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1.  Effect of rAd5-Vector HIV-1 Preventive Vaccines on HIV-1 Acquisition: A Participant-Level Meta-Analysis of Randomized Trials 
PLoS ONE  2015;10(9):e0136626.
Background
Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow–up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.
Methods
We included participant-level data from all three efficacy trials, and three Phase 1–2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.
Findings
Results are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99–1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11–1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61–1.26, P = 0.48). Results were similar when including the Phase 1–2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58−1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61–1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89–1.14, P = 0.18).
Interpretation and Significance
The data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations.
doi:10.1371/journal.pone.0136626
PMCID: PMC4558095  PMID: 26332672
2.  Specificity and 6-Month Durability of Immune Responses Induced by DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-Like Particles 
Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)–uninfected adults for safety, immunogenicity, and 6-month durability of immune responses.
Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections.
Results. At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4+ T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8+ T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4+ and CD8+ T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold.
Conclusions. DDMM and MMM vaccinations with virus-like particle–expressing immunogens elicited durable antibody and T-cell responses.
doi:10.1093/infdis/jiu003
PMCID: PMC4072895  PMID: 24403557
HIV/AIDS; vaccines; clinical trial; T cells; antibodies; DNA; recombinant MVA
3.  Patterns of Geographic Mobility Predict Barriers to Engagement in HIV Care and Antiretroviral Treatment Adherence 
AIDS Patient Care and STDs  2014;28(6):284-295.
Abstract
Migration and geographic mobility increase risk for HIV infection and may influence engagement in HIV care and adherence to antiretroviral therapy. Our goal is to use the migration-linked communities of Santo Domingo, Dominican Republic, and New York City, New York, to determine the impact of geographic mobility on HIV care engagement and adherence to treatment. In-depth interviews were conducted with HIV+Dominicans receiving antiretroviral therapy, reporting travel or migration in the past 6 months and key informants (n=45). Mobility maps, visual representations of individual migration histories, including lifetime residence(s) and all trips over the past 2 years, were generated for all HIV+ Dominicans. Data from interviews and field observation were iteratively reviewed for themes. Mobility mapping revealed five distinct mobility patterns: travel for care, work-related travel, transnational travel (nuclear family at both sites), frequent long-stay travel, and vacation. Mobility patterns, including distance, duration, and complexity, varied by motivation for travel. There were two dominant barriers to care. First, a fear of HIV-related stigma at the destination led to delays seeking care and poor adherence. Second, longer trips led to treatment interruptions due to limited medication supply (30-day maximum dictated by programs or insurers). There was a notable discordance between what patients and providers perceived as mobility-induced barriers to care and the most common barriers found in the analysis. Interventions to improve HIV care for mobile populations should consider motivation for travel and address structural barriers to engagement in care and adherence.
doi:10.1089/apc.2014.0028
PMCID: PMC4046197  PMID: 24839872
4.  Phase I/II Randomized Trial of Safety and Immunogenicity of LIPO-5 Alone, ALVAC-HIV (vCP1452) Alone, and ALVAC-HIV (vCP1452) Prime/LIPO-5 Boost in Healthy, HIV-1-Uninfected Adult Participants 
Clinical and Vaccine Immunology : CVI  2014;21(11):1589-1599.
Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 μg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 μg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063.
doi:10.1128/CVI.00450-14
PMCID: PMC4248765  PMID: 25253665
5.  Low-Frequency Nevirapine (NVP)–Resistant HIV-1 Variants Are Not Associated With Failure of Antiretroviral Therapy in Women Without Prior Exposure to Single-Dose NVP 
The Journal of Infectious Diseases  2014;209(5):703-710.
Background. Low-frequency nevirapine (NVP)–resistant variants have been associated with virologic failure (VF) of initial NVP-based combination antiretroviral therapy (cART) in women with prior exposure to single-dose NVP (sdNVP). We investigated whether a similar association exists in women without prior sdNVP exposure.
Methods. Pre-cART plasma was analyzed by allele-specific polymerase chain reaction to quantify NVP-resistant mutants in human immunodeficiency virus–infected African women without prior sdNVP who were starting first-line NVP-based cART in the OCTANE/A5208 trial 2. Associations between NVP-resistant mutants and VF or death were determined and compared with published results from women participating in the OCTANE/A5208 trial 1 who had taken sdNVP and initiated NVP-based cART.
Results. Pre-cART NVP-resistant variants were detected in 18% (39/219) of women without prior sdNVP exposure, compared to 45% (51/114) with prior sdNVP exposure (P < .001). Among women without prior sdNVP exposure, 8 of 39 (21%) with NVP-resistant variants experienced VF or death vs 31 of 180 (17%) without such variants (P = .65); this compares with 21 of 51 (41%) vs 9 of 63 (14%) among women with prior exposure (P = .001).
Conclusions. The risk of VF on NVP-based cART from NVP-resistant variants differs between sdNVP-exposed and -unexposed women. This difference may be driven by drug-resistance mutations emerging after sdNVP exposure that are linked on the same viral genome.
Clinical Trials Registration NCT00089505.
doi:10.1093/infdis/jit635
PMCID: PMC3923545  PMID: 24443547
minor drug-resistant variants; single-dose nevirapine; antiretroviral therapy failure
6.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
doi:10.1093/cid/cit747
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
7.  A Randomized, Placebo-Controlled Trial of Abacavir Intensification in HIV-1–Infected Adults With Virologic Suppression on a Protease Inhibitor–Containing Regimen 
HIV clinical trials  2010;11(6):312-324.
Background and Objective
Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure.
Methods
Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels <500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs >200 copies/mL) and treatment discontinuation.
Results
At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P = .77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P = .22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms.
Conclusions
The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/mL can be further reduced and what influence this may have on latent HIV reservoirs.
doi:10.1310/hct1106-312
PMCID: PMC3108099  PMID: 21239359
abacavir; antiretroviral therapy; intensification
8.  In Pursuit of an HIV Vaccine: Designing Efficacy Trials in the Context of Partially Effective Nonvaccine Prevention Modalities 
AIDS Research and Human Retroviruses  2013;29(11):1513-1523.
Abstract
The HIV prevention landscape is evolving rapidly, and future efficacy trials of candidate vaccines, which remain the best long-term option for stemming the HIV epidemic, will be conducted in the context of partially effective nonvaccine prevention modalities. It is essential that these trials provide for valid and efficient evaluation of vaccine efficacy and immune correlates. The availability of partially effective prevention modalities presents opportunities to study their interactions with vaccines to maximally reduce HIV incidence. This article proposes an approach for conducting future vaccine efficacy trials in the context of background use of partially effective nonvaccine prevention modalities, and for conducting future vaccine efficacy trials that provide nonvaccine prevention modalities in one or more of the randomized study groups. Strategies are discussed for responding to emerging evidence on nonvaccine prevention modalities during ongoing vaccine trials. Next-generation HIV vaccine efficacy trials will almost certainly be more complex in their design and implementation but may become more relevant to at-risk populations and better suited to the ultimate goal of reducing HIV incidence at the population level.
doi:10.1089/aid.2012.0385
PMCID: PMC3809388  PMID: 23597282
9.  Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy 
Fiscus, Susan A. | Cu-Uvin, Susan | Eshete, Abel Tilahun | Hughes, Michael D. | Bao, Yajing | Hosseinipour, Mina | Grinsztejn, Beatriz | Badal-Faesen, Sharlaa | Dragavon, Joan | Coombs, Robert W. | Braun, Ken | Moran, Laura | Hakim, James | Flanigan, Timothy | Kumarasamy, N. | Campbell, Thomas B. | Klingman, Karin L. | Nair, Apsara | Walawander, Ann | Smeaton, Laura M. | De Gruttola, Victor | Martinez, Ana I. | Swann, Edith | Barnett, Ronald L. | Brizz, Barbara | Delph, Yvette | Gettinger, Nikki | Mitsuyasu, Ronald T. | Eshleman, Susan | Safren, Steven | Andrade, Adriana | Haas, David W. | Amod, Farida | Berthaud, Vladimir | Bollinger, Robert C. | Bryson, Yvonne | Celentano, David | Chilongozi, David | Cohen, Myron | Collier, Ann C. | Currier, Judith Silverstein | Eron, Joseph | Firnhaber, Cynthia | Flexner, Charles | Gallant, Joel E. | Gulick, Roy M. | Hammer, Scott M. | Hoffman, Irving | Kazembe, Peter | Kumwenda, Johnstone | Kumwenda, Newton | Lama, Javier R. | Lawrence, Jody | Maponga, Chiedza | Martinson, Francis | Mayer, Kenneth | Nielsen, Karin | Pendame, Richard B. | Ramratnam, Bharat | Rooney, James F. | Sanchez, Jorge | Sanne, Ian | Schooley, Robert T. | Snowden, Wendy | Solomon, Suniti | Tabet, Steve | Taha, Taha | Uy, Jonathan | van der Horst, Charles | Wanke, Christine | Gormley, Joan | Marcus, Cheryl J. | Putnam, Beverly | Ntshele, Smanga | Loeliger, Edde | Pappa, Keith A. | Webb, Nancy | Shugarts, David L. | Winters, Mark A. | Descallar, Renard S. | Sharma, Jabin | Poongulali, S. | Cardoso, Sandra Wagner | Faria, Deise Lucia | Berendes, Sima | Burke, Kelly | Kanyama, Cecelia | Kayoyo, Virginia | Samaneka, Wadzanai P. | Chisada, Anthony | Santos, Breno | La Rosa, Alberto | Infante, Rosa | Balfour, Henry H. | Mullan, Beth | Kim, Ge-Youl | Klebert, Michael K. | Mildvan, Donna | Revuelta, Manuel | Jan Geiseler, P. | Santos, Bartolo | Daar, Eric S. | Lopez, Ruben | Frarey, Laurie | Currin, David | Haas, David H. | Bailey, Vicki L. | Tebas, Pablo | Zifchak, Larisa | Sha, Beverly E. | Fritsche, Janice M.
Women with human immunodeficiency virus (HIV)–1 subtype C had significantly higher genital tract viral loads compared to women with HIV-1 subtype B and men with HIV-1 subtype C or B. Women in general were significantly less likely to have genital tract viral load below the lower limit of quantification compared to men.
Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype.
Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens.
Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected.
Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.
doi:10.1093/cid/cit195
PMCID: PMC3689341  PMID: 23532477
HIV-1 genital tract RNA; HIV-1 subtypes B and C; antiretroviral drugs
10.  Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine 
The New England journal of medicine  2013;369(22):2083-2092.
Background
A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States.
Methods
At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24.
Results
In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, −25.0%; 95% confidence interval, −121.2 to 29.3; P = 0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P = 0.28). The vaccine regimen had an acceptable side-effect profile.
Conclusions
The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.)
doi:10.1056/NEJMoa1310566
PMCID: PMC4030634  PMID: 24099601
11.  207-nm UV Light - A Promising Tool for Safe Low-Cost Reduction of Surgical Site Infections. I: In Vitro Studies 
PLoS ONE  2013;8(10):e76968.
Background
0.5% to 10% of clean surgeries result in surgical-site infections, and attempts to reduce this rate have had limited success. Germicidal UV lamps, with a broad wavelength spectrum from 200 to 400 nm are an effective bactericidal option against drug-resistant and drug-sensitive bacteria, but represent a health hazard to patient and staff. By contrast, because of its limited penetration, ∼200 nm far-UVC light is predicted to be effective in killing bacteria, but without the human health hazards to skin and eyes associated with conventional germicidal UV exposure.
Aims
The aim of this work was to test the biophysically-based hypothesis that ∼200 nm UV light is significantly cytotoxic to bacteria, but minimally cytotoxic or mutagenic to human cells either isolated or within tissues.
Methods
A Kr-Br excimer lamp was used, which produces 207-nm UV light, with a filter to remove higher-wavelength components. Comparisons were made with results from a conventional broad spectrum 254-nm UV germicidal lamp. First, cell inactivation vs. UV fluence data were generated for methicillin-resistant S. aureus (MRSA) bacteria and also for normal human fibroblasts. Second, yields of the main UV-associated pre-mutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) were measured, for both UV radiations incident on 3-D human skin tissue.
Results
We found that 207-nm UV light kills MRSA efficiently but, unlike conventional germicidal UV lamps, produces little cell killing in human cells. In a 3-D human skin model, 207-nm UV light produced almost no pre-mutagenic UV-associated DNA lesions, in contrast to significant yields induced by a conventional germicidal UV lamp.
Conclusions
As predicted based on biophysical considerations, 207-nm light kills bacteria efficiently but does not appear to be significantly cytotoxic or mutagenic to human cells. Used appropriately, 207-nm light may have the potential for safely and inexpensively reducing surgical-site infection rates, including those of drug-resistant origin.
doi:10.1371/journal.pone.0076968
PMCID: PMC3797730  PMID: 24146947
12.  Immune Activation While on Potent Antiretroviral Therapy Can Predict Subsequent CD4+ T-Cell Increases Through 15 Years of Treatment 
HIV clinical trials  2013;14(2):61-67.
Background
While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)–mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery.
Objective
We assessed whether the extent of persistent CD8+ T-cell activation (% CD38+/HLA-DR+) in the fi rst few years of ART-mediated viral suppression predicted subsequent CD4+ T-cell recovery in 95 subjects with up to 15 years of observation on suppressive ART.
Results
Lower CD8+ T-cell activation and higher naïve CD4+ T-cell frequencies (CD45RA+/CD62L+) measured at year 3 to 5 after starting ART independently predicted greater subsequent CD4+ T-cell increases. The mean CD4 count increase from year 0 to year 5 and the increase to the average of year 10 to 15 in the low CD8 activation group (≤18.5%; mean = 13%) were 342 and 458 cells/mm,3 and the increases were 248 and 349 cells/mm3 for the high CD8 activation group (>18.5%; mean = 29%) (P = .002 and P = .016, respectively, comparing groups). At years 10 to 15, the mean CD4 counts in the groups were 579 and 484 cells/mm3, respectively (P = .026).
Conclusion
These fi ndings support the need to identify approaches to reduce immune activation in treated HIV disease.
doi:10.1310/hct1402-61
PMCID: PMC3788605  PMID: 23611826
antiretroviral therapy; CD4+ T-cell counts; HIV; immune activation
13.  Transmitted Drug Resistance Among Antiretroviral-Naive Patients with Established HIV Type 1 Infection in Santo Domingo, Dominican Republic and Review of the Latin American and Caribbean Literature 
Abstract
Emergence of HIV resistance is a concerning consequence of global scale-up of antiretroviral therapy (ART). To date, there is no published information about HIV resistance from the Dominican Republic. The study's aim was to determine the prevalence of transmitted drug resistance (TDR) to reverse transcriptase and protease inhibitors in a sample of chronically HIV-1-infected patients in one clinic in Santo Domingo. The data are presented in the context of a review of the TDR literature from Latin America and the Caribbean. Genotype testing was successfully performed on 103 treatment-naive adults planning to initiate antiretroviral therapy; the World Health Organization (WHO) list of surveillance drug resistance mutations (SDRM) was used to determine the presence of TDR mutations. WHO SDRM were identified in eight patients (7.8%); none had received sdNVP. There were no significant differences in epidemiologic or clinical variables between those with or without WHO SDRM. The prevalence of WHO SDRM was 1.0% and 6.8% for nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. No WHO SDRMs for protease inhibitors were identified. Among 12 studies of TDR in the region with a sample size of at least 100 subjects, the reported prevalence of SDRM ranged from 2.8% to 8.1%. The most commonly identified SDRM was K103N. This information adds to our understanding of the epidemiology of TDR in the region and the possible role such mutations could play in undermining first-line treatment. Ongoing surveillance is clearly needed to better understand the TDR phenomenon in the Caribbean.
doi:10.1089/aid.2010.0355
PMCID: PMC3380383  PMID: 21851324
14.  The Challenge of HIV-1 Subtype Diversity 
The New England journal of medicine  2008;358(15):1590-1602.
doi:10.1056/NEJMra0706737
PMCID: PMC2614444  PMID: 18403767
16.  A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens 
Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection.
PMCID: PMC3502884  PMID: 23181167
HIV vaccine efficacy clinical trial; immune correlate of protection; one-way crossover design; surrogate endpoint for HIV infection; two-phase sampling
17.  Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults 
Abstract
The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 × 109 or 1 × 1010 viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-γ ELISPOT gag 15-mer assay with positive responses defined as ≥55 SFC/106 PBMCs and ≥4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/106 PBMCs in the placebo, 1 × 109 vp/dose, and 1 × 1010 vp/dose groups, respectively. Overall, responses to 1 × 1010 vp were 85% and 68% in subjects with low (≤200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 × 1010 vp/dose groups than in the 1 × 109 vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity.
doi:10.1089/aid.2010.0151
PMCID: PMC3422055  PMID: 20854108
18.  Statistical Interpretation of the RV144 HIV Vaccine Efficacy Trial in Thailand: A Case Study for Statistical Issues in Efficacy Trials 
The Journal of Infectious Diseases  2011;203(7):969-975.
Recently, the RV144 randomized, double-blind, efficacy trial in Thailand reported that a prime-boost human immunodeficiency virus (HIV) vaccine regimen conferred ∼30% protection against HIV acquisition. However, different analyses seemed to give conflicting results, and a heated debate ensued as scientists and the broader public struggled with their interpretation. The lack of accounting for statistical principles helped flame the debate, and we leverage these principles to provide a more scientific interpretation. We first address interpretation of frequentist results, including interpretation of P values, synthesis of results from multiple analyses (ie, intention-to-treat versus per-protocol/fully immunized), and accounting for external efficacy trials. Second, we address how Bayesian statistics, which provide clearly interpretable statements about probabilities that the vaccine efficacy takes certain values, provide more information for weighing the evidence about efficacy than do frequentist statistics alone. Third, we evaluate RV144 for completeness of end point ascertainment and integrity of blinding, necessary tasks for establishing robustly interpretable results.
doi:10.1093/infdis/jiq152
PMCID: PMC3068028  PMID: 21402548
19.  Lessons Drawn from Recent HIV Vaccine Efficacy Trials 
A safe and effective HIV vaccine is needed to curtail the US and global epidemics. However, the search for a preventive vaccine has been elusive, despite more than 25 years of focused research. Results from the RV144 Thai efficacy trial have renewed hope that a vaccine may protect against HIV acquisition. We can draw several scientific and operational lessons from RV144 and other recent tests of concept efficacy trials. Here we describe how trial results, some unexpected, highlight the fundamental role these clinical studies play in HIV vaccine discovery. These trials also teach us that transparency in data analysis and results dissemination can yield substantial rewards and that efforts to engage communities, particularly those most heavily affected by the epidemic, are needed to augment research literacy and trial recruitment. Future efficacy trial designs may incorporate novel, partially effective prevention strategies. Although greater in size and complexity, these trials may offer unique opportunities to explore synergies with vaccines under study.
doi:10.1097/QAI.0b013e3181fbca02
PMCID: PMC3079543  PMID: 21406982
HIV vaccines; clinical trials; efficacy trials; combination prevention
20.  Pre-Existing Adenovirus Immunity Modifies a Complex Mixed Th1 and Th2 Cytokine Response to an Ad5/HIV-1 Vaccine Candidate in Humans 
PLoS ONE  2011;6(4):e18526.
The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms.
doi:10.1371/journal.pone.0018526
PMCID: PMC3076372  PMID: 21533229
21.  Low Frequency NNRTI-Resistant Variants Contribute to Failure of Efavirenz-Containing Regimens in Treatment-Experienced Patients 
The Journal of infectious diseases  2010;201(5):672-680.
Background
The contribution of low frequency drug-resistant HIV-1 variants to failure of antiretroviral therapy is not well-defined in treatment-experienced patients.
Objective
We sought to detect minor non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants at the onset of multidrug efavirenz-containing therapy in both NNRTI-naïve and NNRTI-experienced patients and to determine their association with virologic response.
Methods
Plasma samples at entry and virologic failure from patients enrolled in the AIDS Clinical Trials Group study 398 were analyzed by standard genotype, single-genome sequencing and allele-specific PCR (K103N and Y181C) to detect and quantify minor NNRTI-resistant variants.
Results
Minor populations of NNRTI-resistant variants that were missed by standard genotype were detected more often at study entry in NNRTI-experienced patients than NNRTI-naïve patients by both single-genome sequencing (8 of 12 vs. 3 of 15; P=0.022) and allele-specific PCR (>1% Y181C: 5 of 22 vs. 3 of 72, respectively, P = 0.016). K103N variants at frequencies >1% were associated with inferior HIV-1 RNA response to efavirenz-containing therapy between entry and week 24 (+0.5 vs −1.1 log10 copies/ml; P <0.001).
Conclusions
Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens.
doi:10.1086/650542
PMCID: PMC2835354  PMID: 20102272
HIV-1 Drug-resistance; Minority Variants; Virologic Response
22.  Immunologic Markers as Predictors of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV and Tuberculosis Coinfected Persons in Thailand 
AIDS Research and Human Retroviruses  2009;25(11):1083-1089.
Abstract
This study analyzes immunologic markers to predict and diagnose tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV and TB coinfected adults who initiated antiretroviral therapy (ART) in Thailand. T helper 1 cytokines interleukin (IL)-2, IL-12, and interferon-gamma (IFN-γ) levels in response to PPD and RD1 antigens were assessed prior to ART, at weeks 6, 12, and 24 of treatment, and at time of TB-IRIS. Of 126 subjects, 22 (17.5%) developed TB-IRIS; 14 (64%) subjects received steroid treatment and 3 (14%) received NSAIDs; none of the subjects died. Median interval between ART initiation and TB-IRIS development was 14 days. IFN-γ, IL-2, and IL-12 responses did not differ between TB-IRIS and no TB-IRIS subjects (p > 0.05). More research into the immunopathogenesis of TB-IRIS and diagnostic potential of cytokine markers is warranted.
doi:10.1089/aid.2009.0055
PMCID: PMC2828258  PMID: 19886838
23.  Persistent Minority K103N Mutations among Women Exposed to Single-Dose Nevirapine and Virologic Response to Nonnucleoside Reverse-Transcriptase Inhibitor–Based Therapy 
Objective
We investigated whether there are long-lasting effects of exposure to single-dose nevirapine (sdNVP) treatment on virologic response to nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based therapy among human immunodeficiency virus (HIV)–infected women.
Methods
An observational epidemiologic study was conducted in Johannesburg, South Africa. Initial and sustained virologic response to NNRTI-based therapy was compared between 94 HIV-infected women who had received sdNVP 18–36 months earlier and 60 unexposed, HIV-infected women who had been pregnant 12–36 months earlier. Viral load was measured every 4 weeks up to week 24 and then every 12 weeks up to week 78. Time to viral suppression (viral load, <50 copies/mL) and confirmed rebound in the viral load (viral load, >400 copies/mL) were compared. Drug resistance was assessed using K103N allele–specific real-time polymerase chain reaction assay and population sequencing.
Results
Almost all women (97.5% of sdNVP-exposed women and 91.3% of sdNVP-unexposed women; P = .21) achieved viral suppression by week 24, and similar percentages of sdNVP-exposed and -unexposed women (19.4% and 15.1%, respectively) experienced viral rebound within 78 weeks after treatment (P = .57). K103N was detected with the K103N allele–specific real-time polymerase chain reaction assay among sdNVP-exposed and - unexposed women before treatment; detection was strongly predictive of inadequate viral response: 60.9% of women for whom K103N was detected in either viral RNA or DNA did not experience viral suppression or experienced viral rebound, compared with 15.1% of women for whom K103N was not detected (P < .001). After treatment, the M184V mutation occurred less frequently among sdNVP-exposed women than among sdNVP-unexposed women, but the frequency of NNRTI-associated mutations was similar between these groups of women with inadequate virologic response.
Conclusions
Exposure to sdNVP in the prior 18–36 months was not associated with a reduced likelihood of achieving and sustaining viral suppression while receiving NNRTI-based therapy. However, women with minority K103N mutations before treatment had a reduced durability of virologic suppression.
doi:10.1086/596486
PMCID: PMC2810158  PMID: 19133804
24.  Combining Google Earth and GIS mapping technologies in a dengue surveillance system for developing countries 
Background
Dengue fever is a mosquito-borne illness that places significant burden on tropical developing countries with unplanned urbanization. A surveillance system using Google Earth and GIS mapping technologies was developed in Nicaragua as a management tool.
Methods and Results
Satellite imagery of the town of Bluefields, Nicaragua captured from Google Earth was used to create a base-map in ArcGIS 9. Indices of larval infestation, locations of tire dumps, cemeteries, large areas of standing water, etc. that may act as larval development sites, and locations of the homes of dengue cases collected during routine epidemiologic surveying were overlaid onto this map. Visual imagery of the location of dengue cases, larval infestation, and locations of potential larval development sites were used by dengue control specialists to prioritize specific neighborhoods for targeted control interventions.
Conclusion
This dengue surveillance program allows public health workers in resource-limited settings to accurately identify areas with high indices of mosquito infestation and interpret the spatial relationship of these areas with potential larval development sites such as garbage piles and large pools of standing water. As a result, it is possible to prioritize control strategies and to target interventions to highest risk areas in order to eliminate the likely origin of the mosquito vector. This program is well-suited for resource-limited settings since it utilizes readily available technologies that do not rely on Internet access for daily use and can easily be implemented in many developing countries for very little cost.
doi:10.1186/1476-072X-8-49
PMCID: PMC2729741  PMID: 19627614
25.  Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects 
Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (Cmin) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median Cmin for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum Cmin range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the Cmin for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (Vss/F) (P = 0.25), and half-life (t1/2) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (Cmaxs) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the Cmins were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), Vss/F (P = 0.33), and t1/2 (P = 0.37) were similar regardless of the dosing regimen. The median Cmax, Cmin, CL/F, Vss/F, and t1/2 for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h.
doi:10.1128/AAC.47.6.1929-1935.2003
PMCID: PMC155818  PMID: 12760869

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