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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.  Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection 
BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at under registration no. NCT00664625.)
PMCID: PMC4068419  PMID: 24733462
3.  In Vitro and In Vivo Effects of IGF-I on Adiposity in HIV-associated Metabolic Disease: A Pilot Study 
Archives of medical research  2013;44(5):361-369.
Background and Aims
We tested the effects of recombinant insulin-like growth factor-I (IGF-I) in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV lipodystrophy.
The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in vitro. We assessed lipid accumulation, IGF signaling, apoptosis, and gene expression. We conducted a 24-week open label trial of recombinant IGF-I in ten adults with HIV associated lipoatrophy. Laboratory assessments included glucose, insulin, lipids, and IGF-I. At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh.
In vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect. In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7% vs. 34.6 ± 7%, p = 0.007). IGF-I levels increased with treatment (143 ± 28 µg/L at week 0 vs. 453 ± 212 µg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L vs. 3.235 ± 1.151 mg/L, p = 0.02). Insulin at week 12 week decreased significantly (90.1 ± 39.8 pmol/L vs. 33.2 ± 19.6 pmol/L, p = 0.002). There was a nonsignificant decrease in visceral adipose tissue (155.2 ± 68 cm2 at week 0 vs. 140.6 ± 70 cm2 at week 24, p = 0.08).
Use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection. Further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted.
PMCID: PMC4234118  PMID: 23867790
Lipodystrophy; Lipoatrophy; IGF-I; HIV; Mecasermin
4.  Low Baseline CD4+ Count Is Associated With Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation 
Low pretreatment CD4+ cell count is an independent risk factor for bone loss after antiretroviral therapy (ART) initiation, providing further evidence for the benefits of early ART. Initiation of ART at higher CD4+ counts may reduce the burden of osteoporosis and fragility fracture.
Background. Bone mineral density (BMD) decreases 2%–6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss.
Methods. We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4+ and 16-week CD4+ change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)– or tenofovir-containing regimen on 96-week total BMD change.
Results. The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4+ cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4+ <50 cells/µL lost significantly more BMD compared to those with CD4+ ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4+ count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4+ count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline.
Conclusions. Low pretreatment CD4+ count, but not greater CD4+ count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4+ counts may reduce the burden of osteoporosis and fragility fractures.
PMCID: PMC3805172  PMID: 23943825
anti-HIV agents; administration and dosage; HIV infections; drug therapy/virology; bone density
5.  Massively Parallel Pyrosequencing in HIV Research 
AIDS (London, England)  2008;22(12):1411-1415.
The new massively parallel sequencing methods are so astonishing one wonders whether space aliens are secretly behind them. One technician, running a single instrument, can obtain up to ~1 billion bases of DNA sequence in a few days. Here we describe the new sequencing methods, briefly present a few applications in HIV research, and then speculate on future directions.
PMCID: PMC4221253  PMID: 18614863
6.  Tolerability of intramuscular and intradermal delivery by CELLECTRA® adaptive constant current electroporation device in healthy volunteers 
Human Vaccines & Immunotherapeutics  2013;9(10):2246-2252.
DNA vaccines are being developed as a potentially safe and effective immunization platform. However, translation of DNA vaccines into a clinical setting has produced results that have fallen short of those generated in a preclinical setting. Various strategies are being developed to address this lack of potency, including improvements in delivery methods. Electroporation (EP) creates transient increases in cell membrane permeability, thus enhancing DNA uptake and leading to a more robust immune response. Here, we report on the safety and tolerability of delivering sterile saline via intramuscular (IM) or intradermal (ID) injection followed by in vivo electroporation using the CELLECTRA® adaptive constant current device in healthy adults from two open-label studies. Pain, as assessed by VAS, was highest immediately after EP but diminishes by about 50% within 5 min. Mean VAS scores appear to correlate with the amount of energy delivered and depth of needle insertion, especially for intramuscular EP. Mean scores did not exceed 7 out of 10 or 3 out of 10 for IM and ID EP, respectively. The majority of adverse events included mild to moderate injection site reactions that resolved within one day. No deaths or serious adverse events were reported during the course of either study. Overall, injection followed by EP with the CELLECTRA® device was well-tolerated and no significant safety concerns were identified. These studies support the further development of electroporation as a vaccine delivery method to enhance immunogenicity, particularly for diseases in which traditional vaccination approaches are ineffective.
PMCID: PMC3906411  PMID: 24051434
electroporation; vaccination; intramuscular; intradermal; visual analog scale
7.  Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV 
The New England journal of medicine  2014;370(10):901-910.
CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene (“gene editing”) — in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN) — is safe.
We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance.
One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (−1.81 cells per day) was significantly less than the decline in unmodified cells (−7.25 cells per day) (P = 0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.
CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; number, NCT00842634.)
PMCID: PMC4084652  PMID: 24597865
8.  The RADAR Study: Week 48 Safety and Efficacy of RAltegravir Combined with Boosted DARunavir Compared to Tenofovir/Emtricitabine Combined with Boosted Darunavir in Antiretroviral-Naive Patients. Impact on Bone Health 
PLoS ONE  2014;9(8):e106221.
NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression.
In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48.
Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP).
The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health.
Trial Registration NCT 00677300
PMCID: PMC4149560  PMID: 25170938
9.  Addition of Nitazoxanide to PEG-IFN and Ribavirin to Improve HCV Treatment Response in HIV-1 and HCV Genotype 1 Coinfected Persons Naïve to HCV Therapy: Results of the ACTG A5269 Trial 
HIV clinical trials  2013;14(6):274-283.
We hypothesized that nitazoxanide (NTZ) added to pegylated inter-feron alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coin-fected persons.
Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to his­torical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR).
Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%–75.3%), cEVR in 38.8% (28.8%–49.6%). and SVR in 32.8% (23.4%–43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated.
Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
PMCID: PMC4113390  PMID: 24334180
genotype 1; hepatitis C; HIV; nitazoxanide; pegylated interferon; ribavirin
10.  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
11.  Weight and Lean Body Mass Change with Antiretroviral Initiation and Impact on Bone Mineral Density: AIDS Clinical Trials Group Study A5224s 
AIDS (London, England)  2013;27(13):2069-2079.
To compare the effect initiating different antiretroviral therapy (ART) regimens have on weight, body mass index (BMI), and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD).
A5224s was a substudy of A5202, a prospective trial of 1857 ART-naïve participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). All subjects underwent dual-energy absorptiometry (DXA) and abdominal CT for body composition. Analyses used 2-sample t-tests and linear regression.
A5224s included 269 subjects: 85% male, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 233 cells/µL. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks post randomization (all p<0.001). Assignment to ATV/r (vs EFV) resulted in significantly greater weight (mean difference 3.35 kg) and BMI gain (0.88 kg/m2; both p=0.02), but not LBM (0.67 kg; p=0.15), while ABC/3TC and TDF/FTC were not significantly different (p≥0.10). In multivariable analysis, only lower baseline CD4 count and higher HIV-1 RNA were associated with greater increase in weight, BMI, or LBM. In multivariable analyses, increased LBM was associated with an increased hip BMD.
ABC/3TC vs. TDF/FTC did not differ in change in weight, BMI, or LBM; ATV/r vs. EFV resulted in greater weight and BMI gain but not LBM. A positive association between increased LBM and increased hip BMD should be further investigated through prospective interventional studies to verify the impact of increased LBM on hip BMD.
PMCID: PMC3966569  PMID: 24384588
antiretroviral therapy; HIV; body composition; body weight; lean body mass; bone mineral density; randomized clinical trial
12.  Pegylated Interferon Alfa-2a Monotherapy Results in Suppression of HIV Type 1 Replication and Decreased Cell-Associated HIV DNA Integration 
The Journal of Infectious Diseases  2012;207(2):213-222.
Background. Antiretroviral therapy (ART)–mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication.
Methods. A total of 23 HIV type 1 (HIV-1)–infected, virologically suppressed subjects receiving ART (CD4+ T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg–interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed.
Results. At week 12 of Peg–interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end-point failure.
Conclusions. Peg–interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication.
Clinical Trials Registration. NCT00594880.
PMCID: PMC3532820  PMID: 23105144
HIV-1; interferon-alpha; viral integration; immunotherapy
13.  Risk of Hip Fracture Associated with Hepatitis C Virus Infection and Hepatitis C/HIV Coinfection 
Hepatology (Baltimore, Md.)  2012;56(5):1688-1698.
Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our objectives were to determine whether persons with HCV infection alone are at increased risk for hip fracture compared to uninfected individuals and to examine if the risk of hip fracture is higher among HCV/HIV-coinfected persons compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999–2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1000 person-years), increased with the presence of either HIV infection (1.95 events/1000 person-years) or HCV infection (2.69 events/1000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [95% confidence interval]) of hip fracture compared to HCV-monoinfected (1.38 [1.25–1.53]), HIV-monoinfected (females: 1.76 [1.44–2.16]; males: 1.36 [1.20–1.55]), and uninfected persons (females: 2.65 [2.21–3.17]; males: 2.20 [1.97–2.47]). HCV monoinfection was associated with an increased risk of hip fracture compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18–39 years: 3.56 [2.93–4.32]; males, 18–39 years: 2.40 [2.02–2.84]).
Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture compared to uninfected individuals.
PMCID: PMC3433632  PMID: 22619086
Hepatitis C virus; HCV; HIV; fracture; coinfection
14.  The Use of HAART Is Associated With Decreased Risk of Death During Initial Treatment of Cryptococcal Meningitis in Adults in Botswana 
The objective of this study was to evaluate outcomes among adults with a first episode of cryptococcal meningitis (CM), comparing those on highly active antiretroviral therapy (HAART) with those not on HAART.
We conducted a prospective cohort study among HIV-infected adults (aged 18 years and older) with a first episode of CM at the Princess Marina Hospital, in Gaborone, Botswana. The proportions surviving to discharge were compared. Logistic regression was used to evaluate the relationship between HAART use and risk of death in the hospital, adjusting for potential confounders.
Ninety-two patients [median CD4 41 cells/mm3 (inter-quartile range 22–85)] were included, 26 of whom were on HAART at the time that they developed CM. The in-hospital mortality was lower among those on HAART {2 of 26 (8%) vs 14 of 66 (21%); odds ratio = 0.36 [95% confidence interval (CI) 0.09 to 1.49]}, and this result was statistically significant after adjustment for male sex and tuberculosis [adjusted odds ratio = 0.19 (95% CI 0.04 to 1.00)].
HAART use at the time of a first admission with CM is associated with decreased risk of death during the acute phase of disease. Reasons for this association should be explored.
PMCID: PMC3704195  PMID: 18769344
cryptococcal meningitis; HAART; Africa; cohort study
15.  Vitamin D Levels, Natural H1N1 Infection and Response to H1N1 Vaccine among HIV-Infected Individuals 
Beyond its role in calcium homeostasis, vitamin D plays a critical role in immunological responses to pathogens. We evaluated the relationship between 25-OH vitamin D levels and susceptibility to natural H1N1 infection and H1N1 vaccine responses in HIV infected individuals.
This was a sub study of an H1N1 vaccine trial conducted at the University of Pennsylvania in 2009/10. We compared the 25-OH vitamin D levels among individuals with and without baseline evidence of prior H1N1 infection and between vaccine responders and non-responders.
120 participants enrolled in the trial, 71% male, 68% African American, median age 46 years. The majority had controlled HIV disease. At baseline, 86% had 25-OH vitamin D levels < 30 ng/ml and 54% had levels < 20 ng/ml. Thirty participants (25%) had evidence of prior H1N1 exposure. There was no difference in mean 25-OH vitamin D levels among patients with or without prior natural H1N1 infection (21 ng/ml vs 20 ng/ml, p=0.72). Among participants without previous H1N1 exposure, only 61% developed protective antibody titers following vaccination. 25-OH vitamin D levels were similar between vaccine responders (20 ng/ml) and non-responders (20 ng/ml) (p=0.83).
Although 25-OH vitamin D deficiency was very common among HIV-infected individuals, it was not associated with natural susceptibility to H1N1 or to vaccine responses.
PMCID: PMC3514974  PMID: 23227442
HIV; H1N1; Influenza; Vitamin D deficiency; Vaccine response
16.  Phase I/II Trial of the Anti-HIV Activity of Mifepristone in HIV-Infected Subjects ACTG 5200 
Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug’s safety and anti-HIV activity.
A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts ≥350 cells per cubic millimeter who had no recent antiretroviral therapy.
Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash.
Mifepristone at doses of 75–225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity.
PMCID: PMC3477637  PMID: 20130470
antiretroviral; clinical trial; mifepristone
17.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
PMCID: PMC3448095  PMID: 22352336
18.  HIV mediated PI3K/Akt activation in antigen presenting cells leads to PD-1 ligand upregulation and suppression of HIV specific CD8 T-cells 
Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death 1 (PD-1) on virus-specific CD8+ T cells. PD-1 is induced upon T cell activation and its prolonged expression facilitates CD8+ T cell inhibitory signals when bound to its B7 family ligands, PD-L1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by antibodies may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1, in which virus-mediated upregulation induced a state of non-responsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1 after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. Additionally, we identify a critical role for the PI3K/Akt signaling pathway in PD-L1 upregulation of APC’s by HIV, as inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.
PMCID: PMC3197696  PMID: 21856939
19.  Peripheral and Central Fat Changes in Subjects Randomized to Abacavir-Lamivudine or Tenofovir-Emtricitabine With Atazanavir-Ritonavir or Efavirenz: ACTG Study A5224s 
A5224s compared fat changes with abacavir/lamivudine (ABC/3TC) or TenofovirDF/Emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). TDF/FTC- and ABC/3TC-regimens similarly increased limb and visceral fat. ATV/r led to greater gains in limb fat, and a trend towards greater gains in visceral fat than EFV.
Background. We compare the effect of 4 different antiretroviral regimens on limb and visceral fat.
Methods. A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)–infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test.
Results. A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log10 copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm2, and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT.
Conclusions. ABC-3TC– and TDF-FTC–based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3165963  PMID: 21690627
20.  Anti-HIV-1 Activity of the Neurokinin-1 Receptor Antagonist Aprepitant and Synergistic Interactions with other Antiretrovirals 
AIDS (London, England)  2010;24(18):2789-2796.
Neurokinin-1 receptor (NK1R) antagonists interfere with binding of neuropeptide substance P (SP) to NK1R and exhibit novel anti-HIV-1 activities. Since NK1R antagonists effectively penetrate the blood-brain barrier to reduce the inflammatory response within the brain, we wished to evaluate their potential as anti-HIV-1 candidates for targeting HIV-1 infections of the central nervous system.
A series of small molecule agents were evaluated for anti-NK1R and anti-HIV-1 activity using peripheral blood mononuclear cells (PBMC). The most promising of these, aprepitant (Emend, Merck and Co. Inc.), was investigated for potential synergies with other antiretroviral drugs.
Anti-NK1R activity was tested by measuring intracellular calcium increase triggered by substance P. Anti-HIV-1 activity was evaluated by measuring p24 antigen in culture supernatants of PBMC following exposure to HIV. The concentration of drug which produced 50% reduction in intracellular calcium levels or viral production in 7-day PBMC cultures was determined. The combined effect of aprepitant with each of the major classes of anti-HIV-1 drugs was evaluated in synergy studies.
Aprepitant had the highest anti-HIV-1 activity of the NK1R antagonists examined and was equally active against all major HIV-1 subtypes. Aprepitant acted synergistically with protease inhibitors (ritonavir and saquinavir), but not with nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, or viral entry inhibitors.
The ability of aprepitant to penetrate the blood-brain barrier, its safety record as an FDA approved drug for reducing nausea and vomiting in chemotherapy, and synergistic activity with other anti-HIV-1 drugs make it a promising candidate for treatment of HIV infection.
PMCID: PMC3378647  PMID: 20975512
Human Immunodeficiency Virus Type 1 (HIV-1); Aprepitant (Emend, Merck and Co.); Antiretroviral drugs; Neurokinin-1 Receptor (NK1R) antagonists; Synergy
21.  Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202 
The Journal of Infectious Diseases  2011;203(12):1791-1801.
(See the editorial commentary by Yin and Overton, on pages 1705-7.)
Background.  Long-term effects of abacavir (ABC)–lamivudine (3TC), compared with tenofovir (TDF)–emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed.
Methods.  A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests.
Results.  Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log10 copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components.
Conclusions. Compared with ABC-3TC, TDF-FTC–treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3100514  PMID: 21606537
22.  Vitamin D Deficiency is Associated with Type 2 Diabetes Mellitus in HIV Infection 
AIDS (London, England)  2011;25(4):525-529.
Metabolic complications, including type 2 diabetes mellitus (DM) and metabolic syndrome, are increasingly recognized among HIV-infected individuals. Low vitamin D levels increase the risk of type 2 DM, and vitamin D supplementation has been shown to decrease the risk of type 2 DM in patients without HIV infection.
The primary objective was to determine whether vitamin D deficiency (serum 25-hyrdoxyvitamin D<20 ng/mL) was associated with type 2 DM among HIV-infected patients. Our secondary objective was to determine whether vitamin D deficiency was associated with metabolic syndrome in HIV.
We conducted a cross-sectional study among subjects enrolled in the prospective Modena (Italy) HIV Metabolic Clinic Cohort. Clinical and laboratory data, including history of type 2 DM, fasting blood glucose, components of metabolic syndrome, and 25-hydroxyvitamin D levels, were obtained for all subjects.
After adjusting for vitamin D supplementation, sex, age, body mass index, and hepatitis C virus co-infection, vitamin D deficiency was associated with type 2 DM (adjusted OR, 1.85; 95% CI, 1.03–3.32; p=.038). The association between vitamin D deficiency and metabolic syndrome was not significant after adjusting for vitamin D supplementation, sex age and body mass index (adjusted OR 1.32; 95% CI, 1.00–1.75;p=.053).
Our study demonstrates an association between vitamin D deficiency and type 2 DM. Clinical trials are needed to better characterize the association between vitamin D deficiency and type 2 DM in HIV infection and to evaluate whether vitamin D is able to prevent or delay the onset of type 2 DM.
PMCID: PMC3366629  PMID: 21178753
vitamin D deficiency; type 2 DM; insulin resistance; metabolic syndrome
23.  European Mitochondrial DNA Haplogroups and Metabolic Changes during Antiretroviral Therapy in AIDS Clinical Trials Group Study A5142 
AIDS (London, England)  2011;25(1):37-47.
Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants.
757 ART-naïve subjects were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Non-randomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white subjects. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup.
Median age was 39 years, 9% were female, and 37%, 32%, and 30% were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N=10) had higher baseline non-HDL cholesterol (160 mg/dL [interquartile range 137–171] vs. 120 mg/dL [104–136]; p=0.005), a decrease in non-HDL cholesterol over 96 weeks (−14% [−20-+6] vs. +25% [+8-+51]; p<0.001), tended to have more baseline extremity fat, and had more extremity fat loss by DEXA (−13% [−31-+12] vs. +9% [−13-+26]; p=0.08) and lipoatrophy (50% vs. 20%; p=0.04). Haplogroup W (N=5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat (+35.5% [+26.8 - +54.9]; P=0.02).
Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.
PMCID: PMC2995830  PMID: 20871389
Mitochondrial genome; DNA; Mitochondrial; Antiretroviral Therapy; Highly Active; Dyslipidemias; HIV-Associated Lipodystrophy Syndrome; Metabolic Diseases
24.  Risk Factors for Medication Non-Adherence in an HIV Infected Population in the Dominican Republic 
AIDS and behavior  2011;15(7):1410-1415.
High levels of medication adherence are central to HIV treatment success. Barriers to medication adherence may differ by cultural setting. We aimed to determine risk factors for medication non-adherence in HIV infected individuals in the Dominican Republic. Adherence was measured in 300 individuals using a visual analog scale assessing the prior month and dichotomized at 95%. High levels of adherence were reported by 228 (76%). Risk factors for non-adherence included heavy alcohol use: 2.5 times odds (95% CI: 1.4-4.5), having children: 2.2 times higher odds (95% CI: 1.1-4.9) and perceptions of less social support related to adherence: 2 times higher odds (95% CI: 1.1-3.6). Culturally appropriate interventions are needed to address alcohol use, which is common in this setting. Parenting may represent a competing demand on time and resources and be an adherence barrier. Self-reported perceived lack of adherence support may be a useful marker for need for adherence interventions.
PMCID: PMC3022963  PMID: 20721615
25.  Insulin Resistance in HIV Protease Inhibitor–Associated Diabetes 
Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy.
To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI–associated diabetes.
Cross-sectional evaluation.
8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir.
Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 μM) on rat pancreatic [beta]-cell function in vitro.
In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat [beta]-cells.
The pathogenesis of HIV PI–associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic [beta]-cell function was not impaired by indinavir. HIV PI–associated diabetes mirrors that of non–insulin-dependent diabetes mellitus and impaired insulin action in the periphery.
PMCID: PMC3182110  PMID: 10421244
AIDS; Metabolic complications; Glucose metabolism; Pancreatic [beta]-cells; Insulin release

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