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1.  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.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
2.  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.
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.
PMCID: PMC3809388  PMID: 23597282
3.  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.
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.
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.
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.
PMCID: PMC3108099  PMID: 21239359
abacavir; antiretroviral therapy; intensification
4.  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.
PMCID: PMC3689341  PMID: 23532477
HIV-1 genital tract RNA; HIV-1 subtypes B and C; antiretroviral drugs
5.  Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine 
The New England journal of medicine  2013;369(22):2083-2092.
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.
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.
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.
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; number, NCT00865566.)
PMCID: PMC4030634  PMID: 24099601
6.  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.
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.
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.
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.
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.
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.
PMCID: PMC3797730  PMID: 24146947
7.  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.
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.
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.
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).
These fi ndings support the need to identify approaches to reduce immune activation in treated HIV disease.
PMCID: PMC3788605  PMID: 23611826
antiretroviral therapy; CD4+ T-cell counts; HIV; immune activation
8.  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 
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.
PMCID: PMC3380383  PMID: 21851324
9.  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
10.  The Challenge of HIV-1 Subtype Diversity 
The New England journal of medicine  2008;358(15):1590-1602.
PMCID: PMC2614444  PMID: 18403767
12.  Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults 
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.
PMCID: PMC3422055  PMID: 20854108
13.  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.
PMCID: PMC3068028  PMID: 21402548
14.  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.
PMCID: PMC3079543  PMID: 21406982
HIV vaccines; clinical trials; efficacy trials; combination prevention
15.  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, #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.
PMCID: PMC3076372  PMID: 21533229
16.  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.
The contribution of low frequency drug-resistant HIV-1 variants to failure of antiretroviral therapy is not well-defined in treatment-experienced patients.
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.
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.
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).
Minor NNRTI-resistant variants were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens.
PMCID: PMC2835354  PMID: 20102272
HIV-1 Drug-resistance; Minority Variants; Virologic Response
17.  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.
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.
PMCID: PMC2828258  PMID: 19886838
18.  Persistent Minority K103N Mutations among Women Exposed to Single-Dose Nevirapine and Virologic Response to Nonnucleoside Reverse-Transcriptase Inhibitor–Based Therapy 
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.
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.
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.
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.
PMCID: PMC2810158  PMID: 19133804
19.  Combining Google Earth and GIS mapping technologies in a dengue surveillance system for developing countries 
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.
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.
PMCID: PMC2729741  PMID: 19627614
20.  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.
PMCID: PMC155818  PMID: 12760869
21.  Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398 
The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.
PMCID: PMC148981  PMID: 12499180
22.  Detection of Replication-Competent Human Immunodeficiency Virus Type 1 (HIV-1) in Cultures from Patients with Levels of HIV-1 RNA in Plasma Suppressed to Less Than 500 or 50 Copies Per Milliliter† 
Journal of Clinical Microbiology  2002;40(6):2089-2094.
We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 107 fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of ≥500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of ≥500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load.
PMCID: PMC130703  PMID: 12037070

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