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Browsing by Author "Grinsztejn, Beatriz"

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A picture is worth a thousand words: maps of HIV indicators to inform research, programs, and policy from NA-ACCORD and CCASAnet clinical cohorts
(2016-04-04) Althoff, Keri N; Rebeiro, Peter F; Hanna, David B; Padgett, Denis; Horberg, Michael A; Grinsztejn, Beatriz; Abraham, Alison G; Hogg, Robert; Gill, M John; Wolff, Marcelo J; Mayor, Angel; Rachlis, Anita; Williams, Carolyn; Sterling, Timothy R; Kitahata, Mari M; Buchacz, Kate; Thorne, Jennifer E; Cesar, Carina; Cordero, Fernando M; Rourke, Sean B; Sierra-Madero, Juan; Pape, Jean W; Cahn, Pedro; McGowan, Catherine
Antiretroviral therapy and Kaposi’s sarcoma trends and outcomes among adults with HIV in Latin America
(2021-01-06) Castilho, Jessica L; Kim, Ahra; Jenkins, Cathy a; Grinsztejn, Beatriz; Gotuzzo, Eduardo; Fink, Valeria; Padgett, Denis; Belaunzaran-Zamudio, Pablo F; Crabtree-Ramírez, Brenda; Escuder, Maria Mercedes; Souza, Rosa Alencar; Tenore, Simone B; Pimentel, Sidnei R; Rodrigues Ikeda, Maria Letícia; de Alencastro, Paulo R; Tupinanbas, Unai; Brites, Carlos; Luz, Estela; Netto, Juliana; Cortes, Claudia; Grangeiro, Alexandre; Shepherd, Bryan E; McGowan, Catherine C; The Caribbean, Central, South America network for HIV Epidemiology (CCASAnet)
Abstract Introduction Kaposi’s sarcoma (KS) remains the most frequent malignancy in persons living with HIV (PWH) in Latin America. We examined KS trends and outcomes from Latin American clinical sites in the era of increased access to antiretroviral therapy (ART). Methods Cohorts in Brazil, Peru, Mexico, Honduras, Argentina and Chile contributed clinical data of PWH ≥16 years old from 2000 to 2017, excluding patients with KS diagnosed before clinic enrolment. We compared KS incidence over time using multivariable incidence rate ratios. Predictors of KS before/at or after ART initiation and of mortality after KS were examined using Cox regression. Results Of 25 981 PWH, 481 had incident KS, including 200 ART-naïve and 281 ART-treated patients. From 2000 to 2017, the incidence of KS decreased from 55.1 to 3.0 per 1000 person-years. In models adjusting for CD4 and other factors, the relative risk for KS decreased from 2000 to 2008. Since 2010, the adjusted risk of KS increased in the periods before and ≤90 days after ART initiation but decreased >90 days after ART. In addition to low CD4 and male-to-male sex, KS risk after ART was associated with age and history of other AIDS-defining illnesses. Mortality after KS (approximately 25% after five years) was not associated with either year of KS diagnosis nor timing of diagnosis relative to ART initiation. Conclusions KS incidence in Latin America has remained stable in recent years and risk is highest before and shortly after ART initiation. Early diagnosis of HIV and ART initiation remain critical priorities in the region.
Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women
(2021-08) Landovitz, Raphael; Donnell, Deborah J.; Clement, Meredith; Hanscom, Brett; Cottle, Leslie; Coelho, Lara; Cabello, Robinson; Chariyalertsak, Suwat; Dunne, Eileen F.; Frank, Ian; Gallardo-Cartagena, Jorge A.; Gaur, Aditya H.; Gonzales, Pedro; Tran, Ha V.; Hinojosa, Juan C.; Kallas, Esper; Kelley, Colleen F.; Losso, Marcelo H.; Valdez Madruga, J.; Middelkoop, Keren; Phanuphak, Nittaya; Santos, Breno R.; Sued, Omar; Valencia Huamaní, Javier; Overton, Edgar T.; Swaminathan, Shobha; del Rio, Carlos; Gulick, Roy M.; Richardson, Paul; Sullivan, Philip; Piwowar-Manning, Estelle M.; Marzinke, Mark; Hendrix, Craig; Li, Maoji; Wang, Zhe; Marrazzo, Jeanne; Daar, Eric; Asmelash, Aida; Brown, Todd T.; Anderson, Peter; Eshleman, Susan H.; Bryan, Marcus; Blanchette, Cheryl; Lucas, Jonathan; Psaros, Christina; Safren, Steven A.; Sugarman, Jeremy; Scott, Hyman; Eron, Joseph; Fields, Sheldon D.; Sista, Nirupama D.; Gomez, Kailazarid; Jennings, Andrea; Kofron, Ryan M.; Holtz, Timothy H.; Shin, Katherine; Rooney, James F.; Smith, Kimberly; Spreen, William; Margolis, David; Rinehart, Alex; Adeyeye, Adeola; Cohen, Myron; McCauley, Marybeth; Grinsztejn, Beatriz
BACKGROUND Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate–emtricitabine (TDF–FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF–FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF–FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS CAB-LA was superior to daily oral TDF–FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.)
Can herpes simplex virus type 2 suppression slow HIV disease progression: A study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial
(2010) Tan, Darrell H. S. T.; Raboud, Janet M.; Kaul, Rupert; Grinsztejn, Beatriz; Cahn, Pedro; Walmsley, Sharon L.
Background: Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression. Methods/design: The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4+ T-cell count ≤ 350 cells/mm(3) or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log10 HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms. Discussion: Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications. Trial registration: Current Controlled Trials ISRCTN66756285. ClinicalTrials.gov NCT00860977.
Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results from the randomised, double-blind, non-inferiority SAILING study
(2013) Cahn, Pedro; Pozniak, A. L.; Mingrone, H.; Shuldyakov, A.; Brites, C.; Andrade-Villanueva, Jaime; Gary, Richmond; Buendia, C. B.; Fourie, J.; Ramgopal, M.; Hagins, D.; Felizarta, F.; Madruga, J.; Reuter, T.; Newman, T.; Small, C. B.; Lombaard, J.; Grinsztejn, Beatriz; Dorey, D.; Underwood, M.; Griffith, S.; Min, S.
Background: Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. Methods: ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Findings: Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). Interpretation: Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group.
Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial
(2019-03-28) Dooley, Kelly E; Kaplan, Richard; Mwelase, Noluthando; Grinsztejn, Beatriz; Ticona, Eduardo; Lacerda, Marcus; Sued, Omar; Belonosova, Elena; Ait-Khaled, Mounir; Angelis, Konstantinos; Brown, Dannae; Singh, Rajendra; Talarico, Christine L; Tenorio, Allan R; Keegan, Michael R; Aboud, Michael; International Study of Patients with HIV on Rifampicin ING study group
Background The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis. Methods International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1–infected antiretroviral therapy–naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. Results For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65–86%) for DTG and 82% (36/44, 95% CI 70–93%) for EFV. The DTG nonresponses were driven by non–treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS. Conclusions Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated. Clinical Trials Registration NCT02178592.
Early Retention in Care Neither Mediates Nor Modifies the Effect of Sex and Sexual Mode of HIV Acquisition on HIV Survival in the Americas
(https://doi.org/10.1089/apc.2018.0028, 2018-08-01) Coelho, Lara; Rebeiro, Peter F; Castilho, Jessica L; Caro-Vega, Yanink; Mejia, Fernando A; Cesar, Carina; Cortes, Claudia; Padgett, Denis; McGowan, Catherine C; Veloso, Valdiléa G; Sterling, Timothy R; Grinsztejn, Beatriz; Shepherd, Bryan E; Luz, Paula M; for the CCASAnet
Early retention in care, sex, and sexual mode of HIV acquisition has been associated with mortality risk among persons living with HIV (PLWH). We assessed whether early retention in care mediates or modifies the association between mortality and sex and sexual mode of HIV acquisition among PLWH on antiretroviral therapy (ART) in the Americas. ART-naïve, adult PLWH (≥18 years) enrolling at Caribbean, Central and South America network for HIV epidemiology (CCASAnet) and Vanderbilt Comprehensive Care Clinic sites 2000–2015, starting ART, and with ≥1 visit after ART-start were included. Early retention in care was defined as ≥2 HIV care visits/labs ≥90 days apart in the first year of ART. Cox models assessed the association between early retention in care, sex, and sexual mode of HIV acquisition [i.e., women, heterosexual men and men who have sex with men (MSM)], and mortality. Associations were estimated separately by site and pooled. Among 11,721 included PLWH (median follow-up, 4.3 years; interquartile range, 2.0–7.6), 647 died (rate = 10.9/1000 person-years) and 1985 were lost to follow-up (rate = 33.6/1000 person-years). After adjustment for confounders, early retention in care was associated with lower mortality during subsequent years (pooled hazard ratio = 0.47; 95% confidence interval = 0.39–0.57). MSM had lower and heterosexual men had comparable mortality risk to women; risks were similar when adjusting for early retention in care. Additionally, no evidence of an interaction between early retention in care and sex and sexual mode of HIV acquisition on mortality was observed (p > 0.05). Early retention in care substantially reduced mortality but does not mediate or modify the association between sex and sexual mode of HIV acquisition and mortality in our population.
Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial
(2007) Madruga, Jose Valdez; Cahn, Pedro; Grinsztejn, Beatriz; Haubrich, Richard; Lalezari, Jacob; Mills, Andrew; Pialoux, Gilles; Wilkin, Timothy; Peeters, Monika; Vingerhoets, Johan; de Smedt, Goedele; Leopold, Ludovic; Trefiglio, Ronald; Woodfall, Brian; DUET-1 study group
Background: Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). Methods: DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. Findings: 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9-25; p=0.005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). Interpretation: In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.
Fostemsavir in Adults with Multidrug Resistant HIV-1 Infection
(2020-3) Kozal, Michael; Aberg, Judith; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean-Michel; Grinsztejn, Beatriz; Diaz, Ricardo; Castagna, Antonella; Kumar, Princy; Latiff, Gulam; DeJesus, Edwin; Gummel, Mark; Gartland, Margaret; Pierce, Amy; Ackerman, Peter; Llamoso, Cyril; Lataillade, Max
BACKGROUND Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.)
Health outcomes among HIV-positive Latinos initiating antiretroviral therapy in North America versus Central and South America
(2016-03-18) Cesar, Carina; Koethe, John R; Giganti, Mark J; Rebeiro, Peter; Althoff, Keri N; Napravnik, Sonia; Mayor, Angel; Grinsztejn, Beatriz; Wolff, Marcelo; Padgett, Denis; Sierra-Madero, Juan; Gotuzzo, Eduardo; Sterling, Timothy R; Willig, James; Levison, Julie; Kitahata, Mari; Rodriguez-Barradas, Maria C; Moore, Richard D; McGowan, Catherine; Bryan E, Shepherd; Cahn, Pedro; for the Caribbean, Central and South America Network for HIV epidemiology (CCASAnet) and the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)
Introduction Latinos living with HIV in the Americas share a common ethnic and cultural heritage. In North America, Latinos have a relatively high rate of new HIV infections but lower rates of engagement at all stages of the care continuum, whereas in Latin America antiretroviral therapy (ART) services continue to expand to meet treatment needs. In this analysis, we compare HIV treatment outcomes between Latinos receiving ART in North America versus Latin America. Methods HIV-positive adults initiating ART at Caribbean, Central and South America Network for HIV (CCASAnet) sites were compared to Latino patients (based on country of origin or ethnic identity) starting treatment at North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) sites in the United States and Canada between 2000 and 2011. Cox proportional hazards models compared mortality, treatment interruption, antiretroviral regimen change, virologic failure and loss to follow-up between cohorts. Results The study included 8400 CCASAnet and 2786 NA-ACCORD patients initiating ART. CCASAnet patients were younger (median 35 vs. 37 years), more likely to be female (27% vs. 20%) and had lower nadir CD4 count (median 148 vs. 195 cells/µL, p<0.001 for all). In multivariable analyses, CCASAnet patients had a higher risk of mortality after ART initiation (adjusted hazard ratio (AHR) 1.61; 95% confidence interval (CI): 1.32 to 1.96), particularly during the first year, but a lower hazard of treatment interruption (AHR: 0.46; 95% CI: 0.42 to 0.50), change to second-line ART (AHR: 0.56; 95% CI: 0.51 to 0.62) and virologic failure (AHR: 0.52; 95% CI: 0.48 to 0.57). Conclusions HIV-positive Latinos initiating ART in Latin America have greater continuity of treatment but are at higher risk of death than Latinos in North America. Factors underlying these differences, such as HIV testing, linkage and access to care, warrant further investigation.
HIV/AIDS prevention, care and treatment in the Region of the Americas: achievements, challenges and perspectives
(2016-12) Pérez, Freddy; Ravasi, Giovanni; Figueroa J, Peter; Grinsztejn, Beatriz; Kamb, Mary; Sued, Omar; Ghidinelli, Massimo
The world has pledged within the Sustainable Development Goals to end the AIDS epidemic by 2030. In Latin America and the Caribbean in 2015 approximately 2.0 million people were living with HIV and an estimated 100 000 new infections occurred. Yet, significant progress has been made in the Region of the Americas over the past ten years in expanding access and coverage of HIV care and treatment and in achieving elimination of mother-to-child transmission of HIV and syphilis (1, 2). Regarding HIV prevention, and HIV stigma and discrimination new regional elimination targets have also been developed and endorsed (3). However, challenges still persist; among them, a 3% increase in the rate of new HIV infections in the Region between 2010 and 2015 (4). This special issue on HIV/AIDS prevention, care and treatment in the Region of the Americas: achievements, challenges and perspectives provides an opportunity to present the current response to HIV/AIDS in the Region with a focus on three main areas: HIV prevention, HIV care and treatment, and the elimination of mother-to-child transmission of HIV and congenital syphilis. A call for papers was issued in early 2016, and 12 articles were selected for publication—nine original research papers, one brief communication, one review, and one opinion and analysis article. The papers represent seven different countries as well as an overview of the Caribbean sub-region. A successful HIV prevention program requires a combination of structural, biomedical, and behavioral interventions that are mutually reinforcing, continually evaluated, and tailored to the needs and risks of specific key populations and others who are vulnerable to infection. Previous reports have shown the importance of combination prevention strategies (5). The special issue addresses this by focusing on HIV prevention strategies available for men who have sex with men in the United States (6), as well as the social vulnerability of transgender persons (7). Both papers highlight the need for tailored interventions that take into account local epidemiological contexts.
Monitoring of HIV treatment in seven countries in the WHO Region of the Americas
(2015-8) Belaunzarán-Zamudio, Pablo; Caro-Vega, Yanink; Shepherd, Bryan E; Crabtree-Ramirez, Brenda; Luz, Paula; Grinsztejn, Beatriz; Cesar, Carina; Cahn, Pedro; Cortes, Claudia; Wolff, Marcelo; Pape, Jean W; Padgett, Denis; Gotuzzo, Eduardo; McGowan, Catherine; Sierra Madero, Juan; CCASAnet
Objective: To determine the prevalence of adequate monitoring and the costs of measuring CD4+ T-lymphocytes (CD4+ cell) and human immunodeficiency virus (HIV) viral load in people receiving antiretroviral therapy (ART) in seven countries in the WHO Region of the Americas. Methods: We obtained retrospective, longitudinal data for 14 476 adults who started a first ART regimen at seven HIV clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru between 2000 and 2011. We estimated the proportion of 180-day periods with adequate monitoring, which we defined as at least one CD4+ cell count and one viral load measurement. Factors associated with adequate monitoring were analysed using regression methods. The costs of the tests were estimated. Findings: The median follow-up time was 50.4 months; the proportion of 180-day periods with adequate CD4+ cell counts was 69% while the proportion with adequate monitoring was 62%. Adequate monitoring was more likely in participants who were older, who started ART more recently, whose first regimen included a non-nucleoside reverse transcriptase inhibitor or who had a CD4+ cell count less than 200 cells/µl at ART initiation. The cost of one CD4+ cell count ranged from 7.37 United States dollars (US$) in Argentina to US$ 64.09 in Chile; the cost of one viral load measurement ranged from US$ 20.34 in Brazil to US$ 186.28 in Haiti. Conclusion: In HIV-infected participants receiving ART in the WHO Region of the Americas, CD4+ cell count and viral load monitoring was often carried out less frequently than regional guidelines recommend. The laboratory costs of monitoring varied greatly.
Rapid Development of an Integrated Network Infrastructure to Conduct Phase 3 COVID-19 Vaccine Trials
(2023-01) Mena Lora, Alfredo J.; Long, Jessica E.; Huang, Yunda; Baden, Lindsey R.; El Sahly, Hana M.; Follmann, Dean; Goepfert, Paul; Gray, Glenda; Grinsztejn, Beatriz; Kotloff, Karen; Rouphael, Nadine; Sobieszczyk, Magdelena; Walsh, Stephen R.; Andriesen, Jessica; Shah, Karan A.; Zhang, Yuanyuan; Gilbert, Peter; Janes, Holly; Gay, Cynthia L.; Falsey, Ann R.; Tripp, Rebecca L.; Gorman, Richard L.; Tong, Tina; Marovich, Mary; Neuzil, Kathleen; Corey, Lawrence; Kublin, James G.
Importance The COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts. Observations To support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing clinical and laboratory infrastructure, community partnerships, and research expertise to quickly pivot clinical trial sites to conduct COVID-19 vaccine trials as soon as the investigational products were ready for phase 3 testing. The mission of CoVPN was to operationalize phase 3 vaccine trials using harmonized protocols, laboratory assays, and a single data and safety monitoring board to oversee the various studies. These trials, while staggered in time of initiation, overlapped in time and course of conduct and ultimately led to the successful completion of multiple studies and US Food and Drug Administration–licensed or –authorized vaccines, the first of which was available to the public less than 1 year from the discovery of the virus. Conclusions and Relevance This Special Communication describes the design, geographic distribution, and underlying principles of conduct of these efficacy trials and summarizes data from 136 382 prospectively followed-up participants, including more than 2500 with documented COVID-19. These successful efforts can be replicated for other important research initiatives and point to the importance of investments in clinical trial infrastructure integral to pandemic preparedness.
Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): A phase 3 randomised double-blind active-controlled trial
(2011) Molina, Jean-Michel; Cahn, Pedro; Grinsztejn, Beatriz; Lazzarin, Adriano; Mills, Andrew; Saag, Michael; Supparatpinyo, Khuanchai; Walmsley, Sharon L.; Crauwels, Herta; Rimsky, Laurence T.; Vanveggel, Simon; Boven, Kristof
Background: Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1. Rilpivirine, a new non-nucleoside reverse transcriptase inhibitor, has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors. We aimed to assess the efficacy, safety, and tolerability of rilpivirine versus efavirenz, each combined with tenofovir-disoproxil-fumarate and emtricitabine. Methods: We did a phase 3, randomised, double-blind, double-dummy, active-controlled trial, in patients infected with HIV-1 who were treatment-naive. The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater, and viral sensitivity to all study drugs. Our trial was done at 112 sites across 21 countries. Patients were randomly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz, each with tenofovir-disoproxil-fumarate and emtricitabine. Our primary objective was to show non-inferiority (12% margin) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response (viral load <50 copies per mL intention-to-treat time-to-loss-of-virological-response [ITT-TLOVR] algorithm) at week 48. Our primary analysis was by intention-to-treat. We also used logistic regression to adjust for baseline viral load. This trial is registered with ClinicalTrials.gov, number NCT00540449. Findings: 346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was -0.4 (95% CI -5.9 to 5.2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11%vs 4% by ITT-TLOVR). Grade 2-4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p<0.0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine. Interpretation: Rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological-failure rate, but a more favourable safety and tolerability profile. Funding: Tibotec.
Ritonavir-Boosted Tipranavir Demonstrates Superior Efficacy to Ritonavir-Boosted Protease Inhibitors in Treatment-Experienced HIV-Infected Patients: 24-Week Results of the RESIST-2 Trial
(2006-11-15) Cahn, Pedro; Villacian, Jorge; Lazzarin, Adriano; Katlama, Christine; Grinsztejn, Beatriz; Arasteh, Keikawus; López, Paulo; Clumeck, Nathan; Gerstoft, Jan; Stavrianeas, Nikolas; Moreno, Santiago; Antunes, Francisco; Neubacher, Dietmar; Mayers, Douglas
Background. Tipranavir, a novel protease inhibitor, has demonstrated antiviral activity against protease inhibitor—resistant human immunodeficiency virus type 1 (HIV-1) isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-2) trial is an ongoing, open-label, phase III trial comparing ritonavir-boosted tipranavir (TPV/r) plus an optimized background regimen with an individually optimized, ritonavir-boosted protease inhibitor in treatment-experienced, HIV-1-infected patients. Methods. Patients at 171 sites in Europe and Latin America who had received ⩾2 previous protease inhibitor regimens, had triple-antiretroviral class experience, had an HIV-1 RNA level ⩾1000 copies/mL, and had genotypically demonstrated primary protease inhibitor resistance were eligible. After genotypic resistance tests were performed, a protease inhibitor and optimized background regimen were selected before randomization. Patients were randomized to receive either TPV/r or comparator protease inhibitor—ritonavir (CPI/r) and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed HIV-1 load reduction ⩾1 log10 less than the baseline value without a treatment change at week 24. Results. A total of 863 patients were randomized and treated. At baseline, the mean HIV-1 load was 4.73 log10 copies/mL, and the mean CD4+ cell count was 218 cells/mm3. The preplanned 24-week efficacy analyses of 539 patients demonstrated treatment response rates of 41% in the TPV/r arm and 14.9% in the CPI/r arm (intent-to-treat analysis; P < .0001). The mean CD4+ cell count increased by 51 cells/mm3 in the TPV/r arm and by 18 cells/mm3 in the CPI/r arm. The most common adverse events were mild-to-moderate diarrhea, nausea, and headache. Grade 3 or greater elevations in serum transaminase, cholesterol, and triglyceride levels were more frequent in the TPV/r arm. Conclusions. TPV/r had superior antiviral activity and increased immunologic benefits, compared with CPI/r, at week 24 among treatment-experienced patients infected with multidrug-resistant HIV-1.
Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study
(Elsevier, 2020) Lataillade, Max; Lalezari, Jacob P.; Kozal, Michael; Aberg, Judith A.; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean-Michel; Moreno, Santiago; Grinsztejn, Beatriz; Diaz, Ricardo S.; Castagna, Antonella; Kumar, Princy N.; Latiff, Gulam H.; De Jesus, Edwin; Wang, Marcia; Chabria, Shiven; Gartland, Margaret; Pierce, Amy; Ackerman, Peter; Llamoso, Cyril
Background Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. Methods BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. Findings Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per μL (SD 191) in the randomised cohort and 119 cells per μL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per μL. Interpretation In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population.
Segurança e eficácia da terapia antirretroviral baseada em dolutegravir, na semana 48, em adultos coinfectados hiv/tb
(2018-12) Dooley, Kelly E; Kaplan, Richard; Mwelase, Noluthando; Grinsztejn, Beatriz; Ticona, Eduardo; Lacerda, Marcus; Sued, Omar; Belonosova, Elena; Ait‐Khaled, Mounir; Angelis, Kostas; Brown, Dannae; Singh, Rajendra; Talarico, Christine; Tenorio, Allan; Keegan, Michael; Aboud, Michael; Zajdenverg, Roberto
Introdução: O tratamento concomitante da tuberculose e do HIV é desafiador devido às interações medicamentosas, à sobreposição de toxicidades e à síndrome de reconstituição imune (IRIS/SIRI). Objetivo: A eficácia e a segurança de dolutegravir (DTG) foram avaliadas nos adultos coinfectados com HIV e tuberculose. Metodologia: Inspiring é um estudo fase 3 b, aberto, não comparativo, com controle ativo, randomizado, em adultos que vivem com HIV‐1, virgens de tratamento (CD4+ > ou = 50 cels/mm3) com TB responsiva ao tratamento. Os participantes em tratamento para TB baseado em rifampicina até oito semanas foram randomizados (3:2) para receber DTG (50 mg duas vezes ao dia até duas semanas após término do tratamento da TB, seguido por 50 mg uma vez ao dia) ou EFV (600 mg uma vez ao dia) com dois ITRNs por 52 semanas. O desfecho primário foi a proporção de voluntários em uso de DTG com HIV‐1 < 50 c/mL (respondedores). Resultado: Os participantes foram randomizados para DTG (n = 69) ou EFV (n = 44). A proporção de respondedores na semana 48 (ITT‐E) foi 52/69 (75%) para DTG e 36/44 (82%) para EFV. Ausência de resposta ao DTG foi decorrente primordialmente por interrupções não relacionadas ao tratamento: 11 voluntários (16%) com DTG e três (7%) com EFV descontinuaram por razões não relacionadas ao tratamento, embora suprimidos (principalmente por perda de seguimento). Houve duas falhas virológicas definidas pelo protocolo (PDVF), mas sem emergência de mutações de resistência ao tratamento (RAMs) no braço de DTG e uma PDVF com EFV, com RAMs para ITRN e ITRNN. A mediana de aumento da contagem de CD4+ na semana 48 foi de 220 cels/mm3 com DTG e 190 cels/mm3 com EFV. Dois voluntários em uso de EFV interromperam o tratamento por eventos adversos. As taxas de IRIS associada à TB foram baixas (DTG, n = 4 [6%]; EFV, n = 4 [9%]). Nenhum participante interrompeu o tratamento por causa de IRIS nem por eventos hepáticos. O sucesso do tratamento da tuberculose foi de 61/69 (88%) e 39/44 (89%) com DTG e EFV, respectivamente. A mediana de concentração mínima de DTG durante o uso de dolutegravir duas vezes ao dia com rifampicina foi semelhante à de dolutegravir uma vez ao dia sem rifampicina. Discussão/conclusão: Esses resultados revelam que dolutegravir (DTG) é eficaz e bem tolerado em adultos coinfectados por TB e HIV que recebem tratamento para tuberculose com rifampicina.
Substance use and adherence among people living with HIV/ AIDS receiving cART in Latin America
(2016-04) De Boni, Raquel B; Shepherd, Bryan E; Grinsztejn, Beatriz; Cesar, Carina; Cortes, Claudia; Padgett, Denis; Gotuzzo, Eduardo; Belaunzarán-Zamudio, Pablo; Rebeiro, Peter F; Duda, Stephany N; McGowan, Catherine C
This cross-sectional study describes substance use prevalence and its association with combination antiretroviral therapy (cART) adherence among 3343 individuals receiving care at HIV clinics in Argentina, Brazil, Chile, Honduras, Mexico, and Peru. A rapid screening tool evaluated self-reported 7-day recall of alcohol, marijuana, cocaine, heroin, and methamphetamine use, and missed cART doses. Overall, 29.3 % individuals reported having ≥1 alcoholic drinks, 5.0 % reported any illicit drug use and 17.0 % reported missed cART doses. In the logistic regression model, compared to no substance use, alcohol use [adjusted odds ratio (AOR) = 2.46, 95 % confidence interval (CI): 1.99–3.05], illicit drug use (AOR = 3.57, 95 % CI: 2.02–6.30), and using both alcohol and illicit drugs (AOR = 4.98, 95 % CI: 3.19–7.79) were associated with missed cART doses. The associations between substance use and likelihood of missing cART doses point to the need of targeting alcohol and illicit drug use to improve adherence among people living with HIV in Latin America
Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America
(2018-05-08) Fink, Valeria; Jenkins, Cathy A; Castilho, Jessica L; Person, Anna K; Shepherd, Bryan E; Grinsztejn, Beatriz; Netto, Juliana; Crabtree-Ramirez, Brenda; Cortes, Claudia; Padgett, Denis; Jayathilake, Karu; McGowan, Catherine; Cahn, Pedro
Background This study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort. Methods Demographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer ≤ 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type. Results Among 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range [IQR]: 32–47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio [aHR] = 1.63, p = 0.02), age (aHR = 1.02 per year, p = 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year, p = 0.01). Conclusion ADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.
The HIV epidemic in Latin America: a time to reflect on the history of success and the challenges ahead
(2020-01) Crabtree-Ramírez, Brenda; Belaunzarán-Zamudio, Pablo F; Cortes, Claudia P; Morales, Miguel; Sued, Omar; Sierra-Madero, Juan; Cahn, Pedro; Pozniak, Anton; Grinsztejn, Beatriz

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