Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Characteristics of Human Immunodeficiency Virus (HIV) Seroconversions in a Large Prospective Implementation Cohort Study of Oral HIV Preexposure Prophylaxis in Men Who Have Sex with Men (EPIC-NSW).

BACKGROUND: Most human immunodeficiency virus (HIV) seroconversions in people who have initiated preexposure prophylaxis (PrEP) occur in the context of insufficient adherence. We describe participants who seroconverted after being dispensed PrEP in a large PrEP implementation study in Australia. METHODS: Expanded PrEP Implementation in Communities in New South Wales was an implementation study of daily oral PrEP in individuals aged ≥18 years at high risk for acquiring HIV. HIV seroconversions were defined as a positive HIV test by either antigen, antibody, or detectable HIV viral load after enrollment. Insufficient adherence, measured by dispensing logs or participant self-report, was defined as <4 PrEP doses per week. RESULTS: A total of 9596 participants were enrolled and dispensed PrEP between 1 March 2016 and 30 April 2018; 30 were diagnosed with HIV by 31 March 2019. The median (interquartile range [IQR]) age was 31 (25-38) years, all identified as male, 29 (97%) identified as gay or homosexual, and 20 (69%) lived in a postcode with a low concentration of gay male residents. The median (IQR) days from first PrEP dispensing to diagnosis was 409 (347-656). There was no evidence that participants who seroconverted had been sufficiently adherent to PrEP. Nineteen (63%) participants who seroconverted were diagnosed with chlamydia, gonorrhoea, syphilis, or new hepatitis C infection. One participant had resistance to emtricitabine (M184V mutation) at diagnosis. CONCLUSIONS: Participants who seroconverted were insufficiently adherent to PrEP despite being at high risk for acquiring HIV. Understanding the reasons for poor PrEP adherence in individuals who subsequently acquire HIV is critical to improving PrEP effectiveness.

Non-AIDS complexity amongst patients living with HIV in Sydney: risk factors and health outcomes.

OBJECTIVE: To assess the prevalence of non-AIDS co-morbidities (NACs) and predictors of adverse health outcomes amongst people living with HIV in order to identify health needs and potential gaps in patient management. DESIGN: Retrospective, non-consecutive medical record audit of patients attending a publicly funded HIV clinic in metropolitan Sydney analysed for predictors of adverse health outcomes. We developed a scoring system based on the validated Charlson score method for NACs, mental health and social issues and confounders were selected using directed acyclic graph theory under the principles of causal inference. RESULTS: 211 patient files were audited non-consecutively over 6 weeks. 89.5% were male; 41.8% culturally and linguistically diverse and 4.1% were of Aboriginal/Torres Strait Islander origin. Half of patients had no general practitioner and 25% were ineligible for Medicare subsidised care. The most common NACs were: cardiovascular disease (25%), hepatic disease (21%), and endocrinopathies (20%). One-third of patients had clinical anxiety, one-third major depression and almost half of patients had a lifetime history of tobacco smoking. Five predictors of poor health outcomes were identified: (1) co-morbidity score was associated with hospitalisation (odds ratio, OR 1.58; 95% CI 1.01-2.46; p = 0.044); (2) mental health score was associated with hospitalisation (OR 1.79; 95% CI 1.22-2.62; p = 0.003) and poor adherence to ART (OR 2.34; 95% CI 1.52-3.59; p = 0.001); (3) social issues score was associated with genotypic resistance (OR 2.61; 95% CI 1.48-4.59; p = 0.001), co-morbidity score (OR 1.69; 95% CI 1.24-2.3; p = 0.001) and hospitalisation (OR 1.72; 95% CI 1.1-2.7; p = 0.018); (4) body mass index < 20 was associated with genotypic resistance (OR 6.25; 95% CI 1.49-26.24; p = 0.012); and (5) Medicare eligibility was associated with co-morbidity score (OR 2.21; 95% CI 1.24-3.95; p = 0.007). CONCLUSION: Most HIV patients are healthy due to effective antiretroviral therapy; however, NACs and social/mental health issues are adding to patient complexity. The current findings underpin the need for multidisciplinary management beyond routine viral load and CD4 count monitoring.

Funding antiretroviral treatment for HIV-positive temporary residents in Australia prevents transmission and is inexpensive.

Background The aim of this study is to estimate the reduction in new HIV infections and resultant cost outcomes of providing antiretroviral treatment (ART) through Australia's 'universal access' health scheme to all temporary residents with HIV infection living legally in Australia, but currently deemed ineligible to access subsidised ART via this scheme. METHODS: A mathematical model to estimate the number of new HIV infections averted and the associated lifetime costs over 5 years if all HIV-positive temporary residents in Australia had access to ART and subsidised medical care was developed. Input data came from a cohort of 180 HIV-positive temporary residents living in Australia who are receiving free ART donated by pharmaceutical companies for up to 4 years. RESULTS: Expanding ART access to an estimated total 450 HIV+ temporary residents in Australia for 5 years could avert 80 new infections. The model estimated the total median discounted (5%) cost for ART and associated care to be A$36million, while the total savings in lifetime-discounted costs for the new infections averted was A$22million. CONCLUSIONS: It is estimated that expanded access to ART for all HIV-positive temporary residents in Australia will substantially reduce HIV transmission to their sexual partners at little additional cost. In the context of Australia's National HIV strategy and Australia's endorsement of global goals to provide universal access to ART for all people with HIV, this is an important measure to remove inequities in the provision of HIV-related treatment and care.

Concomitant medication polypharmacy, interactions and imperfect adherence are common in Australian adults on suppressive antiretroviral therapy.

OBJECTIVES: We quantified concomitant medication polypharmacy, pharmacokinetic and pharmacodynamic interactions, adverse effects and adherence in Australian adults on effective antiretroviral therapy. DESIGN: Cross-sectional. METHODS: Patients recruited into a nationwide cohort and assessed for prevalence and type of concomitant medication (including polypharmacy, defined as ≥5 concomitant medications), pharmacokinetic or pharmacodynamic interactions, potential concomitant medication adverse effects and concomitant medication adherence. Factors associated with concomitant medication polypharmacy and with imperfect adherence were identified using multivariable logistic regression. RESULTS: Of 522 participants, 392 (75%) took a concomitant medication (mostly cardiovascular, nonprescription or antidepressant). Overall, 280 participants (54%) had polypharmacy of concomitant medications and/or a drug interaction or contraindication. Polypharmacy was present in 122 (23%) and independently associated with clinical trial participation, renal impairment, major comorbidity, hospital/general practice-based HIV care (versus sexual health clinic) and benzodiazepine use. Seventeen participants (3%) took at least one concomitant medication contraindicated with their antiretroviral therapy, and 237 (45%) had at least one pharmacokinetic/pharmacodynamic interaction. Concomitant medication use was significantly associated with sleep disturbance and myalgia, and polypharmacy of concomitant medications with diarrhoea, fatigue, myalgia and peripheral neuropathy. Sixty participants (12%) reported imperfect concomitant medication adherence, independently associated with requiring financial support, foregoing necessities for financial reasons, good/very good self-reported general health and at least 1 bed day for illness in the previous 12 months. CONCLUSION: In a resource-rich setting with universal healthcare access, the majority of this sample took a concomitant medication. Over half had at least one of concomitant medication polypharmacy, pharmacokinetic or pharmacodynamic interaction. Concomitant medication use was associated with several adverse clinical outcomes.

Multi-centre evaluation of the Determine HIV Combo assay when used for point of care testing in a high risk clinic-based population.

BACKGROUND: Determine HIV Combo (DHC) is the first point of care assay designed to increase sensitivity in early infection by detecting both HIV antibody and antigen. We conducted a large multi-centre evaluation of DHC performance in Sydney sexual health clinics. METHODS: We compared DHC performance (overall, by test component and in early infection) with conventional laboratory HIV serology (fourth generation screening immunoassay, supplementary HIV antibody, p24 antigen and Western blot tests) when testing gay and bisexual men attending four clinic sites. Early infection was defined as either acute or recent HIV infection acquired within the last six months. RESULTS: Of 3,190 evaluation specimens, 39 were confirmed as HIV-positive (12 with early infection) and 3,133 were HIV-negative by reference testing. DHC sensitivity was 87.2% overall and 94.4% and 0% for the antibody and antigen components, respectively. Sensitivity in early infection was 66.7% (all DHC antibody reactive) and the DHC antigen component detected none of nine HIV p24 antigen positive specimens. Median HIV RNA was higher in false negative than true positive cases (238,025 vs. 37,591 copies/ml; p = 0.022). Specificity overall was 99.4% with the antigen component contributing to 33% of false positives. CONCLUSIONS: The DHC antibody component detected two thirds of those with early infection, while the DHC antigen component did not enhance performance during point of care HIV testing in a high risk clinic-based population.

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells.

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine.

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption in primary HIV infection: final results from a randomized clinical trial (Pulse).

BACKGROUND: Structured treatment interruptions (STIs) have been postulated to improve virologic control in primary HIV infection (PHI) by stimulating HIV-specific T-lymphocyte immunity. The addition of hydroxyurea (HU) may reduce viral production from activated CD4 cells. METHODS: Patients with PHI received a standardized antiretroviral (ARV) regimen consisting of indinavir 800 mg twice daily (BID), ritonavir 100 mg BID, didanosine 400 mg (QD), and either stavudine 40 mg BID or lamivudine 150 mg BID, for up to 12 months and were randomized to HU 500 mg BID or not. If viral suppression (<50 copies/mL) was achieved, up to 3 STIs were undertaken. Two ARV cycles were allowed after each interruption if virologic rebound to more than 5000 RNA copies/mL occurred. Treatment success was defined as maintaining viral loads below 5000 copies/mL for 6 months after ARV interruption. RESULTS: Sixty-eight male homosexual patients were randomized: 35 to ARV + HU and 33 to ARV-alone. Median baseline HIV RNA was 5.73 log10 copies/mL, and median CD4 T-lymphocyte count was 517 cells/microL. Treatment success was not significantly different between those receiving and not receiving HU, with 9 (26%) and 9 (27%), respectively, maintaining viral load at less than 5000 copies/mL in each group (P = 0.88). Virologic control was achieved by 11 (19%) of 59 after 1 STI, 1 (2%) of 41 after 2 STIs, and 6 (17%) of 36 after the third STI. Serious adverse events were recorded for 9 (26%) of 35 of patients using HU and 3 (9%) of 33 in the ARV-only group (P = 0.28). CD4 cell increases were significantly blunted for the HU group compared to the ARV-alone group after the initial treatment phase (+101 cells vs. +196 cells, respectively, P = 0.006). CONCLUSIONS: Hydroxyurea was not found to be beneficial when used in association with STIs in patients during PHI.

Atazanavir plasma concentrations vary significantly between patients and correlate with increased serum bilirubin concentrations.

BACKGROUND: Atazanavir (ATV) is recommended to be dosed at 400 mg once daily or 300 mg daily coadministered with 100 mg ritonavir (RTV). METHOD: 31 male patients receiving ATV either alone or boosted with RTV for more than 2 weeks had ATV concentration measured by high performance liquid chromatography (HPLC). ATV concentrations were adjusted to obtain a 24-hour trough level using a standard pharmacokinetic formula. RESULTS: 25 samples were taken from patients who received 300 mg ATV, 6 with 200 mg, 3 with 400 mg, and 2 with 150 mg, all boosted with 100 mg RTV. In the unboosted group, patients received 400 mg (7) or 600 mg (2). The median adjusted 24-hour trough ATV concentration was 630 ng/mL (interquartile range [IQR] 355-1034) in the boosted and 113 ng/mL (IQR 50-225) in the unboosted group (p = .001). Median serum bilirubin concentration was 34 IU/L (IQR 27.5-49) and 41 IU/L (IQR 31-45) in the boosted and unboosted groups, respectively. In the boosted group, high ATV concentrations were significantly correlated with increased serum bilirubin concentrations (p = .003). CONCLUSION: ATV concentrations showed considerable interpatient variability. Bilirubin concentrations are an indicator of high ATV concentrations and may prove to be useful in selecting patients for therapeutic drug monitoring (TDM).

Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2.

We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.