Publications by authors named "Sharlaa Badal-Faesen"

26 Publications

  • Page 1 of 1

Efavirenz pharmacokinetics and HIV-1 viral suppression among patients receiving TB treatment containing daily high-dose rifapentine.

Clin Infect Dis 2021 Dec 16. Epub 2021 Dec 16.

University of Nebraska Medical Center, USA.

Background: A four-month regimen containing rifapentine and moxifloxacin has non-inferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with HIV-associated TB.

Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing ART (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB co-treatment (Weeks 4, 8, 12 and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if >80% of participants had mid-interval efavirenz concentrations meeting this target.

Results: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs. without TB drugs was 0.79 [90% CI 0.72-0.85] in EFV1 and 0.84 [90% CI 0.69-0.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations >1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%.

Conclusions: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment.
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http://dx.doi.org/10.1093/cid/ciab1037DOI Listing
December 2021

Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis.

Pharmacogenet Genomics 2022 01;32(1):24-30

Northwestern University Feinberg School of Medicine, Infectious Diseases Division, Chicago, Illinois, USA.

Objective: In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction.

Methods: In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed.

Results: Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing.

Conclusions: Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.
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http://dx.doi.org/10.1097/FPC.0000000000000448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578190PMC
January 2022

Sexually transmitted infections among HIV serodiscordant partners: A secondary analysis of HIV Prevention Trial Network 052.

Int J STD AIDS 2021 11 7;32(13):1204-1211. Epub 2021 Jul 7.

Department of Medicine, 6797University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Sexually transmitted infections (STIs) remain a public health concern because of their interaction(s) with HIV. In the HPTN 052 study, STIs were evaluated in both HIV-positive index cases and their HIV-negative partners at enrollment and at yearly follow-up visits. Our definition for STI was based on any infection with , syphilis, or We used log-binomial regression models to identify factors associated with prevalent STIs. Generalized estimating equation models with the Poisson distribution were used to compare STI incidence between HIV-positive index cases and HIV-negative partners. 8.1% of the participants had STIs at enrollment. The prevalence of STIs (8.9 vs. 7.2) was higher in HIV-positive index cases than HIV-negative partners. Being female (prevalence ratio (PR) = 1.61; 95% CI: 1.20-2.16) or unmarried (PR = 1.92; 95% CI: 1.17-3.14) was associated with prevalent STIs. Compared to HIV-negative male partners, HIV-positive female index cases had a higher risk of STI acquisition (incidence rate ratio (IRR) = 2.25; 95% CI: 1.70-2.97). While we are implementing HIV prevention interventions for HIV-negative people, we should also intensify targeted STI prevention interventions, especially among HIV-positive women.
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http://dx.doi.org/10.1177/09564624211030368DOI Listing
November 2021

Antiretroviral hair levels, self-reported adherence, and virologic failure in second-line regimen patients in resource-limited settings.

AIDS 2021 07;35(9):1439-1449

University of California, San Francisco, California, USA.

Objective: To evaluate associations between hair antiretroviral hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes.

Design: Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line protease inhibitor-based antiretroviral therapy (ART) but were susceptible to at least one nucleoside reverse transcriptase inhibitor (NRTI) and their protease inhibitor, and continued taking their protease inhibitor-based regimen.

Methods: Antiretroviral hair concentrations in participants taking two NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography--tandem-mass-spectrometry assays. Participants' self-reported percentage of doses taken in the previous month; virologic failure was confirmed HIV-1 RNA at least 1000 copies/ml at week 24 or 48.

Results: From 181 participants with hair samples (61% women, median age: 39 years; CD4+ cell count: 167 cells/μl; HIV-1 RNA: 18 648 copies/ml), 91 (50%) experienced virologic failure at either visit. At 24 weeks, median hair concentrations were 2.95 [interquartile range (IQR) 0.49-4.60] ng/mg for atazanavir, 2.64 (IQR 0.73--7.16) for lopinavir, and 0.44 (IQR 0.11--0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with virologic failure, the hazard ratio (95% CI) for ATV, LPV, and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27), respectively.

Conclusion: Protease inhibitor hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of second-line treatment failure in need of interventions.
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http://dx.doi.org/10.1097/QAD.0000000000002901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243835PMC
July 2021

Resistance to Mycobacterium tuberculosis Infection Among Household Contacts: A Multinational Study.

Clin Infect Dis 2021 09;73(6):1037-1045

Emory Rollins School of Public Health, Atlanta, Georgia, USA.

Background: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to M. tuberculosis (resisters).

Methods: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cutoffs (0 vs <5 mm), classification of missing test results, and exposure level.

Results: In total, 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. And 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cutoffs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, human immunodeficiency virus (HIV) coinfection, or comorbid conditions.

Conclusions: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.
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http://dx.doi.org/10.1093/cid/ciab269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442792PMC
September 2021

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BMC Infect Dis 2021 Feb 24;21(1):205. Epub 2021 Feb 24.

Department of Internal Medicine, Section of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-8106, USA.

Background: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).

Methods: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.

Results: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.

Conclusions: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
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http://dx.doi.org/10.1186/s12879-021-05884-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903693PMC
February 2021

Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S20-S30

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial.

Methods: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model.

Results: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy.

Conclusions: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed.

Clinical Trials Registration: NCT0234429.
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http://dx.doi.org/10.1093/infdis/jiaa214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347076PMC
July 2020

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination.

HIV Res Clin Pract 2020 02 11;21(1):11-23. Epub 2020 Mar 11.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities. To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process. Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support. Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino. REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams.
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http://dx.doi.org/10.1080/25787489.2020.1733794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664829PMC
February 2020

Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial.

Lancet Digit Health 2019 05 6;1(1):e26-e34. Epub 2019 May 6.

University of Washington, Seattle, WA, USA.

Summary:

Background: Antiretroviral therapy (ART) non-adherence causes HIV treatment failure. Past behaviour might predict future behaviour; failing second-line ART could indicate ongoing risk for subsequent non-adherence. We aimed to find out whether a two-way mobile phone-based communication intervention would increase HIV treatment success by improving medication adherence.

Methods: We did a multinational, randomised controlled trial of patients at 17 sites in nine lower-income and middle-income countries in Africa, Asia, and the Americas. Patients aged 18 years and older, with HIV infection, and on second-line protease-inhibitor-based antiretroviral regimens, were randomly assigned (1:1) to either two-way mobile phone intervention plus standard of care (MPI + SOC) adherence support or standard-of-care alone (SOC). Our study was nested within a strategy study of ART after second-line ART failure (the main study, A5288). The main study had four cohorts, which were assigned regimens according to ART history and real-time genotype. Randomisation was stratified by the main study cohort with dynamic institutional balancing. Only the clinical management committee was masked, not the participants or site personnel. Text messages were sent over 48 weeks starting once a day and tapering down to once per week; participants were to respond once to each message if taking ART without issues. Repeated non-response to three messages over a 2-week period for the first 8 weeks, and then two messages over a 2-week period for the remainder of the study, triggered problem-solving counselling by staff. For this study, the primary endpoint was plasma HIV-1 RNA 200 copies per mL or less at 48 weeks and the secondary endpoint was virological failure (two consecutive HIV-1 RNA ≥1000 copies per mL) at 24 or more weeks. Prespecified intention-to- treat analyses were adjusted for cohort. Follow-up continued until the last participant had reached 48 weeks, with a median follow-up time of 72 weeks. The trial is registered with ClinicalTrials.gov, number .

Findings: Enrolment began on Feb 22, 2013, and ended on Dec 21, 2015, with the last participant completing follow-up on Feb 13, 2017. Of 545 participants in the main study, 521 (96%) were enrolled and randomly assigned to MPI + SOC (n=257) or SOC alone (n=264). 52% of patients were men and the median HIV-1 RNA 4-4 log copies per mL (IQR 3.5 to 5-2). At week 48, HIV-1 RNA 200 copies per mL or less was reached in 169 (66%) of 257 patients in the MPI + SOC group and 164 (62%) of 264 patients in the SOC group (estimated difference 3-6% [95% CI -4-6% to 11-9%]; p=0-39). The adjusted odds ratio comparing MPI + SOC and SOC was 1-23 (0-82 to 1-84; p=0-32). Virological failure occurred in 66 (26%) patients in the MPI + SOC group and 89 (34%) patients in the SOC group during the median 72 weeks follow-up (adjusted p=0-027). Observed difference in virological failure favoured MPI + SOC in all cohorts. 23 (4%) participants died, 11 (4%) in the MPI + SOC group and 12 (5%) in the SOC group (p=0-89), with none of the deaths ascribed to ART, the MPI, or study procedures.

Interpretation: Two-way MPI did not significantly improve week 48 suppression, but it did modestly affect virological failure. People failing second-line ART might not achieve benefits from phone-based triggers or enhanced adherence support (or both). More effective strategies are needed.
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http://dx.doi.org/10.1016/S2589-7500(19)30006-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746315PMC
May 2019

Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency.

Clin Infect Dis 2020 07;71(3):517-524

Northwestern University Feinberg School of Medicine, Infectious Diseases Division, Chicago, Illinois, USA.

Background: Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation.

Methods: This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis.

Results: Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration.

Conclusions: DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed.

Clinical Trials Registration: NCT02412436.
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http://dx.doi.org/10.1093/cid/ciz863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384316PMC
July 2020

Human Immunodeficiency Virus-associated Neurocognitive Impairment in Diverse Resource-limited Settings.

Clin Infect Dis 2019 05;68(10):1733-1738

Frontier Science & Technology Research Foundation, Buffalo, New York.

Background: Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment.

Methods: The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations.

Results: Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168.

Conclusions: Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments.

Clinical Trials Registration: NCT00096824.
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http://dx.doi.org/10.1093/cid/ciy767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495019PMC
May 2019

Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial.

Clin Nutr 2019 06 29;38(3):1303-1309. Epub 2018 May 29.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address:

Background & Aims: Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation.

Methods: We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B, B, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation.

Results: In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status.

Conclusions: In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.
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http://dx.doi.org/10.1016/j.clnu.2018.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265110PMC
June 2019

Predictors of switch to and early outcomes on third-line antiretroviral therapy at a large public-sector clinic in Johannesburg, South Africa.

AIDS Res Ther 2018 04 10;15(1):10. Epub 2018 Apr 10.

Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: While efficacy data exist, there are limited data on the outcomes of patients on third-line antiretroviral therapy (ART) in sub-Saharan Africa in actual practice. Being able to identify predictors of switch to third-line ART will be essential for planning for future need. We identify predictors of switch to third-line ART among patients with significant viraemia on a protease inhibitor (PI)-based second-line ART regimen. Additionally, we describe characteristics of all patients on third-line at a large public sector HIV clinic and present their early outcomes.

Methods: Retrospective analysis of adults (≥ 18 years) on a PI-based second-line ART regimen at Themba Lethu Clinic, Johannesburg, South Africa as of 01 August 2012, when third-line treatment became available in South Africa, with significant viraemia on second-line ART (defined as at least one viral load ≥ 1000 copies/mL on second-line ART after 01 August 2012) to identify predictors of switch to third-line (determined by genotype resistance testing). Third-line ART was defined as a regimen containing etravirine, raltegravir or ritonavir boosted darunavir, between August 2012 and January 2016. To assess predictors of switch to third-line ART we used Cox proportional hazards regression among those with significant viraemia on second-line ART after 01 August 2012. Then among all patients on third-line ART we describe viral load suppression, defined as a viral load < 400 copies/mL, after starting third-line ART.

Results: Among 719 patients in care and on second-line ART as of August 2012 (with at least one viral load ≥ 1000 copies/mL after 01 August 2012), 36 (5.0% over a median time of 54 months) switched to third-line. Time on second-line therapy (≥ 96 vs. < 96 weeks) (adjusted Hazard Ratio (aHR): 2.53 95% CI 1.03-6.22) and never reaching virologic suppression while on second-line ART (aHR: 3.37 95% CI 1.47-7.73) were identified as predictors of switch. In a separate cohort of patients on third-line ART, 78.3% (47/60) and 83.3% (35/42) of those in care and with a viral load suppressed their viral load at 6 and 12 months, respectively.

Conclusions: Our results show that the need for third-line is low (5%), but that patients' who switch to third-line ART have good early treatment outcomes and are able to suppress their viral load. Adherence counselling and resistance testing should be prioritized for patients that are at risk of failure, in particular those who never suppress on second-line and those who have been on PI-based regimen for extended periods.
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http://dx.doi.org/10.1186/s12981-018-0196-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891887PMC
April 2018

HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy: HPTN 052.

J Acquir Immune Defic Syndr 2018 04;77(5):484-491

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Introduction: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015.

Methods: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure.

Results: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure.

Conclusions: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.
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http://dx.doi.org/10.1097/QAI.0000000000001623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844834PMC
April 2018

Impact of Larger Sputum Volume on Xpert MTB/RIF Assay Detection of Mycobacterium tuberculosis in Smear-Negative Individuals with Suspected Tuberculosis.

J Clin Med 2017 Aug 7;6(8). Epub 2017 Aug 7.

Clinical HIV Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg 2092, South Africa.

As a strategy to improve the sensitivity of nucleic acid-based testing in acid-fast bacilli (AFB) negative samples, larger volumes of sputum (5-10 mL) were tested with Xpert MTB/RIF from 176 individuals with smear-negative sputum undergoing tuberculosis evaluation. Despite larger volumes, this strategy had a suboptimal sensitivity of 50% (4/8).
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http://dx.doi.org/10.3390/jcm6080078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575580PMC
August 2017

Comparison of Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Participants Enrolled in a Multinational Clinical Trial: HPTN 052.

J Acquir Immune Defic Syndr 2017 12;76(4):388-393

*Department of Pathology, Johns Hopkins Hospital, Baltimore, MD;†Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;‡Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;§FHI 360, Washington, DC;‖FHI 360, Durham, NC;¶Research Institute for Health Sciences, Chiang Mai University, Chaing Mai, Thailand;#University of North Carolina at Chapel Hill, Chapel Hill, NC;**UNC Project-Malawi, Institute for Global Health and Infectious Diseases, Lilongwe, Malawi;††YRGCARE Medical Centre, VHS, Chennai, India;‡‡College of Medicine-Johns Hopkins Project, Blantyre, Malawi;§§Instituto Nacional de Infectologia Evandro Chagas-INI-Fiocruz, Rio de Janeiro, Brazil;‖‖Hospital Geral de Nova Iguacu and Laboratorio de AIDS e Imunologia Molecular-IOC/Fiocruz, Rio de Janeiro, Brazil;¶¶Hospital Nossa Senhora da Conceição, Porto Alegre RS, Brazil;##Botswana Harvard AIDS Institute, Gaborone, Botswana;***Kenya Medical Research Institute, Kisumu, Kenya;†††Center for Disease Control, Kisumu, Kenya;‡‡‡University of the Witwatersrand, Perinatal HIV Research Unit, Soweto HPTN CRS, Soweto, South Africa;§§§University of Witwatersrand, Johannesburg, South Africa;‖‖‖Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; and¶¶¶Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(-)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052).

Method: HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with χ, Fisher exact, and median tests.

Results: Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(-) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(-) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(-). In HIV(+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase ≤ grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase ≤ grade 2, 26% vs. 6.0%, P < 0.001), CD4 trended lower, and HIV RNA was similar.

Conclusions: HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4.
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http://dx.doi.org/10.1097/QAI.0000000000001511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659928PMC
December 2017

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial.

J Bone Miner Res 2017 Sep 26;32(9):1945-1955. Epub 2017 Jun 26.

St Vincent's Hospital, Sydney, Australia.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual-energy X-ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent-to-treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow-up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non-white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow-up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow-up, immediate ART resulted in greater BMD declines than deferred ART at the hip (-2.5% versus -1.0%; difference -1.5%, 95% confidence interval [CI] -2.2 to -0.8, p < 0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV-related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer-term consequences of the observed reductions in BMD is needed.

Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555813PMC
September 2017

Insulin-Like Growth Factor Is Associated with Changes in Body Composition with Antiretroviral Therapy Initiation.

AIDS Res Hum Retroviruses 2017 Sep 16;33(9):929-934. Epub 2017 May 16.

11 Department of Medicine, Johns Hopkins University , Baltimore, Maryland.

Growth hormone (GH)/insulin-like growth factor (IGF)-1 axis abnormalities have been associated with body composition changes among HIV-infected persons with wasting or lipodystrophy. Little is known of GH/IGF-1 axis alterations with antiretroviral therapy (ART) initiation or differing ART therapies. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized clinical trial of ART initiation with emtricitabine/tenofovir + efavirenz (FTC/TDF+EFV) versus lamivudine/zidovudine + efavirenz (3TC/ZDV+EFV) in HIV-1-infected individuals from resource-diverse settings. IGF-1 was measured from baseline, week 48, and week 96 stored serum samples. Multivariate models were constructed. 415 participants were included: 170 (41%) were randomized to FTC/TDF+EFV and 245 (59%) to 3TC/ZDV+EFV. The mean age was 35 years, 60% were black, 42% women. The mean IGF-1 level did not change significantly from baseline to week 96 (-0.65 ng/ml; 95% confidence interval (CI) -5.18-3.87), p = .78 and there were no differences by treatment arm at week 96, p = .74. Lower baseline IGF-1 was associated with age, non-white race, greater waist-hip ratio (WHR), low CD4 count, and lower baseline albumin (all p < .01) but not plasma HIV-1 RNA, body mass index, or treatment arm. Greater change in IGF-1 from baseline to 96 weeks was associated with female sex, smaller WHR change, lower baseline albumin, and higher baseline HIV-1 RNA (all p < .01). ART initiation with either ZDV or TDF did not significantly impact overall IGF-1 levels. Baseline and on-treatment changes in IGF-1 with ART initiation may be related to the body composition changes that occur after ART initiation.
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http://dx.doi.org/10.1089/AID.2016.0327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576217PMC
September 2017

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial.

Lancet 2016 Mar;387(10024):1198-209

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Funding: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.
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http://dx.doi.org/10.1016/S0140-6736(16)00546-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931281PMC
March 2016

Brief Report: HIV Drug Resistance in Adults Failing Early Antiretroviral Treatment: Results From the HIV Prevention Trials Network 052 Trial.

J Acquir Immune Defic Syndr 2016 07;72(3):304-9

1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; 2Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 3Frontier Science & Technology Research Foundation, Amherst, NY; 4Specialty Molecular Division, Lancet Laboratories and BARC-SA, Johannesburg, South Africa; 5Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil; 6Y. R. Gaitonde Centre for AIDS Research and Education, Chennai, India; 7National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India; 8Science Facilitation Department, FHI 360, Washington, DC; 9Science Facilitation Department, FHI 360, Durham, NC; 10Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; 11Southwest CARE Center, Santa Fe, NM; 12College of Medicine-Johns Hopkins Project, Blantyre, Malawi; 13Botswana Harvard AIDS Institute, Gaborone, Botswana; 14YRGCARE Medical Centre, VHS, Chennai, India; 15Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; 16Department of Medicine, University of Zimbabwe, Harare, Zimbabwe; 17Wits Reproductive Health and HIV Institute, University of Witwatersrand, Johannesburg, South Africa; 18Kenya Medical Research Institute, Center for Disease Control, Kisumu, Kenya; 19Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC; 20UNC Project-Malawi, Institute for Global Health and Infectious Diseases, Lilongwe, Malawi; 21Serviço de Infectologia, Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil; 22Department of Epidemiology and Biostatistics, National AIDS Research Institute (ICMR), Pune, India; 23Hospital Geral de Nova Iguacu and Laboratorio de AIDS e Imunologia Molecular-IOC/Fiocruz, Rio de Janeiro, Brazil; 24Instituto Nacional de Infectologia Evandro Chagas-INI-Fiocruz, Rio de Janeiro, Brazil; 25Perinatal HIV Research Unit, University of the Witwatersrand, Soweto HPTN CRS, S

Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.
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http://dx.doi.org/10.1097/QAI.0000000000000951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911290PMC
July 2016

Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study.

J Acquir Immune Defic Syndr 2015 Oct;70(2):163-71

*Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; †Department of Medicine, University of California Davis, Sacramento, CA; ‡Department of Medicine, University of Colorado Denver, Aurora, CO; §Harvard University Center for AIDS Research, Harvard School of Public Health, Boston, MA; ‖University of North Carolina Project, Lilongwe, Malawi; ¶Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil; #Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil; **Department of Medicine, Chiang Mai University, Chiang Mai, Thailand; ††Department of Medicine, University of Witwatersrand, Johannesburg, South Africa; ‡‡IMPACTA PERU Clinical Trials Unit, Asociacion Civil Impacta Salud y Educacion, Lima, Peru; §§Department of Pulmonology, Nelson R Mandela School of Medicine, University of KwaZulu Natal, Durban, South Africa; ‖‖Malawi College of Medicine-Johns Hopkins Research Project, Kachere Rehabilitation Centre, Blantyre, Malawi; ¶¶National AIDS Research Institute, Pune, India; ##Les Centres GHESKIO, Port-au-Prince, Haïti; ***YR Gaitonde Center for AIDS Research and Education, Chennai, India; †††Department of Medicine, University of Zimbabwe, Harare, Zimbabwe; ‡‡‡Department of Medicine, University of California Davis, Sacramento, CA; and §§§Department of Ophthalmology, Johns Hopkins University, Baltimore, MD.

Background: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators.

Methods: A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models.

Results: Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21).

Conclusions: Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
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http://dx.doi.org/10.1097/QAI.0000000000000696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573329PMC
October 2015

Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230.

Clin Infect Dis 2015 May 18;60(10):1552-8. Epub 2015 Feb 18.

Duke University Medical Center, Durham, North Carolina.

Background: The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia.

Methods: Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models.

Results: One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively.

Conclusions: LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.

Clinical Trials Registration: NCT00357552.
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http://dx.doi.org/10.1093/cid/civ109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425828PMC
May 2015

Changes in HIV-1 subtypes B and C genital tract RNA in women and men after initiation of antiretroviral therapy.

Clin Infect Dis 2013 Jul 26;57(2):290-7. Epub 2013 Mar 26.

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 709 Mary Ellen Jones Bldg, CB7209, Chapel Hill, NC 27599-7209, USA.

Background: Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype.

Methods: HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens.

Results: One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4(+) cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected.

Conclusions: The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.
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http://dx.doi.org/10.1093/cid/cit195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689341PMC
July 2013

Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings.

AIDS 2012 Jul;26(11):1345-54

Duke University Medical Center, Durham, NC 27710, USA.

Objective: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs).

Design: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000  copies/ml.

Methods: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100  mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r.

Results: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400  copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40  copies/ml and 30 had levels 40-200  copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400  copies/ml.

Conclusion: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.
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http://dx.doi.org/10.1097/QAD.0b013e328353b066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443745PMC
July 2012

The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda and South Africa.

J Int AIDS Soc 2012 Jan 26;15(1). Epub 2012 Jan 26.

Pfizer Inc., New York, NY 10017, USA.

Background: The introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions.

Methods: HIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analyzed with disease characteristics, including viral load and CD4(+) and CD8(+) T cell counts.

Results: CCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naïve (TN) and treatment-experienced (TE) patients in India, 71% of TE South African patients, and 86% (subtype A/A1) and 71% (subtype D) of TN and TE Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (TE: 94%, TN: 97%) than in subtypes A (TE: 59%; TN: 91%) and D (TE: 30%; TN: 79%). R5 virus infection in all three subtypes correlated with higher CD4(+) count.

Conclusions: R5 HIV-1 was predominant in TN individuals with HIV-1 subtypes C, A, and D and TE individuals with subtypes C and A. Higher CD4(+) count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.
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http://dx.doi.org/10.1186/1758-2652-15-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298508PMC
January 2012

Similar safety and efficacy of once- and twice-daily lopinavir/ritonavir tablets in treatment-experienced HIV-1-infected subjects at 48 weeks.

J Acquir Immune Defic Syndr 2010 Jun;54(2):143-51

Projeto Praça Onze, UFRJ, Rio de Janeiro, Brazil.

Objectives: To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-experienced subjects.

Methods: Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed.

Results: Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups.

Conclusion: LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.
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http://dx.doi.org/10.1097/QAI.0b013e3181cbd21eDOI Listing
June 2010
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