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Tenofovir disoproxil fumarate is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30–69 mL/min who switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001), and significant increases in hip and spine bone mineral density through 96 weeks (P < 0.001). Eighty-eight percent maintained HIV-1 RNA

Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 μg/kg of palifermin on 3 consecutive days.The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-μg/kg dose [11 (2, 32) cells/mm], the 40-μg/kg dose [12 (-2, 25) cells/mm], or the 60-μg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants.Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.

Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials.

The contribution of current antiretroviral treatment regimens to the long-term survival of HIV-infected individuals is accompanied by increased risk of glucose metabolism abnormalities in this patient population. The risk of insulin resistance and diabetes in HIV-infected patients receiving antiretroviral treatment stems from 2 sources: exposure to the same environmental factors that have led to an increased incidence of these conditions in the general population and the negative effects on glucose metabolism inherent to components of antiretroviral treatment regimens. This article reviews the pathogenesis and diagnosis of insulin resistance and diabetes and the contribution of components of antiretroviral therapy regimens to increased risk for these conditions. Optimization of antiretroviral treatment regimens for HIV-infected patients with or at increased risk for development of abnormalities in glucose metabolism is discussed.

OBJECTIVE: 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. METHODS: 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. RESULTS: Ninety-two patients [median CD4 41 cells/mm (interquartile 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)]. CONCLUSIONS: 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.

OBJECTIVE The aim of this study was to examine the influence of kidney disease and hemodialysis on the pharmacokinetics ofenfuvirtide. DESIGN An open-label, multicenter, parallel group study of HIV-1-infected patients with varying degrees of kidney dysfunction. METHODS A 90-mg dose of enfuvirtide was administered by subcutaneous injection to 3 groups of patients: group A, patients with normal kidney function; group B, patients with chronic kidney disease; and group C, patients with end-stage renal disease (ESRD) requiring dialysis. Patients with ESRD requiring dialysis received the 90-mg dose of enfuvirtide on 2 separate occasions; a dialysis day and a nondialysis day. After each dose, a full 48-hour pharmacokinetic profile was collected and pharmacokinetic parameters were estimated using model-independent techniques. RESULTS Enfuvirtide area under the curve (AUCinfinity) and maximum observed enfuvirtide plasma concentration (Cmax) for patients with normal kidney function (group A) was 49.6 microg h/mL and 3.79 microg/mL, respectively. Patients with chronic kidney disease (group B) had higher AUCinfinity (80.3 microg h/mL) and Cmax (5.72 microg/mL), which was similar to patients with ESRD (group C) on both nondialysis days (AUCinfinity 71.1 microg h/mL; Cmax 5.34 microg/mL) and dialysis days (AUCinfinity 66.9 microg h/mL; Cmax 6.31 microg/mL). An average of< 13% of enfuvirtide was removed during the dialysis procedure. The incidence of adverse events was comparable for all study groups. CONCLUSION Enfuvirtide exposure observed in patients with ESRD requiring dialysis or chronic kidney disease was slightly higher than in patients with normal kidney function and similar to historical Cmax and AUC values from studies in patients with normal kidney function. Thus, enfuvirtide does not require dosage adjustment in patients with impaired kidney function.

Background: Occult hepatitis B virus (HBV) is defined by the presence of HBV DNA in individuals with HBV core antibodies (anti-HBc) but without HBV surface antigen (HBsAg). The prevalence of occult HBV in HIV-infected patients remains controversial, and the risk factors and clinical significance are unknown. Objectives: To determine the prevalence, risk factors, and clinical significance of occult HBV among HIV-infected patients. Hypothesized risk factors include chronic hepatitis C virus (HCV), CD4 count 1000 copies/mL, and lack of use of anti-HBV antiretrovirals. Methods: We examined randomly selected HBsAg - /anti-HBC HIV-infected patients in the Penn Center for AIDS Research Adult/Adolescent Database and Specimen Repository. HBV DNA was qualitatively detected using a transcription-mediated amplification assay. Risk factors and transaminases were ascertained at the time sera were collected. Results: A total of 699 HBsAg - /anti-HBc + HIV-infected patients were identified. Of 179 randomly selected subjects, 17 (10%; 95% confidence interval [CI]: 5% to 14%) had occult HBV Differences in the prevalence of HBV surface antibody (anti-HBs) between those with (7 [41%]) and without (94 [58%]) occult HBV were not statistically significant (P = 0.3). An HIV RNA level >1000 copies/mL (adjusted odds ratio [OR] = 4.88, 95% CI: 1.01 to 30.26) and the absence of chronic HCV (adjusted OR = 0.26, 95% CI: 0.05 to 0.95) were associated with occult HBV Occult HBV did not increase the risk of transaminitis (adjusted OR = 0.42, 95% CI: 0.12 to 1.45). Conclusions: Occult HBV occurred in a sizable proportion of HIV-infected patients and was associated with detectable HIV and the absence of chronic HCV It did not increase the risk of transaminitis. The presence of anti-HBs does not rule out occult HBV Future studies should examine the long-term clinical implications of occult HBV in HIV-infected patients.

Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy.The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of350 cells/mm as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts ofor =500 cells/mm or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n = 23) or arm B (ART alone, n = 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count ofor =500 cells/mm or more stopped ART until a CD4 count of350 cells/mm (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms.IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8.IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.

Obesity and HIV infection are ongoing epidemics in the United States. Obesity predisposes to diabetes and cardiovascular disease, which are complications also associated with HIV and/or its treatment.To determine the prevalence and risk factors for overweight and obesity in HIV-infected individuals.Retrospective cross-sectional study in which 1689 patients enrolled in the University of Pennsylvania Center for AIDS Research Adult/Adolescent Database at 1 university hospital clinic, 2 affiliated practices, and 1 Veterans Administration clinic in Philadelphia had demographic, social, and medical data collected prospectively since 1999.Body mass index (BMI) data were available for 1669 HIV-infected subjects: 78% were men, and 60% were African American. The median CD4 count was 381 cells/microL, 47% of subjects had a viral load400 copies/mL, and 9% of subjects were treatment naive.The prevalence and risk factors for overweight (BMI: 25-29.9 kg/m) and obesity (BMIor=30 kg/m) in HIV-infected subjects.Obesity and overweight were more prevalent than wasting (14%, 31%, and 9%, respectively; P0.0005), but they were not more common than in the general population. Although women and men were equally overweight (30% vs. 31%), women were more obese than men (28% vs. 11%; P0.001). Among women, African American race (odds ratio [OR]=1.8, 95% confidence interval [CI]: 1.1-2.9) and a CD4 countor=200 cells/microL (OR=2.8, 95% CI: 1.6-4.9) were associated with overweight and obesity. Among men, only a CD4 countor=200 cells/microL (OR=1.6, 95% CI: 1.04-2.4) was associated with increased BMI. In men and women, smoking was associated with decreased obesity and overweight (OR=0.59, 95% CI: 0.47-0.74 and OR=0.65, 95% CI: 0.43-0.98, respectively). Age, income, employment, education, past or current intravenous drugs, being on HIV treatment, and viral load were not associated with obesity in the multivariate model. There was a positive correlation between BMI and total cholesterol, triglycerides, and glucose.Obesity is more common than wasting in this therapeutic era. Women, particularly those of African American race, are at high risk. Obesity might add to metabolic abnormalities associated with HIV or its treatment and contribute to morbidity, as patients with HIV live longer.

Background: Osteopenia and osteoporosis are frequent complications of HIV infection and/or its treatment. Alendronate is the only bisphosphonate approved for the treatment of osteoporosis in men and women. We conducted a 48-week prospective, randomized, open-label study to evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone mineral density (BMD) in patients with HIV infection. Methods: Thirty-one HIV-infected subjects with lumbar spine BMD t-scores less than - 1.0 on antiretroviral therapy for a minimum of 6 months were randomized to receive (n = 15) or not to receive (n = 16) 70 mg of alendronate weekly for 48 weeks. All subjects received calcium (1000 mg daily as calcium carbonate) and vitamin D supplementation (400 IU daily). The study was powered to detect 3% changes in BMD in the lumbar spine within arms at 48 weeks. Results: Thirty-one patients were enrolled; most were male, with an average length of HIV infection of 8 years. Eighty-four percent had an HIV RNA load below 400 copies/mL, with a current median CD4 + T-cell count of 561 cells/mm 3 (median nadir CD4 cell count of 167 ceils/mm 3 ). At baseline, the median t-score in the lumbar spine was - 1.52 and the median t-score in the hip was -1.02. Alendronate in combination with vitamin D and calcium increased lumbar spine BMD by 5.2% (95% confidence interval [CI]: 1.3-6.4) at 48 weeks compared with an increase of 1.3% (95% CI: -2.4 to 4.0) in subjects receiving vitamin D and calcium alone. One subject discontinued treatment in each arm. There were no serious adverse events. Conclusions: Alendronate, vitamin D, and calcium are safe and potentially useful in the treatment of osteopenia/osteoporosis associated with HIV infection.

Summary: From 1999 to 2001, the overall prevalence of resistance in the antiretroviral (ART)-naive population in St. Louis, Missouri, was 17%. We sought to determine if resistance testing in ART-naive HIV-positive pregnant women identified resistant mutations, which would modify our initial choice of therapy. A retrospective chart review was performed on all HIV-positive pregnant women seen from January 2000 to December 2001 at a university hospital. There were 72 pregnancies. Twenty-seven of 72 patients were ART naive. Genotype testing was performed in 18 of 27 naive patients. Three of 18 ART-naive patients (17%) had primary resistance (95% CI: 4%–41%) by genotype to NNRTIs. The primary mutation, G190S, conferring resistance to NNRTIs was present in 1 patient. Another had the K103N mutation. One had the K103R mutation, which conferred phenotypic resistance to NNRTIs by 8.3-fold, warranting a change in the initial regimen. In our community, resistance testing in ART-naive pregnant patients is warranted. Switching later to a more complex regimen during pregnancy may adversely affect adherence, resulting in virologic failure. Strategies to avoid prescribing a suboptimal regimen include waiting to initiate ART until the resistance testing results are available and/or beginning ART with a protease inhibitor–based regimen if the patient is already in the third trimester of pregnancy at the time of her initial clinic presentation.