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Browsing by Author "Cahn, Pedro"

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A phase 4, single-arm, open-label, pilot study of maraviroc, raltegravir and darunavir/r in HIV-1 adults with triple class failure: TERCETO study
(2012) Patterson, Patricia; Magneres, Claudia; Sued, Omar; Fink, Valeria; Figueroa, Maria Ines; Cesar, Carina; Gun, Ana; Cahn, Pedro; Krolewiecki, Alejandro J.
The purpose of this phase 4, single-arm, open-label study was to evaluate the safety, tolerability, efficacy, antiviral and immunological activity of maraviroc (MVC) in combination with raltegravir (RGV) and darunavir/r (DRV/r) in adult HIV-1 infected patients (pts) with limited treatment options. HIV-1 pts with documented virologic triple class failure or multi-drug class resistance defined as the presence of Q151 complex, 69 insertion complex and/or≥3 TAMs for NRTIs and K103N, G190S+Y181C or Y188L mutants for NNRTIs and≥3 RAMs (L10F/I/R/V; M46I/L; I54V/M/L; V82A/F/T/S; I84V; L90M) for protease inhibitors (PIs) were offered a triple drug regimen consisting of MVC 150 mg BID, RGV 400 mg BID and DRV/r 600/100 mg BID. Safety, lipid profile and virologic efficacy were evaluated at week 4, 12, 24, 36 and 48. Between January 2010 and March 2012, 27 pts were enrolled. Screening failure rate was 52% due to undetectable viral load (pVL) or non R5 tropism type (Trofile™). Despite being heavily pre-treated pts, only 26% had negative tropism test at SCR. Baseline characteristics of 13 included pts were: 77% male, median age 43 years (IQR: 40.1–48.6), 38% had a prior AIDS-defining condition. Median BSL pVL was 23,350 cps/mL (4.4 log10) (IQR: 11,236–55,785) and median CD4 was 222 cells/mm3 (IQR: 179–318). Median time on NRTIs, NNRTIs and PIs were 10.7 (8.6–13.7), 1.7 (1.3–7.6) and 5.4 (4.7–10) years respectively. Pts had received a median of 2 PIs (IQR: 2–3). 8/13 pts showed thymidine analogue-associated mutations (TAMs), and≥2 were present in 5/13. Detectable NNRTI resistance-associated mutations (RAMs) were present in 10/13 patients. 9/13 had≥4 primary PI RAMs. At 48 weeks, 2 pts had discontinued therapy (OIs related death (cryptococcal meningitis)=1, withdrawn from the study on W36 due to blips despite not achieving criteria for virologic failure=1) and the remaining pts (11/13) achieved undetectable pVL and increased CD4 in 133 cell/mm3 from BSL (IQR: 81–174.5). Median total cholesterol levels increased from 162 mg/dL (IQR: 135-188) to 215 mg/dL (IQR: 182–237) between BSL/W48; median change in cholesterol levels: 40 mg/dL (IQR: 6.5-66). Salvage therapy including MVC, RGV and DRV/r achieved sustained reductions in pVL (<50 copies/mL) through 48 weeks of therapy in this pilot study with no treatment limiting toxicity.
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
A Randomized Clinical Trial Comparing Nelfinavir Or Nevirapine Associated to Zidovudine/Lamivudine in HIV-Infected Naive Patients (The Combine Study)
(2002-07) Podzamczer, Daniel; Ferrer, Elena; Consiglio, Ezequiel; Mariá Gatell, José; Perez, Pepa; Perez, José Luis; Luna, Elena; González, Alicia; Pedrol, Enric; Lozano, Luisa; Ocaña, Imma; Llibre, Josep María; Casiró, Arnaldo; Aranda, Miquel; Barrufet, Pilar; Martínez-Lacasa, Javier; Miró, José María; Badía, Xavier; Casado, Alfonso; Lupo, Sergio; Cahn, Pedro; Maños, Manel; Estela, Jordi; The Combine Study Team (Members Listed In Appendix)
Background Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. Objective To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. Design Randomized, open-label, multicentre trial. Setting Twelve centres in Spain (9) and Argentina (3). Patients One hundred and forty-two HIV-infected naive patients without AIDS. Interventions Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. Results At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5–71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65–85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3–61.7) and 65% (95% CI 54.2–76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100 000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/ nevirapine in 25%, due to toxicity (P>0.2). Conclusions Our results suggest that zidovudine/ lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.
A Randomized, Open-Label Study of a Nucleoside Analogue Reverse Transcriptase Inhibitor-Sparing Regimen in Antiretroviral-Naive HIV-Infected Patients
(2009-03) Harris, Marianne; Côté, Hélène; Ochoa, Claudia; Allavena, Clotilde; Negredo, Eugenia; Thorne, Anona; Cahn, Pedro; Raffi, Francois; Clotet, Bonaventura; Singer, Joel; Montaner, Julio; The CTN 177 Study Team
A small cluster randomised clinical trial to improve health outcomes among Argentine patients disengaged from HIV care
(2022-06) Sued, Omar; Cecchini, Diego; Rolón, María José; Calanni, Liliana; David, Daniel; Lupo, Sergio; Cahn, Pedro; Cassetti, Isabel; Weiss, Stephen M.; Alcaide, Maria Luisa; Rodriguez, Violeta J.; Mantero, Alejandro; Jones, Deborah L.
Background Patients disengaged from HIV care, e.g., missed medication pick-ups, not attending physician visits, account for ≥70% of new HIV infections. Re-engaging and sustaining engagement is essential to controlling the HIV pandemic. This study tested a physician-delivered evidence-based intervention, Motivational Interviewing (MI), to improve health outcomes, adherence to antiretroviral therapy (ART), HIV virologic suppression, CD4+ count, retention in HIV care, and self-efficacy among patients disengaged from care in Argentina. Methods Regional clinics (n = 6) were randomised to condition, MI Intervention or Enhanced Standard of Care (ESOC), and recruited N = 360 patients disengaged from HIV care. ART adherence, HIV RNA viral load, CD4+ count retention, and self-efficacy were assessed at baseline, 6, 12, 18, and 24-months. Indirect effects from condition to main outcomes were examined using patient–provider relationship as a mediator. The study was a cluster-randomised clinical trial entitled Conexiones y Opciones Positivas en la Argentina 2 (COPA2) and was registered at clinicaltrials.gov, NCT02846350. Findings Participants were an average age of 39·15 (SD = 10·96), 51% were women; intervention participants were older (p = ·019), and more ESOC participants were women (60% vs. 42%, p = 0·001). Using mixed models, the intervention had no effect on ART adherence over time by condition on HIV RNA viral load, CD4+ count retention, or self-efficacy. However, analysing mediated paths, there was an indirect effect of condition on ART adherence (B = 0·188, p = 0·009), HIV viral load (B = -0·095, p = 0·027), and self-efficacy (B = 0·063, p = 0·001), suggesting the intervention was associated with improved patient–provider relationships, which was in turn associated with increased ART adherence, lower HIV viral load, and higher self-efficacy. Interpretation These findings suggest that physician-delivered MI may enhance the patient-provider relationship, self-efficacy, and ART adherence, and reduced HIV viral load in patients disengaged from HIV care. However, these findings are preliminary due to the small number of clusters randomised, and replication is warranted.
Abacavir Once or Twice Daily Combined With Once-Daily Lamivudine and Efavirenz for the Treatment of Antiretroviral-Naive HIV-Infected Adults: Results of the Ziagen Once Daily in Antiretroviral Combination Study
(2005-04-01) Moyle, Graeme J; DeJesus, Edwin; Cahn, Pedro; Castillo, Steve A; Zhao, Henry; Gordon, David N; Craig, Charles; Scott, Trevor R
The long intracellular half-life of abacavir (ABC) supports its once-daily use, and this would be expected to simplify treatment if ABC could be given as part of a complete once-daily regimen. A randomized double-blind clinical trial compared the efficacy and safety of 600 mg of ABC administered once daily (n = 384) versus 300 mg of ABC administered twice daily (n = 386) in combination with 300 mg of lamivudine (3TC) and 600 mg of efavirenz (EFV) administered once daily in antiretroviral-naive patients over 48 weeks. The baseline median plasma HIV-1 RNA level was 4.89 log10 copies/mL (44% with viral load >100,000 copies/mL), and the median CD4+ cell count was 262 cells/mm3. ABC administered once daily was non-inferior to the twice-daily regimen, with 66% and 68% of patients in these respective treatment arms achieving a confirmed plasma HIV-1 RNA level <50 copies/mL (95% confidence interval: −8.4%, 4.9%). The ABC once-daily and twice-daily regimens were similar with respect to infrequency of virologic failure (10% vs. 8%), emergence of resistance mutations, CD4+ cell increases from baseline (median, 188 vs. 200 cells/mm3), safety profile, and incidence of ABC-related hypersensitivity reactions (9% vs. 7%). ABC administered once daily in combination with 3TC and EFV administered once daily was non-inferior to the ABC twice-daily dosing schedule when combined with 3TC and EFV over 48 weeks. Current clinical management of HIV-1 disease necessitates use of a multidrug regimen generally including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent.1 Good adherence to potent antiretroviral therapy is critical in achieving a successful outcome. High pill burdens, dosing frequencies, risk of adverse events (AEs), drug interactions, and inconvenient dietary restrictions all potentially affect adherence and, ultimately, treatment efficacy.2,3 Patient preference surveys suggest that persons with HIV may prefer compact once-daily regimens if the efficacy and tolerability of these regimens are similar to those of the twice-daily standard of care regimens.3 Some antiretroviral drugs that have half-lives suitable for administration once a day (OAD) cannot be used together because of drug interactions and dietary restrictions. An expansion in the number of antiretroviral drugs approved for OAD dosing increases the potential for OAD therapy to become the preferred initial therapy. The NRTI abacavir (ABC) has demonstrated durable efficacy as a component of numerous regimens administered at a dose of 300 mg twice daily.4-6 A multidrug combination of 300 mg of ABC administered twice daily with lamivudine (3TC) and efavirenz (EFV) has been compared with 300 mg of zidovudine (ZDV) administered twice daily with 3TC and EFV and has resulted in similarly potent and durable virologic suppression (<50 copies/mL), superior CD4+ cell recovery, and good tolerability, including an improved hematologic profile over 48 weeks.7 Recent pharmacokinetic studies in HIV-1-infected adults have shown that the active drug moiety of ABC, carbovir triphosphate (CBV-TP), has a long intracellular half-life (>20 hours) that would support OAD dosing of 600 mg of ABC.8-10 A small clinical study in which 600 mg of ABC administered OAD was compared with 300 mg of ABC 300 administered twice daily suggested that ABC could be administered OAD and supported further investigation of this dosing schedule.11 The Ziagen Once Daily in Antiretroviral Combination (ZODIAC) therapy study was a noninferiority clinical trial conducted over 48 weeks that compared the efficacy and safety of triple drug therapy with 600 mg of ABC administered OAD versus 300 mg of ABC administered twice daily, combined with OAD 3TC and EFV, in the treatment of antiretroviral-naive adults.
Acceptability of dual HIV/syphilis rapid test in community- and home-based testing strategy among transgender women in Buenos Aires, Argentina
(2021-02-03) Zalazar, Virginia; Frola, Claudia; Gun, Ana; Radusky, Pablo; Panis, Natalia k; Cardozo, Nadir F; Fabian, Solange; Duarte, Mariana I; Aristegui, Ines; Cahn, Pedro; Sued, Omar
Background: Little is known of acceptability and feasibility of dual HIV and syphilis rapid tests in community- and home-based provider-initiated strategies among transgender women (TGW), in Latin America. Objectives were (1) to assess the acceptability of this strategy and, (2) to determine the percentage of positive results of HIV and syphilis, analyze the correlates of HIV or syphilis positive results, and measure the rates of effective referral and treatment completion among TGW. Methods: A multidisciplinary team tested 89 TGW in Buenos Aires. An acceptability survey was administered after the HIV/syphilis Duo test was used. All confirmed cases were referred for treatment initiation. Results: We found high levels of acceptability (98.8%) of this strategy among TGW. However, only 60.7% preferred simultaneous HIV and syphilis diagnosis test. Moreover, we found 9% of positive results of HIV, 51.7% of syphilis, and 3.4% of positive results for both infections. Only not being tested before was associated with an HIV positive result, and only low level of education was associated with a positive syphilis result. Among 8 TGW who tested positive for HIV, 37.5% (n = 3) started antiretroviral therapy. Of 46 who tested positive for syphilis, only 73.9% (n = 34) were effectively referred and from 23 who started treatment, only 39.1% completed it. Conclusions: Community- and home-based dual HIV and syphilis rapid test is a feasible and highly acceptable approach for this hard-to-reach population. Implementing similar strategies could improve screening uptake and accessibility. However, these results highlight the need to improve strategies for treatment uptake, in order to reduce morbidity and risk of onward transmission.
Acute HIV Seroconversion Presenting with Active Tuberculosis and Associated with High Levels of T-Regulatory Cells
(2011) Sued, Omar; Quiroga, Maria F.; Socias, Maria E.; Turk, Gabriela; Salomon, Horacio; Cahn, Pedro
A patient with well-defined acute HIV infection who developed concomitant pulmonary tuberculosis during the retroviral acute syndrome is reported here. In this patient high levels of T-regulatory cells (Tregs) and a low proliferation response to M. tuberculosis were initially detected, which normalized throughout follow-up. This case calls for the consideration of tuberculosis in patients in the early stages of HIV, and emphasizes the need for further study of the potential causal relationship between Treg cells and the risk of TB reactivation in HIV patients.
AIDS 2006 and beyond
(2006-10-28) Cahn, Pedro; McClure, Craig
The International AIDS Society (IAS) commends Richard Horton (Aug 26, p 716)1 for his provocative analysis of the XVI International AIDS Conference (AIDS 2006), which took place this past August in Toronto, Canada. Critical analysis and debate—two of the hallmarks of the conference—can only strengthen our collective response to this crisis. Yet Horton's claims that the conference is “disengaged”, and that the opportunity to produce a road map for the future was “squandered”, as outlined in the ten points of his Comment, merit a response from the IAS as lead organiser of these meetings.
Antiretroviral Drugs for Preventing Mother-to-Child Transmission of HIV: A Review of Potential Effects on HIV-Exposed but Uninfected Children
(2011) Heidari, Shirin; Mofenson, Lynne; Cotton, Mark F.; Marlink, Richard; Cahn, Pedro; Katabira, Elly
Objective Antiretroviral drugs (ARVs) can prevent HIV mother-to-child transmission (PMTCT), but in utero ARV exposure may be associated with neurologic symptoms due to mitochondrial toxicity (MT). We sought to identify the currently recommended PMTCT regimen that optimally balances risks of pediatric HIV infection and neurologic MT. Design Published MTCT and MT data were used in a decision analytic model of MTCT among women in sub-Saharan Africa. Methods We investigated the HIV and MT risks associated with no ARV prophylaxis and five recommended regimens ranging from single-dose nevirapine to 3-drug ART. Sensitivity analyses varied all parameters, including infant feeding strategy and the disability of MT relative to HIV. Results Provision of no ARVs is the least effective and least toxic strategy, with 18-month HIV risk of 30.4% and MT risk of 0.2% (breastfed infants). With increasing drug number and duration, HIV risk decreases markedly (to 4.9% with 3-drug ART), but MT risk also increases (to 2.2%, also with 3-drug ART). Despite increased toxicity, 3-drug ART minimizes total adverse pediatric outcomes (HIV plus MT), unless the highest published risks are true for both HIV and MT, or the disability from MT exceeds 6.4 times that of HIV infection. Conclusions The risk of pediatric MT from effective PMTCT regimens is at least an order of magnitude lower than the risk of HIV infection associated with less effective regimens. Concern regarding MT should not currently limit the use of 3-drug ART for PMTCT where it is available.
Antiretroviral Treatment of Adult HIV Infection 2010 Recommendations of the International AIDS Society-USA Panel
(2010) Thompson, Melanie A.; Aberg, Judith A.; Cahn, Pedro; Montaner, Julio; Rizzardini, Giuliano; Telenti, Amalio; Gatell, Jose; Günthard, Huldrych F.; Hammer, Scott M.; Hirsch, Martin S.; Jacobsen, Donna M.; Reiss, Peter; Richman, Douglas D.; Volberding, Paul A.; Yeni, Patrick; Schooley, Robert T.; International AIDS Society-USA
Context Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviralnaive and antiretroviral-experienced patients warrant an update of the International AIDS Society–USA guidelines for the use of antiretroviral therapy in adults with HIV infection. Objectives To provide updated recommendations for management of HIVinfected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. Data Sources and Study Selection A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. Data Extraction and Synthesis New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. Conclusions Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count 500/µL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count 500/µL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.
Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the International AIDS Society–USA Panel
(2008) Hammer, Scott M.; Eron, Joseph J. Jr.; Reiss, Peter; Schooley, Robert T.; Thompson, Melanie A.; Walmsley, Sharon L.; Cahn, Pedro; Fischl, Margaret A.; Gatell, Jose; Hirsch, Martin S.; Jacobsen, Donna M.; Montaner, Julio; Richman, Douglas D.; Yeni, Patrick; Volberding, Paul A.; International AIDS Society-USA
Context: The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection. Objectives: To summarize new data in the field and to provide current recommendations for the antiretroviral management and laboratory monitoring of HIV infection. This report provides guidelines in key areas of antiretroviral management: when to initiate therapy, choice of initial regimens, patient monitoring, when to change therapy, and how best to approach treatment options, including optimal use of recently approved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced patients. Data sources and study selection: A 14-member panel with expertise in HIV research and clinical care was appointed. Data published or presented at selected scientific conferences since the last panel report (August 2006) through June 2008 were identified. Data extraction and synthesis: Data that changed the previous guidelines were reviewed by the panel (according to section). Guidelines were drafted by section writing committees and were then reviewed and edited by the entire panel. Recommendations were made by panel consensus. Conclusions: New data and considerations support initiating therapy before CD4 cell count declines to less than 350/microL. In patients with 350 CD4 cells/microL or more, the decision to begin therapy should be individualized based on the presence of comorbidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readiness for treatment. In addition to the prior recommendation that a high plasma viral load (eg, >100,000 copies/mL) and rapidly declining CD4 cell count (>100/microL per year) should prompt treatment initiation, active hepatitis B or C virus coinfection, cardiovascular disease risk, and HIV-associated nephropathy increasingly prompt earlier therapy. The initial regimen must be individualized, particularly in the presence of comorbid conditions, but usually will include efavirenz or a ritonavir-boosted protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine). Treatment failure should be identified and managed promptly, with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNA level below assay detection limits.
Apricitabine: A Novel Deoxycytidine Analogue Nucleoside Reverse Transcriptase Inhibitor for the Treatment of Nucleoside-Resistant HIV Infection
(2007-04) Wainberg, Mark A; Cahn, Pedro; Bethell, Richard C; Sawyer, James; Cox, Susan
Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65–80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6–7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10 HIV RNA copies/ml, respectively, after 10 days of treatment (P<0.0001 versus placebo). ATC showed a low propensity to select for resistance mutants in vitro and during clinical monotherapy. ATC was well tolerated in volunteers and in HIV-infected patients. This promising profile suggests that ATC may be useful in treating patients who have failed previous lamivudine- or emtricitabine-containing regimens. Further studies to evaluate the long-term efficacy and tolerability of ATC are underway.
Asking the right questions: developing evidence-based strategies for treating HIV in women and children
(2011) Karim, Quarraisha A.; Banegura, Antoine; Cahn, Pedro; Christie, Charmagne D.; Dintruff, Robin; Distel, Michael; Hankins, Catherine; Hellmann, Nicholas; Katabira, Elly; Lehrman, Sandra; Montaner, Julio; Purdon, Scott; Rooney, James F.; Woof, Robin; Heidari, Shirin
In July 2010, the World Health Organization (WHO) issued formal revisions of its guidelines on the use of highly active antiretroviral therapy for HIV. The new guidelines greatly expand eligibility for treatment of adults and children, as well as for pregnant women seeking prophylaxis for vertical HIV transmission. WHO's new recommendations bring the guidelines closer to practices in developed countries, and its shift to earlier treatment alone will increase the number of treatment-eligible people by 50% or more. Scaling up access to HIV treatment is revealing important gaps in our understanding of how best to provide for all those in need. This knowledge gap is especially significant in developing countries, where women and children comprise a majority of those living with HIV infection. Given the magnitude and significance of these populations, the International AIDS Society, through its Industry Liaison Forum, prioritized HIV treatment and prophylaxis of women and children. In March 2010, the International AIDS Society and 15 partners launched a Consensus Statement outlining priority areas in which a relative lack of knowledge impedes delivery of optimal prevention of mother to child transmission (PMTCT) and treatment to women and children. The Consensus Statement, "Asking the Right Questions: Advancing an HIV Research Agenda for Women and Children", makes a special appeal for a more gender-sensitive approach to HIV research at all stages, from conception to design and implementation. It particularly emphasizes research to enhance the understanding of sex-based differences and paediatric needs in treatment uptake and response. In addition to clinical issues, the statement focuses on programmatic research that facilitates access and adherence to antiretroviral regimens. Better coordination of HIV management with sexual and reproductive healthcare delivery is one such approach. We discuss here our knowledge gaps concerning effective, safe PMTCT and treatment for women and children in light of the expansion envisioned by WHO's revised guidelines. The guideline's new goals present an opportunity for advancing the women and children's agenda outlined in the Consensus Statement.
Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression
(2016-04-08) Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortes, Claudia; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro
Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings.
Atazanavir—A Once-daily HIV Protease Inhibitor That Does Not Cause Dyslipidemia in Newly Treated Patients: Results from Two Randomized Clinical Trials
(2004) Cahn, Pedro; Gatell, Jose; Squires, Kathleen; Percival, Lisa D; Piliero, Peter J; Sanne, Ian A; Shelton, Sarah; Lazzarin, Adriano; Odeshoo, Linda; Kelleher, Thomas D; Thiry, Alexandra; Giordano, Michael D; Schnittman, Stephen M
Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.
Beyond the first 25 years: The International AIDS Society and its role in the global response to AIDS
(2006-12-01) Cahn, Pedro; McClure, Craig
Dr. Pedro Cahn, International AIDS Society (IAS) President and Mr. Craig McClure, IAS Executive Director, provide their thoughts and analysis on the current and future role of the IAS as part of the global response to HIV/AIDS.
Bioinformatic analysis of post-transmission viral readaptation in Argentine patients with acute HIV-1 infection
(2020-07) Damilano, G; Sued, Omar; Satorres, S; Ruiz, Maria; Ghiglione, Y; Guzman, F; Turk, Gabriela ; Quiroga, F; Cahn, Pedro; Salomon, Horacio; Dilernia, Dario
During the acute phase of HIV-1 infection, a strong readaptation occurs in the viral population. Our objective was to analyze the post-transmission mutations associated with escape to the cytotoxic immune response and its relationship with the progression of the infection. In this study, a total of 17 patients were enrolled during acute/early primary HIV infection and 8 subjects that were the HIV positive partner resulting in 8 transmission pairs. Genotyping of the genetic polymorphisms of HLA class I A and B was performed using PCR-SSOP. Viral RNA extraction was from plasma. 570 single Gag-gene amplifications were obtained by limiting-dilution RT-PCR. Epitope prediction was performed with NetMHC CBS prediction server for the 19 HLA-A and single bondB alleles. Cytotoxic response prediction was performed by using the IEDB Analysis Resource. From our results, we deduce that the transmitted CTL / gag escape frequency in the founder virus was at least double compared to the post-transmission events. Additionally, by means of an algorithm that combines these frequencies, we observed that the founder viruses better adapted to the HLA A / B alleles of the recipient could contribute to a greater progression of the infection. Our results suggest that there is a large adaptation of HIV-1 to the HLA A / B alleles prevalent in our population. However, despite this adaptive advantage, the virus needs to make “readjustments” through new escape and compensatory mutations. Interestingly, according to our results, this readaptation could have a role in the progression of the infection.
Biterapia con atazanavir/ritonavir más raltegravir versus terapia triple en segunda línea: Ensayo ARTE
(Fundación Huésped - Sociedad Argentina de Infectología, 2023-07) Figueroa, María Inés; Sued, Omar; Cesar, Carina; Patterson, Patricia; Yamamoto, Cleyton; Fink, Valeria; Luna, Norma; Camiro-Zúñiga, Antonio; Gun, Ana; Cahn, Pedro
Antecedentes: La terapia dual ha surgido como un nuevo concepto para el tratamiento del VIH. Este estudio tenía como objetivo comparar un régimen dual basado en ATV/r + RAL (TD) frente a estándar de tres drogas con ATV/r + TDF/FTC (TT) luego del fracaso de un primer esquema ba- sado en INNTR.ClinicalTrials.gov, Número: NCT01829802. Método: Estudio piloto abierto, multicéntrico y aleatoriza- do. Resultado primario: proporción de sujetos con ARN del VIH-1 menor a 50 copias/mL en semana 48 (S48). Resulta- dos secundarios: discontinuaciones asociadas a eventos adversos (EA), tiempo transcurrido hasta la supresión viral, desarrollo de mutaciones de resistencia a la integrasa y proteasa, cambio en recuento de CD4. Resultados: De los 57 participantes seleccionados, 34 fue- ron asignados aleatoriamente para recibir: TD (n: 18) o TT (n: 16). En semana 48, 67% (n: 12/18) en TD tuvo respues- ta virológica y 88% (n: 14/16) en rama según el análisis FDA, intención de tratamiento/expuestos (p = NS) y 73% (TD) y 93% (TT) según análisis por protocolo (p = NS). El cambio de CD4 entre basal - S48: +119 y +52 células/μL en DT y TT, respectivamente. Cuatro participantes en TD y uno en TT presentaron fracaso virológico en la semana 48. Un participante desarrolló una mutación de resistencia a integrasa (155H). Conclusión: ATV/r+RAL como terapia dual de segunda línea mostró una tendencia al fracaso virológico más frecuente, en comparación con TT, aunque el estudio piloto no tenía potencia para demostrar esta diferencia. Este estudio está registrado en ClinicalTrials.gov, Número: NCT01829802.
Boosting HIV Treatment Options: Good News, New Challenges
(2013) Cahn, Pedro; Sued, Omar
For >15 years, ritonavir (RTV) has been the only pharmacokinetic enhancer (ie, booster) for human immunodeficiency virus (HIV) protease inhibitors. The development of cobicistat (COBI) promises to provide an alternative to RTV without direct antiviral effects of its own. COBI, a potent cytochrome P450 3A (CYP3A) inhibitor recently approved by the Food and Drug Administration (FDA) for use in a single-tablet regimen of elvitegravir/COBI/emtricitabine(FTC)/tenofovir disoproxil fumarate (TDF), is currently being studied in phase 3 trials as booster of other antiretroviral drugs. In vitro studies demonstrate that COBI, unlike RTV, is a weak inhibitor for CYP2D6 and does not have inhibitory effects on other CYP isoforms (ie, CYP1A2, CYP2C09, and CYP2c19), making pharmacologic interactions more predictable [1]. COBI also seems to have less impact than RTV on normal adipocyte functions, such as lipid accumulation and/or response to insulin, which may offer the potential for fewer adverse biochemical effects relative to RTV [2]. In addition, the better solubility of COBI allows creation of a tablet formulation and coformulations that might foster the availability of other single-tablet regimens. In this issue of the Journal, Gallant et al report the 48-week results of a study comparing COBI with RTV as a pharmacoenhancer for atazanavir (ATV) plus FTC/TDF in 698 treatment-naive HIV type 1 (HIV-1)–infected patients. Study subjects were recruited in the United States, the Dominican Republic, Mexico, Thailand, Portugal, Germany, the United Kingdom, Italy, and Switzerland and were randomly assigned in a 1:1 ratio to receive COBI or RTV. Most of the participants (60%) were white, and similar to other large trials, the proportion of women (17%) was low. Twenty-four percent reported Hispanic/Latino ethnicity. The study allowed the inclusion of individuals with active hepatitis, with hepatitis B present in 3.6% of patients and hepatitis C in 5.3%. The immunologic status of the patients was relatively good, with 48% having CD4+ T-cell count of >350 cells/mL, reflecting the latest recommendations for treatment initiation [3]. Randomization was stratified by viral load, with 39.7% of patients having >100 000 HIV RNA copies/mL at baseline. Of the 692 patients who initiated treatment with the study medication, 344 were in the COBI arm and 348 were in the RTV arm. At 48 weeks, COBI-boosted ATV was shown to be virologically noninferior to RTV-boosted ATV, with 293 patients (85.2%) and 304 patients (87.4%) in the COBI and RTV arms, respectively, achieving an HIV-1 RNA load of <50 copies/mL, in accordance with the FDA snapshot intention-to-treat analysis (observed difference, −2.2% [95% confidence interval, −7.4% to 3.0%]). Mean increases in CD4+ T-cell counts were also similar in the COBI and RTV groups (+213 cells/mm3 and +219 cells/mm3, respectively at week 48). Favorable responses were comparable in patients with a high viral load (86.4% in the COBI group vs 86.0% in the RTV group). Of the 95 subjects who were not reported as having achieved virologic success, treatment in 34 was defined as virologic failure (5.8% and 4% in the COBI and RTV arms, respectively), but this small difference was not statistically significant. The remaining 61 patients discontinued the protocol because of adverse events or other reasons, despite having undetectable viral loads. No major tolerability issues were reported. Gastrointestinal adverse events were not statistically different between the COBI and RTV groups, with similar rates of nausea (17.7% and 16.4%, respectively), vomiting (7.3% and 4.6%, respectively), or diarrhea (15.4% and 20.4%, respectively), but only 2 patients (1 in each arm) had to stop treatment because of gastrointestinal complaints. A similar tolerability profile was shown in another study comparing elvitegravir/COBI/FTC/TFV with COBI-boosted ATV [4]. The most common adverse events were those related to an elevated bilirubin level, a well-known side effect of ATV use, and included jaundice and scleral icterus, reaching rates of 40.7% and 36.2% in the COBI and RTV groups, respectively, although these rarely led to treatment discontinuation (3.5% in the COBI arm and 3.2% in the RTV group). A small increase in serum creatinine level, usually within the first 8 weeks of treatment, was observed in both arms (median change from baseline, + 0.13 mg/dL vs + 0.09 mg/dL; P < .001) with a concomitant decrease in the estimated glomerular filtration rate (eGFR; median change, −12.9 mL/min vs −9.1 mL/min; P < .001), although renal adverse events leading to treatment discontinuation were rarely reported. Only 6 patients (1.7%) in the COBI arm and 5 patients (1.4%) in the RTV group stopped receiving study drugs, and no patient required dialysis. Of note, in the COBI arm most of the patients (5 of 6) who stopped treatment had laboratory findings consistent with proximal tubulopathy, such as hypophosphatemia, proteinuria, or normoglycemic glycosuria, that resolved or improved after treatment discontinuation, whereas in the RTV group most of the patients (3 of 5) who stopped treatment showed an increase in their serum creatinine level without evidence of tubular dysfunction. Renal safety emerged as a potential concern early in the development of COBI, as increases in the serum creatinine level were observed in patients treated with COBI-containing regimens. This increase is not associated with an actual decrease in the actual GFR; instead, COBI drives a reduction in the eGFR, because of an inhibition of the secretion of creatinine, without affecting the actual GFR [5]. An increase of ≥0.4 mg/dL from baseline was proposed for distinguishing the effect of cobicistat on the serum creatinine level from genuine renal dysfunction [6]. In the study by Gallant et al, changes in renal measurements were observed in both groups, and abnormalities reverted after discontinuation of study drugs. It has been previously reported that TDF, which was used in both study arms, can cause proximal tubulopathy [7]. Observational studies have also shown that this toxicity might be more frequent when TDF is associated with ritonavir-boosted protease inhibitors [8]. Experiments in vitro [9] have shown that COBI increases the intestinal absorption of protease inhibitors and TDF. The clinical relevance of these findings remains unclear and deserves further research. Of note, although the number of patients who discontinued participation in this phase 3 study because of renal events was small, proximal tubulopathy features were observed in 5 of 6 subjects in the COBI arm and in 2 of 5 subjects in the RTV arm. During COBI use, routine renal monitoring (eg, urine protein level, urine glucose level, serum creatinine level, and calculated creatinine clearance rate) every 6 months (as recommended for patients receiving TDF) is advised for early identification of tubulopathy. A tenofovir prodrug in development, tenofovir alafenamide fumarate (TAF), formerly known as GS-7340, has antiviral potency similar to or exceeding that of TDF. It was designed to reach higher concentrations in cells and lymphoid tissues, with lower levels in blood serum, which may minimize its detrimental effects on kidneys and bones [10]. Studies to evaluate the efficacy of TAF in a tablet coformulated with elvitegravir/COBI and FTC are underway [11]. How this new drug will interact with COBI remains a research question. The results of the study by Gallant et al validate those reported by Elion et al in the phase 2 study of COBI versus RIT [12]. In that study, 89 patients were randomly assigned in a 2:1 ratio to the ATV/COBI arm. Through week 48, both groups achieved and maintained similar rates of virologic suppression and similar CD4+ T-cell count increases. Similarly, the most common toxicity was also driven by high bilirubin levels. Actually, slightly higher bilirubin levels in the COBI arm were found in the studies by Elion et al and Gallant et al; it was hypothesized that differences between COBI and RTV in the affinity for off-target metabolic enzymes could be implicated, although levels of ATV measured in a subsample of patients were not significantly different between arms. Gilead has submitted a New Drug Application to the FDA for marketing approval of cobicistat as a boosting agent for darunavir and ATV [13]. Studies of coformulations with these drugs are ongoing [14]. Of note, Gilead, the COBI patent holder, signed an agreement with the Medicines Patent Pool to transfer the manufacturing technology to Indian companies in order to produce generic versions of this drug, making it potentially available in 102 low- and middle-income countries [15]. In conclusion, this phase 3 study shows that COBI-boosted ATV has high a efficacy, a good tolerability profile, and is noninferior to RTV-boosted ATV. Its potential role in novel ART combinations will depend on the confirmation of its promising data as a new boosting agent, cost comparisons to ritonavir, and the availability of new coformulations. HIV caregivers now have a new tool for managing their patients, as well as a new challenge in understanding the implications of changes in results of renal function tests.

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