates similar to those who stayed on baseline regimens (100% vs 95.9%, p = 0.2485), with no treatment-emergent resistance. Drug-related AEs occurred in three participants in each arm; none were serious. No participants discontinued the study drug because of AEs, and no deaths were observed. No significant differences were observed between the arms in the median changes in estimated glomerular filtration rate, body weight, and most lipid parameters. Switching from tenofovir disoproxil fumarate-containing regimens to B/F/TAF resulted in a significant decrease in tubular proteinuria compared with those who stayed on baseline regimens (p < 0.01). CONCLUSIONS: Virologically suppressed Asian people living with HIV who switched to B/F/TAF maintained 100% virological suppression at week 48, with no treatment-emergent drug resistance and safety profiles comparable to those seen in people who stayed on baseline regimens. CLINICAL TRIAL NUMBER: ClinicalTrials.gov (NCT02603120, NCT02652624, and NCT02603107).

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Recommendations from Thai stakeholders about protecting HIV remission ('cure') trial participants: report from a participatory workshop.

BACKGROUND: The social/behavioral HIV Decision-Making Study (DMS) assesses informed consent and trial experiences of individuals in HIV remission trials in Thailand. We convened a 1-d multi-stakeholder participatory workshop in Bangkok. We provide a meeting summary and reactions from DMS investigators. METHODS: Workshop members viewed de-identified interview excerpts from DMS participants. They deliberated on the findings and made recommendations regarding informed choice for remission trials. Notes and recordings were used to create a summary report, which was reviewed by members and refined. RESULTS: Workshop members' recommendations included HIV education and psychosocial support to establish the basis for informed choice, key trial information to be provided in everyday language, supportive decision-making processes and psychosocial care during and after the trial. Concerns included participant willingness to restart antiretrovirals after trial-mandated treatment interruption, unintended influence of the research team on decision-making and seemingly altruistic motivations for trial participation that may signal attempts to atone for stigmatized behavior. CONCLUSIONS: The workshop highlighted community perspectives and resulted in recommendations for supporting informed choice and psychosocial and physical health. These are the first such recommendations arising from a deliberative process. Although some elements are rooted in the Thai context, most are applicable across remission trials.

Successful drug desensitization in patients with delayed-type allergic reactions to anti-tuberculosis drugs.

OBJECTIVE: To evaluate the outcomes of anti-tuberculosis drug desensitization. METHODS: This was a retrospective study. Inclusion criteria were as follows: age >18years, documented tuberculosis infection, a previous cutaneous allergic reaction to anti-tuberculosis drugs, and having undergone drug desensitization between January 2003 and March 2014. The definition of allergic reaction to anti-tuberculosis drugs included (1) a temporal relationship between drug use and the allergic reaction; (2) improvement in the allergic reaction after drug withdrawal; (3) recurrence of the allergic reaction after reintroduction of only the offending drug; and (4) absence of other causes. RESULTS: A total of 19 desensitization procedures were performed. The drugs used for these procedures were isoniazid (n=7), rifampicin (n=6), or ethambutol (n=6). Of note, severe allergic reactions (Stevens-Johnson syndrome (n=4), erythema multiforme (n=3), and drug rash with eosinophilia and systemic syndrome (n=1)) were included. All patients underwent resolution of the previous allergic reactions before desensitization. The median duration of desensitization was 18 days. The success rate was 78.9%. The allergic reactions following failed desensitization were not severe; most were maculopapular rashes. CONCLUSIONS: The desensitization protocol for anti-tuberculosis drugs was associated with a high success rate, and the individuals who failed desensitization experienced mild allergic reactions.

Ritonavir-boosted lopinavir as maintenance monotherapy in HIV-infected patients who achieved viral suppression during a second-line protease inhibitor-based regimen: a pilot randomized trial (BIDI-MONO).

Eligibility criteria were (I) having previously failed first-line nonnucleoside reverse transcriptase inhibitor-based regimens and (2) having achieved virologic suppression >6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (I) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs.

Ritonavir-boosted lopinavir as maintenance monotherapy in HIV-infected patients who achieved viral suppression during a second-line protease inhibitor-based regimen: a pilot randomized trial (BIDI-MONO).

Eligibility criteria were (I) having previously failed first-line nonnucleoside reverse transcriptase inhibitor-based regimens and (2) having achieved virologic suppression >6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (I) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs.

Virological failure of staggered and simultaneous treatment interruption in HIV patients who began Efavirenz-based regimens after allergic reactions to nevirapine.

OBJECTIVE: The objective of this work was to study the virological outcomes associated with two different types of treatment interruption strategies in patients with allergic reactions to nevirapine (NVP). We compared the virological outcomes of (1) HIV-1-infected patients who discontinued an initial NVP-based regimen because of cutaneous allergic reactions to NVP; different types of interruption strategies were used, and second-line regimen was based on efavirenz (EFV); and (2) HIV-1-infected patients who began an EFV-based regimen as a first-line therapy (controls). METHODS: This retrospective cohort included patients who began an EFV-based regimen, between January 2002 and December 2008, as either an initial regimen or as a subsequent regimen after resolving a cutaneous allergic reaction against an initial NVP-based regimen. The study ended in March 2010. The primary outcome was virological failure, which was defined as either (a) two consecutive plasma HIV-1 RNA levels >400 copies/mL or (b) a plasma HIV-1 RNA level >1,000 copies/mL plus any genotypic resistance mutation. RESULTS: A total of 559 patients were stratified into three groups: (a) Simultaneous Interruption, in which the subjects simultaneously discontinued all the drugs in an NVP-based regimen following an allergic reaction (n=161); (b) Staggered Interruption, in which the subjects discontinued NVP treatment while continuing nucleoside reverse transcriptase inhibitor (NRTI) backbone therapy for a median of 7 days (n=82); and (c) Control, in which the subjects were naïve to antiretroviral therapy (n=316). The overall median follow-up time was 43 months. Incidence of virological failure in Simultaneous Interruption was 12.9 cases per 1,000 person-years, which trended toward being higher than the incidences in Staggered Interruption (5.4) and Control (6.6). However, differences were not statistically significant. CONCLUSIONS: Among the patients who had an acute allergic reaction to first-line NVP-based therapy and later began an EFV-based regimen, virological outcomes resulting from a staggered interruption of treatment (with a continuation of NRTI backbone therapy for 7 days after discontinuing NVP) did not differ from those of the patients who began an EFV-based regimen as their initial therapy (Control). However, the virological failure of Simultaneous Interruption was possibly higher than those of Control and Staggered Interruption.

Effectiveness of boosted protease inhibitor-based regimens in HIV type 1-infected patients who experienced virological failure with NNRTI-based antiretroviral therapy in a resource-limited setting.

A number of patients have experienced treatment failure while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART), particularly in resource-limited countries. The need remains for clinical data on protease inhibitor (PI)-based regimens in these patients. A retrospective cohort study was conducted among HIV-1-infected patients who had failed NNRTI-based regimens, were naive to protease inhibitors (PIs), and subsequently initiated a salvage PI-based regimen between January 2004 and December 2006. The study period ended on 30 December 2007. One hundred and forty patients received a single-boosted PI +/- optimized background regimen (OBR) and 64 received double-boosted PIs. The median (IQR) duration of follow-up was 19 (13-29) months. The overall virological failure rate at 24 months was 15.2%. No statistically significant difference was detected between the two regimen groups (single-boosted PI +/- OBR 16.4% vs. double-boosted PIs 12.5%, log rank p = 0.818). At the end of the study, the median (IQR) change in CD4 cell counts for patients in the double-boosted PI group was higher than for patients in the single-boosted PI +/- OBR group [149 (53-322) vs. 105 (23-199), respectively, p = 0.012]. Patients receiving double-boosted PI regimens displayed a higher frequency of hypertriglyceridemia than those patients who received a single boosted PI +/- OBR (31% vs. 11%, respectively, p = 0.001). Boosted PI-based regimens showed acceptable virological outcomes among patients who had failed NNRTI-based ART. In the subgroup analysis, patients who received double-boosted PIs demonstrated a superior immunological response but not better virological outcomes compared to the single-boosted PI +/- OBR group.

Three suitable antigens for delayed-type hypersensitivity skin testing in a tropical country like Thailand.

Delayed type hypersensitivity (DTH) skin test is a standard tool to assess in vivo cell-mediated immunity. Mantoux method using 4-5 common recalled antigens is recommended. However, not all antigens are widely available and appropriate antigens for tropical countries are not known. The objective of this study is to investigate what and how many antigens should be included in the DTH testing panel that suitable for Thailand and may be for this region. The DTH skin tests were done by Mantoux method in a double blinded fashion. Average induration size of > or = 5 mm defined as a positive test. Antigens included purified protein derivative (PPD), Candida albicans, tetanus toxoid (TT), Trichophyton mentagrophytes and hepatitis B vaccine (HBV). The negative control was normal saline. Of 95 healthy subjects, all showed DTH positive to > or = 1 antigen. The positivity to C. albicans, tetanus toxoid, PPD, T. mentagrophytes, and HBV was 92.6%, 83.2%, 82.1%, 50.5%, and 5.3%, respectively. When three antigens: PPD, TT and C. albicans were analyzed, 100% of subjects showed a positive response to > or = 1 antigen and 96.8% showed a positive response to > or = 2 antigens. When only PPD and TT were analyzed, 100% of subjects showed > or = 1 antigen positive and 68.4% showed both antigens positive. C. albicans antigen at 1:100 was associated with a high incidence of fever (2/20) and large local reaction (7/20), 1:500 was found to be the optimal concentration. PPD, TT and C. albicans are suitable to be included in a DTH skin testing in a tropical country like Thailand. However, in a setting where C. albicans extract is not available, testing with only two antigens of PPD and tetanus toxoid may be an alternative, but with a lower sensitivity.