Antiretrovirals and Weight Change: Weighing the Evidence.

Body weight is influenced by an interplay of individual and environmental factors. In people with HIV (PWH), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy (ART). Weight changes in comparative ART trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors (INSTIs) dolutegravir and bictegravir, particularly when co-administered with tenofovir alafenamide fumarate (TAF), compared to regimens that include agents such as tenofovir disoproxil fumarate (TDF) that attenuate weight gain. We review weight changes in major randomized trials of pre-exposure prophylaxis (PrEP) and initial and switch HIV therapy, highlighting the challenges to assessing the role of ART in weight change. This examination forms the basis for a model that questions assumptions regarding an association between INSTI and TAF and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions.

Predictors of short-term diabetes remission after laparoscopic Roux-en-Y gastric bypass.

PURPOSE: A remission of type 2 diabetes mellitus (T2DM) is one of the major goals of the contemporary bariatric surgery. The goal of our study is to identify predictors of short-term postoperative diabetes remission in order to facilitate preoperative patient selection. MATERIALS AND METHODS: Two hundred forty-five obese (body mass index (BMI) ≥35 kg/m2) T2DM subjects who underwent laparoscopic Roux-en-Y gastric bypass (RYGB) were followed up to 1 year after bariatric surgery. Diabetes remission was defined as hemoglobin A1c (HbA1c) ≤6 % and fasting blood glucose (FBG) <100 mg/dl in absence of all diabetic medications. RESULTS: Twenty-six percent of the patients seen in f/u achieved complete remission at 1 year. Average Hba1c decreased from 8 to 6.7% and 6.4% after 6 and 12 months, respectively. Regression analysis showed that age (p = 0.01), number of diabetes complications (p = 0.03), family history of diabetes (p = 0.04), preoperative use of insulin (p = 0.04), and peri- and postoperative weight loss (p = 0.05, for both) were the best preoperative predictors of diabetes remission at 6 and 12 months (R(2) = 0.3). CONCLUSION: Younger patients, with fewer diabetic complications, no family history of diabetes, not using insulin, and with greater peri- and postoperative weight loss were the best candidates to achieve a rapid diabetes remission after RYGB.

Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study.

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race.

An academic center's delivery of care after the Haitian earthquake.

The Miller School of Medicine of the University of Miami and Project Medishare, an affiliated not-for-profit organization, provided a large-scale relief effort in Haiti after the earthquake of 12 January 2010. Their experience demonstrates that academic medical centers in proximity to natural disasters can help deliver effective medical care through a coordinated process involving mobilization of their own resources, establishment of focused management teams at home and on the ground with formal organizational oversight, and partnership with governmental and nongovernmental relief agencies. Proximity to the disaster area allows for prompt arrival of medical personnel and equipment. The recruitment and organized deployment of large numbers of local and national volunteers are indispensable parts of this effort. Multidisciplinary teams on short rotations can form the core of the medical response.

Infection control in field hospitals after a natural disaster: lessons learned after the 2010 earthquake in Haiti.

After the January 12, 2010, earthquake in Haiti, Project Medishare and the University of Miami organized, built, and staffed a 200-bed field hospital (the University of Miami Hospital in Haiti [UMHH]) on the outskirts of Port-au-Prince. We describe the operational challenges of providing a safe environment at the UMHH. Furthermore, we compared how these issues were addressed at this ad hoc hospital with how they were addressed at the field hospital of the Israel Defense Force, a fully deployable hospital with an organization fine-tuned as a result of prior disaster situations, also in Haiti.

Predictors of loss of virologic response in subjects who simplified to lopinavir/ritonavir monotherapy from lopinavir/ritonavir plus zidovudine/lamivudine.

Previous studies have demonstrated that lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a lopinavir/ritonavir-based combination regimen followed by simplification to lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4(+) T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA <50 copies/ml prior to simplification, and lopinavir concentrations. By the Cox proportional hazards model, higher reported adherence levels and higher baseline CD4(+) T cell counts were associated with a greater likelihood of maintaining virologic suppression while receiving lopinavir/ritonavir monotherapy. Lopinavir concentrations, including trough concentrations, were not significantly associated with virologic outcomes. This analysis suggests that adherence and higher baseline CD4(+) T cell counts may help to predict who will sustain virologic suppression with lopinavir/ritonavir monotherapy. The data also suggest that measuring lopinavir concentrations is not useful in predicting virologic response in these patients.

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis.

BACKGROUND: As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important. METHODS: A regimen of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior virologic, immunologic and morphologic effects compared with a regimen of fixed-dose zidovudine/lamivudine (ZDV/3TC) and EFV through 96 weeks in a randomized open-label trial. After 96 weeks, patients on TDF + FTC transitioned to fixed-dose combination TDF/FTC. RESULTS: Through 144 weeks, significantly more patients in the TDF/FTC arm reached and maintained an HIV RNA level <400 copies/mL (71% receiving TDF/FTC and EFV vs. 58% receiving ZDV/3TC and EFV; P = 0.004), with a trend toward greater CD4 cell increase in the TDF/FTC arm (312 vs. 271 cells/mm; P = 0.09). Over 144 weeks of follow-up, more patients in the ZDV/3TC arm discontinued therapy because of adverse events (11% vs. 5%; P = 0.01) and no patients discontinued because of renal events. Patients in the ZDV/3TC arm had significantly less limb fat than patients in the TDF/FTC arm (5.4 vs. 7.9 kg; P < 0.001) at 144 weeks. CONCLUSIONS: Cumulative results from 3 years of follow-up suggest that a regimen of TDF/FTC and EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV.

Factors influencing the acceptance of changes in antiretroviral therapy among HIV-1-infected patients.

Physicians routinely consider modifying antiretroviral therapy (ART) regimen for their patients with HIV. Little is known about the factors associated with patients' willingness to accept providers' recommended ART changes. This multicenter prospective observational study examined factors associated with willingness to accept ART changes recommended by their providers among HIV-infected adults from six urban outpatient HIV clinics. Patients were surveyed using the Patient Attitudes about Altering Antiretroviral Therapy Survey questionnaire (PAAARTS). Factors associated with willingness to accept ART changes were assessed using a multivariate generalized estimating equation (GEE) model to account for correlated responses. The Classification and Regression Trees (CART) analysis was also performed to determine subgroups of patients with higher acceptance of change. 216 of 289 patients (75%) definitely accepted recommended changes. Odds for acceptance were 3.2, 2.3, and 2.8 times higher for patients with higher attitudes and beliefs about ART (p < 0.01; 95% confidence interval [CI] = 1.59, 6.52), patients who rated their provider's care as excellent (p < 0.05; 95% CI = 1.07, 4.78), and non-Hispanic patients (p < 0.05; 95% CI 1.03, 7.57), respectively. CART analysis showed similar results and identified that when patients had less positive attitude about ART, acceptance rates were higher for non-Hispanic patients with higher assessments of their patient-provider communication. While most patients accepted providers' recommendation for ART changes, this willingness was influenced by both patients' attitudes and beliefs about ART and their assessment of either the effectiveness of patient-provider communication or their rating of providers' care. ART acceptance rates among Hispanic patients were lower.

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis.

BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.

Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.

BACKGROUND: Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere. METHODS: We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study. RESULTS: Through week 48, significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P=0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P=0.002). More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R mutation develop. CONCLUSIONS: Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.)

Antiretroviral treatment considerations in Latino patients.

Latinos in the United States have been disproportionately affected by HIV, with a higher rate of infection, later diagnosis, and a higher death rate than Caucasians. Complicating the issue is that "Latino" is a broad term that encompasses diverse ethnic and racial groups, requiring a targeted approach to prevention and management of HIV infection. This article explores the demographics of HIV infection among Latinos in the United States, discusses cultural beliefs among Latinos that have an impact on prevention and access to care, and reviews strategies for managing HIV infection in this population.

Differences in presentation and outcome of invasive pneumococcal disease among patients with and without HIV infection in the pre-HAART era.

Invasive pneumococcal disease (PD) occurs frequently among HIV-infected patients, but it is unclear whether its manifestations and outcome are different compared to those observed among patients without HIV-1 infection. Because the immune reconstitution that accompanies antiretroviral therapy may change some of these features and because most cases of HIV- 1 infection occur in resource-poor settings of the world where access to antiretroviral agents is limited, we compared PD among patients with and without HIV-1 infection in a North American population before the introduction of highly active antiretroviral therapy (HAART). The records of all pneumococcal cultures processed at this medical center over a period of 20 months were used to identify patients with invasive PD. Hospital records were reviewed for 103 of these patients (52 with and 51 without HIV-1 infection) and demographic, clinical, laboratory, radiographic, and microbiologic information was abstracted and subsequently analyzed. Despite similarities in presenting signs and symptoms, we found a higher incidence of bacteremia but a more favorable outcome with less frequent requirements for intubation and admission to intensive care units and better survival among individuals with HIV infection. Factors such as less advanced age, the presence of fewer comorbid conditions, or a less florid inflammatory response among HIV-infected individuals may account for differences in outcome of invasive PD.

Impact of resistance to antiretroviral therapy in the minority community.

The development of resistance to antiretroviral therapies has become a formidable barrier to providing optimal treatment of HIV infection in the United States. The emergence of new mutations resistant to antiretroviral agents and a rise in transmission of resistant viruses contribute to an increased risk of treatment failure. Resistance testing of both treatment-experienced and treatment-naive patients i snow recommended for identification of the most effective treatment regimen; however, resistance testing is not universally available or easily interpreted. Furthermore, poor adherence to a treatment regimen or treatment with less potent antiretroviral agents can lead to exposure of virus to subinhibitory levels of drug and the development of resistance. In this article, we discuss several issues that specifically impact the development and transmission of resistant HIV in patients belonging to ethnic minorities and teh implementation of strategies that will overcome resistance as an obstacle to optimal treatment.

Development of anti-retroviral resistance of HIV-1 infected individuals on therapy: is it inevitable?

Highly active antiretroviral therapy directed against HIV-1 has dramatically modified morbidity and mortality in infected individuals. Enthusiasm for the success of these medications have been tempered by an inability to clear virus from the infected host leaving a virus poised to leverage any advantage into one of productive survival. One mechanism used to accomplish escape from suppression secondary to antiretroviral therapy is by developing mutations. The goal of therapy has been to diminish viral replication, thereby effectively abrogating the development of these resistance-bearing mutations. This strategy has met with significant success but numerous host-viral factors impact on the ability of the clinician to persistently suppress viral load, thereby providing a window of opportunity for the virus to mutate. In particular we review evidence for ongoing viral replication in the face of suppressive antiretroviral therapy and viral replication in tissue compartments. We discuss whether viral resistance can develop during transient elevations in viral load (viral blips) or as a function of the rate of viral load decay while on therapy. Finally, we touch on the therapeutic strategy that diminished viral replication capacity of mutational species can maintain host immunity.

HIV-related pneumonia care in older patients hospitalized in the early HAART era.

Age-related variations in care have been identified for HIV-associated Pneumocystis carinii pneumonia (PCP) in both the 1980s and 1990s. We evaluated if age-related variations affected all aspects of HIV-specific and non-HIV-specific care for HIV-infected individuals with PCP or community-acquired pneumonia (CAP), or whether age-related variations were primarily limited to HIV-specific aspects of care. Subjects were HIV-infected persons with PCP (n = 1855) or CAP (n = 1415) hospitalized in 8 cities from 1995 to 1997. Nine percent of our study patients had received protease inhibitors and 39% had received any type of antiretroviral therapy prior to hospitalization. Data were abstracted from medical records and included severity of illness, HIV-specific aspects of care (initiation of PCP medications), general measures of care [initiation of CAP medications, intubation, and intensive care units (ICU)], and inpatient mortality. Compared to younger patients, pneumonia patients 50 years of age or older were significantly more likely to: be severely ill (PCP, 20.4% vs. 10.4%; CAP, 27.5% vs. 14.9%; each p = 0.001), receive ICU care (PCP, 22.0% vs. 12.8%, p = 0.002; CAP: 15.1% vs. 9.4%; p = 0.02), and be intubated (PCP, 14.6% vs. 8.4%, p = 0.01; CAP, 9.9% vs. 5.6%, p = 0.03). Compared to younger patients, older patients (>/=50 years) had similar rates of timely medications for CAP (48.5% vs. 50.8%) but had lower rates of receiving anti-PCP medications (85.8% vs. 92.9%, p = 0.002). Differences by age in timely initiation of PCP medications, ICU use, and intubation were limited to the nonseverely ill patients. Older hospitalized patients were more likely to die (PCP, 18.3% vs. 10.4%; CAP, 13.4% vs. 8.5%; each p < 0.05). After adjustment for disease severity and timeliness of antibiotic use, mortality rates were similar for both age groups. Physicians should develop strategies that increase awareness of the possibility of HIV infection in older individuals.

Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures.

OBJECTIVE: To assess responses to indinavir (IDV)-ritonavir (RTV)-based regimens among HIV-1 infected patients with prior failure of protease inhibitors, and to assess the effects of adherence to therapy and pre-existing genotypic and phenotypic resistance on this response. METHODS: Twenty-eight patients initiating salvage regimens with IDV-RTV (800 mg and 200 mg twice daily, respectively) plus one or more reverse transcriptase inhibitor (RTI) were identified retrospectively. Genotypic and phenotypic susceptibilities to multiple antiretroviral agents were determined on viral samples collected at initiation of the salvage regimens, and adherence to therapy was determined through patient self-reporting. Response to therapy (viral RNA

Effect of class-specific therapy interruption on persistence of HIV type 1 antiretroviral resistance.

Interruption of all antiretroviral therapy for HIV-1 infection when therapy is failing and antiretroviral resistance has emerged is frequently associated with the disappearance of detectable resistance-associated protease and reverse transcriptase substitutions. However, the effect that discontinuation of treatment with a particular antiretroviral class has on resistance to that class when other antiretroviral therapy is continued is unknown. We investigated differences in detectable genotypic resistance to protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) among two populations: patients undergoing testing at the moment class-specific treatment failed (Group 1) and patients undergoing testing for varying periods after class-specific treatment failed and was discontinued but therapy with other antiretroviral classes continued with incomplete viral suppression (Group 2). We found that the prevalence of detectable resistance to the PI and NNRTI classes was similar in both groups despite the absence of class-specific selective pressure for lengthy periods of time in Group 2. We hypothesize that this finding may be due to nonspecific selective pressure (i.e., to nucleoside reverse transcriptase inhibitors) selecting out PI- and, to a lesser extent, NNRTI-resistant viral variants.

Differences in the frequency of resistance to antiretroviral drug classes among human immunodeficiency virus type 1 clinical isolates.

Genotypic resistance to all antiretroviral classes was widespread among human immunodeficiency virus type 1 isolates failing therapy. Resistance to nonnucleoside reverse transcriptase inhibitors was found most frequently and resistance to protease inhibitors was found least frequently, most likely due to differences in the number of enzymatic amino acid substitutions leading to resistance to each particular drug class.

Avances recientes en HIV-SIDA: patogénesis, historia natural y carga viral / Recent developments in HIV/SIDA: pathogenesis, natural history and viral load

Results of recent research investigations have given us a new understanding of the pathogenesis of HIV infection. This findings provide us with a kinetic model of pathogenesis in which continuous, high grade viral replication is the principal force driving the destruction of CD4 lymphocytes. This knowledge will lead us to design better treatment strategies directed to curtail viral replication and prevent the emergence of viral resistance, and the use of combination antiretroviral therapy is a first example of these new strategies. The concept of viral load is introduced, and we discuss the usefulness of viral load in the clinical prognosis of this disease, and its use as an aid in the decision making process when starting or modifying antiretroviral therapy in our patients.