Change In CD4 Cell Count Research Articles

Immunodeficiency at Start of Antiretroviral Therapy: The Persistent Problem of Late Presentation to Care

Immunodeficiency at Start of Antiretroviral Therapy: The Persistent Problem of Late Presentation to Care

The effects of HIV-1 subtype and ethnicity on the rate of CD4 cell count decline in patients naive to antiretroviral therapy: a Canadian-European collaborative retrospective cohort study.

Ethnic differences have the potential to confound associations between HIV-1 subtype and immunologic progression. We compared declines in CD4 cell counts during untreated infection for the most prevalent HIV-1 subtypes, focusing on distinguishing between the effects of viral subtype and ethnicity. We combined data from 4 European and 6 Canadian cohorts, selecting adults in the stable chronic phase of untreated HIV infection. We estimated the change in square root CD4 cell count over time for subtypes and ethnicities using mixed models, adjusting for covariates selected for their potential effect on initial CD4 cell count or its decline. Data from 9772 patients were analyzed, contributing 79175 measurements of CD4 cell count and 24157 person-years of follow-up. Overall, there were no appreciable differences in CD4 cell count decline for viral subtypes A, CRF01_AE, CRF02_AG, C and G compared with viral subtype B; whereas the decline in CD4 cell count in patients of African ancestry was considerably slower than in patients of other ethnicity. When ethnic groups were studied separately, there was evidence for slower declines in CD4 cell count in viral subtypes C, and possibly A and G, compared with viral subtype B in patients of African ancestry but not among patients of other ethnicities, suggesting an interaction between subtype and ethnicity. Ethnicity is a major determinant of CD4 cell count decline; viral subtype differences may have existed but were small compared with the effect of ethnicity and were most apparent in patients of African ancestry. In developing countries, slower CD4 cell count declines among individuals of African descent may translate to a longer asymptomatic phase and increase the opportunity for HIV transmission.

Predictors of emphysema progression in HIV-positive patients.

IntroductionThe aim of the study was to find factors associated with emphysema progression (EP), assessed on sequential thoracic CT scans, in a large cohort of HIV-positive patients.Materials and MethodsThis was an observational, prospective study of 448 consecutive HIV-positive patients on antiretroviral therapy who underwent two sequential ECG-gated coronary artery calcium scoring CT scans. Images were reviewed by three radiologists by consensus to assess lung emphysema using a visual semi-quantitative score (0 to 4) for each of six lobes. EP was defined as an increase in emphysema score. Heavy smoking habit was defined as a self-reported number of cigarettes per day smoked greater than 10. Immune reconstitution was defined as the change in CD4 cell count between first CT scan and CD4 nadir and it was divided into tertiles. Progressors and non-progressors were compared using X2-test for categorical variables and T-test of Mann–Whitney U test for continuous variables where appropriate. Factors independently associated with EP were explored using multivariable logistic regression analyses. A p-value <.05 was considered statistically significant.ResultsThe mean age of the included patients was 47,9±7,7 years, 24,1% of them were females and 39,3% were smokers. The median interval between the two CT scans was 2,4 years (interquartile range 0,69–5,9 years). EP was significantly associated with HIV-infection duration (p=0,056), smoking (p=0,007) and in particular heavy smoking habit (p=0,015) and time interval between the two scans (p=0,021), while the highest tertile of immune reconstitution was borderline in significance (p=0,075). Age and sex were not significantly related to EP and were not included in further analyses. HIV infection duration (OR=1,01; p=0,013), time interval between the two scans (OR=1,51; p=0,032) and heavy smoking habit (OR=3,36; p=0,041) remained independently associated with EP in multivariate analysis.ConclusionsIn this large cohort of HIV positive patients on antiretroviral therapy, HIV infection duration, time between CT scans and continued heavy cigarette smoking were independently associated with EP.

G-102 Patients Infected with CRF07_BC Have Significantly Lower Viral Loads than Patients with HIV-1 Subtype B

Background: The circulating recombinant form (CRF) 07_BC is the most prevalent HIV-1 strain among injection drug users in Taiwan. It contains a 7 amino-acid deletion (7d) in its p6gag. The objectives of this study were to conduct a cohort study to compare viral load and CD4 cell count changes between patients infected with subtype B and CRF07_BC and to elucidate its mechanism. Methods: Twenty-one patients infected with CRF07_BC and 59 patients with subtype B were selected from a cohort of 667 HIV-1/AIDS patients whom have been followed up for more than 3 years. Generalized estimated equation was used for statistical analysis. The replicative kinetics, tropism and cytopathic effects were determined. HIV-1 NL4-3 which containing a 7 amino-acid deletion in p6gag (7d virus) was generated and its virological properties were compared with the wild-type. Results: Patients infected with CRF07_BC had significantly lower viral load than patients with subtype B. CRF07_BC isolates had lower replicative capacity than subtype B isolates although they were all CCR5 tropic. 7d virus had significantly lower gag processing efficiency and slower viral life cycle. Electronic microscopy showed 7d virus had poorer viral maturation processes: more viruses attached to the cell membrane and less mature virions. The interaction between p6gag and Alix protein was less efficient in cells infected with 7d virus. Conclusions: Patients infected with CRF07_BC had significantly slower disease progression. The differences of virological characteristics between CRF07_BC and subtype B were due to its 7 amino-acid deletion in p6gag.

Impact of hepatitis B virus infection on HIV response to antiretroviral therapy in a Chinese antiretroviral therapy center

Co-infection with hepatitis B virus (HBV) and HIV is common in China; however, the impact of HBV on long-term antiretroviral therapy (ART) outcomes has not been fully characterized. Patients were classified as being HIV mono-infected (hepatitis B surface antigen (HBsAg)-negative) or HIV/HBV co-infected (HBsAg-positive). The effects of HBV on HIV virological response, changes in CD4 cell counts, hepatotoxicity, and mortality among Chinese patients receiving ART were evaluated. The HIV/HBV co-infection rate in our cohort was 9.9% (354/3562). Five hundred and fifty HIV mono-infected and 78 HIV/HBV co-infected individuals fulfilled the inclusion criteria. HIV/HBV co-infected individuals were less likely to achieve HIV-RNA suppression and a CD4 increase than HIV mono-infected individuals at 48 months post-ART. Greater hepatotoxicity and a more rapid occurrence of death were observed in HIV/HBV co-infected subjects. HBV-related mortality accounted for 84.2% (16/19) of the total deaths in HIV/HBV co-infected subjects. HBV co-infection can affect late immunological and virological responses to ART and increase the risk of hepatotoxicity. Mortality due to liver disease was high among HIV/HBV co-infected individuals in this study, despite HBV-active ART. As long as HIV/HBV co-infected persons need anti-HBV therapy, they should be recommended ART that includes agents with activity against both HIV and HBV, regardless of the CD4 cell count level.

Humanized PA14 (a monoclonal CCR5 antibody) for treatment of people with HIV infection

PRO 140 (a humanized form of the PA14 antibody, a monoclonal CCR5 antibody) inhibits CCR5-tropic (R5) type 1 human immunodeficiency virus (HIV). This may be an effective new treatment with the potential to address the limitations of currently available therapies for HIV-infected patients. We aimed to assess the efficacy, safety, clinical disease progression and immunologic (CD4 count/percentage) and virologic (plasma HIV RNA viral load) markers of PRO 140 for HIV-infected patients in randomized controlled trials (RCTs) and quasi-randomized controlled trials (quasi-RCTs). We searched databases including The Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 4), MEDLINE (PubMed, January 1966 to April 2014), EMBASE (January 1978 to April 2014) and ISI Web of Knowledge (January 1966 to April 2014), online trials registries and other sources. We also screened the reference lists of related literature and eligible studies, and presentations from major HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) conferences. We included RCTs and quasi-RCTs comparing PRO 140 with placebo or other antiretroviral drugs, or different doses of PRO 140 for individuals infected with HIV. Two reviewers (L Li and JH Tian) independently screened all retrieved citations and selected eligible studies. Two authors (P Zhang and WQ Jia) independently extracted data. Any disagreements when selecting studies and extracting data were adjudicated by the review mentor (KH Yang). We used Review Manager (RevMan) software for statistical analysis based on an intention-to-treat analysis. We examined heterogeneity using the Chi(2) statistic. We regarded I(2) estimates greater than 50% as moderate or high levels of heterogeneity. According to the level of heterogeneity, we used either a fixed or random-effects model.If significant heterogeneity existed and the reasons could not be found, we reported the results qualitatively. We included three trials comparing PRO 140 with placebo in adult patients with HIV infection. Our review indicates that PRO 140 may offer significant dose-dependent HIV-1 RNA suppression with tolerable side effects. PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly, and 324 mg weekly showed statistically significant differences in the changes of HIV-1 RNA levels. HIV-1 RNA levels were reduced by intravenous (IV) infusion of PRO 140 2 mg/kg or 5 mg/kg on day 10, 5 mg/kg or 10 mg/kg on day 12, 162 mg weekly, 324 mg biweekly, or 324 mg weekly on day 22. PRO 140 2 mg/kg, 5 mg/kg, 10 mg/kg, 162 mg weekly, 324 mg biweekly, and 324 mg weekly demonstrated greater antiviral response. PRO 140 324 mg weekly, 5 mg/kg, and 10 mg/kg showed more patients with ≦ 400 copies/mL HIV-1 RNA. Only PRO 140 5 mg/kg showed greater change in CD4(+) cell count on day eight. Headache, lymphadenopathy, diarrhoea, fatigue, hypertension, nasal congestion and pruritus were reported to be the most frequent adverse events. Limited evidence from three small trials suggests that PRO 140 might demonstrate potent, short-term, dose-dependent, highly significant antiviral activity. However, as the evidence is insufficient, recommendations cannot yet be made. Larger, longer-term, double-blind RCTs are required to provide conclusive evidence.

Virologic and Immunologic Responses in Treatment-Naive Patients to Ritonavir-Boosted Atazanavir or Efavirenz With a Common Backbone

Background: Atazanavir boosted with ritonavir (ATV/r) and efavirenz (EFV) are both recommended as first-line therapies for HIV-infected patients. We compared the 2 therapies for virologic efficacy and immune recovery. Methods: We included all treatment-naïve patients in the Swiss HIV Cohort Study starting therapy after May 2003 with either ATV/r or EFV and a backbone of tenofovir and either emtricitabine or lamivudine. We used Cox models to assess time to virologic failure and repeated measures models to assess the change in CD4 cell counts over time. All models were fit as marginal structural models using both point of treatment and censoring weights. Intent-to-treat and various as-treated analyses were carried out: In the latter, patients were censored at their last recorded measurement if they changed therapy or if they were no longer adherent to therapy. Results: Patients starting EFV (n = 1,097) and ATV/r (n = 384) were followed for a median of 35 and 37 months, respectively. During follow-up, 51% patients on EFV and 33% patients on ATV/r remained adherent and made no change to their first-line therapy. Although intent-to-treat analyses suggest virologic failure was more likely with ATV/r, there was no evidence for this disadvantage in patients who adhered to first-line therapy. Patients starting ATV/r had a greater increase in CD4 cell count during the first year of therapy, but this advantage disappeared after one year. Conclusions: In this observational study, there was no good evidence of any intrinsic advantage for one therapy over the other, consistent with earlier clinical trials. Differences between therapies may arise in a clinical setting because of differences in adherence to therapy.

Factors associated with short-term changes in HIV viral load and CD4+ cell count in antiretroviral-naive individuals

Objectives:Among antiretroviral therapy (ART)-naive individuals, viral load levels tend to increase and CD4+ cell counts decline over time. We sought to explore the rate of change and influence of other factors associated with these markers of HIV progression.Design:An observational cohort collaboration study.Methods:A total of 158 385 pairs of consecutive viral load and CD4+ cell count simultaneously measured from 34 384 ART-naive individuals in the COHERE database were analysed. Annual changes and factors associated with these changes were estimated using generalized estimating equations.Results:Viral load continued to rise at a mean [95% confidence interval (CI)] rate of 0.091 (0.086–0.096) log10 copies/ml per year. A faster rise in viral load was significantly associated with older age, such that for every 10 years older, it was a mean 0.022 log10 copies/ml per year greater. The mean (95% CI) CD4+ cell count change was −78.0 (−80.1 to −76.0) cell/μl per year and it was strongly associated with a higher current viral load: for every 1 log10 copies/ml higher, CD4+ cell count declined by an additional 37.6 cells/μl per year (P < 0.001). Current viral load was a stronger predictor of CD4+ cell count depletion than baseline viral load. Neither sex, race nor transmission by injecting drug use was associated with change in either the viral load or CD4+ cell count.Discussion:We found that in ART-naive individuals, viral load continues to increase over time and more sharply in those who are older. Our results also suggest that higher current viral load is strongly associated with ongoing rate of CD4+ cell count depletion.

Low Alcohol Consumption as a Predictor of Higher CD4+ Cell Count in HIV-Treated Patients

Low Alcohol Consumption as a Predictor of Higher CD4+ Cell Count in HIV-Treated Patients

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

Do HIV-1 non-B subtypes differentially impact resistance mutations and clinical disease progression in treated populations? Evidence from a systematic review.

There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.

Effect of aerobic exercise training on cardiovascular parameters and CD4 cell count of people living with human immunodeficiency virus/acquired immune deficiency syndrome: a randomized controlled trial.

Despite the significant positive effect of Highly Active Antiretroviral Therapy on physical and psychosocial well-being of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) (PLWHA); decreased physical activity and its associated cardiovascular risk still pose some consequences for health and general well-being. This study investigated the effect of an 8 week aerobic exercise training on cardiovascular parameters and CD4 cell (T-cells) count of PLWHA. This randomized controlled trial recruited 30 age matched PLWHA who were randomly assigned into exercise group (EG) ( n = 15) and control group (CG) ( n = 15) respectively. The PLWHA were patients receiving treatment in President's Emergency Plan for AIDS relief at the HIV clinic of the University of Nigeria Teaching Hospital, Nigeria. The EG in addition to conventional therapy received moderate intensity continuous exercise training (60-79% of the maximum heart rate [max]) of between 45 and 60 min, 3 times/week for 8 weeks, while the CG received conventional therapy involving antiretroviral therapy and counseling only. Systolic blood pressure (SBP), diastolic blood pressure (DBP), maximum oxygen uptake (VO₂ max) and CD4 cell count were assessed at baseline (week 1) and week 8 respectively. Analysis of co-variance and Pearson correlation tests were used in data analysis. Findings of the study revealed a significant effect (ANCOVA test) of moderate intensity continuous exercise training program on, SBP, DBP, VO₂ max and CD4 cell count at P < 0.05. Changes in VO₂ max significantly correlated (Pearson correlation test) with changes in CD4 cell count ( r = 0.528) at P < 0.05. Moderate intensity aerobic exercise is an effective complementary therapy in lowering blood pressure and increasing CD4 cell count in PLWHA.

Prevalence and Outcomes of Recycling NNRTIs Despite Documented NNRTI Resistance in HIV-Infected Children and Youth

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly used in pediatric patients; however, rapid development of resistance, due to non-adherence and cross-resistance, results in their discontinuation and limits their recycling. We evaluated the clinical experience of recycling NNRTIs despite documented NNRTI resistance (NNRTI-R), and examined virologic and CD4 cell count outcomes among participants enrolled in Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY), a national HIV-infected pediatric cohort. We conducted a retrospective analysis of LEGACY participants with major NNRTI-R. Using chi-square analyses and logistic regression, we examined demographic and clinical factors associated with prescription of NNRTIs despite documented NNRTI-R, and associated changes in plasma HIV RNA viral load and CD4 cell counts. Sixteen of 133 (12%) participants with documented NNRTI-R re-started NNRTIs for a median of 370 days (IQR 105-919) with a median 402 days (IQR 70-841) between documentation of NNRTI-R to NNRTI recycling. Participants recycling NNRTIs were less likely to have documented past non-adherence (40.0% vs. 69.2%; p = 0.02). Among twelve patients with virologic data at 24 (± 8) weeks; seven (58.3%) experienced virologic suppression while on the recycled NNRTI-based regimens. Of the five who failed to suppress, three with subsequent genotyping developed additional NNRTI-R mutations compromising higher generation NNRTIs. While NNRTI's were recycled in only a small fraction of LEGACY participants harboring NNRTI-R mutations, such recycling increased the risk of inducing further resistance mutations that compromised use of higher generation NNRTIs.

7.0 Managing virological failure

7.0 Managing virological failure

Association of Alcohol Consumption and HIV Surrogate Markers in Participants of the Swiss HIV Cohort Study

Alcohol consumption may affect the course of HIV infection and/or antiretroviral therapy (ART). The authors investigated the association between self-reported alcohol consumption and HIV surrogate markers in both treated and untreated individuals. Prospective cohort study. Over a 7-year period, the authors analyzed 2 groups of individuals in the Swiss HIV Cohort Study: (1) ART-naïve individuals remaining off ART and (2) individuals initiating first ART. For individuals initiating first ART, time-dependent Cox proportional hazards models were used to assess the association between alcohol consumption, virological failure, and ART interruption. For both groups, trajectories of log-transformed CD4 cell counts were analyzed using linear mixed models with repeated measures. The authors included 2982 individuals initiating first ART and 2085 ART naives. In individuals initiating first ART, 241 (8%) experienced virological failure. Alcohol consumption was not associated with virological failure. ART interruption was noted in 449 (15%) individuals and was more prevalent in severe compared with none/light health risk drinkers [hazard ratio: 2.24, 95% confidence interval: 1.42 to 3.52]. The association remained significant even after adjusting for nonadherence. The authors did not find an association between alcohol consumption and change in CD4 cell count over time in either group. No effect of alcohol consumption on either virological failure or CD4 cell count in both groups of ART-initiating and ART-naive individuals was found. However, severe drinkers were more likely to interrupt ART. Efforts on ART continuation should be especially implemented in individuals reporting high alcohol consumption.

Retinal vascular changes and immune restoration in a cohort of HIV/AIDS patients on highly active antiretroviral therapy

BackgroundRetinal microvascular changes have been shown to reflect systemic inflammation in vivo. We aimed to investigate whether retinal microvascular changes are correlated with, and predictive of, CD4 and CD8 cell count changes in patients with HIV/AIDS being treated with highly active antiretroviral therapy (HAART). MethodsWe did a longitudinal hospital-based study. 50 HIV/AIDS patients being treated with HAART were sequentially recruited from March, 2011, to September, 2011, from the Communicable Disease Center, Singapore, and then followed up at a 9 month visit. Demographic and socioeconomic information and history of HIV infection were collected at baseline. Blood pressure and anthropometric measurements, blood tests for immune status assessment (CD4 and CD8 cell counts), and retinal photography were done at baseline and at 9 months. Retinal vascular parameters (calibre, tortuosity, branching angle, and fractal dimension) were assessed by a semiautomated computer-based programme (Singapore I vessel assessment [SIVA], version 3.0, Singapore Eye Research Institute, Singapore). Changes of retinal vascular parameters and CD4 and CD8 cell counts were defined as the difference between baseline and 9 months. FindingsThe mean age of the 50 participants was 46·36 years (SD 8·67). Participants were ethnically Chinese, Malay, and Indian; most (82%) were Chinese and most male (96%). 35 of 50 patients had CD4 counts of fewer than 200 cells per μL at baseline. Years of HAART ranged from 0 to 11 years. There were significant increments in CD4 cell counts (153·42 vs 227·74 cells per μL; p<0·0001) and CD8 cell counts (819·90 vs 1014·1 cells per μL; p=0·012) between baseline and the 9 month visit, respectively. There were no temporal changes in retinal vascular parameters during this period. After adjustment for age, sex, ethnicity, and years of HAART, each 10 μm reduction in retinal venular calibre at baseline was associated with a 191·08 cells per μL increase in CD8 count (SE 63·54; p=0·004), but not in CD4 cell count, during the 9 month period. Changes of retinal arteriolar calibre and other retinal vascular geometric parameters were not associated with CD4 or CD8 cell count changes. InterpretationRetinal venular narrowing was associated with an increase in CD8 cell counts over time. Our findings suggest that improved retinal venular health was predictive of immune restoration in HIV/AIDS patients who had been on HAART for at least 9 months. Longer follow-up is warranted to monitor the retinal vascular calibre changes in response to HAART treatment. FundingSingapore Medical Research Counsel SIG/11016.

HLA B*5701 status, disease progression, and response to antiretroviral therapy

Objective:In addition to hypersensitivity reactions to abacavir, HLA B∗5701 has been associated with slow or nonprogression of HIV infection. We explored the effect of HLA B∗5701 on CD4+ cell count and viral load in untreated patients and on responses to nonabacavir-containing combination antiretroviral therapy (cART) in a large UK-based cohort.Design:Analysis of a cohort of HIV-infected adults.Methods:In untreated patients, CD4+ cell count and viral load at study entry were compared in HLAB∗5701-positive and HLAB∗5701-negative individuals and linear regression tested for an interaction effect of viral load and HLA B∗5701 on CD4+ cell count. In patients starting a nonabacavir cART regimen, Cox proportional hazards models compared virological responses to cART among HLA B∗5701-negative, HLA B∗5701-positive, and those not tested. Six-month and 12-month changes in CD4+ cell count were used as outcomes in linear regression to compare immunological response to cART in these groups.Results:ART-naive HLA B∗5701-positive individuals had higher CD4+ cell count (P <0.0001) and lower viral load (P <0.0001) at study entry than negatives; however, HLA B∗5701 status was not found to effect the association between viral load and CD4+ cell count (interaction P value = 0.09). HLA B∗5701-positive patients were more likely to achieve viral suppression than negative patients on a nonabacavir regimen [hazard ratio = 1.29, 95% confidence interval, CI (1.15–1.54)] and less likely to experience viral rebound [hazard ratio = 0.61, 95% CI (0.37–0.99)].Conclusion:Better virological but not immunological responses to cART were seen in HLA B∗5701-positive patients on nonabacavir regimens. This study provides further evidence of the potentially beneficial effect of HLA B∗5701 on HIV progression.

Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial

In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4∙5%, 95% CI -1∙1% to 10∙0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.

A Systematic Review and Meta-regression of Temporal Trends in Adult CD4+ Cell Count at Presentation to HIV Care, 1992-2011

The clinical status of human immunodeficiency virus (HIV)-positive persons at the time of presentation to medical care has important individual- and population-level implications. We synthesized the literature on clinical status of adults newly presenting to care for HIV infection in developed countries to generate an estimate of the time trend for CD4 cell count at the initiation of HIV care. We systematically searched PubMed for studies published between January 2000 and November 2011 to identify those that reported CD4 cell count for patients newly presenting to HIV care according to standardized inclusion criteria. We abstracted the mean or median CD4 cell count or reconstructed the mean CD4 cell count from the presented data describing the number or proportion of patients in CD4 cell count categories. We estimated the change in CD4 cell count over time by modeling it as a weighted linear function of calendar year. Based on a meta-regression of 197 point estimates encompassing CD4 cell count measurements from 169 007 patients in 44 studies, mean CD4 cell count at presentation increased minimally by 1.5 cells/μL per year (95% CI, -6.1 to 5.5 cells/μL per year), from 307 cells/μL in 1992 to 336 cells/μL in 2011. In developed countries, patients' CD4 cell counts at first presentation to medical care have not increased meaningfully over the past 20 years. New and innovative strategies are imperative to identify persons earlier in the course of their infection and link them promptly with medical care.

Virologic and immunologic effectiveness of darunavir-based salvage therapy in HIV-1-infected adults in a Brazilian clinical practice setting: results of a multicenter and retrospective cohort study

BackgroundDarunavir has been proven efficacious for antiretroviral-experienced HIV-1-infected patients in randomized trials. However, effectiveness of darunavir-based salvage therapy is understudied in routine care in Brazil. MethodsRetrospective cohort study of HIV-1-infected patients from three public referral centers in Belo Horizonte, who received a darunavir-based therapy between 2008 and 2010, after virologic failure. Primary endpoint was the proportion of patients with viral load<50copies/mL at week 48. Change in CD4 cell count was also evaluated. Outcome measures were analyzed on an intent-to-treat basis applied to observational studies. Sensitivity analysis was conducted to evaluate the impact of missing data at week 48. Predictors of virologic failure were examined using rare-event, finite sample, bias-corrected logistic regression. ResultsAmong 108 patients, the median age was 44.2 years, and 72.2% were male. They had long-standing HIV-1 infection (median 11.6 years) and advanced disease (76.9% had an AIDS-defining event). All patients had previously received protease inhibitors and nucleoside reverse transcriptase inhibitors, 75% nonnucleoside reverse transcriptase inhibitors, and 4.6% enfuvirtide. The median length of protease inhibitor use was 8.9 years, and 90.8% of patients had prior exposure to unboosted protease inhibitor. Genotypic resistance profile showed a median of three primary protease inhibitor mutations and 10.2% had three or more darunavir resistance-associated mutations. Virologic success at week 48 was achieved by 78.7% (95% CI=69.7–86%) of patients and mean CD4 cell count increase from baseline was 131.5cells/μL (95% CI=103.4–159.6). In multiple logistic regression analysis, higher baseline viral load (RR=1.04 per 10,000copies/mL increase; 95% CI=1.01–1.09) and higher number of darunavir resistance-associated mutations (RR=1.23 per each; 95% CI=0.95–1.48) were independently associated with virologic failure. ConclusionVirologic suppression is a realistic endpoint for most treatment-experienced patients who begin a darunavir-based therapy outside the controlled conditions of a randomized trial, at routine care settings.