Ambulatory induction phase treatment of cryptococcal meningitis in HIV integrated primary care clinics, Yangon, Myanmar.

BACKGROUND: Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. METHOD: This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day). RESULTS: Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. CONCLUSION: Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.

Attitudes to disclosure of HIV-serostatus to new sexual partners and sexual behaviours among HIV-diagnosed gay, bisexual and other men who have sex with men in the UK.

We assessed attitudes to disclosure to new sexual partners and association with sexual behaviours among HIV-diagnosed gay, bisexual, and other men who have sex with men (GBMSM) in the UK Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) study in 2011-12. Among 1373 GBMSM diagnosed with HIV for ≥3 months and reporting sex in the past three months (84% on antiretroviral therapy (ART), 75% viral load (VL) ≤50c/mL), 56.3% reported higher sexual disclosure ("agree" or "tend to agree" with "I'd expect to tell a new partner I'm HIV-positive before we have sex"). GBMSM on ART with self-reported undetectable VL had lower disclosure than those on ART without self-reported undetectable VL and those not on ART. Higher sexual disclosure was associated with higher prevalence of CLS in the past three months; this was due to its association with CLS with other HIV-positive partners. Higher sexual disclosure was more common among GBMSM who had CLS with other HIV-positive partners only (72.1%) compared to those who had higher-risk CLS with HIV-serodifferent partners (55.6%), other CLS with HIV-serodifferent partners (45.9%), or condom-protected sex only (47.6%). Findings suggest mutual HIV-disclosure and HIV-serosorting were occurring in this population. Knowledge of VL status may have impacted on disclosure to sexual partners.

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy.

OBJECTIVE: The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial. METHODS: PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models. RESULTS: Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year <50 copies/ml; P < 0.001), CD4 cell count (hazard ratio 0.73 per additional 100 cells/µl for CD4 nadir; P = 0.008); ethnicity (hazard ratio 1.87 for nonwhite versus white, P = 0.025) but not the protease inhibitor agent used (P = 0.27). Patients whose viral load was analysed with the Roche TaqMan-2 assay had a 1.87-fold risk for viral load rebound compared with Abbott RealTime assay (P = 0.012). CONCLUSION: A number of factors can identify patients at low risk of rebound with protease inhibitor monotherapy, and this may help to better target those who may benefit from this management strategy.

A randomized comparative trial of continued abacavir/lamivudine plus efavirenz or replacement with efavirenz/emtricitabine/tenofovir DF in hypercholesterolemic HIV-1 infected individuals.

BACKGROUND: Drug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection. METHODS: A randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF. RESULTS: 157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32 mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74 mmol/l (95% CI -1.00, -0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86 mmol/l (p < 0.001) compared with +0.01 mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (-0.47 mmol/L [-0.70, -0.25]), HDL cholesterol (-0.15 mmol/L [-0.21, -0.08]), triglycerides (-0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (-0.56 mmol/L [-0.80, -0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of -0.73 mmol/L (p < 0.001). CONCLUSIONS: Switching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT00615810.

Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults.

OBJECTIVES: To compare the safety and efficacy of the two single-tablet regimens (STRs), rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This is a phase 3b, randomized, open-label, multicenter, international, 96-week study. METHODS: Participants were randomized 1:1 to receive either RPV/FTC/TDF or EFV/FTC/TDF. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm. RESULTS: A total of 786 participants were randomized. RPV/FTC/TDF was noninferior to EFV/FTC/TDF (85.8 vs. 81.6%) at week 48 for HIV-1 RNA less than 50 copies/ml [difference 4.1%, 95% confidence interval (CI) -1.1 to 9.2%]. A statistically significant difference in efficacy favoring RPV/FTC/TDF was demonstrated for participants with baseline HIV-1 RNA 100000  copies/ml or less [(n=510) 88.8% RPV/FTC/TDF vs. 81.6% EFV/FTC/TDF (difference 7.2%, 95% CI 1.1-13.4%)]. In participants with baseline HIV-1 RNA more than 100000 copies/ml (n=276), RPV/FTC/TDF demonstrated noninferior efficacy compared with EFV/FTC/TDF (79.9 vs. 81.7%, respectively, difference -1.8%, 95% CI -11.1 to 7.5%). In the RPV/FTC/TDF arm, more virologic failure was observed as baseline HIV-1 RNA levels increased. There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (4 vs. 1%, respectively). There were fewer discontinuations because of adverse events with RPV/FTC/TDF (2.5%) than with EFV/FTC/TDF (8.7%). CONCLUSION: In treatment-naive participants, RPV/FTC/TDF demonstrated noninferior efficacy and improved tolerability compared with EFV/FTC/TDF, as well as a statistically significant difference in efficacy for participants with baseline HIV-1 RNA 100000  copies/ml or less at week 48.

In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study.

Modern anti-retroviral therapy is highly effective at suppressing viral replication and restoring immune function in HIV-infected persons. However, such individuals show reduced physiological performance and increased frailty compared with age-matched uninfected persons. Contemporary anti-retroviral therapy is thought to be largely free from neuromuscular complications, whereas several anti-retroviral drugs previously in common usage have been associated with mitochondrial toxicity. It has recently been established that patients with prior exposure to such drugs exhibit irreversible cellular and molecular mitochondrial defects. However the functional significance of such damage remains unknown. Here we use phosphorus magnetic resonance spectroscopy ((31)P-MRS) to measure in vivo muscle mitochondrial oxidative function, in patients treated with contemporary anti-retroviral therapy, and compare with biopsy findings (cytochrome c oxidase (COX) histochemistry). We show that dynamic oxidative function (post-exertional ATP (adenosine triphosphate) resynthesis) was largely maintained in the face of mild to moderate COX defects (affecting up to ∼10% of fibers): τ½ ADP (half-life of adenosine diphosphate clearance), HIV-infected 22.1±9.9 s, HIV-uninfected 18.8±4.4 s, p = 0.09. In contrast, HIV-infected patients had a significant derangement of resting state ATP metabolism compared with controls: ADP/ATP ratio, HIV-infected 1.24±0.08×10(-3), HIV-uninfected 1.16±0.05×10(-3), p = 0.001. These observations are broadly reassuring in that they suggest that in vivo mitochondrial function in patients on contemporary anti-retroviral therapy is largely maintained at the whole organ level, despite histochemical (COX) defects within individual cells. Basal energy requirements may nevertheless be increased.

Safety, immunogenicity and efficacy assessment of HIV immunotherapy in a multi-centre, double-blind, randomised, Placebo-controlled Phase Ib human trial.

BACKGROUND: Combination antiretroviral therapy (cART) is the main therapeutic management tool for HIV/AIDS. Despite its success in controlling viral load and disease progression, cART is expensive, associated with a range of significant side effects and depends for its efficacy on the patient's life-long commitment to high levels of treatment adherence. Immunotherapeutic agents can provide potential solutions to these shortcomings. Here we describe a Phase Ib trial of HIV-v, a synthetic immunotherapy that elicits T- and B-cell effector responses against HIV infected cells. METHODS: Fifty-nine cART-naive HIV-infected males aged 18-50 years with viral load of 5000-500,000 copies/ml and CD4 counts >350/µl were recruited for this multi-centre, randomised, double blind study. Volunteers received one low (250 µg) or high (500 µg) dose of HIV-v, either alone or adjuvanted (ISA-51). Safety, immunogenicity, CD4 count and viral load were monitored over 168 Days. RESULTS: HIV-v was well tolerated and the adjuvanted formulations elicited IgG responses in up to 75% of volunteers. The high adjuvanted dose also elicited cellular responses in 45% of tested volunteers. In these responding subjects viral loads were reduced by over 1 log (p=0.04) compared to Placebo and non-responders. No changes in CD4 count were observed. CONCLUSIONS: HIV-v is safe and can elicit T- and B-cell responses in ART-naive HIV patients that significantly reduce viral load. Improved dosing regimens and further research on long term efficacy are required, but HIV-v appears to have potential as an immunotherapeutic anti-viral agent. Trial registered as EudraCT-2009-010593-37 (ClinicalTrials.gov Identifier: NCT01071031).

A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results.

: This 96-week, double-blind, active-controlled, phase 3 study, randomized subjects to elvitegravir once daily or raltegravir twice daily with a fully active, ritonavir-boosted protease inhibitor plus a third agent. The proportion of subjects randomized to elvitegravir that achieved and maintained HIV-1 RNA < 50 copies/mL through week 96 was 47.6% (167/351) compared with 45.0% (158/351) for raltegravir with a treatment difference of 2.6% (95% confidence interval: 4.6% to 9.9%). Both regimens were well tolerated, with comparable rates of adverse events and laboratory abnormalities through week 96. Once-daily elvitegravir was noninferior to twice-daily raltegravir, showed durable long-term efficacy, and was well tolerated in HIV+ treatment-experienced patients.

Real-life outcomes of maraviroc-based regimens in HIV-1-infected individuals.

PURPOSE: The use of maraviroc in our unit was reviewed with regard to efficacy and safety and also reviewed with regard to how our experience reflects the data presented in clinical trials. METHODS: We utilized the pharmacy dispensary system to identify any patient dispensed maraviroc and conducted a case note review. RESULTS: We identified 27 patients who have been prescribed maraviroc as part of their antiretroviral treatment. In all, 81% were men and 81% were white British. There were 26 treatment-experienced patients and 1 treatment-naive patient. At the time of switching to maraviroc, 17 patients had detectable HIV viral loads and 10 had HIV RNA levels <40 copies/mL. At completion, 6 undetectable patients maintained undetectability and 10 viremically detectable patients achieved viral suppression. Maraviroc was discontinued in 18.5% of patients and the only adverse drug reaction reported was a rash. CONCLUSIONS: The experience of using maraviroc by our study participants shows similarity in terms of efficacy and safety to the MERIT and MOTIVATE clinical trials.

Does interferon-sparing tenofovir disoproxil fumarate-based therapy have a role in the management of severe acute hepatitis delta superinfection?

Infection with hepatitis delta virus (HDV) always occurs in association with hepatitis B virus (HBV) and is a cause of significant morbidity and mortality. We present a case of severe acute HDV infection superimposed on a previously unrecognized HBV infection, in which an interferon-sparing antiviral therapy consisting of tenofovir disoproxil fumarate (TDF) and lamivudine was initiated and subsequently maintained. Evidence of successful suppression of HDV ribonucleic acid (RNA) was obtained after 65 weeks of TDF-based treatment. This was mirrored by a significant reduction in the levels of HBV DNA and HBV surface antigen. HDV RNA subsequently rebounded after our patient stopped antiviral therapy of his own accord. Interferon-sparing TDF-based antiviral therapy was safe and effective in achieving HDV RNA suppression in acute HDV superinfection. Further research into the utility of interferon-sparing TDF-based regimes in the treatment of acute HDV infection is needed.

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection with antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naïve to therapy; (ii)support of patients on treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines.

A randomized comparative trial of continued zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated HIV-1-infected individuals.

BACKGROUND: Long-term antiretroviral therapy dramatically reduces HIV-related morbidity and mortality but is also associated with metabolic and morphological changes and requires high levels of adherence. METHODS: A randomized, 48-week, open-label, comparative study of continuation of twice-daily zidovudine/lamivudine or replacement with once-daily tenofovir disoproxil fumarate/emtricitabine in individuals on successful efavirenz-based antiretroviral therapy. Limb fat mass was assessed by dual x-ray absorptiometry in a subset of participants through week 48. RESULTS: Two hundred thirty-four individuals were randomized and treated (117 each to continue or switch) with 206 subjects completing 48 weeks of study. Five percent subjects in the continue group and 3% subjects in the switch group discontinued due to adverse events. By intent-to-treat, missing = failure analysis, no differences in virological efficacy were observed at any time point (week 48 <50 copies/mL continue 85%, switch 88%). At week 24, switching was associated with significant increases in hemoglobin (mean difference 0.37 g/dL, 95% confidence interval: 0.15 to 0.58 g/dL, P < 0.001) and significant declines in total cholesterol and triglycerides. In the dual x-ray absorptiometry substudy (n = 100), fat was preserved or increased in the switch group but declined in the continue group (mean difference 448 g, 95% confidence interval: 57 to 839 g, P = 0.025). Individuals with longer exposure to zidovudine and lower baseline limb fat experienced less limb fat increase after switching. No differences in renal adverse events were observed between groups. CONCLUSIONS: Switching from zidovudine/lamivudine to tenofovir disoproxil fumarate/emtricitabine in persons on efavirenz therapy maintains virological control, establishes a once-daily regimen, results in improvements in hemoglobin and key lipid parameters, and preserves and restores limb fat relative to continuation of zidovudine/lamivudine.

Audit of the management of antiretroviral treatment-naïve HIV patients in Greater Manchester, UK.

We evaluated the management of antiretroviral treatment (ART)-naïve HIV-positive patients in Greater Manchester against the 2005 British HIV association (BHIVA) guidelines. Fifty-seven HIV patients (median age 36 years, 61% males, 53% black Africans) commenced their first ART regimen between 1 October and 31 December 2005. Most of them presented with advanced HIV disease (74% had CD4 lymphocytes <200 and 33% were Centers for Disease Control and Prevention stage C) and 51% commenced ART within three months of their HIV diagnosis. Ninety-six percent had baseline laboratory investigations performed but only 53% had baseline blood pressure estimation. Only 25% had urinalysis performed. A combination of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-NRTI was chosen in 76% of patients. Eighty-two percent of patients had a clinical review and blood tests within five weeks of starting treatment.

HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options.

Lipodystrophy (LD) is a common adverse effect of HIV treatment with highly active antiretroviral therapy, which comprises morphological and metabolic changes. The underlying mechanisms for LD are thought to be due to mitochondrial toxicity and insulin resistance, which results from derangements in levels of adipose tissue-derived proteins (adipocytokines) that are actively involved in energy homeostasis. Several management strategies for combating this syndrome are available, but they all have limitations. They include: switching from thymidine analogues to tenofovir or abacavir in lipoatrophy, or switching from protease inhibitors associated with hyperlipidaemia to a protease-sparing option; injection into the face with either biodegradable fillers such as poly-L-lactic acid and hyaluronic acid (a temporary measure requiring re-treatment) or permanent fillers such as bio-alcamid (with the risk of foreign body reaction or granuloma formation); and structured treatment interruption with the risk of loss of virological control and disease progression. There is therefore a need to explore alternative therapeutic options. Some new approaches including adipocytokines, uridine supplementation, glitazones, growth hormone (or growth hormone-releasing hormone analogues), metformin and statins (used alone or in combination) merit further investigation.

Thalidomide treatment for refractory HIV-associated colitis: a case series.

Thalidomide has been used as a treatment for various human immunodeficiency virus (HIV)-associated and non-HIV-associated illnesses, generally in cases in which inflammatory disease is refractory to standard therapy. Here, we discuss the successful use of thalidomide in 3 patients with severe, idiopathic HIV-associated colitis.

Predictors of renal outcome in HIV-associated nephropathy.

BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS: We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS: From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS: Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.

A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy.

BACKGROUND: Long-term antiretroviral therapy, while dramatically reducing HIV-related morbidity and mortality, is associated with metabolic and morphological changes. Peripheral fat loss, lipoatrophy, appears most associated with prolonged therapy with thymidine nucleoside analogues. METHODS: A randomized, open-label, comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate (DF) or abacavir in 105 individuals on successful antiretroviral therapy with clinically evident moderate to severe lipoatrophy. RESULTS: Individuals were randomized to tenofovir DF (52) or abacavir (53). The switch was well tolerated and the majority of patients completed 48 weeks of study. One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events. Both groups similarly maintained virological control. Limb fat mass increased similarly in both groups: mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups, respectively [mean 95% confidence interval for difference, -154.3 (range -492.8 to 184.3)]. This change from baseline was statistically significant in both groups (tenofovir DF, P = 0.01; abacavir, P = 0.0001). Mean total cholesterol, low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir. The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir. CONCLUSIONS: Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks. Tenofovir DF may have modest advantages over abacavir for changes in lipids. Peripheral lipoatrophy, when clinically apparent, resolves slowly following treatment switching.

Pharmacologic optimization of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (POPIN)--a randomized controlled trial of therapeutic drug monitoring and adherence support.

We evaluated the feasibility and effectiveness of therapeutic drug monitoring (TDM) and adherence support (collectively, AT) vs standard of care (SOC) in patients receiving HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) within a nurse-led clinic. Primary end points were failure to achieve viral load of <50 copies/mL at 24 weeks, viral rebound, or development of treatment limiting toxicity. One hundred twenty-two patients (AT 63 and SOC 59) were followed-up every 12 weeks, for a median of 72 weeks. No difference was observed between arms in risk of reaching a study end point or between groups of patients with abnormal vs "therapeutic" drug concentrations. Interindividual variabilities (coefficient of variation) were the following: efavirenz, 77.5%; nevirapine, 74.5%; lopinavir, 73.4%; nelfinavir, 83.7%; indinavir, 80.8%; saquinavir, 112.4%. Intraindividual variabilities (median coefficient of variation) were the following: NNRTIs, approximately 25%; PIs, 48.4%. Despite persistently abnormal results in 26 of patients in the AT arm (38%), dosage adjustment was only undertaken in 9 patients (35%).A significant proportion of patients had drug concentrations outside the therapeutic range. The Pharmacologic Optimization of PIs and NNRTIs (POPIN) study confirms that TDM trials are complex to interpret and statistically underpowered, with effectiveness better assessed through the clinical utility of a TDM result, whether normal or abnormal. Although TDM of PIs and NNRTIs may be useful in selected patients, routine and unselected use is not supported by current evidence.