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Objectives: To examine risk factors for sub-optimal CD4 recovery on suppressive highly active antiretroviral therapy (HAART) and assess long-term clinical and immunological outcomes., Methods: Retrospective analysis of 286 HIV-positive patients from a university clinic who initiated HAART with CD4 count <350 cells/microL between January 1996 and July 2006 and achieved > or =52 weeks of viral suppression (VS). Sub-optimal and optimal CD4 count recovery were defined by gains of <150 and > or =150 cells/microL during the first year of VS, respectively. Risk factors were analysed by multivariate logistic regression and markers of immune maturation and activation were evaluated prospectively for a sub-group of patients with prolonged (>5 years) VS., Results: One hundred and two (36%) patients had sub-optimal CD4 recovery. Male gender, lower pre-HAART viral load, HAART toxicity and use of opportunistic infection (OI) prophylaxis were independent risk factors on multivariate analysis (P<0.05). Outcomes of duration of VS on HAART (4 years), new OI events (1%) and mortality (5%) were similar between groups. Markers of immune maturation and activation were higher among patients with sub-optimal CD4 recovery (P<0.05)., Conclusions: Among HIV-positive patients with long-term VS, sub-optimal CD4 recovery was common but morbidity and mortality remained low. In addition, persistent CD4 T-cell activation appeared to blunt long-term CD4 gains.

Background: HIV infection and its treatment, specifically protease inhibitor (PI) therapy, have been associated with an increased risk for cardiovascular disease. Heart rate recovery (HRR) following peak exercise is predictive of future cardiovascular events and mortality in the general population. Nothing is known regarding HRR in individuals infected with HIV on highly active antiretroviral therapy (HAART)., Subjects and Methods: HIV-positive subjects on HAART that included a PI (HIV+PI, n=19), HIV-positive subjects on HAART that did not include a PI (HIV+noPI, n=19) and HIV-seronegative age, gender and body mass index (BMI) matched controls (Cntl, n=15) underwent a graded maximal exercise test on a cycle ergometer to volitional exhaustion. A continuous electrocardiogram was recorded and HRR was monitored every 30 s for 2 min post exercise., Results: HRR at 1.5 and 2 min was significantly delayed in HIV-positive subjects both on and not on PI-based HAART compared with controls (P<0.01)., Conclusion: HRR is impaired in HIV-positive individuals on HAART, whether or not the HAART includes a PI, compared with age, gender, BMI, and activity level matched HIV-seronegative controls. Abnormal HRR may reflect cardio-autonomic dysfunction and may be an independent risk factor for future cardiac events in HIV-positive individuals that receive HAART.

The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV (n=12), HAART but no PI (n=10), and HIV-seronegative controls (n=10). Stable isotope tracers [1-(13)C]palmitate and [1,1,2,3,3-(2)H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50% VO2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV+RTV 5.1+/-1.2 vs. HIV+no PI 5.9+/-2.8 vs. Control 7.4+/-2.2 micromol.kg fat-free mass (FFM)-1.min-1; palmitate oxidation: HIV+RTV 1.6+/-0.8 vs. HIV+no PI 1.6+/-0.8 vs. Control 2.5+/-1.7 micromol.kg FFM.min, P<0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.

Objective: To assess the prognostic significance of persistent low-level viraemia (PLV, defined as persistent plasma viral loads of 51-1000 HIV-1 RNA copies/mL for at least 3 months) in patients who had achieved viral suppression on antiretroviral therapy (ART)., Methods: A retrospective cohort of HIV-infected patients who received ART, were followed-up for > or =12 months, made regular visits to the clinic during which blood tests were performed for an ultrasensitive HIV RNA assay every 3 months, and achieved viral loads <50 copies/mL were evaluated. Virological failure was defined as two consecutive viral load measurements >1000 copies/mL., Results: Of 362 patients, 78 (27.5%) experienced PLV. The demographics of patients with and without PLV were similar. PLV occurred at a mean (+/-standard deviation) of 22.6+/-16.9 months after ART initiation and lasted for 6.4+/-3.4 months. During a median follow-up of 29.5 months, patients with PLV had a higher rate of virological failure (39.7% vs 9.2%; P < 0.001). The median time to failure was 68.4 months [95% confidence interval (CI) 37.0-99.7] for patients with PLV and >72 months for patients without PLV (log rank test, P < 0.001). By Cox regression, patients with PLV had a greater risk of virological failure [hazard ratio (HR) 3.8; 95% CI 2.2-6.4; P < 0.001]. Among patients with PLV, a PLV of >400 copies/mL (HR 3.3; 95% CI 1.5-7.1; P = 0.003) and a history of ART (HR 2.4; 95% CI 1.0-5.7; P = 0.042) predicted virological failure., Conclusions: PLV is associated with virological failure. Patients with a PLV >400 copies/mL and a history of ART experience are more likely to experience virological failure. Patients with PLV should be considered for treatment optimization and interventional studies.

Background: Intermittent episodes of detectable human immunodeficiency virus (HIV) viremia (hereafter referred to as "blips") are generally not predictive of subsequent virologic failure. Limited data are available for patients treated with nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens., Methods: A retrospective cohort study evaluated patients receiving highly active antiretroviral therapy who were followed for > or =12 months, achieved an HIV RNA load of <50 copies/mL, and underwent evaluation every 2-3 months. A blip was defined as 1 HIV RNA load measurement of 50-1000 copies/mL that was preceded and followed by another HIV RNA load measurement of <50 copies/mL. The frequency and predictors of blips and virologic failure were studied., Results: There were 244 patients in the NNRTI group and 136 patients in the protease inhibitor (PI) group. Baseline characteristics between the 2 groups were similar. A total of 34% of patients in the NNRTI group and 33% in the PI group experienced viral blips (P=.855), with corresponding incidences of 19.2 and 19.7 blips, respectively, per 100 person-years. Median time to blips was 50.0 months after initiation of therapy in the NNRTI group (95% confidence interval [CI], 44.8-55.3 months) and 43.6 months in the PI group (95% CI, 33.7-53.6 months; P=.632, by the log-rank test). By Cox proportional hazards model analysis, only a history of antiretroviral therapy use (hazard ratio [HR], 2.01; P<.001) and a CD4 cell count of <200 cells/ mu L (HR, 1.70; P=.021) increased the risk for having a blip. During a median follow-up period of 23.5 months, 7.8% of patients in the NNRTI group and 8.1% in the PI group experienced virologic failure (P=.917). Cox proportional hazards model analysis showed that only a baseline CD4 cell count of <200 cells/ mu L predicted virologic failure (HR, 2.74; P=.032)., Conclusions: There is no difference in the frequency or prognostic significance of viral blips between patients receiving NNRTI-based therapy and patients receiving PI-based therapy. Our results suggest that viral blips occur at a similar rate among patients receiving NNRTI-based regimens and patients receiving PI-based regimens and that they are not predictive of virologic failure.

Use of protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) has been associated with altered regional fat distribution, insulin resistance, and dyslipidemias. To assess how PI-based HAART affects adipocyte gene expression in male HIV-1-infected patients, reverse transcription-polymerase chain reaction was used to quantify messenger RNA expression of adipocyte transcription factors and adipocytokines in thigh and abdominal subcutaneous adipose tissue from male (1) HIV-1 seronegative subjects (control, n = 9), (2) asymptomatic treatment-naive HIV-1-infected patients (naive, n = 6), (3) HIV-1-infected patients who were receiving antiretroviral agents but never received PIs (PI naive, n = 5), (4) HIV-1-infected patients who were receiving PI-based HAART (PI, n = 7), and (5) HIV-1-infected patients who discontinued the PI component of their antiviral therapy more than 6 months before enrollment (past PI, n =7). In the PI group, the messenger RNA expression levels of the CCAAT/enhancer-binding protein alpha , leptin, and adiponectin (18%, P < .01; 23%, P < .05; and 13%, P < .05, respectively) were significantly lower than the levels measured in the PI-naive group. These results are consistent with previous studies on the effects of PIs on cultured adipocytes. Prospective longitudinal studies of thigh fat adipose tissue gene expression could provide further insights on the pathogenesis of metabolic complications associated with PI-based HAART.

Background: Extended release (ER)-niacin therapy, which has been associated with reduced glucose tolerance in human immunodeficiency virus (HIV)-seronegative individuals, has not been evaluated in the HIV-infected population., Methods: This open, prospective trial evaluated the safety and efficacy of ER-niacin therapy for antiretroviral therapy-associated dyslipidemia. Fourteen individuals received ER-niacin at maximum doses of 2000 mg per day for 14 weeks., Results: Significant reductions in serum levels of triglycerides (P=.02), total cholesterol (P=.005), and non-HDL cholesterol (P=.04) were seen after ER-niacin therapy. Seven of 11 subjects were glucose intolerant after ER-niacin therapy; for 3 of these subjects, this was a new finding. Beta-cell sensitivity to basal glucose levels increased significantly without concomitant increase in overall glucose disposition indices. The values for the homeostasis model of insulin resistance index increased significantly (P=.005)., Conclusion: ER-niacin's role in the treatment of antiretroviral therapy-associated dyslipidemia requires further evaluation, but the results of this pilot study indicate that it is safe and tolerated and provides a valuable treatment option.

This study evaluates the change in CD4(+) T cell counts among patients who achieved complete viral suppression and subsequently discontinued highly active antiretroviral therapy (HAART). We included 72 human immunodeficiency virus (HIV)-1-infected patients with plasma HIV RNA loads of <500 copies/mL for at least 3 months who then discontinued therapy for at least 12 weeks. The median CD4(+) T decay while off HAART was 16 cells/mm(3)/month (interquartile range, -6 to -34 cells/month). The mean follow-up after therapy ended was 45 weeks. The slope of the CD4(+) T cell decay was inversely correlated with the increase of CD4(+) T cells while receiving HAART, baseline virus load, CD4(+) T cell count at the time therapy was discontinued, age, and duration HIV RNA levels were undetectable. In a multiple regression analysis model, the increase of CD4(+) T cells while receiving therapy and age were independently associated with the rate of CD4(+) T cell loss.

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.

The current era of effective antiretroviral therapy has led to a marked reduction in opportunistic infections (OIs) in those countries where such therapies are available. Opportunistic fungal infections are no exception, and the incidence of such infections is now 20% to 25% of that seen in the mid-1990s. Infections associated with very advanced HIV disease, such as azole-resistant candidiasis and aspergillosis, are also rarely seen, reflecting the improvement in immune function. Indeed, the most common issue now is whether patients who have had a systemic mycosis require life-long therapy as had been recommended. Preliminary data from small studies suggest that as with other OIs, it may be possible to stop suppressive therapy in patients with a history of mycosis whose CD4+ lymphocyte count rises with antiretroviral therapy. Thus, it appears that the future of HIV-associated mycoses is linked to the future of effective treatment for HIV itself.

Potent antiretroviral treatment is associated with dramatic improvements in immune function in many human immunodeficiency virus-infected patients. This has led to new US Public Health Service/Infectious Diseases Society of America guidelines that suggest that in certain circumstances (primary prophylaxis for Pneumocystis carinii pneumonia and disseminated Mycobacterium avium complex infection, and secondary prophylaxis for cytomegalovirus retinitis), antimicrobial prophylaxis can be discontinued for patients whose CD4 T-cell counts rise above threshold levels for at least 3-6 months. The new guidelines are probably too conservative, and effective antiretroviral treatment almost certainly provides protection against all major opportunistic pathogens. Therefore, in the future, specific prophylaxis will be needed only for those patients who do not benefit from or fail to adhere to the current more effective treatment of human immunodeficiency virus infection.

Opportunistic infections (OIs) are the hallmark of the immunodeficiency associated with HIV infection. Prophylaxis strategies have improved the morbidity and mortality associated with AIDS. The widespread use of highly active antiretroviral therapy (HAART) has brought about a change in the natural history and clinical manifestations of OIs; a decline in the incidence of most OIs; and an improvement in the clinical outcome of many OIs. The possibility of immune reconstitution raises questions about whether withdrawal or prophylaxis is safe and, in some cases, whether certain diseases may be curable without lifelong maintenance prophylaxis. Ongoing studies should provide information about the safety of removing primary and secondary prophylaxis in patients who respond to HAART. This review will update clinicians on the current state of the art of prophylaxis and treatment of OIs in patients taking HAART.