AIDS

Revisiting the mechanism of enfuvirtide and designing an analog with improved fusion inhibitory activity by targeting triple sites in gp41 Objective: To revisit the mechanism of action of enfuvirtide (T20) and based on the newly defined mechanism, design an analogous peptide of T20 with improved antiviral activity. Design: We compared the inhibitory activity of T20 with that of T1144 on six-helix bundle (6HB) formation at different time after coculture of HIV type 1 (HIV-1) envelope (Env)-expressing Chinese hamster ovary (CHO-Env) cells and CD4+-expressing MT-2 cells at 31.5 °C and with that of T20-SF, an analogous peptide of T20 with an additional tryptophan-rich motif, on hemolysis mediated by FP-P, which contains fusion peptide and fusion peptide (FP) proximal region (FPPR), and HIV-1 infection. Methods: Inhibitory activity of peptides on 6HB formation was tested in a temperature-controlled cell–cell fusion assay by flow cytometry using 6HB-specific mAb 2G8; on HIV-1 infection and fusion was assessed by p24 and cell–cell fusion assays. Interaction between different peptides or peptide and antibody was evaluated by ELISA. Results: T20 could inhibit 6HB formation at early, but not late, stage of HIV-1 fusion, whereas T1144 was effective at both stages. T20-SF is much more effective than T20 in binding to FP-P and inhibiting infection of HIV-1, including T20-resistant strains, and FP-P-mediated hemolysis. Conclusion: Results suggest that T20 has a double-target mechanism, by which its N-terminal and C-terminal portions bind to N-terminal heptad repeat and FPPR, respectively. T20-SF designed based on this new mechanism exhibits significantly improved anti-HIV-1 activity because it targets the triple sites in gp41, including N-terminal heptad repeat, FPPR, and fusion peptide. Thus, this study provides clues for designing novel HIV fusion inhibitors with improved antiviral activity.

Elevated indoleamine-2,3-dioxygenase enzyme activity in a novel mouse model of HIV-associated atherosclerosis Objective: HIV atherosclerosis and cardiovascular disease (CVD) represent a significant human health burden in the era of combination antiretroviral therapy (cART). The pathogenesis of HIV atherosclerosis is still poorly understood, due, in part, to the lack of a suitable small animal model. Indoleamine-2,3-dioxygenase (IDO) enzyme activity is the first and rate-limiting step in tryptophan catabolism and is measured by the kynurenine to tryptophan ratio (KTR). The serum KTR is a biomarker of inflammation and has recently been implicated as an important risk factor for CVD in patients living with HIV (PLWH) who are virologically suppressed under cART. However, IDO activity in HIV-associated CVD has not been studied in mouse model before. Design: A novel mouse model of HIV atherosclerosis (Tg26+/−/ApoE−/−) was generated and examined for IDO activity and atherogenesis throughout 8 weeks on a high-fat diet. Tg26+/−/ApoE−/− mice were compared with Tg26+/− and ApoE−/− single transgenic mice, before and during a high-fat diet. Method: Serum kynurenine, tryptophan and percentage of aortic plaque formation were measured. Additionally, levels of relevant cytokines were investigated in Tg26+/−/ApoE−/− and ApoE−/−. Results: Tg26+/−/ApoE−/− developed an accelerated atherosclerosis with increasing levels of KTR that were associated with plaque progression. This accelerated plaque was potentially driven by elevated levels of circulating IL-6. Conclusion: These results indicate that Tg26+/−/ApoE−/− serve as a new mouse model for HIV-induced atherogenesis, and aid in understanding the role of tryptophan catabolism in the pathogenesis of HIV atherosclerosis/CVD.

Suboptimal stimulation by weak agonist epitope variants does not drive dysfunction of HIV-1-specific cytotoxic T lymphocyte clones Objective: To assess whether weakly recognized epitope variants induce anergy in HIV-1-specific CD8+ T lymphocyte (CTL) clones as a mechanism of dysfunction. Design: HIV-1-specific CTL clones were exposed to suboptimally recognized epitope variants, and screened for anergy and other T-cell dysfunction markers, and subsequent capability to kill target cells bearing index epitope. Methods: In addition to the optimally recognized index epitope, two suboptimally recognized epitope variants were selected based on titration curves for killing of peptide-labeled target cells by three HIV-1-specific CTL clones targeting the epitopes SLYNTVATL (Gag 77-85, A*02-restricted), RPAEPVPLQL (Rev 66-75, B*07-restricted), and KRWIIMGLNK (Gag 263-272, B*27-restricted). Consequences of suboptimal stimulation were assessed by cytokine secretion, gene expression, and capacity to kill index epitope-labeled target cells upon rechallenge. Results: Suboptimal recognition of epitope variants reduced cytokine production by CTL similarly to reduction in killing of target cells. Gene expression profiles after suboptimal stimulation demonstrated no patterns consistent with T-cell dysfunction due to anergy, exhaustion, or apoptosis. Preexposure of CTL to epitope variants had no discernable impact on their subsequent capacity to kill index epitope-bearing target cells. Conclusion: Our data explore the hypothesis that poorly recognized epitope variants not only facilitate HIV-1 evasion of CTL recognition, but also induce CTL dysfunction through suboptimal signaling causing anergy. However, the results do not suggest that suboptimal signaling induces anergy (or exhaustion or apoptosis), indicating that the major role of CTL epitope variation is likely viral escape.

Catechol-O-methyltransferase polymorphism Val158Met is associated with distal neuropathic pain in HIV-associated sensory neuropathy Background: Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), Val158Met. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of Val158Met as a predictor of DNP in HIV-SN. Methods: In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between Val158Met and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background. Findings: Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, Val158Met was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4+. Stratified by genetic ancestry, the association between Val158Met and DNP was significant in European and African genetic ancestry. Interpretation: Val158Met may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.

Randomized study evaluating the efficacy and safety of switching from an an abacavir/lamivudine-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet regimen Objective: To evaluate the efficacy and safety of switching from an abacavir/lamivudine (ABC/3TC)-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically suppressed, HIV-1-infected adults. Design: Randomized, open-label, noninferiority study. Methods: Participants with HIV-1 RNA levels less than 50 copies/ml receiving ABC/3TC plus a third agent for at least 6 months were randomized 2 : 1 to switch immediately to E/C/F/TAF (immediate-switch group) for 48 weeks or to continue receiving ABC/3TC plus a third agent for 24 weeks followed by E/C/F/TAF for 24 weeks (delayed-switch group). The primary endpoint was HIV-1 RNA less than 50 copies/ml at Week 24 by Food and Drug Administration Snapshot algorithm (−12% noninferiority margin). Results: Baseline characteristics of 274 participants (183 in immediate-switch group and 91 in delayed-switch group) were similar. Virologic response was maintained at Week 24 by 93.4 and 97.8% of participants in the immediate-switch and delayed-switch groups, respectively, with a treatment difference of −4.4% (95% confidence interval: −9.4 to 1.9%), confirming noninferiority. Adverse events of any grade were similar between groups through Week 24 (66% E/C/F/TAF, 64% ABC/3TC); adverse event-related drug discontinuations occurred in 4% of participants switching to E/C/F/TAF (no discontinuations because of renal events) and no participants continuing ABC/3TC. Renal biomarkers of urine albumin:creatinine and beta-2-microglobulin:creatinine ratios significantly improved on E/C/F/TAF. Self-reported treatment satisfaction was significantly higher with E/C/F/TAF. Conclusion: Switching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent for maintenance of HIV RNA suppression at Week 24. This study supports E/C/F/TAF as an efficacious and well tolerated option for participants switching from ABC/3TC-based regimens.

Hyperglycemia and insulin function in antiretroviral treatment-naive HIV patients in Ethiopia: a potential new entity of diabetes in HIV? Background: Although diabetes is more common in HIV patients, the direct link between HIV and diabetes is unknown. Glucose abnormalities should be assessed among antiretroviral treatment (ART)-naive patients to reduce confounding by ART. We assessed diabetes status, insulin function and association with inflammation among Ethiopian ART-naive HIV patients. Methods: Among HIV patients initiating ART, we used glycosylated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) to define prediabetes and diabetes. Insulin during OGTT was determined to calculate insulin function, and C-reactive protein and α1-acid glycoprotein were used as same-day markers of inflammation. Results: Among 332 HIV patients, mean (SD) age was 32.9 (8.8) years, and 222 (66.9%) were women. None had known diabetes, but we found diabetes prevalence using OGTT and HbA1c to be 7.6 and 8.5%, respectively. C-reactive protein and α1-acid glycoprotein were positively associated with hyperglycemia and insulin deficiency, but not insulin resistance. We found poor correlation between traditional risk factors (age and anthropometry) and diabetes, but participants generally had low BMI and waist circumference. Conclusion: ART-naive Ethiopian HIV patients had a high prevalence of prediabetes and diabetes, with a poor agreement between HbA1c and OGTT. Diabetes was associated with inflammation, but not with adiposity and age. Diabetes was linked to insulin deficiency, rather than insulin resistance, which may represent a different entity than type 1 and 2 diabetes. This has implications for choice of drugs, when managing diabetes in African HIV patients.

Frailty in medically complex individuals with chronic HIV Objectives: Multimorbidity and frailty are consequences of aging with HIV, yet not everyone with medical disease is frail. Our objective was to identify factors associated with frailty in a multimorbid HIV-infected cohort. Design: Analysis of a prospective, observational, longitudinal cohort. Methods: Three hundred and thirty-two participants in the medically advanced National NeuroAIDS Tissue Consortium (NNTC) study were categorized as frail, prefrail, or robust with the Fried Frailty Index. A series of logistic regression analyses (first univariate, then multivariable) were conducted to determine whether medical comorbidities, immunologic and virologic parameters, and/or neuropsychiatric variables predicted increased odds of frailty. Results: The mean number of medical comorbidities per participant was 2.7, mean CD4+ T-cell count was 530 cells/μl, and 77% had undetectable HIV RNA in blood. Twenty-two percent were frail, 55% prefrail, and 23% robust. Significant predictors of frailty in multivariable analysis were cognitive diagnosis rendered by Frascati criteria, depressive symptoms, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and sex. Men were less likely to be frail than women. Higher odds of frailty were seen with: symptomatic, but not asymptomatic, cognitive impairment (compared with cognitive normals); more depressive symptoms; diabetes mellitus; and COPD. Conclusion: Neuropsychiatric illness increased odds of being frail on a predominantly physical/motoric measure, but only when symptomatic. Lack of association with asymptomatic impairment may reflect the importance of functional limitation to frailty, or possibly a unique resilience phenotype. Understanding why sex and symptomatic neuropsychiatric illness are associated with frailty will be important in managing HIV-associated morbidity in aging populations.

E157Q integrase strand-transfer inhibitor substitution in patients with acute/recent HIV infection Objectives: Integrase strand-transfer inhibitor (InSTI)-based regimens are the preferred combinations for naïve HIV-infected individuals. Polymorphic substitutions that reduce InSTIs activity have been described, with E157Q being one of the most frequently found. This study aimed to evaluate the prevalence of E157Q substitution in newly diagnosed acute/recent HIV cases and the presence of transmission clusters. Design: Prospective cohort study in patients with acute/recent HIV infection. Methods: Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of less than 6 months from May 2015 to May 2017. Sequences were obtained by ultra-deep sequencing. Phylogenetic inferences were performed using maximum likelihood trees constructed with Mega 6.06. Bootstrap values of 75% or greater were defined for cluster assignment. Follow-up was, at least, 1 year. Results: In six out of 67 consecutive patients (8.95%, 95% confidence interval 4.17–18.19) with acute/recent HIV infection, strains carrying the E157Q InSTI substitution were detected. All cases were MSM patients infected with subtype B strains. No other resistance substitutions were detected in these cases. Median viral load was 5.33 (interquartile range: 4.54–5.71) log10 copies/ml and, in all cases, the mutational viral load was high (>95%). Three cases were included in transmission clusters. Three cases responded to dolutegravir-based regimens; nonnucleoside reverse transcriptase inhibitor-based regimens were used for the other case(s). Conclusion: E157Q substitution, reducing raltegravir and elvitegravir activity, was frequently found in acute/recent HIV cases. All cases were infected with subtype B, and some were included in clusters. Cases treated with dolutegravir-based regimens had good virological response.

Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study Objective: Observational studies have associated use of intramuscular injectable depot medroxyprogesterone acetate (DMPA-IM) with increased risk of HIV-1 acquisition, but limited data are available to assess HIV-1 risk for alternate contraceptive methods. Methods: Within a randomized trial of the dapivirine vaginal ring for HIV-1 prevention, we assessed HIV-1 incidence by contraceptive method. We limited analyses to participants from South African sites and to women who used DMPA-IM, the alternative injectable norethisterone enanthate, implants, or copper intrauterine devices (IUDs). Contraceptive method was assessed as a time-dependent exposure and multivariate models adjusted for trial randomization arm, age, sexual behaviour, and incident sexually transmitted infections. Results: A total of 95 incident HIV-1 infections were observed: incidence 5.8 (DMPA-IM, n = 52), 6.2 (norethisterone enanthate, n = 28), 1.9 (implant, n = 3), and 4.5 (IUD, n = 12) cases per 100 woman-years. In multivariable models, there were no statistically significant differences between contraceptive methods in the risk of HIV-1 acquisition. However, compared with the IUD, the three hormonal methods each had point estimates near 1 while the implant had risk that was approximately half that of the IUD. When the three hormonal methods were combined, their relative risk compared with IUD was 0.90 (95% confidence interval 0.45–1.76). Conclusion: Among women at risk of HIV-1 infections in South Africa, we found no statistically significant differences in HIV-1 incidence by contraceptive method. Implants had the lowest point estimate for HIV-1 incidence, and IUDs had risk comparable with injectable methods in multivariate models. Large, prospective studies are needed to define better the relative HIV-1 risks across different contraceptive methods.

Perinatal outcomes associated with maternal HIV and antiretroviral therapy in pregnancies with accurate gestational age in South Africa Objective: To assess the association of maternal HIV infection and antiretroviral therapy (ART) with perinatal outcomes among women with accurate pregnancy dating and birth weights. Design: Prospective pregnancy cohort study in Soweto, South Africa. Methods: Gestational age was estimated by first-trimester ultrasound and birth weight was measured in a standardized manner within 24 h of birth. The primary composite outcome ‘adverse perinatal outcome’ included preterm birth, low birth weight, small for gestational age, stillbirth and neonatal death (NND). Specific adverse perinatal outcomes were secondary outcomes. Logistic regression models adjusted for multiple confounders. Results: Of 633 women included in the analysis, 229 (36.2%) were HIV positive and 404 (63.8%) HIV negative. Among 125 HIV-positive women who provided detailed information on HIV and ART, 96.7% had clinical stage 1 of HIV disease and 98.4% were on ART during pregnancy, mostly WHO-recommended efavirenz-based ART. Among 109 HIV-positive women with information on timing of ART initiation, 38 (34.9%) initiated ART preconception and 71 (65.1%) antenatally. No newborns were HIV positive. In univariable analysis, maternal HIV infection was associated with increased risk of the composite ‘adverse perinatal outcome’ [odds ratio (OR) 1.44; 95% confidence interval (CI) 1.03, 2.03], NND (OR 6.15; 95% CI 1.27, 29.88) and small for gestational age (OR 1.55; 95% CI 1.01, 2.37). After adjusting for confounders, maternal HIV infection remained associated with ‘adverse perinatal outcome’ (adjusted OR 1.47; 95% CI 1.01, 2.14) and NND (adjusted OR 7.82; 95% CI 1.32, 46.42). No associations with timing of ART initiation were observed. Conclusion: Despite high ART coverage, good maternal health and very low vertical HIV transmission rate, maternal HIV infection remained associated with increased risk of adverse perinatal outcomes. Larger studies using first trimester ultrasound for pregnancy dating are needed to further assess associations with specific adverse perinatal outcomes.

Correspondence

Dolutegravir monotherapy and body weight gain in antiretroviral naïve patients

Rizzardo, Sebastiano; Lanzafame, Massimiliano; Lattuada, Emanuela; More

AIDS. 33(10):1673-1674, August 1, 2019.

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Perinatal HIV and response to vaccination

Dauby, Nicolas

AIDS. 33(10):1674-1675, August 1, 2019.

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Response to correspondence entitled Perinatal HIV and response to vaccination

Flynn, Patricia M.; Abrams, Elaine J.

AIDS. 33(10):1675-1677, August 1, 2019.

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Drug interactions are not always predictable the curious case of valproic acid and dolutegravir and a possible explanation

Tseng, Alice L.; Wong, Alison Y.J.; McLelland, Cassandra J.; More

AIDS. 33(10):1677-1679, August 1, 2019.

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Recurrent posterior reversible encephalopathy syndrome in an HIV-HCV coinfected liver transplant recipient

Cappelletti, Anna; Peri, Anna Maria; Bisi, Luca; More

AIDS. 33(10):1679-1681, August 1, 2019.

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BASIC SCIENCE
Revisiting the mechanism of enfuvirtide and designing an analog with improved fusion inhibitory activity by targeting triple sites in gp41
Xu, Wei; Pu, Jing; Su, Shan; More
AIDS. 33(10):1545-1555, August 1, 2019.

Abstract
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Objective:
To revisit the mechanism of action of enfuvirtide (T20) and based on the newly defined mechanism, design an analogous peptide of T20 with improved antiviral activity.

Design:
We compared the inhibitory activity of T20 with that of T1144 on six-helix bundle (6HB) formation at different time after coculture of HIV type 1 (HIV-1) envelope (Env)-expressing Chinese hamster ovary (CHO-Env) cells and CD4 + -expressing MT-2 cells at 31.5 °C and with that of T20-SF, an analogous peptide of T20 with an additional tryptophan-rich motif, on hemolysis mediated by FP-P, which contains fusion peptide and fusion peptide (FP) proximal region (FPPR), and HIV-1 infection.

Methods:
Inhibitory activity of peptides on 6HB formation was tested in a temperature-controlled cell–cell fusion assay by flow cytometry using 6HB-specific mAb 2G8; on HIV-1 infection and fusion was assessed by p24 and cell–cell fusion assays. Interaction between different peptides or peptide and antibody was evaluated by ELISA.

Results:
T20 could inhibit 6HB formation at early, but not late, stage of HIV-1 fusion, whereas T1144 was effective at both stages. T20-SF is much more effective than T20 in binding to FP-P and inhibiting infection of HIV-1, including T20-resistant strains, and FP-P-mediated hemolysis.

Conclusion:
Results suggest that T20 has a double-target mechanism, by which its N-terminal and C-terminal portions bind to N-terminal heptad repeat and FPPR, respectively. T20-SF designed based on this new mechanism exhibits significantly improved anti-HIV-1 activity because it targets the triple sites in gp41, including N-terminal heptad repeat, FPPR, and fusion peptide. Thus, this study provides clues for designing novel HIV fusion inhibitors with improved antiviral activity.

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Elevated indoleamine-2,3-dioxygenase enzyme activity in a novel mouse model of HIV-associated atherosclerosis
Kearns, Alison C.; Velasquez, Stephani; Liu, Fengming; More
AIDS. 33(10):1557-1564, August 1, 2019.

Abstract
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Objective:
HIV atherosclerosis and cardiovascular disease (CVD) represent a significant human health burden in the era of combination antiretroviral therapy (cART). The pathogenesis of HIV atherosclerosis is still poorly understood, due, in part, to the lack of a suitable small animal model. Indoleamine-2,3-dioxygenase (IDO) enzyme activity is the first and rate-limiting step in tryptophan catabolism and is measured by the kynurenine to tryptophan ratio (KTR). The serum KTR is a biomarker of inflammation and has recently been implicated as an important risk factor for CVD in patients living with HIV (PLWH) who are virologically suppressed under cART. However, IDO activity in HIV-associated CVD has not been studied in mouse model before.

Design:
A novel mouse model of HIV atherosclerosis ( Tg26 +/− /ApoE −/− ) was generated and examined for IDO activity and atherogenesis throughout 8 weeks on a high-fat diet. Tg26 +/− /ApoE −/− mice were compared with Tg26 +/− and ApoE −/− single transgenic mice, before and during a high-fat diet.

Method:
Serum kynurenine, tryptophan and percentage of aortic plaque formation were measured. Additionally, levels of relevant cytokines were investigated in Tg26 +/− /ApoE −/− and ApoE −/− .

Results:
Tg26 +/− /ApoE −/− developed an accelerated atherosclerosis with increasing levels of KTR that were associated with plaque progression. This accelerated plaque was potentially driven by elevated levels of circulating IL-6.

Conclusion:
These results indicate that Tg26 +/− /ApoE −/− serve as a new mouse model for HIV-induced atherogenesis, and aid in understanding the role of tryptophan catabolism in the pathogenesis of HIV atherosclerosis/CVD.

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SDC
Suboptimal stimulation by weak agonist epitope variants does not drive dysfunction of HIV-1-specific cytotoxic T lymphocyte clones
Grossman, Mark A.; Hofmann, Christian; Ng, Hwee L.; More
AIDS. 33(10):1565-1574, August 1, 2019.

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Objective:
To assess whether weakly recognized epitope variants induce anergy in HIV-1-specific CD8 + T lymphocyte (CTL) clones as a mechanism of dysfunction.

Design:
HIV-1-specific CTL clones were exposed to suboptimally recognized epitope variants, and screened for anergy and other T-cell dysfunction markers, and subsequent capability to kill target cells bearing index epitope.

Methods:
In addition to the optimally recognized index epitope, two suboptimally recognized epitope variants were selected based on titration curves for killing of peptide-labeled target cells by three HIV-1-specific CTL clones targeting the epitopes SLYNTVATL (Gag 77-85, A * 02-restricted), RPAEPVPLQL (Rev 66-75, B * 07-restricted), and KRWIIMGLNK (Gag 263-272, B * 27-restricted). Consequences of suboptimal stimulation were assessed by cytokine secretion, gene expression, and capacity to kill index epitope-labeled target cells upon rechallenge.

Results:
Suboptimal recognition of epitope variants reduced cytokine production by CTL similarly to reduction in killing of target cells. Gene expression profiles after suboptimal stimulation demonstrated no patterns consistent with T-cell dysfunction due to anergy, exhaustion, or apoptosis. Preexposure of CTL to epitope variants had no discernable impact on their subsequent capacity to kill index epitope-bearing target cells.

Conclusion:
Our data explore the hypothesis that poorly recognized epitope variants not only facilitate HIV-1 evasion of CTL recognition, but also induce CTL dysfunction through suboptimal signaling causing anergy. However, the results do not suggest that suboptimal signaling induces anergy (or exhaustion or apoptosis), indicating that the major role of CTL epitope variation is likely viral escape.

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 Collapse Box CLINICAL SCIENCE
Catechol-O-methyltransferase polymorphism Val158Met is associated with distal neuropathic pain in HIV-associated sensory neuropathy
Xu, Jennie; Umlauf, Anya; Letendre, Scott; More
AIDS. 33(10):1575-1582, August 1, 2019.

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Background:
Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol- O -methyltransferase (COMT), Val 158 Met. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of Val 158 Met as a predictor of DNP in HIV-SN.

Methods:
In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between Val 158 Met and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background.

Findings:
Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, Val 158 Met was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4 + . Stratified by genetic ancestry, the association between Val 158 Met and DNP was significant in European and African genetic ancestry.

Interpretation:
Val 158 Met may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.

BUY
Randomized study evaluating the efficacy and safety of switching from an an abacavir/lamivudine-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet regimen
Rizzardini, Giuliano; Gori, Andrea; Miralles, Celia; More
AIDS. 33(10):1583-1593, August 1, 2019.

Abstract
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Objective:
To evaluate the efficacy and safety of switching from an abacavir/lamivudine (ABC/3TC)-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically suppressed, HIV-1-infected adults.

Design:
Randomized, open-label, noninferiority study.

Methods:
Participants with HIV-1 RNA levels less than 50 copies/ml receiving ABC/3TC plus a third agent for at least 6 months were randomized 2 : 1 to switch immediately to E/C/F/TAF (immediate-switch group) for 48 weeks or to continue receiving ABC/3TC plus a third agent for 24 weeks followed by E/C/F/TAF for 24 weeks (delayed-switch group). The primary endpoint was HIV-1 RNA less than 50 copies/ml at Week 24 by Food and Drug Administration Snapshot algorithm (−12% noninferiority margin).

Results:
Baseline characteristics of 274 participants (183 in immediate-switch group and 91 in delayed-switch group) were similar. Virologic response was maintained at Week 24 by 93.4 and 97.8% of participants in the immediate-switch and delayed-switch groups, respectively, with a treatment difference of −4.4% (95% confidence interval: −9.4 to 1.9%), confirming noninferiority. Adverse events of any grade were similar between groups through Week 24 (66% E/C/F/TAF, 64% ABC/3TC); adverse event-related drug discontinuations occurred in 4% of participants switching to E/C/F/TAF (no discontinuations because of renal events) and no participants continuing ABC/3TC. Renal biomarkers of urine albumin:creatinine and beta-2-microglobulin:creatinine ratios significantly improved on E/C/F/TAF. Self-reported treatment satisfaction was significantly higher with E/C/F/TAF.

Conclusion:
Switching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent for maintenance of HIV RNA suppression at Week 24. This study supports E/C/F/TAF as an efficacious and well tolerated option for participants switching from ABC/3TC-based regimens.

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SDC
Hyperglycemia and insulin function in antiretroviral treatment-naive HIV patients in Ethiopia a potential new entity of diabetes in HIV?
Faurholt-Jepsen, Daniel; Olsen, Mette F.; Andersen, Anna B.; More
AIDS. 33(10):1595-1602, August 1, 2019.

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Background:
Although diabetes is more common in HIV patients, the direct link between HIV and diabetes is unknown. Glucose abnormalities should be assessed among antiretroviral treatment (ART)-naive patients to reduce confounding by ART. We assessed diabetes status, insulin function and association with inflammation among Ethiopian ART-naive HIV patients.

Methods:
Among HIV patients initiating ART, we used glycosylated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) to define prediabetes and diabetes. Insulin during OGTT was determined to calculate insulin function, and C-reactive protein and α1-acid glycoprotein were used as same-day markers of inflammation.

Results:
Among 332 HIV patients, mean (SD) age was 32.9 (8.8) years, and 222 (66.9%) were women. None had known diabetes, but we found diabetes prevalence using OGTT and HbA1c to be 7.6 and 8.5%, respectively. C-reactive protein and α1-acid glycoprotein were positively associated with hyperglycemia and insulin deficiency, but not insulin resistance. We found poor correlation between traditional risk factors (age and anthropometry) and diabetes, but participants generally had low BMI and waist circumference.

Conclusion:
ART-naive Ethiopian HIV patients had a high prevalence of prediabetes and diabetes, with a poor agreement between HbA1c and OGTT. Diabetes was associated with inflammation, but not with adiposity and age. Diabetes was linked to insulin deficiency, rather than insulin resistance, which may represent a different entity than type 1 and 2 diabetes. This has implications for choice of drugs, when managing diabetes in African HIV patients.

BUY
Frailty in medically complex individuals with chronic HIV
Morgello, Susan; Gensler, Gary; Sherman, Seth; More
AIDS. 33(10):1603-1611, August 1, 2019.

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Objectives:
Multimorbidity and frailty are consequences of aging with HIV, yet not everyone with medical disease is frail. Our objective was to identify factors associated with frailty in a multimorbid HIV-infected cohort.

Design:
Analysis of a prospective, observational, longitudinal cohort.

Methods:
Three hundred and thirty-two participants in the medically advanced National NeuroAIDS Tissue Consortium (NNTC) study were categorized as frail, prefrail, or robust with the Fried Frailty Index. A series of logistic regression analyses (first univariate, then multivariable) were conducted to determine whether medical comorbidities, immunologic and virologic parameters, and/or neuropsychiatric variables predicted increased odds of frailty.

Results:
The mean number of medical comorbidities per participant was 2.7, mean CD4 + T-cell count was 530 cells/μl, and 77% had undetectable HIV RNA in blood. Twenty-two percent were frail, 55% prefrail, and 23% robust. Significant predictors of frailty in multivariable analysis were cognitive diagnosis rendered by Frascati criteria, depressive symptoms, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and sex. Men were less likely to be frail than women. Higher odds of frailty were seen with: symptomatic, but not asymptomatic, cognitive impairment (compared with cognitive normals); more depressive symptoms; diabetes mellitus; and COPD.

Conclusion:
Neuropsychiatric illness increased odds of being frail on a predominantly physical/motoric measure, but only when symptomatic. Lack of association with asymptomatic impairment may reflect the importance of functional limitation to frailty, or possibly a unique resilience phenotype. Understanding why sex and symptomatic neuropsychiatric illness are associated with frailty will be important in managing HIV-associated morbidity in aging populations.

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E157Q integrase strand-transfer inhibitor substitution in patients with acute/recent HIV infection
Ambrosioni, Juan; Rico, José Ángel Fernández-Caballero; Nicolás, David; More
AIDS. 33(10):1613-1617, August 1, 2019.

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Objectives:
Integrase strand-transfer inhibitor (InSTI)-based regimens are the preferred combinations for naïve HIV-infected individuals. Polymorphic substitutions that reduce InSTIs activity have been described, with E157Q being one of the most frequently found. This study aimed to evaluate the prevalence of E157Q substitution in newly diagnosed acute/recent HIV cases and the presence of transmission clusters.

Design:
Prospective cohort study in patients with acute/recent HIV infection.

Methods:
Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of less than 6 months from May 2015 to May 2017. Sequences were obtained by ultra-deep sequencing. Phylogenetic inferences were performed using maximum likelihood trees constructed with Mega 6.06. Bootstrap values of 75% or greater were defined for cluster assignment. Follow-up was, at least, 1 year.

Results:
In six out of 67 consecutive patients (8.95%, 95% confidence interval 4.17–18.19) with acute/recent HIV infection, strains carrying the E157Q InSTI substitution were detected. All cases were MSM patients infected with subtype B strains. No other resistance substitutions were detected in these cases. Median viral load was 5.33 (interquartile range: 4.54–5.71) log10 copies/ml and, in all cases, the mutational viral load was high (>95%). Three cases were included in transmission clusters. Three cases responded to dolutegravir-based regimens; nonnucleoside reverse transcriptase inhibitor-based regimens were used for the other case(s).

Conclusion:
E157Q substitution, reducing raltegravir and elvitegravir activity, was frequently found in acute/recent HIV cases. All cases were infected with subtype B, and some were included in clusters. Cases treated with dolutegravir-based regimens had good virological response.

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SDC
Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study
Palanee-Phillips, Thesla; Brown, Elizabeth R.; Szydlo, Daniel; More
AIDS. 33(10):1619-1622, August 1, 2019.

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Objective:
Observational studies have associated use of intramuscular injectable depot medroxyprogesterone acetate (DMPA-IM) with increased risk of HIV-1 acquisition, but limited data are available to assess HIV-1 risk for alternate contraceptive methods.

Methods:
Within a randomized trial of the dapivirine vaginal ring for HIV-1 prevention, we assessed HIV-1 incidence by contraceptive method. We limited analyses to participants from South African sites and to women who used DMPA-IM, the alternative injectable norethisterone enanthate, implants, or copper intrauterine devices (IUDs). Contraceptive method was assessed as a time-dependent exposure and multivariate models adjusted for trial randomization arm, age, sexual behaviour, and incident sexually transmitted infections.

Results:
A total of 95 incident HIV-1 infections were observed: incidence 5.8 (DMPA-IM, n  = 52), 6.2 (norethisterone enanthate, n  = 28), 1.9 (implant, n  = 3), and 4.5 (IUD, n  = 12) cases per 100 woman-years. In multivariable models, there were no statistically significant differences between contraceptive methods in the risk of HIV-1 acquisition. However, compared with the IUD, the three hormonal methods each had point estimates near 1 while the implant had risk that was approximately half that of the IUD. When the three hormonal methods were combined, their relative risk compared with IUD was 0.90 (95% confidence interval 0.45–1.76).

Conclusion:
Among women at risk of HIV-1 infections in South Africa, we found no statistically significant differences in HIV-1 incidence by contraceptive method. Implants had the lowest point estimate for HIV-1 incidence, and IUDs had risk comparable with injectable methods in multivariate models. Large, prospective studies are needed to define better the relative HIV-1 risks across different contraceptive methods.

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Perinatal outcomes associated with maternal HIV and antiretroviral therapy in pregnancies with accurate gestational age in South Africa
Santosa, Wahyu B.; Staines-Urias, Eleonora; Tshivuila-Matala, Chrystelle O.O.; More
AIDS. 33(10):1623-1633, August 1, 2019.

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Objective:
To assess the association of maternal HIV infection and antiretroviral therapy (ART) with perinatal outcomes among women with accurate pregnancy dating and birth weights.

Design:
Prospective pregnancy cohort study in Soweto, South Africa.

Methods:
Gestational age was estimated by first-trimester ultrasound and birth weight was measured in a standardized manner within 24 h of birth. The primary composite outcome ‘adverse perinatal outcome’ included preterm birth, low birth weight, small for gestational age, stillbirth and neonatal death (NND). Specific adverse perinatal outcomes were secondary outcomes. Logistic regression models adjusted for multiple confounders.

Results:
Of 633 women included in the analysis, 229 (36.2%) were HIV positive and 404 (63.8%) HIV negative. Among 125 HIV-positive women who provided detailed information on HIV and ART, 96.7% had clinical stage 1 of HIV disease and 98.4% were on ART during pregnancy, mostly WHO-recommended efavirenz-based ART. Among 109 HIV-positive women with information on timing of ART initiation, 38 (34.9%) initiated ART preconception and 71 (65.1%) antenatally. No newborns were HIV positive. In univariable analysis, maternal HIV infection was associated with increased risk of the composite ‘adverse perinatal outcome’ [odds ratio (OR) 1.44; 95% confidence interval (CI) 1.03, 2.03], NND (OR 6.15; 95% CI 1.27, 29.88) and small for gestational age (OR 1.55; 95% CI 1.01, 2.37). After adjusting for confounders, maternal HIV infection remained associated with ‘adverse perinatal outcome’ (adjusted OR 1.47; 95% CI 1.01, 2.14) and NND (adjusted OR 7.82; 95% CI 1.32, 46.42). No associations with timing of ART initiation were observed.

Conclusion:
Despite high ART coverage, good maternal health and very low vertical HIV transmission rate, maternal HIV infection remained associated with increased risk of adverse perinatal outcomes. Larger studies using first trimester ultrasound for pregnancy dating are needed to further assess associations with specific adverse perinatal outcomes.

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SDC
Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa predicted effect of using a single viral load to define efavirenz-based first-line failure
Shroufi, Amir; Van Cutsem, Gilles; Cambiano, Valentina; More
AIDS. 33(10):1635-1644, August 1, 2019.

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Background:
Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.

Methods:
To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.

Findings:
The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14–20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6–30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8–49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67–3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.

Interpretation:
As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

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SDC
Long-term evolution of CD4+ cell count in patients under combined antiretroviral therapy
Pantazis, Nikos; Papastamopoulos, Vasilios; Paparizos, Vasilios; Metallidis, Simeon; Adamis, Georgios; Antoniadou, Anastasia; Psichogiou, Mina; Chini, Maria; Sambatakou, Helen; Sipsas, Nikolaos V.; Gogos, Charalambos; Chrysos, Georgios; Panagopoulos, Periklis; Katsarou, Olga; Gikas, Achilleas; Touloumi, Giota; on behalf of the AMACS Less
AIDS. 33(10):1645-1655, August 1, 2019.

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Objective:
Combined antiretroviral treatment (cART) results in profound immunologic improvement, but it is unclear whether CD4 + cell counts return to levels similar to those of HIV-negative individuals. We explore long-term CD4 + cell count evolution post-cART and its association with baseline levels, virologic suppression, pre-cART cumulative viremia and other factors.

Design:
Data were derived from the AMACS. Included individuals were adults who started cART, at least 2003, while previously ART-naive.

Methods:
Changes in CD4 + cell counts were modeled through piecewise linear mixed models.

Results:
A total of 3405 individuals were included. The majority was male (86.0%), homosexual (58.8%) with median (IQR) age at cART initiation 36 (31–44) years and a median (IQR) follow-up of 3.9 (2.0–6.9) years. Most persons (57%) starting cART with less than 200 cells/μl did not reach 600 cells/μl after 7 years of treatment. Those starting cART with 200–349 CD4 + cells/μl could reach 600 cells/μl within less than 2 years of fully suppressive treatment. Probability of CD4 + normalization (i.e. >800 cells/μl) after 7 years of suppressive treatment was 24 and 46% for those starting treatment with less than 200 or 200–349 CD4 + cells/μl, respectively. Lower pre-cART cumulative viremia was associated with faster CD4 + recovery. CD4 + cell count increases after 4 years were either insignificant or very slow, irrespectively of baseline levels.

Conclusion:
cART initiation before CD4 + cell count drops below 350 cells/μl is crucial for achieving normal CD4 + levels. These findings underline the importance of timely diagnosis and cART initiation as the risk of both AIDS and non-AIDS-related morbidity/mortality remains increased in patients with incomplete CD4 + recovery.

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Tenofovir concentrations in hair strongly predict virologic suppression in breastfeeding women
Murnane, Pamela M.; Bacchetti, Peter; Currier, Judith S.; Brummel, Sean; Okochi, Hideaki; Phung, Nhi; Louie, Alexander; Kuncze, Karen; Hoffman, Risa M.; Nematadzira, Teacler; Soko, Dean K.; Owor, Maxensia; Saidi, Friday; Flynn, Patricia M.; Fowler, Mary G.; Gandhi, Monica Less
AIDS. 33(10):1657-1662, August 1, 2019.

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Background:
Antiretroviral treatment (ART) adherence is often suboptimal in the perinatal period. We measured hair tenofovir (TFV) concentrations as a metric of adherence in postpartum women to understand patterns and predictors of adherence throughout this critical period. In addition, we examined the association between hair TFV concentrations and virologic outcomes.

Methods:
Between 12/2012 and 09/2016, hair samples were collected longitudinally from delivery through breastfeeding from women on ART in the Promoting Maternal and Infant Survival Everywhere study (NCT01061151) in sub-Saharan Africa. Hair TFV levels were measured using validated methods. Using generalized estimating equations, we estimated the association between hair TFV levels and virologic suppression (<400 copies/ml) over time and assessed predictors of hair TFV levels.

Results:
Hair TFV levels were measured at 370 visits in 71 women from delivery through a median of 14 months (interquartile range 12–15) of breastfeeding. Levels ranged from below detection (0.002) to 1.067 ng/mg (geometric mean: 0.047). After at least 90 days on ART, 69 women had at least one viral load measured (median 5 measures, range 1–9); 18 (26%) experienced viremia at least once. Each doubling of TFV level more than doubled odds of concurrent virologic suppression [odds ratio 2.35, 95% confidence interval (CI): 1.44–3.84, P  = 0.0006] and was associated with 1.43 times the odds of future suppression (95% CI: 0.75–2.73, P  = 0.28). Relative to the first 3 months after delivery, hair levels were highest in months 6–12 (1.42-fold higher, 95% CI: 1.09–1.85, P  = 0.01).

Conclusion:
Hair TFV levels strongly predicted concurrent virologic suppression among breastfeeding women. Objective adherence metrics can supplement virologic monitoring to optimize treatment outcomes in this important transition period.

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Comparative effectiveness of first-line antiretroviral therapy results from a large real-world cohort after the implementation of dolutegravir
Meireles, Mariana Veloso; Pascom, Ana Roberta P.; Duarte, Elisabeth C.; More
AIDS. 33(10):1663-1668, August 1, 2019.

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Objective:
We aimed to assess the effectiveness of first-line antiretroviral therapy (ART) regimens in achieving viral suppression at 12 months, from 2014 to 2017 in Brazil.

Design:
A retrospective cohort study utilizing programmatic data from the Brazilian HIV Program.

Methods:
Adults (aged 15–80 years) who started ART from January 2014 to July 2017 and had a viral load 365 (±90) days after treatment initiation were included. Associations with achieving viral suppression (<50 copies/ml) at 365 (±90) days were assessed using logistic regression. Our main study variable was ART regimen, and covariates included year of ART initiation, sex/exposure group, age, education, race, region, baseline CD4 + and viral load counts, and adherence measured by pharmacy refill data. We performed both intent-to-treat and per-protocol analogous analyses.

Results:
Out of 107 647 ART-naive patients, 71.5% initiated with tenofovir/lamivudine/efavirenz (TLE) and 10.5% with tenofovir/lamivudine/dolutegravir (TLD). Median age and CD4 + cell counts were 34 [interquartile range (IQR) 26–46] and 379 cells/μl (IQR 190–568), respectively; 68.0% were men. Viral suppression by 12 months was 84.0% [95% confidence interval (95% CI) 83.7–84.2] with TLE and 90.5% (95% CI 90.0–91.0) with TLD, and below 80% for protease-inhibitor-based regimens. In the multivariable intent-to-treat-analogous analysis, controlling for cofactors related to viral suppression including adherence, the adjusted odds ratio (aOR) for TLD's viral suppression relative to TLE was 1.56 (95% CI 1.40–1.75). Findings were robust to secondary per-protocol analogous and sensitivity analysis.

Conclusion:
Our results showed the superiority of dolutegravir- over efavirenz- and protease-inhibitor-based regimens in suppressing viral replication in a real-word cohort of HIV-positive adults. This superiority was not driven by higher levels of adherence with dolutegravir-based regimens.

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GCH1 haplotypes and cardiovascular risk in HIV
Slaven, James E.; Haas, David W.; Liu, Ziyue; More
AIDS. 33(10):1669-1671, August 1, 2019.

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Heightened systemic inflammation contributes to cardiovascular (CVD) events in people living with HIV (PLWH), although not all PLWH develop CVD, thus suggesting a genetic modifying role. We examined GCH1 polymorphisms, which have been associated with reduced endothelial function in European populations with CVD and increased inflammation, in a racially diverse cohort of US PLWH initiating antiretroviral therapy (ART). GCH1 polymorphisms differed by race and were not associated with flow-mediated dilation or carotid intima–media thickness before or after 48 weeks of ART.