Jordan E. Lake

Metabolic disease in HIV infection

The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs.

Vitamin D in HIV-Infected Patients

Observational studies have noted very high rates of low 25(OH)D (vitamin D) levels in both the general and HIV-infected populations. In HIV-infected patients, low 25(OH)D levels are likely a combination of both traditional risk factors and HIV-specific and antiretroviral therapy–specific contributors. Because of this unique risk profile, HIV-infected persons may be at greater risk for low 25(OH)D levels and frank deficiency and/or may respond to standard repletion regimens differently than HIV-uninfected patients. Currently, the optimal repletion and maintenance dosing regimens for HIV-infected patients remain unknown, as do potential benefits of supplementation that may be unique to the HIV-infected population. This paper reviews data published on HIV infection and vitamin D health in adults over the last year.

Regional fat deposition and cardiovascular risk in HIV infection: the FRAM study

Abstract HIV-infected individuals are at increased risk for cardiovascular disease (CVD) and lipodystrophy, but the relationship between regional adipose tissue (AT) depots and CVD risk is not well described. We determined regional AT volumes and CVD risk in an analysis of 586 HIV-infected and 280 control FRAM study subjects using whole-body magnetic resonance imaging (MRI) and the Framingham Risk Score (FRS). Median FRS and FRS >10% were higher in HIV than control men (4.7% vs. 3.7%, p=0.0002; 16% vs. 4%, p<0.0001). HIV and control women had similarly low FRS (1.1% vs. 1.2%, p=0.91). In controls, total AT and all regional AT depots showed strong positive correlations with FRS (p<0.001) in men and weaker positive correlations in women. Greater visceral AT (VAT) and lower leg subcutaneous AT (SAT) volumes were associated with elevated FRS in HIV subjects with a trend for upper trunk SAT. Controls in the lowest quartile of leg SAT had the lowest FRS (1.5%), whereas HIV with similarly low leg SAT had the highest FRS (4.0%, p<0.001 vs. controls). Increased VAT is associated with CVD risk, but the risk is higher in HIV-infected individuals relative to controls at every level of VAT. Peripheral lipoatrophy (as measured by leg SAT) is associated with striking increased CVD risk in HIV-infected patients even after controlling for VAT, whereas low leg SAT is associated with low CVD risk in controls.

A Novel Combination HIV Prevention Strategy: Post-Exposure Prophylaxis with Contingency Management for Substance Abuse Treatment Among Methamphetamine-Using Men Who Have Sex with Men

Methamphetamine use has been associated with HIV transmission among men who have sex with men (MSM). However, providers have been hesitant to utilize post-exposure prophylaxis (PEP) in populations of stimulant users. This single-arm, open label pilot study sought to demonstrate the safety, feasibility, and acceptability of PEP combined with the drug abstinence intervention of contingency management (CM) in methamphetamine-using MSM. HIV-uninfected MSM reporting recent methamphetamine use were recruited to a CM intervention. Those who reported a recent high-risk sexual or injection drug exposure to an HIV-infected or serostatus unknown source were initiated on tenofovir/emtricitabine (Truvada)-based PEP. Participants were followed over 3 months for infectious/biologic, behavioral, and drug use outcomes. Fifty-three participants enrolled in the study; 35 participants (66%) initiated PEP after a high-risk exposure. The median time from exposure to medication administration was 37.8 h (range 12.5-68.0 h). Twenty-five (71.4%) PEP initiators successfully completed the treatment course. Median medication adherence was 96% (IQR 57-100%), and medication was generally well tolerated. Methamphetamine abstinence during CM treatment increased PEP adherence (2% [95% CI +1-+3%]) per clean urine toxicology sample provided), and increased the odds of PEP course completion (OR 1.17, 95% CI 1.04-1.31). One incident of HIV seroconversion was observed in a participant who did not complete PEP treatment, and reported multiple subsequent exposures. Findings demonstrate that PEP, when combined with CM, is safe, feasible, and acceptable as an HIV prevention strategy in methamphetamine-using MSM.

A Randomized Trial of Raltegravir Replacement for Protease Inhibitor or Non-Nucleoside Reverse Transcriptase Inhibitor in HIV-Infected Women with Lipohypertrophy

Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m(2). After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol (p=0.04), self-reported belly size (p=0.02) and composite body size (p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm.

Bringing testing to the people – benefits of mobile unit HIV/syphilis testing in Lima, Peru, 2007–2009

Mobile unit (MU) HIV testing is an alternative method of providing healthcare access. We compared demographic and behavioural characteristics, HIV testing history and HIV prevalence between participants seeking testing at a MU vs. fixed clinic (FC) in Lima, Peru. Our analysis included men and transgender women (TW) in Lima aged ≥ 18 years old seeking HIV testing at their first visit to a community-based MU or FC from October 2007 to November 2009. HIV testing history, HIV serostatus and behavioural characteristics were analysed. A large percentage of MU attendees self-identified as transgender (13%) or heterosexual (41%). MU attendees were more likely to engage in transactional sex (24% MU vs. 10% FC, p < 0.001), use alcohol/drugs during their last sexual encounter (24% MU vs. 20% FC, p < 0.01) and/or be a first-time HIV tester (48% MU vs. 41% FC, p < 0.001). MU HIV prevalence was 9% overall and 5% among first-time testers (49% in TW and 11% in men who have sex with men [MSM] first-time testers). MU testing reached large numbers of at-risk (MSM/TW) populations engaged in unsafe sexual behaviours, making MU outreach a worthy complement to FC testing. Investigation into whether MU attendees would otherwise access HIV testing is warranted to determine the impact of MU testing.

A cross-sectional study of low HIV testing frequency and high-risk behaviour among men who have sex with men and transgender women in Lima, Peru

BackgroundIncreased HIV testing frequency among high-risk populations such as men who have sex with men (MSM) and male-to-female transgender women (TW) can lead to earlier treatment and potentially reduce HIV transmission.MethodsWe analyzed baseline survey data from 718 high-risk, young (median age 29 [interquartile range 23–35]) MSM/TW enrolled in a community-based HIV prevention trial between 2008–2009. Participants were recruited from 24 neighborhoods in and around Lima, Peru. We assessed HIV testing frequency, testing behaviour, and motivations and barriers to testing. Multivariate analysis identified correlates to prior HIV testing.ResultsOverall, 79.6% reported HIV testing within their lifetimes, however, only 6.2% reported an average of two tests per year, as per Peruvian Ministry of Health guidelines. The most commonly reported motivators for testing were to check one’s health (23.3%), lack of condom use (19.7%), and availability of free testing (14.0%), while low self-perceived risk for HIV (46.9%), fear of a positive result (42.0%), and lack of access to testing services (35.7%) were the most frequently reported barriers. In multivariate analysis, factors independently associated with HIV testing included age [adjusted prevalence ratio (APR) 1.00, 95% CI (1.00-1.01)], transgender-identification vs. gay-identification [APR 1.11, 95% CI (1.03-1.20)], history of transactional sex [APR 1.16, 95% CI (1.07-1.27)], and prior sexually transmitted infection diagnosis [APR 1.15, 95% CI (1.07-1.24)].ConclusionsAn overwhelming majority of participants did not meet the standard-of-care for testing frequency. The reported motivations and barriers to testing highlight issues of risk perception and accessibility. Our findings suggest utilizing non-traditional outreach methods and promoting HIV testing as a routine part of healthcare in Peru to encourage testing and knowledge of HIV serostatus.

A pilot study of telmisartan for visceral adiposity in HIV infection: the metabolic abnormalities, telmisartan, and HIV infection (MATH) trial.

Background Visceral adiposity in the setting of HIV infection and antiretroviral therapy (ART) is not fully understood, and treatment options remain limited. Telmisartan, an angiotensin receptor blocker and partial PPAR-γ agonist, has been shown to decrease visceral fat and improve metabolic and inflammatory parameters in HIV-uninfected subjects. Methods HIV-infected subjects with HIV-1 RNA <50 copies/mL on ART and (women/men) waist circumference >94/95 cm or waist: hip ratio >0.88/0.94 received open-label telmisartan 40 mg po daily for 24 weeks. Adipose tissue (AT) volumes were quantified by L4–L5 single slice computed tomography. Metabolic and inflammatory markers were obtained fasting. Thirty-five subjects provided 80% power to detect a 10% 24-week decrease in visceral AT (VAT, two-sided α = 0.05). Results Thirty-five subjects enrolled and completed the protocol. At entry (median or %): age 49 years, 43% female, 77% non-white, 91% non-smokers, CD4+ T cell count 590 cells/mm3, BMI 31 kg/m2. AT responses were heterogeneous, with statistically significant losses of median (IQR) total (TAT, 2.9% (−9.8, 0.7), p = 0.03) and subcutaneous (SAT, −2.7% (−9.8, 1.1), p = 0.03) AT, but not VAT (−2.7% (−20.5, 14.2), p = 0.53). Significant decreases in waist circumference and waist:hip ratio occurred (both p<0.001) without BMI or weight changes. In an exploratory analysis, significant increases in TNF-α occurred among female subjects without changes in other inflammatory or metabolic markers. No related adverse events occurred. Conclusions Telmisartan was well tolerated. Small losses of AT from all depots were observed after 24 weeks of telmisartan therapy. Further study is needed to determine whether HIV-infected patients can receive metabolic benefits from telmisartan. Trial Registration ClinicalTrials.gov NCT01088295

Switch to raltegravir decreases soluble CD14 in virologically suppressed overweight women: the Women, Integrase and Fat Accumulation Trial†

Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48‐week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV‐infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).

Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study

BACKGROUND Simplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). METHODS The STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24. RESULTS Of 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART. CONCLUSIONS Data demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.