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1.  The Pharmacokinetics and Pharmacogenomics of Efavirenz and Lopinavir/Ritonavir in HIV-Infected Persons Requiring Hemodialysis 
AIDS (London, England)  2008;22(15):1919-1927.
To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.
Prospective, observational study of HIV-infected hemodialysis subjects receiving one 600mg tablet daily of EFV (N=13) or three 133.3/33.3mg capsules twice daily of LPV/RTV (N=13).
24-hour EFV and 12-hour LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.
The geometric mean (95% CI, %CV) Cmin, Cmax, and AUC for the EFV group were 1.81µg/mL (0.93, 3.53; 103%), 5.04µg/mL (3.48, 7.29; 72%), and 71.5µg·h/mL (43.2, 118.3; 93%), respectively. These parameters were 2.76µg/mL (1.86, 4.11; 53%), 8.45µg/mL (6.41, 11.15; 52%), and 69.6µg·h/mL (55.6, 87.2; 37%) for LPV and 0.08µg/mL (0.05, 0.14; 63%), 0.58µg/mL (0.44, 0.76; 41%), and 3.74µg·h/mL (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.
The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggest that no dosing adjustments are necessary in treatment-naïve patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease inhibitor-experienced patients.
PMCID: PMC2675161  PMID: 18784455
Pharmacokinetics; Pharmacogenomics; Renal Failure; Dialysis; HIV; Efavirenz; Lopinavir; Ritonavir
2.  A Phase III Comparative Study of the Efficacy and Tolerability of Three Non-Nucleoside Reverse Transcriptase Inhibitor-Sparing Antiretroviral Regimens for Treatment-Naïve HIV-1-Infected Volunteers: A Randomized, Controlled Trial 
Annals of internal medicine  2014;161(7):461-471.
Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naïve HIV-infected persons.
Perform a rigorous evaluation of three NNRTI-sparing initial antiretroviral regimens to demonstrate equivalence for virologic efficacy and tolerability.
Phase-III, 1:1:1 randomized, open label, >96 week study.
Fifty-seven sites in United States and Puerto Rico.
Treatment naïve, ≥18 years, HIV-1 RNA >1000 copies/mL, no nucleoside reverse transcriptase or protease inhibitor resistance.
Atazanavir 300 mg with ritonavir 100 mg, daily; or raltegravir 400 mg twice daily; or darunavir 800 mg with ritonavir 100 mg, daily; plus emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg daily.
Virologic failure defined as confirmed HIV-1 RNA >1000 copies/mL between 16 and 24 weeks, or >200 copies/mL at or after 24 weeks; tolerability failure defined as discontinuation of atazanavir, raltegravir or darunavir for toxicity. A secondary endpoint was a combination of virologic efficacy and tolerability.
Among 1,809 participants all pairwise comparisons of incidence of virologic failure over 96-weeks demonstrated equivalence within ±10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and a 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir respectively, primarily due to hyperbilirubinemia. For combined virologic efficacy and tolerability ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at time of virologic failure was rare but more likely with raltegravir.
Open label; ritonavir not provided
Over 2 years all three regimens attain high and equivalent rates of virologic control. Regimens containing raltegravir or ritonavir-boosted darunavir have superior tolerability compared to the ritonavir-boosted atazanavir regimen.
Primary Funding Source
National Institute of Allergy and Infectious Diseases
PMCID: PMC4412467  PMID: 25285539
3.  Virologic and Serologic Outcomes of Mono vs. Dual HBV Therapy and Characterization of HIV/HBV Coinfection in a US Cohort 
To characterize HIV/HBV coinfection in the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort and compare long-term HBV outcomes between regimens with one (MONO) or two (DUAL) anti-HBV agents.
A retrospective study of coinfected ALLRT subjects who received regimens containing anti-HBV agent(s).
Stored samples at baseline and weeks 16, 32, 48, 144, and 240 were tested for HBV DNA, HBeAg, HBeAb, and HDV antibody. Resistance and genotype were tested in samples with HBV DNA >600 IU/ml. MONO vs. DUAL analyses were limited to HBV treatment-naïve subjects (Naïve-MONO, Naïve-DUAL).
Of 150 study subjects, median age was 40 years, 96% were male; 57% White, 26% Black, 13% Hispanic. Baseline median CD4 was 224 cells/mm3, HIV RNA 4.48 log10 copies/ml, HBV DNA 6.30 log10 IU/ml; 59% HBeAg positive and 65% HBeAb negative; HBV genotypes A=69%, G=18%, D=7%, <2% for A/G, B, C, F, H. Coinfection with HDV was 2%. There were 49 Naïve-MONO (lamivudine) and 22 Naïve-DUAL (11 lamivudine+tenofovir, 11 emtricitabine+tenofovir) with detectable HBV DNA. In the 240-week follow-up, HBV DNA suppression was not significantly higher in Naïve-DUAL (p=0.14); lower baseline HBV DNA (p<0.01) was associated with suppression. Among 32 Naïve-MONO subjects with detectable HBV DNA at baseline and results at week 48, 41% suppressed; among such 15 Naïve-DUAL subjects, 53% suppressed. HBeAg and HBeAb analyses showed similar trends.
While consistent trends toward increased HBV DNA suppression, HBeAg loss and HBeAb seroconversion were observed in Naïve-DUAL compared to Naïve-MONO, they were not statistically significant. Overall, HDV coinfection was low.
PMCID: PMC4169110  PMID: 24694927
coinfection; HIV; HBV; HDV; mono-therapy; dual-therapy; lamivudine; tenofovir
4.  Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin 
There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (Cmax), area under the concentration-time curve from 0 to 24 h (AUC0–24), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. (This study has been registered at under registration no. NCT01571414.)
PMCID: PMC4135849  PMID: 24957823
5.  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
6.  HIV and asthma, is there an association? 
Respiratory medicine  2012;106(4):493-499.
To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.
We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data.
HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported.
The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.
PMCID: PMC4235227  PMID: 22285768
Asthma; Airway hyper-responsiveness; HIV; Antiretroviral
7.  Evidence for risk stratification when monitoring for toxicities following initiation of combination antiretroviral therapy 
AIDS (London, England)  2013;27(10):1593-1602.
Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000–2010 across the United States.
Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort.
Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan–Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation.
A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/μl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid 49 [95% confidence interval (CI) 41– 58]; hematologic = 44 (40–49); hepatic = 24 (20–27); and renal = 9 (7–11), dropping substantially during weeks 17–104 of cART to lipid = 23 (18–29); hematologic = 5 (4–6); hepatic = 6 (5–8); and renal = 2 (1–3) (all P < 0.05). Among patients receiving initial cART with no prior abnormality (N = 1889), strongest associations for hepatic abnormalities after 16 weeks were hepatitis B and C [hazard ratio 2.3 (95% CI 1.2–4.5) and hazard ratio = 3.0 (1.9–4.5), respectively]. The strongest association for renal abnormalities was hypertension [hazard ratio = 2.8 (1.4–5.6)].
New abnormalities decreased after week 16 of cART. For abnormalities not present by week 16, subsequent monitoring should be guided by comorbidities.
PMCID: PMC4108282  PMID: 23435300
hematologic; hepatic; laboratory; lipid; monitoring HIV; renal
8.  Hematologic, Hepatic, Renal and Lipid Laboratory Monitoring Following Initiation of Combination Antiretroviral Therapy in the United States, 2000–2010 
We assessed laboratory monitoring following combination antiretroviral therapy (cART) initiation among 3,678 patients in a large US multi-site clinical cohort, censoring participants at last clinic visit, cART change, or three years. Median days (interquartile range) to first hematologic, hepatic, renal and lipid tests were 30 (18–53), 31 (19–56), 33 (20–59) and 350 (96–1106), respectively. At one year, approximately 80% received more than two hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received one or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities.
PMCID: PMC3654034  PMID: 23446495
Laboratory Monitoring; Antiretroviral Therapy; Antiretroviral Toxicity
9.  Safety of Varenicline Among Smokers Enrolled in the Lung HIV Study 
Nicotine & Tobacco Research  2012;15(1):247-254.
The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population. This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers.
Participants completed 12 weeks of telephone counseling and either varenicline or NRT. Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline. Adverse events (AEs), related to pharmacotherapy, were monitored. Biochemically confirmed abstinence at 3 months was examined. Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT.
Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances. One person reported suicidal ideation; there were no cardiovascular complications. There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART. The percentages of confirmed abstainers were 11.8% in the NRT group and 25.6% in the varenicline group. The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 1.43–4.49).
In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV. In addition, varenicline may be more effective at promoting abstinence in this population. Future randomized clinical trials are warranted.
PMCID: PMC3524069  PMID: 22589421
10.  Human N-acetyltransferase 1 (NAT1) *10 and *11 alleles increase protein expression via distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity 
Pharmacogenetics and genomics  2011;21(10):652-664.
N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared to wild-type NAT1 *4 and to confer cancer risk, via uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.
We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3′-polyadenylation sites in human livers (one of which discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 HIV/AIDS patients treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.
NAT1*10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1*11 (2.4% minor allele frequency) affected 3′polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3′UTR (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3′-UTR polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (‘fast NAT1 acetylators’) were less likely to develop hypersensitivity to SMX, but this was observed only in subjects also carrying a slow NAT2 acetylator genotype.
NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status appears to protect against SMX toxicity by compensating for slow NAT2 acetylator status.
PMCID: PMC3172334  PMID: 21878835
N-acetyltransferase; NAT1; polyadenylation; allelic expression imbalance; sulfamethoxazole; cotrimoxazole; protein translation; acetylator phenotype; idiosyncratic drug reactions
11.  Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients 
BMC Medical Genomics  2012;5:32.
Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity.
Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 – 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 – 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05).
rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.
PMCID: PMC3418550  PMID: 22824134
Idiosyncratic drug reaction; Sulfamethoxazole; Hypersensitivity; Glutamate cysteine ligase catalytic subunit (GCLC); Association; HIV/AIDS
12.  Incidence of Non-AIDS-Defining Cancer in Antiretroviral Treatment-Naïve Subjects after Antiretroviral Treatment Initiation: An ACTG Longitudinal Linked Randomized Trials Analysis 
Oncology  2011;80(1-2):42-49.
Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited.
We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC.
At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤50 cells/mm3 and 25% had CD4 >350 cells/mm3. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin's disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1–4.08)] and recent CD4 (≤50 cells/mm3: 3.58, 1.22–10.45; 51–200 cells/mm3: 2.54, 1.30–5.0; 201–350 cells/mm3: 2.37, 1.32–4.26 vs. >350 cells/mm3) were associated with NADC.
Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.
PMCID: PMC3121543  PMID: 21606663
HIV; Cancer, non-AIDS-defining; Antiretroviral treatment; CD4 T cell counts
13.  Association of Ongoing Drug and Alcohol Use with Non-Adherence to Antiretroviral Therapy and Higher Risk of AIDS and Death: Results from ACTG 362 
AIDS care  2011;23(6):775-785.
Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997–1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR=2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care.
PMCID: PMC3095689  PMID: 21293986
Substance use; drug use; alcohol use; HIV/AIDS; Outcomes; Adherence; Antiretroviral Therapy; Mortality
14.  No Risk of Myocardial Infarction Associated With Initial Antiretroviral Treatment Containing Abacavir: Short and Long-Term Results from ACTG A5001/ALLRT 
In this analysis of 5056 HIV-1 infected individuals initiating randomized antiretroviral treatment in clinical trials, abacavircontaining regimens did not appear associated with increased risk of myocardial infarction (MI). Classic cardiovascular disease risk factors were the strongest predictors of MI.
Background. Observational and retrospective clinical trial cohorts have reported conflicting results for the association of abacavir use with risk of myocardial infarction (MI), possibly related to issues that may bias estimation of treatment effects, such as time-varying confounders, informative dropout, and cohort loss due to competing events.
Methods. We analyzed data from 5056 individuals initiating randomized antiretroviral treatment (ART) in AIDS Clinical Trials Group studies; 1704 started abacavir therapy. An intent-to-treat analysis adjusted for pretreatment covariates and weighting for informative censoring was used to estimate the hazard ratio (HR) of MIs after initiation of a regimen with or without abacavir.
Results. Through 6 years after ART initiation, 36 MI events were observed in 17,404 person-years of follow-up. No evidence of an increased hazard of MI in subjects using abacavir versus no abacavir was seen (over a 1-year period: P = .50; HR, 0.7 [95% confidence interval {CI}, 0.2-2.4]); over a 6-year period: P = .24; HR, 0.6 [95% CI, 0.3-1.4]); these results were robust over as-treated and sensitivity analyses. Although the risk of MI decreased over time, there was no evidence to suggest a time-dependent abacavir effect. Classic cardiovascular disease (CVD) risk factors were the strongest predictors of MI.
Conclusion. We find no evidence to suggest that initial ART containing abacavir increases MI risk over short-term and long-term periods in this population with relatively low MI risk. Traditional CVD risk factors should be the main focus in assessing CVD risk in individuals with human immunodeficiency virus infection.
PMCID: PMC3062545  PMID: 21427402
15.  Relationship between CD4+ T-cell counts/HIV-1 RNA plasma viral load and AIDS defining events among persons followed in the ACTG Longitudinal Linked Randomized Trials (ALLRT) study 
AIDS-defining events (ADEs) decreased in the era of highly active antiretroviral therapy but still lead to hospitalizations and deaths. Understanding factors related to ADEs is important to mitigate events.
We examined the relationship between demographics, behaviors, co-morbidities, laboratory, clinical measurements and ADEs diagnosed among subjects randomized to antiretroviral treatments (ART)/strategies and followed prospectively. Logistic regression models using generalized estimating equations generated odds ratios (ORs) focusing on the relationship between current CD4+ T-cell count (CD4)/HIV-1 RNA viral load (VL) and ADEs in the subsequent 16-week study period.
Among the 2,948 subjects in the analysis, overall incidence of ADEs was 1.53 per 100 person-years. Multivariate regression models adjusted for demographics, BMI and ADE history. A 6-level time-varying variable examined VL (>100,000 copies/mL, ≤ 100,000) at CD4 levels (0–50, 51–200, >200 cells/μl); reference level was CD4>200/VL≤100,000. Among ART-naives, odds of having an ADE in the subsequent 16-week interval were greater among subjects with lower CD4 counts; this relationship was modified by VL level (CD4≤50/VL>100,000: OR 37.2; CD4≤50/VL≤100,000: OR 30.5; CD4 51–200/VL>100,000: OR 13.0; CD4 51–200/VL≤100,000: OR 4.5; all p-values <0.001). Similar results were seen among ART-experienced subjects.
Recent CD4 and VL values are closely associated with development of ADEs even after examining a multitude of potential factors.
PMCID: PMC2927805  PMID: 20622677
HIV; opportunistic infections; CD4 cell counts; viral load
16.  Abacavir–Lamivudine versus Tenofovir–Emtricitabine for Initial HIV-1 Therapy 
The New England journal of medicine  2009;361(23):2230-2240.
The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.
In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily anti retroviral regimens as initial therapy for HIV-1 infection: abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level ≥1000 copies per milliliter at or after 16 weeks and before 24 weeks, or ≥200 copies per milliliter at or after 24 weeks).
A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir–lamivudine group than in the tenofovir DF–emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir–lamivudine group versus 26 (7%) in the tenofovir DF–emtricitabine group. The time to the first adverse event was also shorter in the abacavir–lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.
In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir–lamivudine than in those assigned to tenofovir DF–emtricitabine. ( number, NCT00118898.)
PMCID: PMC2800041  PMID: 19952143
17.  Proteinuria, CrCl, and Immune Activation in Antiretroviral-Naïve HIV-Infected Subjects 
The Journal of infectious diseases  2009;200(4):614-618.
Because both renal disease and immune activation predict progression to AIDS, we evaluated the relationships between dipstick proteinuria ≥1+ [7% of 1012 subjects], CrCl <90mL/min [18% of 1071 subjects], and percentages of peripheral activated CD8 cells (CD8+CD38+HLA-DR+) in antiretroviral-naïve, HIV-infected subjects enrolled into AIDS Clinical Trials Group studies 384 and A5095. Proteinuria, but not CrCl, was associated with higher percentages of CD8+CD38+HLA-DR+ cells [55% vs. 50%; P=0.01], with even more pronounced differences in men and among Blacks and Hispanics. Proteinuria may be a surrogate measure of greater immune activation in HIV-infected patients initiating antiretroviral therapy.
PMCID: PMC2858634  PMID: 19591572
HIV-1; proteinuria; renal failure; nephropathy; immune activation
18.  Hepatotoxicity and Gastrointestinal Intolerance when Healthy Volunteers taking Rifampin add Twice-Daily Atazanavir and Ritonavir 
Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P450 (CYP) 3A by rifampin markedly lowers HIV protease inhibitor plasma concentrations.
This phase I, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included three sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours.
Upon adding atazanavir and ritonavir, the first three subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated.
Co-administration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.
PMCID: PMC2653210  PMID: 19194314
atazanavir; ritonavir; rifampin; tuberculosis; hepatotoxicity
19.  Evaluation of high-protein supplementation in weight-stable HIV-positive subjects with a history of weight loss: a randomized, double-blind, multicenter trial123 
HIV patients with wasting are at increased risk of opportunistic complications and fatality.
We hypothesized that augmenting dietary intake with high-biologic-value protein would enhance weight and lean tissue in weight-stable subjects with a prior unintentional weight loss of >3%.
Fifty-nine subjects with HIV RNA concentrations <5000 copies/mL were randomly assigned to receive a 280-kcal supplement containing 40 g whey protein or a matched isocaloric control supplement without added protein twice daily for 12 wk.
Before the study, intake of total energy and protein exceeded estimated requirements (44.3 ± 12.6 kcal • kg−1 • d−1 and 1.69 ± 0.55 g • kg−1 • d−1, respectively). Both supplements failed to increase total energy intake because of decreases in self-selected food intake. Changes in weight (0.8 ± 2.4 and 0.7 ± 2.4 kg) and lean body mass (0.3 ± 1.4 and 0.3 ± 1.5 kg) did not differ significantly between the whey protein and control groups, respectively. Waist-to-hip ratio improved more with whey protein (−0.02 ± 0.05) than with the control (0.01 ± 0.03; P = 0.025) at week 6 but not at week 12. Fasting triacylglycerol increased by 39 ± 98 mg/dL with the control supplement and decreased by 16 ± 62 mg/dL with whey protein at week 12 (P = 0.03). CD4 lymphocytes increased by 31 ± 84 cells/mm3 with whey protein and decreased by 5 ± 124 cells/mm3 with the control supplement at 12 wk (P = 0.03). Gastrointestinal symptoms occurred more often with whey protein.
A whey protein supplement did not increase weight or lean body mass in HIV-positive subjects who were eating adequately, but it did increase CD4 cell counts. The control supplement with rapidly assimilable carbohydrate substituted for protein increased cardiovascular disease risk factors. Careful dietary and weight history should be obtained before starting nutritional supplements in subjects with stable weight loss and good viral control.
PMCID: PMC2797483  PMID: 18996868
20.  Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients 
AIDS (London, England)  2009;23(16):2133-2141.
Ezetimibe inhibits intestinal absorption of cholesterol.
Multicentered double-blind, randomized, placebo-controlled, crossover study to determine the short-term safety, efficacy, and tolerability of ezetimibe in combination with ongoing statin therapy in HIV-infected adults with elevated low-density lipoprotein cholesterol (LDL-C). Participants on stable HAART with fasting LDL-C at least 130 mg/dl and stable statin were randomized to ezetimibe 10 mg daily or placebo for 12 weeks followed by 4 weeks of washout and then 12 weeks with alternative study assignment. Percentage and absolute change in LDL-C (primary endpoint), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and high sensitivity C-reactive protein were compared. Changes in clinical symptoms and safety laboratory measurements were assessed.
Forty-four participants enrolled: 70% men, median age 49 years, 43% White/Non-Hispanic, median CD4 cell count 547 cells/μl, and 95% HIV RNA less than 50 copies/ml. Median (interquartile range) percentage change in LDL-C was −20.8% (−25.4, −10.7) with ezetimibe and −0.7% (−10.3,18.6) with placebo; the median within-participant effect of ezetimibe was −14.1% (−33.0, −5.0; P < 0.0001). Median difference in absolute LDL-C values between ezetimibe and placebo was −32 mg/dl (−58, −6, P < 0.0001). Significant differences in within-participant effect of ezetimibe were noted for total cholesterol −18.60% (−27.22, −11.67, P < 0.001), non-HDL-C −23.18% (−33.14, −14.36, P < 0.0001), and apolipoprotein B −8.73% (−18.75, 1.99, P = 0.02). No significant changes seen in HDL-C, triglyceride, or high sensitivity C-reactive protein. Ezetimibe was well tolerated. Adverse events were similar between phases.
The present short-term study found adding ezetimibe to ongoing statin therapy was well tolerated and effective in reducing LDL-C, total cholesterol, non-HDL-C, and apolipoprotein B. Adding ezetimibe to statin therapy offers reasonable treatment option for HIV-infected patients with elevated LDL-C.
PMCID: PMC2782438  PMID: 19770624
ACTG A5209 study; elevated low-density lipoprotein cholesterol; ezetimibe; ongoing statin therapy
21.  AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT): Rationale, Design, and Baseline Characteristics 
HIV clinical trials  2008;9(4):269-282.
ALLRT is a longitudinal cohort study of HIV-infected subjects prospectively randomized into selected clinical trials for antiretroviral (ARV) treatment-naïve and ARV treatment-experienced individuals conducted by the AIDS Clinical Trials Group (ACTG). We describe the rationale, design, and baseline characteristics of the ALLRT cohort and its potential to address important research questions related to ARV therapy.
Standardized visits occur every 16 weeks to evaluate long-term clinical, virologic, and immunologic outcomes associated with ARV treatment.
A total of 4,371 subjects enrolled in ALLRT from January 2000 through June 2007. Of these, 3,146 (72%) were ARV naïve at parent study entry (18% female, 44% white, 32% black, 21% Hispanic; median age 37 years, CD4 count 218 cells/μL, follow-up 3.6 years; 343 [11%] followed ≥8 years) and 1,225 (28%) were treatment experienced (13% female, 59% white, 20% black, 17% Hispanic; median age 42 years, CD4 count 325 cells/μL, follow-up 5.7 years).
ALLRT provides the opportunity to understand long-term ramifications of therapeutic ARV choices and determine whether these vary by treatment regimen, timing of treatment initiation, or treatment changes over long-term follow-up. Investigations based on uniform data and specimen collection in the context of randomized ARV treatments will be critical to developing more successful long-term therapeutic strategies for HIV treatment.
PMCID: PMC2704053  PMID: 18753121
CD4 counts; cohort studies; epidemiologic research design; HIV; randomized controlled trials; viral load
22.  Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily▿ † 
The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C12 h) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C12 h values for atazanavir were 44 ng/ml (range, <25 to187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.
PMCID: PMC2043180  PMID: 17576825
23.  Skin Test Reactivity and Cellular Immune Responses to Mycobacterium avium Sensitin in AIDS Patients at Risk for Disseminated M. avium Infection 
Skin tests and lymphocyte proliferation assays (LPA) were performed with Mycobacterium avium sensitin on patients with AIDS. Among 139 subjects, 13% had positive skin test results and 32% had positive LPA results. The LPA may be a more sensitive indicator of prior M. avium infection in this population.
PMCID: PMC96262  PMID: 11687476
24.  Azithromycin as Treatment for Disseminated Mycobacterium avium Complex in AIDS Patients 
Antimicrobial Agents and Chemotherapy  1999;43(12):2869-2872.
This multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1.5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.
PMCID: PMC89578  PMID: 10582873

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