Low-dose growth hormone for 40 weeks induces HIV-1-specific T cell responses in patients on effective combination anti-retroviral therapy.

Recombinant human growth hormone (rhGH) administered to combination anti-retroviral therapy (cART)-treated human immunodeficiency virus-1 (HIV-1)-infected individuals has been found to reverse thymic involution, increase total and naive CD4 T cell counts and reduce the expression of activation and apoptosis markers. To date, such studies have used high, pharmacological doses of rhGH. In this substudy, samples from treated HIV-1(+) subjects, randomized to receive either a physiological dose (0·7 mg) of rhGH (n = 21) or placebo (n = 15) daily for 40 weeks, were assessed. Peptide-based enzyme-linked immunospot (ELISPOT) assays were used to enumerate HIV-1-specific interferon (IFN)-γ-producing T cells at baseline and week 40. Individuals who received rhGH demonstrated increased responses to HIV-1 Gag overlapping 20mer and Gag 9mer peptide pools at week 40 compared to baseline, whereas subjects who received placebo showed no functional changes. Subjects with the most robust responses in the ELISPOT assays had improved thymic function following rhGH administration, as determined using CD4(+) T cell receptor rearrangement excision circle (TREC ) and thymic density data from the original study. T cells from these robust responders were characterized further phenotypically, and showed decreased expression of activation and apoptosis markers at week 40 compared to baseline. Furthermore, CD4 and CD8 T cell populations were found to be shifted towards an effector and central memory phenotype, respectively. Here we report that administration of low-dose rhGH over 40 weeks with effective cART resulted in greater improvement of T lymphocyte function than observed with cART alone, and provide further evidence that such an approach could also reduce levels of immune activation.

Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients.

OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.

Switching from twice-daily abacavir and lamivudine to the once-daily fixed-dose combination tablet of abacavir and lamivudine improves patient adherence and satisfaction with therapy.

BACKGROUND: Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa) qd to achieve a qd regimen. METHODS: A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd. RESULTS: Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7-100%) vs. 96.6% (60.0-100%) (P=0.017); dosing compliance 97.1% (64.3-100%) vs. 91.9% (33.3-100%) (P=0.016); and timing compliance 95.5% (53.8-100%) vs. 86.3% (4.3-100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82-99%) vs. 85% (75-93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC. CONCLUSIONS: Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.

Long-term safety and efficacy of poly-L-lactic acid in the treatment of HIV-related facial lipoatrophy.

OBJECTIVE: We evaluated the long-term safety and efficacy of injectable poly-L-lactic acid (PLLA) for the correction of facial lipoatrophy. METHODS: This was a randomized, open-label, comparative, single-centre study of injected PLLA in patients with HIV-related facial lipoatrophy. Thirty subjects were randomized to immediate or delayed PLLA treatments, administered as three sets of bilateral injections, 2 weeks apart, into the deep dermis above the buccal fat pad. Week 24 results have been published previously (Moyle et al, HIV Medicine 2004, Vol. 5, pp. 82-87). Long-term efficacy was assessed at a recall visit using visual analogue scales (VASs) to record patient satisfaction, and by the Hospital Anxiety and Depression Scale (HADS). Patients also reported any adverse events (AEs) during the treatment period and at the recall visit. RESULTS: Twenty-seven patients returned for the recall visit, a minimum of 18 months post final study treatment. Fourteen of these patients were excluded from the recall visit because of additional treatment with PLLA. Improvements in VAS scores for facial appearance were sustained from baseline to the recall visit in both randomization groups (P<0.05 and P<0.001). Trends in improvement in HADS scores were also noted, with patients in the delayed group experiencing significant improvements in depressive symptoms (P<0.05). One case of injection-site induration and nine cases of injection-site nodules were noted at the recall visit, none of which was described as serious or severe. CONCLUSIONS: Physical and psychological benefits of PLLA are sustained over at least 18 months. Delayed AEs include mild nodularity at the treatment site.

Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone.

BACKGROUND: The use of highly active antiretroviral therapy (HAART) has profoundly altered the life expectancy of individuals infected with HIV. Metabolic abnormalities associated with antiretrovirals and cumulative exposure to combination antiretroviral therapy, including dyslipidaemia and insulin resistance, have been linked to an increased risk of myocardial infarction. METHODS: Longitudinal data from a large prospectively collected clinical database were analysed. All patients who commenced first antiretroviral therapy (ART) [two nucleoside reverse transcriptase inhibitors (NRTIs)+one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one active protease inhibitor (PI)] since 1996 were identified. Patients with elevated cholesterol levels [>5.5 mmol/L (215 mg/dL)] prior to therapy initiation were excluded. Quantitative data were categorized into quartiles and presented stratified by individuals developing abnormal levels of cholesterol during first-line HAART. Event time was defined as time from commencing first-line ART to either development of cholesterol level >6.5 mmol/L (254 mg/dL) or switch of first-line therapy. The Kaplan-Meier product limit survival method was used to estimate time to abnormal cholesterol level, and the chi2 test was used for comparisons between drug classes. Cox's proportional hazards regression analysis was used to identify factors predicting a likelihood of raised cholesterol level. RESULTS: A total of 1664 patients were included in the study: 57.1% on two NRTIs+one NNRTI, 38.4% on two NRTIs+one PI, and 4.4% on two NRTIs+a boosted PI regimen. Regimens containing stavudine or PIs were associated with a significantly higher event risk and earlier time to event. No differences between efavirenz and nevirapine or between didanosine and lamivudine were observed. In 28 patients exposed to the combination of tenofovir+lamivudine+efavirenz, there were no episodes of elevated cholesterol level. CONCLUSION: Dyslipidaemia has emerged as an important issue in HIV-infected individuals receiving antiretroviral therapy. This study demonstrates that age at start of therapy, baseline cholesterol level, stavudine use and PI use are all associated with increased risk of hypercholesterolemia on initial therapy. Both NRTI and NNRTI/PI choice influence risk of hypercholesterolaemia.

Better maintained adherence on switching from twice-daily to once-daily therapy for HIV: a 24-week randomized trial of treatment simplification using stavudine prolonged-release capsules.

BACKGROUND: Adherence to antiretroviral therapy is critical to treatment outcomes. Adherence studies in other therapeutic areas of medicine suggest that once-daily regimens support improved adherence when compared to twice-daily therapy. An expansion in the range of once-daily antiretrovirals is making once-daily therapy possible for persons with HIV infection. METHODS: A 24-week randomized open-label simplification study of twice-daily regimens based on stavudine immediate release or zidovudine to an all once-daily regimen based on the stavudine prolonged-release capsule (PRC), in persons with complete virological suppression on regimens also including efavirenz and lamivudine, was carried out. Subjects were assessed for adherence [using the Medication Event Monitoring System (MEMS) cap; Aardex Corporation, Union City, CA, USA], quality of life, tolerability and efficacy. RESULTS: Forty-three patients were randomly assigned: 21 remained on their original regimen and 22 switched to once-daily therapy with stavudine PRC. Although high levels of adherence and good quality of life were present at study enrollment, adherence declined to a significantly lesser extent at week 24 in the group that switched to once-daily therapy. Efficacy was maintained in both groups and there were no differences in tolerability or toxicity. CONCLUSIONS: Subjects switching from twice-daily therapy to once-daily therapy demonstrate less of a decline in adherence over 24 weeks. A once-daily regimen including stavudine PRC is as effective and tolerable as a regimen containing the twice-daily formulation.

A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection.

BACKGROUND: Polylactic acid (PLA, New-Fill; Medifill, London, UK and Dermic Labs, a division of Eventis, Strasbourg, France) injections into the deep dermis increase fibroblast numbers and collagen production. The substance is widely used in medical applications including cosmetic procedures. METHODS: HIV-positive individuals with facial lipoatrophy (based on physician assessment) were randomized to immediate (weeks 0, 2 and 4) or delayed (weeks 12, 14 and 16) PLA given as three bilateral injections 2 weeks apart into the deep dermis overlying the buccal fat pad. Assessments included facial ultrasound, visual analogue scales, the Hospital Anxiety and Depression Scale (HADS) and assessment using photographs at weeks 0, 12 and 24. RESULTS: All 30 patients completed 24 weeks of treatment. The median age of the patients was 41 years, with a mean of 80 months of nucleoside reverse transcriptase inhibitor (NRTI) therapy and a mean of 44 months of prior protease inhibitor (PI) therapy. The median CD4 count was 428-460 cells/microL, with 47% of patients in the immediate-treatment group and 93% of patients in the delayed-treatment groups with <50 HIV-1 RNA copies/mL at baseline. No differences in immunological, virological, biochemical, haematological or metabolic parameters emerged during the study. Injections were well tolerated with only two adverse events (cellulitis and bruising) recorded, one of which delayed treatment by 1 week. There were no discontinuations. Patient visual analogue assessments, photographic assessments, and anxiety and depression scores improved with treatment. At week 12, immediate-treatment patients had significantly better visual analogue scores (7 vs. 1, P<0.001) and lower anxiety scores (6 vs. 9, P=0.056) than delayed-treatment patients. Benefits on visual analogue and HADS scores persisted until week 24. CONCLUSIONS: PLA injections led to improvements in patient self-perception, anxiety and depression scores in individuals with facial lipoatrophy. Adverse events were uncommon. The benefits of PLA persisted for at least 18 weeks beyond the last injection.

A 48-week, randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy.

BACKGROUND: The mechanisms by which dyslipidemia and lipoatrophy develop during antiretroviral therapy are not clear. No treatment of lipoatrophy is currently established. METHODS: This was an open-label randomized study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of <50 copies/mL. Patients switched d4T to abacavir (ABC) (group 1), a PI or NNRTI to ABC (group 2), or d4T and PI or NNRTI to ABC plus AZT (group 3). Patients were followed-up with fasting blood levels, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT) scans for 48 weeks. RESULTS: Thirty patients were included, with 27 completing 48 weeks of therapy. One ABC hypersensitivity reaction was the only serious adverse event. All patients' viral loads remained at <50 copies/mL. CD4 cell counts rose in groups 2 and 3 but fell modestly in group 1. Total and low-density lipoprotein cholesterol improved significantly in groups 2 and 3. Triglycerides fell significantly in group 2. In contrast, total, arm, and leg fat mass (by DXA) rose significantly in group 1 but fell modestly in groups 2 and 3. Visceral adiposity (by CT scan) was unaffected in all groups. CONCLUSIONS: Abacavir represents a virologically effective replacement for d4T, PI, or NNRTI in persons on successful first-line therapy. Replacement of a PI or NNRTI with ABC leads to modest improvement in both cholesterol and triglycerides. Replacement of d4T with ABC leads to modest improvements in fat mass.

Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV.

AIMS: To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin. METHODS: Fourteen HIV-infected patients provided full steady-state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft-gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study. RESULTS: Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and C(max)(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and C(max)(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note. CONCLUSIONS: Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.

Principles and practice of HIV-protease inhibitor pharmacoenhancement.

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (Ctrough or Cmin) plasma concentrations, which are close to, or below, the plasma protein binding-corrected inhibitory concentration (IC50 or IC95) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug-drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher Cmin levels, and in most cases prolonged elimination half-lives. The long-term clinical benefits of PK enhancing are unknown as are the long-term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low-dose RTV in HIV-infected patients. Head-to-head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.

Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.

BACKGROUND: Therapy with a HIV protease inhibitor is associated with elevations in cholesterol and triglycerides. HMG-CoA reductase inhibitors ('statins') are the established therapy for persons with primary hypercholesterolaemia. Because of drug interactions, pravastatin may represent the preferred choice in those taking HIV protease inhibitors. DESIGN: A randomized, open-label comparative 24 week trial of dietary advice alone or with pravastatin in 31 male patients established on protease inhibitor-based regimens for greater than 12 weeks with viral load < 500 copies/ml and cholesterol > 6.5 mmol/l. RESULTS: There were no significant clinical or laboratory events and no patient discontinuation secondary to adverse effects. Viral rebound did not occur. Relative to baseline, total cholesterol at week 24 fell significantly in the pravastatin (1.2 mmol/l; 17.3%) (P < 0.05) but not in the dietary advice (0.3 mmol/l; 4%) group. The difference between the two groups approached significance at week 24 (P = 0.051). This fall was accounted for entirely by a reduction in low density lipoprotein [calculated change 1.24 mmol/l (19%) and 0.07 mmol (5.5%) in pravastatin and dietary advice groups, respectively] as high density lipoprotein rose non-significantly by 0.6 mmol/l in both groups. Weight, basal metabolic rate, fasting glucose and triglycerides did not change significantly in either group. CONCLUSIONS: Dietary advice plus pravastatin significantly reduced total cholesterol in HIV-positive individuals taking protease inhibitors, without significant adverse effects. The inclusion of pravastatin substantially increases the magnitude of the change, which is comparable with changes achieved in endogenous hyperlipidaemia.

Absence of association between individual thymidine analogues or nonnucleoside analogues and lipid abnormalities in HIV-1-infected persons on initial therapy.

Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.

Efficacy of a nelfinavir- and nevirapine-containing salvage regimen.

PURPOSE: In this study, our purpose was to assess the efficacy of nelfinavir- and nevirapine-containing salvage regimens in nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients virologically failing a protease inhibitor (PI)-based combination. METHOD: A retrospective case note review of all patients virologically failing their PI-based combination who were switched to a regimen containing both nelfinavir (1 g t.d.s.) and nevirapine (200 mg b.d.). CD4 cell counts and viral loads were monitored. Genotypic analysis was performed using RT-PCR sequencing. RESULTS: Nineteen patients commenced a salvage regimen containing nelfinavir and nevirapine. Five patients also changed at least one nucleoside reverse transcriptase inhibitor (NRTI), although in one case this represented recycling. Thirty-eight percent (6/16) of patients achieved a viral load below the level of detection (BLD; <200 copies/mL; complete responders [CR]), 3 achieved <20 copies/mL. Five patients achieved > or =1 log drop (partial responders [PR]) that was not sustained over follow-up, and five failed to respond to therapy (nonresponders [NR]). CRs tended to have wild-type NNRTI and PI sequences relative to PRs and NRs. CONCLUSION: In heavily pretreated patients, a nelfinavir-and nevirapine-containing salvage regimen resulted in a virological response in 38% of patients that was sustained in 31% over 63 weeks.

A risk-benefit assessment of HIV protease inhibitors.

The use of triple regimens, often called highly active antiretroviral therapy (HAART), generally involving 2 nucleoside analogues and an HIV protease inhibitor, have been endorsed as the standard of care for persons with HIV initiating therapy by a number of sets of international guidelines. The widespread availability of protease inhibitor-containing regimens has been associated with a dramatic drop in the incidence of new AIDS events and mortality throughout the developed world. Use of HAART regimens, particularly in treatment-naïve individuals, is also associated with dramatic reductions in HIV RNA load, rises in CD4+ cell numbers and improvements in some aspects of immune function. However, protease inhibitor therapy is associated with a range of adverse effects, which varies between agents, and regimens frequently involve inconvenient administration schedules and disruption to patient's lives. Thus, the undoubted benefits of antiretroviral therapy come at some cost in terms of both physical and psychological morbidity to the recipient. In assessing an individual for therapy, consideration of the risk of disease events and the benefit of therapy in reducing or preventing these events must be weighed against the potential of therapy to cause morbidity. Using these criteria, we suggest that an individual with a 3 year risk of disease progression of less than 10% (based on CD4+ cell count and HIV RNA load) is more likely to a experience a morbidity if treated with HAART than if left untreated and monitored. For individuals with higher risks of HIV progression the risk versus benefit of initiating therapy may, in many cases, still be in favour of no therapy and continued observation. This will vary depending on the individuals risks (such as family and past medical history) and on the choice of agents in the regimen, some regimens having greater risks than others.