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1.  Antiretroviral Therapy and Efficacy After Virologic Failure on First-line Boosted Protease Inhibitor Regimens 
Following virologic failure on a first-line protease inhibitor–based regimen, if no or limited drug resistance is detected, remaining on the same regimen coupled with strategies to improve adherence is a reasonable and effective approach.
Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown.
Methods. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed.
Results. Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4+ cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32–8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40–8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15–.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression.
Conclusions. For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success.
PMCID: PMC4155445  PMID: 24842909
first-line; protease inhibitor; virologic failure; antiretroviral therapy
2.  Switch to Raltegravir Decreases Soluble CD14 in Virologically Suppressed Overweight Women: The Women, Integrase, and Fat Accumulation Trial 
HIV medicine  2014;15(7):431-441.
Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from PI or NNRTI.
HIV-infected women with central adiposity and HIV-1 RNA <50 copies/mL continued their thymidine-sparing NRTI backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma.
Thirty-seven evaluable subjects were 78% non-White and had median age 43 years, BMI 32 kg/m2 and CD4+ T cell count 558 cells/µL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL (−21% (p<0.001) vs. PI/NNRTI −5% (p=0.49), between group p<0.01). After 48 weeks, immediate switch subjects maintained this decline and delayed switch subjects experienced a similar decline following switch to RAL (−10%, within-group p<0.01). Immediate switch subjects also experienced an initial increase in TNF-α that was neither maintained after 48 weeks nor seen in delayed switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant.
In this randomized trial of women with central adiposity, switch to RAL from PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared to PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.
PMCID: PMC4107004  PMID: 24506429
raltegravir; sCD14; monocyte activation; inflammation; women
3.  Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia 
Open Forum Infectious Diseases  2015;2(3):ofv085.
Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257.
Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated.
Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%–36%) in Black, 60% (CI, 32%–84%) in White, and 29% (CI, 8%–58%) in Hispanic participants; negative predictive values were 97% (CI, 93%–99%), 95% (CI, 90%–98%), and 97% (CI, 90%–100%), respectively.
Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.
PMCID: PMC4498287  PMID: 26180834
atazanavir; HIV; pharmacogenomics; pharmacokinetics; UGT1A1
4.  Cardiovascular Disease Risk Factors in HIV-Infected Women Following Initiation of Lopinavir/ritonavir- and Nevirapine-based Antiretroviral Therapy in Sub-Saharan Africa: A5208 (“OCTANE”) 
Limited comparative, prospective data exist regarding cardiovascular risk factors in HIV-infected women starting antiretroviral therapy (ART) in Africa.
In 7 African countries, 741 women with CD4<200 cells/mm3 were randomized to tenofovir/emtricitabine (TDF/FTC) plus either nevirapine (NVP, n=370) or lopinavir/ritonavir (LPV/r, n=371). Lipids and blood pressure (BP) were evaluated at entry, 48, 96, and 144 weeks. Multivariable linear and logistic regression models were used to evaluate mean risk factor changes and clinically relevant risk factor changes.
At entry, both NVP and LPV/r groups were similar regarding age (mean=33.5 [SD=7.1] yrs), CD4 (129 [67] cells/mm3), and HIV-1 RNA (5.1 [0.6] log10 copies/ml). Nearly all women had normal lipids and BP except for HDL. Over 144 weeks, the LPV/r compared to NVP group had significantly greater mean lipid increases (e.g. non-HDL: +29 vs. +13 mg/dL) and smaller HDL increases (+12 vs. +21 mg/dL). In contrast, the NVP compared to LPV/r group had greater mean increases in BP (e.g. diastolic BP: +5 vs. −0.5 mmHg). Significantly more women assigned LPV/r had week 144 “abnormal” lipid levels (e.g. HDL 29.7% vs. 14.8% and triglycerides 28.6% vs. 8.2%), and significantly more women assigned NVP had “abnormal” BP (e.g. diastolic BP 22.7% vs. 6.5%). Most differences remained significant when adjusted for baseline risk factor, age, CD4, and HIV-1 RNA.
In HIV-infected women initiating ART in Africa, LPV/r+TDF/FTC was associated with less favorable changes in lipids, and use of NVP+TDF/FTC was associated with less favorable changes in BP.
PMCID: PMC4109714  PMID: 24562349
HIV-1; women; Africa; nevirapine; lopinavir/ritonavir; cardiovascular disease risk factors
AIDS (London, England)  2014;28(8):1135-1142.
Tenofovir disoproxil fumarate (TDF) has been associated with renal insufficiency. Co-administration with boosted protease inhibitors (PIs), which increases its exposure, may further increase the risk of renal insufficiency.
We compared the incidence of renal events among women taking TDF co-administered with lopinavir/ritonavir (LPV/r) versus those co-administering TDF with nevirapine (NVP). Renal events were defined as a confirmed drop in creatinine clearance associated with a serum creatinine grade 2 or higher, or that leading to treatment modification.
Overall, 741 HIV-infected women were enrolled into the study. Of these, 24 (3.2%) had reportable renal events (18 in LPV/r arm, 6 in NVP arm). In multivariate analysis, renal events were significantly associated with the LPV/r arm (odds ratio [OR]=3.12, 95% confidence interval [CI] 1.21, 8.05]; p=0.019), baseline HIV-1 RNA (OR=2.65, 95% CI: 1.23, 5.69 per 1 log10 copies/mL higher; p=0.013) and baseline creatinine clearance (OR=0.83, 95% CI 0.70–0.98 per 10 mL/min higher; p=0.030). In multivariate analysis evaluating renal events requiring treatment modification, only baseline HIV-1 RNA and creatinine clearance were significantly associated (OR=4.41, 95% CI 1.65, 11.78 per 1 log10 copies/mL higher; p= 0.003 and OR=0.80, 95% CI 0.64, 0.99 per 10 mL/min higher; p= 0.040, respectively).
The rates of renal events were relatively low in the two treatment arms. However, patients taking TDF co-administered with LPV/r had significantly more renal events compared to those co-administered with NVP. Furthermore, higher baseline HIV RNA and lower creatinine clearance were associated with the development of renal insufficiency requiring treatment modification.
PMCID: PMC4176616  PMID: 24445367
renal insufficiency; tenofovir; lopinavir/ritonavir; nevirapine
6.  Success of Standard Dose Vitamin D Supplementation in Treated Human Immunodeficiency Virus Infection 
Open Forum Infectious Diseases  2015;2(2):ofv068.
Vitamin D insufficient, HIV+ adults on ART taking D3 50,000 IU twice weekly x5 weeks then 2000 IU daily demonstrated similar repletion success (25OHD >30ng/mL) as historical, HIV- controls. Tenofovir/abacavir were associated with success/failure (respectively) to maintain 25OHD levels post-repletion.
Background. Vitamin D insufficiency is prevalent in human immunodeficiency virus-positive (HIV+) persons. Human immunodeficiency virus and antiretroviral therapy (ART) may create unique risk factors, and the optimal vitamin D repletion and maintenance regimen in HIV+ persons remains unclear.
Methods. Human immunodeficiency virus-positive adults on suppressive ART underwent routine serum 25-hydroxyvitamin D (25OHD) screening. Persons with vitamin D insufficiency (25OHD <30 ng/mL) received open-label, oral vitamin D3 50 000 international units (IU) twice weekly for 5 weeks, then 2000 IU daily to complete 12 weeks. We predicted 70% (95% confidence interval, 60%–80%) repletion to 25OHD ≥30 ng/mL compared with 85% among historical HIV-negative controls. Eighty participants provided 91% power to detect this difference. Ability to maintain 25OHD ≥30 ng/mL after 24 weeks was also assessed.
Results. Baseline characteristics were similar between the 82 vitamin D insufficient and 40 sufficient persons enrolled: 95% male, 60% white, 88% nonsmokers, median age 49 years, body mass index 26 kg/m2, and CD4+ T lymphocyte count 520 cells/mm3. After 12 weeks, 81% (66 of 82) of insufficient persons achieved 25OHD ≥30 ng/mL (P = .32 vs historical controls), with only older age (odds ratio [OR] = 1.06; P = .06), higher baseline 25OHD (OR = 1.14; P < .01), white race (OR = 3.39; P = .04), and current smoking (OR = 0.25; P = .06) associated with successful repletion. After 24 weeks, 73% (48 of 66) maintained 25OHD ≥30 ng/mL, with tenofovir (OR = 5.00; P = .01) and abacavir use (OR = 0.23; P = .02) associated with success and failure, respectively, to maintain 25OHD levels.
Conclusions. The 25OHD repletion rates were comparable between HIV+ adults on suppressive ART and historical HIV-negative controls, indicating that successful oral repletion can be achieved in this population.
PMCID: PMC4462892  PMID: 26125033
antiretroviral therapy; HIV; vitamin D
7.  “HDL Redox Activity is Increased in HIV-Infected Men in Association with Macrophage Activation and Noncalcified Coronary Atherosclerotic Plaque” 
Antiviral therapy  2014;19(8):805-811.
HIV is associated with atherosclerosis and low HDL. With inflammation, HDL becomes dysfunctional. We previously showed that pro-inflammatory HDL has high HDL redox activity (HRA). In this study, we: 1) compare HRA in HIV-infected versus non-HIV-infected subjects and 2) relate HRA to indices of macrophage activation and cardiovascular disease risk.
102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123(DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DORsubject/DORpooled (nHRA) was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL.
HRA was higher in HIV-infected versus non-HIV subjects (1.4±0.01 versus 1.3±0.01, p=0.03). In multivariate modeling for HRA among all subjects, HIV status remained positively related to HRA (p=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions, and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=−0.32, p=0.002) and log adiponectin (r=−0.28, p=0.006) and correlated positively with log sCD163 (r=0.24, p=0.02) - a monocyte/macrophage activation marker - and with percent non-calcified coronary atherosclerotic plaque (r=0.29, p=0.03). sCD163 remained significantly associated with HRA in multivariate modeling among HIV-infected subjects (p=0.03).
These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function, and CVD risk.
PMCID: PMC4423391  PMID: 24535655
HIV; HDL; atherosclerosis; HDL oxidative potential
8.  Arterial Disease in Patients with Human Immunodeficiency Virus Infection: What Has Imaging Taught Us? 
JACC. Cardiovascular imaging  2014;7(5):515-525.
With advances in antiretroviral therapy, individuals with human immunodeficiency virus (HIV) infection are living longer and increasingly die of non-HIV related diseases such as cardiovascular disease (CVD). Several observational studies suggest that HIV-infected patients on ART are at increased CVD risk; however, the precise mechanisms underlying the association between HIV infection and CVD risk are uncertain. Atherosclerosis and arterial disease in HIV-infected individuals is a multifactorial process with several potential targets for research and therapeutic intervention.
PMCID: PMC4024182  PMID: 24831212
HIV; Coronary arteries; Endothelial function; Ultrasound; Carotid intima-media thickness
9.  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
10.  Switch to Raltegravir From Protease Inhibitor or Nonnucleoside Reverse-Transcriptase Inhibitor Does not Reduce Visceral Fat In Human Immunodeficiency Virus-Infected Women With Central Adiposity 
Open Forum Infectious Diseases  2015;2(2):ofv059.
Human immunodeficiency virus-infected women with central adiposity switched to raltegravir-based antiretroviral therapy immediately or after 24 weeks. No statistically significant changes in computed tomography-quantified visceral adipose tissue (VAT) or subcutaneous fat were observed, although 48 weeks of raltegravir was associated with a 6.4% VAT decline. Raltegravir for 24 weeks was associated with improvements in lipids.
PMCID: PMC4567084  PMID: 26380350
antiretroviral therapy; fat; HIV; raltegravir; visceral; women
11.  Who Provides Primary Care? An Assessment of HIV Patient and Provider Practices and Preferences 
Non-AIDS co-morbidities are emerging as the main health problems for those living with HIV, and primary care for this population is an evolving challenge. Recent studies have raised the question of whether specialists or generalists are best suited to provide HIV primary care, but patients’ actual usage patterns and the preferences of patients and providers have not been well studied.
We anonymously surveyed 98 patients and eight HIV-specialized providers regarding primary care usage patterns and preferences at an academic HIV clinic in Los Angeles that serves insured patients.
Fifty-nine percent of patients use their HIV physician as their primary care provider, and 84% would prefer this model. Physicians were divided on their preferred role, with five out of eight desiring to provide both primary care and HIV care. All eight physicians rated their comfort with antiretroviral therapy and opportunistic infections greater than for non-AIDS co-morbidities. Eighty-one percent of patients and seven of eight providers were supportive of having a co-located primary care physician at the HIV clinic.
We conclude that patients prefer integration of HIV and primary care, but providers have variable desire to serve as primary care physicians and may be uncomfortable with non-AIDS co-morbidities. This raises the need for improved patient-provider communication about primary care needs, and calls for novel ways of systematically providing primary care to HIV-infected patients.
PMCID: PMC4409003  PMID: 25914854
HIV; AIDS; Primary care
12.  The Effect of Hepatitis C Virologic Clearance on Cardiovascular Disease Biomarkers in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection 
Open Forum Infectious Diseases  2014;1(3):ofu104.
 Successful hepatitis C virus (HCV) treatment may reduce cardiovascular disease (CVD) risk and improve levels of CVD biomarkers produced outside the liver (nonhepatic biomarkers).
 Stored serum or plasma from before and 24 weeks after end of HCV treatment (EOT) from human immunodeficiency virus (HIV)/HCV-coinfected subjects who received up to 72 weeks of peginterferon/ribavirin, 27 with and 27 without sustained virologic response (SVR) matched by race, ethnicity and sex, were tested for nonhepatic (soluble intercellular adhesion molecule-1 [sICAM-1], soluble P-selectin [sP-selectin], interleukin [IL]-6, d-dimer, and lipoprotein-associated phospholipase A2 [Lp-PLA2]) and hepatic (cholesterol and high-sensitivity C-reactive protein) CVD and macrophage activation markers (soluble CD163 [sCD163] and soluble CD14). Changes in biomarkers and their association with SVR were examined by t tests or Wilcoxon tests and regression models.
 Of the 54 subjects, 30 were white, 24 were black, and 44 were male. Pretreatment levels of nonhepatic biomarkers were high: sICAM-1 overall median, 439.2 ng/mL (interquartile range [IQR], 365.6–592.8]; sP-selectin, 146.7 ng/mL (IQR, 94.1–209.9), and IL-6, 2.32 pg/mL (IQR, 1.61–3.49). Thirty-seven of 52 (71%) subjects had Lp-PLA2 >235 ng/mL. Sustained virologic response was associated with decrease in sICAM-1 (P = .033) and sCD163 (P = .042); this result was attenuated after controlling for changes in the alanine aminotransferase level. At 24 weeks after EOT, 17 (63%) SVRs had Lp-PLA2 >235 ng/mL vs 25 (93%) non-SVRs (P = .021).
 Hepatitis C virus clearance may reduce hepatic and, subsequently, systemic inflammation and CVD risk in HIV/HCV coinfection.
PMCID: PMC4324212  PMID: 25734172
cholesterol; HIV/HCV coinfection; macrophage activation; sustained virologic response; vascular adhesion molecules
13.  A High Throughput Biochemical Fluorometric Method for Measuring Lipid Peroxidation in HDL 
PLoS ONE  2014;9(11):e111716.
Current cell-based assays for determining the functional properties of high-density lipoproteins (HDL) have limitations. We report here the development of a new, robust fluorometric cell-free biochemical assay that measures HDL lipid peroxidation (HDLox) based on the oxidation of the fluorochrome Amplex Red. HDLox correlated with previously validated cell-based (r = 0.47, p<0.001) and cell-free assays (r = 0.46, p<0.001). HDLox distinguished dysfunctional HDL in established animal models of atherosclerosis and Human Immunodeficiency Virus (HIV) patients. Using an immunoaffinity method for capturing HDL, we demonstrate the utility of this novel assay for measuring HDLox in a high throughput format. Furthermore, HDLox correlated significantly with measures of cardiovascular diseases including carotid intima media thickness (r = 0.35, p<0.01) and subendocardial viability ratio (r = −0.21, p = 0.05) and physiological parameters such as metabolic and anthropometric parameters (p<0.05). In conclusion, we report the development of a new fluorometric method that offers a reproducible and rapid means for determining HDL function/quality that is suitable for high throughput implementation.
PMCID: PMC4219769  PMID: 25368900
14.  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
15.  Body Composition, Soluble Markers of Inflammation, and Bone Mineral Density in Antiretroviral Therapy-Naïve HIV-1 Infected Individuals 
To determine the association between bone mineral density (BMD), inflammatory markers, and alterations in fat and lean mass in untreated HIV-infected individuals.
Cross-sectional analysis of antiretroviral therapy (ART)-naïve persons enrolled into a randomized clinical trial
Dual energy x-ray absorptiometry (DXA) for BMD, lean and fat mass, and a laboratory assessment were performed. Soluble biomarkers included adipocytokines (leptin, adiponectin), inflammatory markers (hsCRP, IL-6), and markers related to bone metabolism (osteoprotegerin (OPG)), receptor activator of NFκB Ligand (RANKL)). BMD at the lumbar spine, total hip, and femoral neck was expressed as a Z-score (number of standard deviations away from an age-, race-, sex-matched reference population).
331 subjects had a median (Q1, Q3) age of 36 (28,45) years, were 89% male, and 44% white. The prevalence of low BMD (Z-score ≤ −2 at any of the 3 sites) was 10%. No associations were detected between Z-scores and hsCRP, IL-6, or RANKL (P≥0.1). In a linear model adjusting for age, gender, race, and total fat mass, lower lumbar spine Z-scores were associated with lower total lean mass, higher serum adiponectin, and lower OPG. Results at the total hip or femoral neck were similar.
Among ART-naïve HIV-infected individuals, lower BMD was associated with lower lean mass, higher adiponectin, and lower OPG, but not HIV disease variables or any of the inflammatory markers. These findings may have implications for bone metabolism in untreated HIV, in which hypoadiponectinemia and higher OPG may mitigate bone loss.
PMCID: PMC3693854  PMID: 23591634
Bone mineral density; Body composition; Human Immunodeficiency Virus; Inflammation
16.  Predictors of suboptimal CD4 response among women achieving virologic suppression in a randomized antiretroviral treatment trial, Africa 
BMC Infectious Diseases  2014;14:331.
A subset of HIV-1 infected patients starting highly active antiretroviral treatment (HAART) experience suboptimal CD4 response (SCR) despite virologic suppression. We studied the rate of and risk factors for SCR among women starting HAART in the ACTG A5208 study conducted in 7 African countries. 741 HAART-naive women with screening CD4 count <200 cells/μL were randomized to start HAART with Tenofovir/Emtricitabine plus either Nevirapine or Lopinavir/Ritonavir.
This analysis includes the 625 women who remained on-study through 48 weeks without experiencing protocol-defined virologic failure. We defined SCR as < 100 CD4 cells/μL increase from baseline and absolute CD4 cell count < 350 cells/μL, both at 48 weeks after HAART initiation.
The baseline characteristics for the 625 women prior to HAART initiation were: median age 33 years, screening CD4 count 134 cells/μL, and HIV-1 RNA 5.1 log10 copies/mL; 184 (29%) were WHO Stage 3 or 4.
Seventy one (11%) of these 625 women experienced SCR. Baseline factors independently associated with increased odds of SCR included older age, lower HIV-1 RNA, positive Hepatitis B surface antigen, and site location. At 96 weeks, only 6% of the SCR group had CD4 ≥ 350 cells/μL compared with 67% in the non SCR group.
After starting HAART, 11% of women with virologic suppression through 48 weeks experienced SCR. These patients were also less likely to achieve CD4 ≥ 350 cells/μL by 96 weeks. The underlying causes and long term clinical implications of SCR deserve further investigation.
Trial registration Identifier: NCT00089505
PMCID: PMC4083139  PMID: 24938526
HIV; Antiretroviral therapy; HAART; Immune response; CD4
17.  Perturbations of Circulating Levels of RANKL-Osteoprotegerin Axis in Relation to Lipids and Progression of Atherosclerosis in HIV-Infected and -Uninfected Adults: ACTG NWCS 332/A5078 Study 
The receptor activator of the NF-κB ligand (RANKL)-osteoprotegerin (OPG) axis has been shown to play a role in the inflammatory process of atherogenesis and may be regulated by changes in levels of cholesterol. However, the interplay between HIV-1 infection, lipids, the RANKL-OPG axis, and atherosclerosis is poorly defined. Serum RANKL, OPG, and RANKL/OPG ratio were retrospectively assessed for 91 subjects from a 3-year study of carotid artery intima-media thickness (CIMT), which enrolled triads of risk factor-matched persons that were HIV-1 uninfected (n=36) or HIV-1+ with (n=29) or without (n=26) continuous protease inhibitor (PI)-based therapy for ≥2 years. Associations of serum RANKL, OPG, and RANKL/OPG ratio to the primary outcomes of levels of circulating lipids and atherosclerosis progression were determined using multivariate regression models. Serum RANKL and RANKL/OPG ratio were significantly lower in HIV-infected versus HIV-uninfected subjects (p<0.01). Multivariate models for HIV-1+ subjects, but not in uninfected controls, demonstrated that perturbations in serum cholesterol levels were significantly associated (p<0.05) with perturbations in serum levels of RANKL and OPG, and their ratio (RANKL/OPG). There were no significant associations of serum RANKL, OPG, and RANKL/OPG with progression of atherosclerosis in HIV-1+ subjects. Our results suggest that HIV-1 infection is associated with reductions in both serum RANKL and the RANKL/OPG ratio, and perturbations in the circulating levels of RANKL and OPG are significantly associated with increases in cholesterol levels, but not with progression of atherosclerosis.
PMCID: PMC3653400  PMID: 23351153
18.  Urinary Eicosanoid Metabolites in HIV-Infected Women with Central Obesity Switching to Raltegravir: An Analysis from the Women, Integrase, and Fat Accumulation Trial 
Mediators of Inflammation  2014;2014:803095.
Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m2 completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus −0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.
PMCID: PMC4058804  PMID: 24991090
19.  Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity 
PLoS ONE  2014;9(3):e89928.
Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons.
We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models.
In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001).
In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.
PMCID: PMC3962339  PMID: 24657960
20.  Characterization of HIV-HBV co-infection in a multi-national HIV-infected cohort 
AIDS (London, England)  2013;27(2):191-201.
To understand the HIV-hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multi-national cohort.
Methods and design
HIV-infected subjects enrolled in two international studies were classified as HIV-HBV co-infected or HIV monoinfected prior to ART. HIV-HBV co-infected subjects were tested for HBV characteristics, hepatitis D virus (HDV), a novel non-invasive marker of liver disease, and drug-resistant HBV. Comparisons between discrete covariates used chi-square or Fisher’s exact tests (and Jonchkheere-Terpstra for trend tests) while continuous covariates were compared using Wilcoxon Rank-Sum Test.
Of the 2105 HIV-infected subjects from 11 countries, the median age was 34 years and 63% were Black. The 115 HIV-HBV co-infected subjects had significantly higher ALT and AST values, lower body mass index, and lower CD4+ T-cell counts than HIV monoinfected subjects (median 159 cells/mL and 137 cells/mL, respectively, P=0.04). In the co-infected subjects, 49.6% had HBeAg-negative HBV, 60.2% had genotype A HBV, and 13% were HDV positive. Of the HBeAg-negative subjects, 66% had HBV DNA ≤2000 IU/ml compared to 5.2% of the HBeAg-positive subjects. Drug-resistant HBV was not detected.
Screening for HBV in HIV-infected patients in resource-limited settings is important since it is associated with lower CD4+ T-cell counts. In settings where HBV DNA is not available, HBeAg may be useful to assess the need for HBV treatment. Screening for drug-resistant HBV is not needed prior to starting ART in settings where this study was conducted.
PMCID: PMC3763734  PMID: 23032418
HIV; HBV; coinfection; global
21.  Biomarkers From Late Pregnancy to 6 Weeks Postpartum in HIV-Infected Women Who Continue Versus Discontinue Antiretroviral Therapy After Delivery 
Journal of acquired immune deficiency syndromes (1999)  2013;63(5):10.1097/QAI.0b013e31829b0b9f.
Women who use antiretroviral therapy (ART) solely for the prevention of mother-to-child transmission of HIV discontinue postpartum. We hypothesized that women discontinuing ART by 6 weeks postpartum (“discontinuers”) would have elevated postpartum inflammatory biomarker levels relative to women remaining on ART postpartum (“continuers”).
Data from HIV-infected pregnant women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 with CD4 counts >350 cells per cubic millimeter before initiating ART or first pregnancy CD4 counts >400 cells per cubic millimeter after starting ART and with available stored plasma samples at >20 weeks of gestation, delivery, and 6 weeks postpartum were analyzed. Plasma samples were tested for highly sensitive C-reactive protein, D-dimer, and interleukin-6. We used longitudinal linear spline regression to model biomarkers over time.
Data from 128 women (65 continuers and 63 discontinuers) were analyzed. All biomarkers increased from late pregnancy to delivery, then decreased postpartum (slopes different from 0, P < 0.001). Continuers had a steeper decrease in log D-dimer between delivery and 6 weeks postpartum than discontinuers (P = 0.002).
In contrast to results from treatment interruption studies in adults, both ART continuers and ART discontinuers had significant decreases in the levels of D-dimer, highly sensitive C-reactive protein, or interleukin-6 postpartum. Continuation was associated with a more rapid decline in D-dimer levels compared with discontinuation.
PMCID: PMC3868443  PMID: 23714738
HIV/AIDS; pregnancy and postpartum; inflammation; antiretroviral therapy
22.  Biomarkers of Microbial Translocation and Macrophage Activation: Association With Progression of Subclinical Atherosclerosis in HIV-1 Infection 
The Journal of Infectious Diseases  2012;206(10):1558-1567.
Background. The relationships between soluble CD14 (sCD14), endotoxin (lipopolysaccharide [LPS]), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection.
Methods. We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group [ACTG] 5078), where subjects were enrolled as risk factor–controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)–based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (ΔCIMT).
Results. In multivariate analysis of the HIV-infected subjects, each 1 µg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 µm/y (95% confidence interval, .07–2.98; P = .04) in the ΔCIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 µm/y (95% confidence interval, .18–.81; P = .003) in the ΔCIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ΔCIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1).
Conclusions. Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.
PMCID: PMC3475633  PMID: 23066162
23.  A Pilot Trial of Adding Maraviroc to Suppressive Antiretroviral Therapy for Suboptimal CD4+ T-Cell Recovery Despite Sustained Virologic Suppression: ACTG A5256 
The Journal of Infectious Diseases  2012;206(4):534-542.
Background. Despite viral suppression, antiretroviral therapy (ART) does not restore CD4+ T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1).
Methods. In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4+ T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/µL in the CD4+ T-cell count.
Results. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4+ T-cell count was 153 cells/µL. The median increase in CD4+ T-cell count from baseline to week 22/24 was 12 cells/µL (90% confidence interval, 1–22). A CD4+ T-cell count increase of at least 20 cells/µL was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc.
Conclusions. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4+ T-cell counts of at least 20 cells/µL. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted.
Clinical Trials Registration. NCT 00709111.
PMCID: PMC3491731  PMID: 22740718
24.  Infant Outcomes After Maternal Antiretroviral Exposure in Resource-Limited Settings 
Pediatrics  2012;129(6):e1525-e1532.
The impact of maternal antiretrovirals (ARVs) during pregnancy, labor, and postpartum on infant outcomes is unclear.
Infants born to HIV-infected mothers in ARV studies were followed for 18 months.
Between June 2006 and December 2008, 236 infants enrolled from Africa (n = 36), India (n = 47), Thailand (n = 152), and Brazil (n = 1). Exposure to ARVs in pregnancy included ≥3 ARVs (10%), zidovudine/intrapartum ARV (81%), and intrapartum ARV (9%). There were 4 infant infections (1 in utero, 3 late postpartum) and 4 deaths with 1.8% mortality (95% confidence interval [CI], 0.1%–3.5%) and 96.4% HIV-1–free survival (95% CI, 94.0%–98.9%). Birth weight was ≥2.5 kg in 86%. In the first 6 months, Indian infants (nonbreastfed) had lowest median weights and lengths and smallest increases in growth. After 6 months, African infants had the lowest median weight and weight-for-age z scores. Infants exposed to highest maternal viral load had the lowest height and height-for-age z scores. Serious adverse events occurred in 38% of infants, did not differ by country, and correlated with less maternal ARV exposure. Clinical diagnoses were seen in 84% of Thai, 31% of African, and 9% of Indian infants. Congenital defects/inborn errors of metabolism were seen in 18 (7.6%) infants, of which 17 were Thai (11%: 95% CI, 6.7%–17.0%); none had first trimester ARV exposure.
Infant follow-up in large international cohorts is feasible and provides important safety and HIV transmission data following maternal ARV exposure. Increased surveillance increases identification of congenital/inborn errors.
PMCID: PMC3362906  PMID: 22585772
maternal ARV exposure; infant safety; ARV toxicities; A5190; P1054; MTCT; HIV
25.  Insights on GRACE (Gender, Race, And Clinical Experience) from the Patient's Perspective: GRACE Participant Survey 
AIDS Patient Care and STDs  2013;27(6):352-362.
The Gender, Race And Clinical Experience (GRACE) study was conducted between October 2006 and December 2008 to evaluate sex- and race-based differences in outcomes after treatment with a darunavir/ritonavir-based antiretroviral regimen. Between June 2010 and June 2011, former participants of the GRACE trial at participating sites were asked to complete a 40-item questionnaire as part of the GRACE Participant Survey study, with a primary objective of assessing patients' characteristics, experiences, and opinions about participation in GRACE. Of 243 potential survey respondents, 151 (62%) completed the survey. Respondents were representative of the overall GRACE population and were predominantly female (64%); fewer were black, and more reported recreational drug use compared with nonrespondents (55% vs. 62% and 17% vs. 10%, respectively). Access to treatment (41%) and too many blood draws (26%) were reported as the best and worst part of GRACE, respectively. Support from study site staff was reported as the most important factor in completing the study (47%). Factors associated with nonadherence, study discontinuation, and poor virologic response in univariate analyses were being the primary caregiver for children, unemployment, and transportation difficulties, respectively. Patients with these characteristics may be at risk of poor study outcomes and may benefit from additional adherence and retention strategies in future studies and routine clinical care.
PMCID: PMC3696933  PMID: 23701200

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