Alan Winston

HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era

Background and purpose:u2002 Data describing the incidence and survival of HIV‐related central nervous system diseases (CNS‐D) in recent years are sparse.

Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial

Summary Background Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. Methods In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patients virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074. Findings Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events. Interpretation Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection. Funding National Institute for Health Research.

Low Rates of Neurocognitive Impairment Are Observed in Neuro-Asymptomatic HIV-Infected Subjects on Effective Antiretroviral Therapy

Abstract Background: Few studies investigating the rate of neurocognitive (NC) impairment in effectively treated neuro-asymptomatic HIV-infected subjects have been performed. Methods: We assessed NC function via a computerized cognitive test in HIV-infected subjects on stable combination antiretroviral therapy (cART) with plasma HIV RNA<50 copies/mL for at least 3 months. Neurologically symptomatic subjects were excluded. Current cART was evaluated for drug class (protease inhibitor [PI]- vs non-nucleoside reverse transcriptase inhibitor [NNRTI]-based) and Clinical Penetration Effectiveness (CPE) score. NC impairment was defined as a NC domain score >1 SD below mean age-matched population scores in at least 2 cognitive domains and global NC composite z-score calculated. Associations between NC scores and clinical parameters were evaluated using linear regression. Results: 101 (88% male) subjects participated. Median (IQR) age was 53 (43–62) years, with current CD4+ 525 (3737–10) and nadir CD4+ 185 (83–260) cells/µL. 25 subjects (25%) had chronic hepatitis C. Median (IQR) CPE score was 1.5 (1.5–2.5), and 53% were receiving NNRTI-based cART. Overall 19 (19%) subjects had NC impairment. No association between presence of NC impairment and clinical parameters were observed (P > .14, all values). Poorer global NC composite z-score was independently associated with lower nadir CD4+ lymphocyte count (P = .04) and older age (P<.001) but not other study parameters (P > .10 all values). Conclusion: In neuro-asymptomatic HIV-infected adults on stable cART, rates of NC impairment are low. HIV disease status (lower nadir CD4+ count) and older age, but not CPE score or cART drug class, are associated with poorer NC performance.

Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting

BACKGROUNDnCerebrospinal fluid (CSF) HIV RNA load may be associated with central nervous system (CNS) disease in HIV infected subjects. We investigated parameters associated with CSF HIV RNA within a large clinical cohort.nnnMETHODSnAll HIV infected subjects undergoing CSF examination including assessment of CSF HIV RNA at St. Marys Hospital, London, UK between January 2008 and October 2010 were included. Parameters associated with a detectable CSF HIV RNA load were assessed using linear regression modelling. CSF viral escape was defined as CSF RNA >0.5 log(10) copies/mL greater than plasma HIV RNA and >200 copies/mL where plasma HIV RNA <50 copies/mL.nnnRESULTSnOf 142 subjects, 99 were receiving antiretroviral therapy (ART). Plasma HIV RNA was <50 copies/mL in 69 subjects. CSF examination was performed for investigation of presumed HIV encephalopathy (IxHE, n = 57), other CNS diseases considered HIV related (n = 39), syphilis (n = 20) and CNS presentations not considered HIV related (n = 26). CSF viral escape was present in 30/142 (21%) subjects overall and in 9/69 (13%) of those on ART with undetectable plasma HIV RNA. Overall, plasma HIV RNA load was significantly associated with detectable CSF HIV RNA (p ≤ 0.001). In subjects with plasma HIV RNA <50 copies/mL, only CNS penetration effectiveness (CPE, 2008) score of <2 was significantly associated with detectable CSF HIV RNA (p = 0.044). In patients undergoing LP for IxHE both plasma HIV RNA and CPE scores were independently associated with detectable CSF HIV RNA (p = 0.019 & 0.003 respectively) which was not observed in subjects undergoing CSF examination for other medical reasons.nnnCONCLUSIONSnIn a clinical setting, CSF viral escape is observed frequently in 21% of subjects and is associated with different parameters depending on the clinical scenario.

Neurocognitive Function in HIV Infected Patients on Antiretroviral Therapy

Objective To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. Design We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. Main outcome measure NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. Results Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was −0.5 (−1.2/−0) overall, and −0.3 (−0.7/0.1) and −1.4 (−2/−0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (pu200a=u200a0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). Conclusions In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. Trial registry ClinicalTrials.gov, NCT01230580

Long-Term Probability of Detecting Drug-Resistant HIV in Treatment-Naive Patients Initiating Combination Antiretroviral Therapy

BACKGROUNDnRobust long-term estimates of the risk of development of drug resistance are needed for human immunodeficiency virus (HIV)-infected patients starting combination antiretroviral therapy (cART) regimens currently used in routine clinical practice.nnnMETHODSnWe followed a large cohort of patients seen in 1 of 11 HIV clinics in the United Kingdom after starting cART with nucleoside reverse-transcriptase inhibitors and either a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Survival analysis was employed to estimate the incidence of virological failure and of detected drug resistance.nnnRESULTSnSeven thousand eight hundred ninety-one patients were included; 6448 (82%) started cART with an NNRTI and 1423 (17%) with a PI/r. The cumulative risk of virological failure by 8 years was 28%. The cumulative probabilities of detecting any mutation, > or =1 major nucleoside reverse-transcriptase inhibitor International AIDS Society-United States of America (IAS-USA) mutation, > or =1 major NNRTI IAS-USA mutation (in those starting an NNRTI), and > or =1 major PI IAS-USA mutation (in those starting a PI) were 17%, 14%, 15%, and 7%, respectively, by 8 years. The probability of detecting PI mutations in people who started PI/r-based regimens was lower than that of detecting NNRTI mutations in those starting NNRTI-based regimens (adjusted relative hazard, 0.36; 95% confidence interval, 0.26-0.50; P<.001). The risk of detecting nucleoside resistance did not vary according to whether an NNRTI or a PI/r was used in the regimen (adjusted relative hazard, 1.00; 95% confidence interval, 0.80-1.26; P=.98).nnnCONCLUSIONSnIn patients who started modern cART in clinical practice in the United Kingdom, virological failure by 8 years was relatively common and was paralleled by an appreciable risk of resistance detection, although the detection rate of class-specific resistance was lower for those who started a PI/r-based regimen.

CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study

BACKGROUNDnWe conducted a pharmacokinetic and in vivo cerebral (1)H magnetic resonance spectroscopy ((1)H-MRS) study to assess CSF exposure and cerebral metabolite ratios (CMRs) following maraviroc intensification.nnnMETHODSnHIV-infected neurologically asymptomatic adults receiving tenofovir, emtricitabine and lopinavir/ritonavir with plasma HIV RNA <50 copies/mL were eligible and received intensified therapy with 150 mg of maraviroc twice daily. (1)H-MRS was performed in several cerebral locations, including the right basal ganglia (RBG), to assess CMRs, including N-acetyl aspartate/creatine (NAA/Cr), at baseline and after 14 days. Subsequently, on day 15, blood samples were obtained to determine plasma concentrations of maraviroc pre-dose (C(trough)) and then paired blood and CSF samples were collected at 4 or 6 h post-dose. Associations between maraviroc exposure, clinical parameters and changes to CMRs were evaluated.nnnTRIAL REGISTRYnClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00982878).nnnRESULTSnTwelve subjects (75% male) participated with a mean (SD) CD4+ cell count of 503 (199) cells/μL. Mean (SD) maraviroc plasma concentrations at pre-dose, 4 h post-dose and 6 h post-dose were 337 (74), 842 (174) and 485 (100) ng/mL and CSF concentrations at 4 h post-dose and 6 h post-dose were 7.5 (1.3) and 5.1 (1.2) ng/mL. The mean maraviroc CSFu200a:u200aplasma ratio (range) was 1.01% (0.57%-1.61%). An increase of 14.8% was observed for the RBG NAA/Cr ratio, which was significantly associated with higher maraviroc plasma C(trough) (P = 0.05, r = 0.61), but not CSF concentration (P = 0.16, r = 0.46).nnnCONCLUSIONSnAfter 14 days of maraviroc intensification, small increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were observed and are associated with maraviroc plasma C(trough).

Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring

OBJECTIVESnThe pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM).nnnMETHODSnData from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification.nnnRESULTSnData from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, Pu200a=u200a0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, Pu200a=u200a0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification.nnnCONCLUSIONSnWith increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation.

Data linkage reduces loss to follow-up in an observational HIV cohort study

OBJECTIVEnTo ascertain the degree of loss to follow-up in a cohort and to identify its predictors.nnnSTUDY DESIGN AND SETTINGnHuman immunodeficiency virus (HIV)-infected individuals without CD4 cell counts for a year or more were defined as potentially lost to follow-up (LFU). Multivariable Poisson regression models identified the risk factors for potential LFU. Multivariable logistic regression models compared demographic and clinical characteristics of those who returned for care and those permanently LFU.nnnRESULTSnOf 16,595 patients under follow-up, 43.6% were potentially LFU at least once. Of these, 39.8% were considered permanently LFU and 60.2% were seen again after 1 year. Of 9,766 episodes when patients were potentially LFU, 59% resulted in the patient returning for care at the same clinic or at a different clinic. Compared with those permanently LFU, patients returning were more likely to have started highly active antiretroviral therapy, to have higher CD4 counts and viral loads, to be younger, and to have had more CD4 tests before LFU. They were less likely to have had a previous episode of potential LFU.nnnCONCLUSIONSnA substantial proportion of patients in the UK Collaborative HIV Cohort study are potentially LFU. Data linkage identifies patients returning for care at different centers. Recognition of factors associated with LFU may help reduce this important source of bias in observational databases.

Factors influencing lopinavir and atazanavir plasma concentration

BACKGROUNDnThe protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.nnnMETHODSnData from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.nnnRESULTSnData from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).nnnCONCLUSIONSnThis analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.