Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks.

Background: We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Methods: Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). Results: At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1-2); no serious drug-related AEs occurred. Conclusions: Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV.

OBJECTIVES: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. DESIGN: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. METHODS: Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). RESULTS: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. CONCLUSION: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Trends in the outcomes of end-stage renal disease secondary to human immunodeficiency virus-associated nephropathy.

BACKGROUND: Little is known about the trends in the incidence and outcomes of patients with end-stage renal disease (ESRD) attributed to human immunodeficiency virus-associated nephropathy (HIVAN). We sought to define relative incidence among ESRD patients, changes in mortality among patients with ESRD attributed to HIVAN, as well as changes in the excess mortality experienced by patients with ESRD attributed to HIVAN compared with otherwise similar ESRD patients with non-HIVAN causes. METHODS: We used the US Renal Data System to identify all individuals with reported HIVAN who initiated treatment for ESRD between 1989 and 2011. We plotted their counts and proportions among all incident ESRD patients and tabulated their characteristics across years. We then compared mortality within the HIVAN group across years using Cox regression. In addition, we studied the trends in relative mortality of HIVAN patients versus those with ESRD not reported as HIVAN. RESULTS: Overall, 14 719 individuals with HIVAN-ESRD were recorded, with significant reductions in recent years (893 in 2006; 525 in 2011). Compared with patients initiating dialysis between 1989 and 1992, mortality declined by 40% (HR = 0.60; 95% CI, 0.55-0.65) and 64% (HR = 0.36; 95% CI, 0.32-0.40) for patients initiating dialysis in 1999/2000 and 2009-11, respectively. The adjusted excess mortality of HIVAN-ESRD patients versus incident ESRD patients from other causes was >5-fold in 1989-92 (HR = 5.21; 95% CI, 4.84-5.60); this excess mortality has subsequently declined but remained at almost 3-fold in recent years (e.g. HR = 2.58; 95% CI, 2.37-2.80, 2009-11 incidence cohort). CONCLUSIONS: Concurrent with the increasing availability of highly active antiretroviral therapy (HAART), both the incidence of ESRD due to HIVAN and the mortality of such patients have decreased substantially. However, HIVAN patients reaching ESRD continue to experience substantial excess mortality compared with other ESRD patients even in the current era of modern HAART.

Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.

BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

Gender inequality and HIV transmission: a global analysis.

INTRODUCTION: The HIV pandemic disproportionately impacts young women. Worldwide, young women aged 15-24 are infected with HIV at rates twice that of young men, and young women alone account for nearly a quarter of all new HIV infections. The incommensurate HIV incidence in young - often poor - women underscores how social and economic inequalities shape the HIV epidemic. Confluent social forces, including political and gender violence, poverty, racism, and sexism impede equal access to therapies and effective care, but most of all constrain the agency of women. METHODS: HIV prevalence data was compiled from the 2010 UNAIDS Global Report. Gender inequality was assessed using the 2011 United Nations Human Development Report Gender Inequality Index (GII). Logistic regression models were created with predominant mode of transmission (heterosexual vs. MSM/IDU) as the dependent variable and GII, Muslim vs. non-Muslim, Democracy Index, male circumcision rate, log gross national income (GNI) per capita at purchasing power parity (PPP), and region as independent variables. RESULTS AND DISCUSSION: There is a significant correlation between having a predominantly heterosexual epidemic and high gender inequality across all models. There is not a significant association between whether a country is predominantly Muslim, has a high/low GNI at PPP, has a high/low circumcision rate, and its primary mode of transmission. In addition, there are only three countries that have had a generalized epidemic in the past but no longer have one: Cambodia, Honduras, and Eritrea. GII data are available only for Cambodia and Honduras, and these countries showed a 37 and 34% improvement, respectively, in their Gender Inequality Indices between 1995 and 2011. During the same period, both countries reduced their HIV prevalence below the 1% threshold of a generalized epidemic. This represents limited but compelling evidence that improvements in gender inequality can lead to the abatement of generalized epidemics. CONCLUSIONS: Gender inequality is an important factor in the maintenance - and possibly in the establishment of - generalized HIV epidemics. We should view improvements in gender inequality as part of a broader public health strategy.

Association between latent proviral characteristics and immune activation in antiretrovirus-treated human immunodeficiency virus type 1-infected adults.

UNLABELLED: Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation. IMPORTANCE: Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

Evolution of HIV treatment guidelines in high- and low-income countries: converging recommendations.

Over the past 15 years, antiretroviral treatment guidelines for HIV infection have evolved significantly, reflecting the major advances in this therapeutic area. Evidenced-based recommendations have largely replaced expert opinion, while diagnostic monitoring and therapeutic interventions have become more sophisticated and effective. Just 10 years ago, there was a marked difference in access to antiretroviral therapy for patients in wealthy and impoverished countries. The increasing availability of therapy across the globe, however, has made it possible for international guidelines to resemble more closely those in high-income countries. This article compares the evolution of antiretroviral therapy treatment guidelines from the United States Department of Health and Human Services and the World Health Organization, focusing on when to initiate ART in asymptomatic patients and in those with an opportunistic infection; initial regimens in the general population and in special populations; when to change and what to change; and laboratory monitoring.

Early virologic response to abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202.

BACKGROUND: ACTG A5202 randomized treatment-naïve individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high screening viral load (VL) stratum (≥100,000 copies/mL) had increased rates of virologic failure with ABC/3TC. OBJECTIVE: To compare regimen-specific early virologic response. METHODS: Using Wilcoxon rank-sum tests, we compared regimen-specific VL changes from entry to week 4 in A5202 subjects (N = 1,813) and from entry to week 1, 2, and 4 in substudy subjects (n = 179). We evaluated associations between week 4 VL change and time to virologic failure with Cox proportional hazards models. RESULTS: TDF/FTC and ABC/3TC produced similar week 4 VL declines in the entire study population and in the high VL stratum. EFV produced greater VL declines from baseline at week 4 than ATV/r (median -2.1 vs -1.9 log10 copies/mL; P < .001). In the substudy of subjects with week 1, 2, and 4 VL data, there was no difference in VL decline in individuals randomized to TDF/FTC versus ABC/3TC, but EFV resulted in greater VL decline from entry at each of these timepoints than ATV/r. Smaller week 4 VL decline was associated with increased risk of virologic failure. CONCLUSIONS: Within all treatment arms, a less robust week 4 virologic response was associated with higher risk for subsequent virologic failure. However, between-regimen differences in week 4 VL declines did not parallel the previously reported differences in longer term virologic efficacy in A5202, suggesting that between-regimen differences in responses were not due to intrinsic differences in antiviral activity.

Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation.

BACKGROUND: Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. METHODS: We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. RESULTS: The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/µL lost significantly more BMD compared to those with CD4(+) ≥500 cells/µL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. CONCLUSIONS: Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.

Test performance of blood beta-glucan for Pneumocystis jirovecii pneumonia in patients with AIDS and respiratory symptoms.

OBJECTIVE: The objective of this study was to define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients with respiratory symptoms. DESIGN: Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms. METHODS: Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164 trial, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if at least 80 pg/ml and negative if less than 80 pg/ml. RESULTS: Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% [95% confidence interval (CI) 87.2-96.5], and specificity 75.0% (95% CI 50.9-91.3). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (95% CI 91.5-98.8). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (95% CI 38.7-78.9). CONCLUSION: Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool on the basis of the pretest probability of PCP in such patients.

Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus-infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear. METHODS: We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels. RESULTS: Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS. CONCLUSIONS: Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.

When to start ART in the setting of acute AIDS-related opportunistic infections: the time is now!

Despite the substantial benefits of combination antiretroviral therapy (ART), a significant proportion of HIV-infected individuals still present with advanced disease and active AIDS-related opportunistic infections (OIs). The weight of evidence from recent studies supports the early initiation of ART (ie, within 2 weeks of initiating treatment for the acute OIs). Initiating ART early in acutely ill patients can reduce AIDS-related progression and death. Early ART has not been associated with increased rates of immune reconstitution inflammatory syndrome in prospective studies of non-tuberculosis OIs, although this concern is frequently cited as a reason to delay ART. Nor has early ART been associated with increased adverse outcomes. Nonetheless, initiating ART early in acute care settings can be challenging to implement and requires a well-coordinated multidisciplinary team with expertise in ART management.

Association of low level viremia with inflammation and mortality in HIV-infected adults.

BACKGROUND: Whether HIV viremia, particularly at low levels is associated with inflammation, increased coagulation, and all-cause mortality is unclear. METHODS: The associations of HIV RNA level with C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and mortality were evaluated in 1116 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. HIV RNA level was categorized as undetectable (i.e., "target not detected"), 1-19, 20-399, 400-9999, and ≥ 10,000 copies/ml. Covariates included demographics, lifestyle, adipose tissue, and HIV-related factors. RESULTS: HIV RNA level had little association with CRP. Categories of HIV RNA below 10,000 copies/ml had similar levels of IL-6 compared with an undetectable HIV RNA level, while HIV RNA ≥ 10,000 copies/ml was associated with 89% higher IL-6 (p<0.001). This association was attenuated by ~50% after adjustment for CD4+ cell count. Higher HIV RNA was associated with higher fibrinogen. Compared to an undetectable HIV RNA level, fibrinogen was 0.6%, 1.9%, 4.5%, 4.6%, and 9.4% higher across HIV RNA categories, respectively, and statistically significant at the highest level (p = 0.0002 for HIV RNA ≥ 10,000 copies/ml). Higher HIV RNA was associated with mortality during follow-up in unadjusted analysis, but showed little association after adjustment for CD4+ cell count and inflammation. CONCLUSION: HIV RNA ≥ 10,000 copies/ml was associated with higher IL-6 and fibrinogen, but lower levels of viremia appeared similar, and there was little association with CRP. The relationship of HIV RNA with IL-6 was strongly affected by CD4 cell depletion. After adjustment for CD4+ cell count and inflammation, viremia did not appear to be substantially associated with mortality risk over 5 years.

Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia.

UNLABELLED: (See the editorial commentary by Morris and Masur, on pages 203-204.) BACKGROUND: Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-ß-D-glucan (ß-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs). METHODS: The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for ß-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites. RESULTS: A total of 252 persons had a ß-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median ß-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of ß-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP. CONCLUSIONS: Blood (1 → 3)-ß-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

Early antiretroviral therapy for patients with acute aids-related opportunistic infections: a cost-effectiveness analysis of ACTG A5164.

PURPOSE: ACTG A5164 demonstrated that early antiretroviral therapy (ART) in HIV-infected patients with acute opportunistic infections (OIs) reduced death and AIDS progression compared to ART initiation 1 month later. We project the life expectancies, costs, and incremental cost-effectiveness ratios (ICERs) of these strategies. METHOD: using an HIV simulation model, we compared 2 strategies for patients with acute OIs: (1) an intervention to deliver early ART, and (2) deferred ART. Parameters from ACTG A5164 included initial mean CD4 count (47/microL), linkage to outpatient care (87%), and immune reconstitution inflammatory syndrome 1 month after ART initiation (7%). The estimated intervention cost was $1,650/patient. RESULTS: early ART lowered projected 1-year mortality from 10.4% to 8.2% and increased life expectancy from 10.07 to 10.39 quality-adjusted life-years (QALYs). Lifetime costs increased from $385,220 with deferred ART to $397,500 with early ART, primarily because life expectancy increased, producing an ICER of $38,600/QALY. Results were most sensitive to increased intervention cost and decreased virologic efficacy in the early ART strategy. CONCLUSIONS: an intervention to initiate ART early in patients with acute OIs improves survival and meets US cost-effectiveness thresholds. Programs should be developed to implement this strategy at sites where HIV-infected patients present with OIs.

Optimal antiretroviral therapy: HIV-1 treatment strategies to avoid and overcome drug resistance.

Potent antiretroviral therapy (ART) has transformed HIV infection into a chronic manageable disease, but drug resistance remains a common problem that limits the effectiveness and clinical benefits of treatment. With increasing experience with ART, the understanding of viral dynamics of HIV improved, and researchers learned how challenging HIV can be to control. With new-class and new-generation drugs, it is hoped that the lessons learned will be useful for limiting drug resistance and optimizing the use of ART for long-term management of HIV infection.

Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort.

OBJECTIVE: To determine the association of inflammatory markers, fibrinogen, and C-reactive protein (CRP), with 5-year mortality risk. METHODS: Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios after adjustment for demographic, cardiovascular, and HIV-related factors. RESULTS: Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile (>406 mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile (<319 mg/dL). Those with high CRP (>3 mg/L) had 2.7-fold higher adjusted odds of death than those with CRP <1 mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [odds ratio (95% confidence intervals)] per 100 mg/dL increase in fibrinogen: 1.93 (1.57 to 2.37); 1.43 (1.14 to 1.79); 1.43 (1.14 to 1.81); and 1.30 (1.04 to 1.63) for CD4 <200, 200-350, >350 to 500, and >500 cells per microliter, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup. CONCLUSIONS: Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500 cells per microliter, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.

Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV Type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial.

BACKGROUND: This phase 2, randomized, active-controlled, 48-week study assessed the noninferiority of the human immunodeficiency virus (HIV) integrase inhibitor elvitegravir to comparator ritonavir-boosted protease inhibitor (CPI/r) in treatment-experienced subjects. METHODS: Subjects had HIV RNA levels 1000 copies/mL and 1 protease resistance mutation. Subjects received nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) with or without T-20 and either CPI/r or once-daily elvitegravir at a dose of 20 mg, 50 mg, or 125 mg (blinded to dose) with ritonavir. After week 8, the independent data monitoring committee stopped the elvitegravir 20 mg arm and allowed subjects in the elvitegravir 50 mg and 125 mg arms to add protease inhibitors. The primary end point was the time-weighted average change from baseline in HIV RNA level through week 24 (DAVG(24)). RESULTS: A total of 278 subjects with a median of 11 protease and 3 thymidine analog mutations were randomized and treated. One-half of subjects received NRTIs without expected antiviral activity. Compared with the DAVG(24) for the CPI/r arm (-1.19 log(10) copies/mL), the elvitegravir 50 mg arm was noninferior (-1.44 log(10) copies/mL), and the elvitegravir 125 mg arm was superior (-1.66 log(10) copies/mL; P = .021). Efficacy was impacted by activity of background agents. There was no relationship between elvitegravir dosage and adverse events. CONCLUSIONS: Elvitegravir was well-tolerated and produced rapid virologic suppression that was durable with active background therapy. Trial registration. ClinicalTrials.gov identifier number: NCT00298350.