DR. BERCOVICH: DIABETES Y HIV

Diabetes Asociada a HIV

Jhon Quin, médico consultor de Royal Sussex County Hospital, Brighton, UK.

Royal Sussex County Hospital, Brighton, UK.

 The co-existence of diabetes mellitus and HIV infection poses significant challenges for both patient and physician. This article reviews the clinical problems, the implications for treatment plans and potential confusions that can arise when managing patients who have both conditions. As a doctor I can tell you that, medically speaking, I’d rather have HIV than diabetes. Dr Max Pemberton, The Spectator, April 2014 Introduction Dr Pemberton’s quote above surprised many but reminds us that HIV-related mortality and morbidity have signifi cantly declined since the widespread use of highly active antiretroviral therapy (HAART).1 Pemberton recalls the ‘sense of crushing dread’ that physicians and the public felt during the early 1980s when faced with the, then incurable, catastrophe that was AIDS. I recall my own first referral to see someone with HIV who had developed diabetes. How to approach and communicate this new diagnosis? Here’s the wrong way: ‘Well, maybe you don’t need to worry about diabetes because…’ Times change. Today it is the concomitant diagnosis of diabetes that is to be feared in those with HIV. This double burden is a significant challenge for patients and carers. Cardiovascular complications and death due to these are now the more pressing challenge for HIV physicians and diabetologists. The DAD study has suggested that the incidence of diabetes increases with cumulative exposure to combination HAART.2 This paper reviews the impact of diabetes on those with HIV and argues for subspecialty-specifi c clinics to help care for these patients. Changes in glucose homoeostasis in HIV Insulin resistance, as opposed to insulin deficiency, is the main pathogenic factor in the development of diabetes in patients with HIV infection. Concomitant hepatitis C infection may also play a role.3 Growth hormone deficiency can be seen in HIV-infected patients and this too may be.

 ABSTRACT Author: Aconsultant physician, Royal Sussex County Hospital, Brighton, UK a factor in the development of insulin resistance along with increased accumulation of visceral adipose tissue. The virus itself may also be implicated in pancreatic dysfunction. Changes associated with HIV therapy Type 2 diabetes mellitus appears to be four times more common in HIV-infected men exposed to HAART compared with an HIV-negative cohort. The protease inhibitors or PIs (eg atazanvir, darunavir and ritonavir) have been shown to increase insulin resistance, reduce insulin secretion and interfere with glucose transporter type 4-mediated glucose transport.7 The PIs have also been shown to interfere with cellular retinoic acid-binding protein type 1 (CRAB-1) which interacts with the peroxisomal proliferator-activated receptor γ (PPARγ). The inhibition of PPARγ leads to insulin resistance and release of free fatty acids.8 A reduction in fi rst phase insulin release has been noted with some forms of HAART.9 Some nucleoside reverse transcriptase inhibitors are thought to cause metabolic abnormalities and increase the risk of diabetes,2 and combination therapy may also be an additional risk factor for its development.10 Further work is likely to help identify the individual propensities of drugs to cause these effects. There is thus the likelihood that future therapeutic regimens may need to be tailored to reduce metabolic derangement. The risks currently seem to be highest with stavudine. Other proposed abnormalities include alteration in leptin/adiponectin dynamics and mitochondrial dysfunction.11 Clearly these concerns do not mean the exclusion of HAART in patients with HIV, but awareness of the development of diabetes may lead to pharmacological ‘tweaking’ of management. HIV lipodystrophy syndrome The development of insulin resistance, hyperglycaemia and diabetes mellitus has also been linked to the HIV lipodystrophy syndrome.12 The aetiology of this condition is unknown. Most patients thought to have the syndrome have central, visceral obesity with peripheral fat wasting. Screening A reasonable case can be made for screening for diabetes mellitus in all newly presenting patients with HIV, and at 3 and 6 months after starting HAART. Equivocal results will necessitate follow-up with oral glucose tolerance testing. As yet CMJv14n6-Quin-Doherty.indd 667 19/11/14 5:58 PM CME Diabetes 668 © Royal College of Physicians 2014. All rights reserved.

 Confusions The following scenarios should be considered. > Night sweats: these may be due to nocturnal hypoglycaemia if over-insulinised. Alternatively it may be a sign of occult infection as a result of immunodefi ciency. In particular tuberculosis must be considered and excluded. > Retinal changes: diabetic retinopathy must be distinguished from cytomegalovirus retinitis. > Weight loss: this may be due to poor diabetes control or poor control of viral load. Tragically it is thought that, in Africa, many cases of type 1 diabetes are misdiagnosed as HIV. Health inequalities mean that, scandalously, all too often neither condition is treated appropriately. > Drug interactions: as highlighted earlier by choice of statin use. There are many other potential interactions of HAART and drugs used in patients with diabetes and CVD. Lessons from the politics of HIV services Services for HIV in the UK have benefi ted enormously from the sustained campaigns of informed patients and carers. There are clear lessons to be learned from this experience for those designing services for people with diabetes. Persistent lobbying and rigorous outlining of the threat that both conditions have to public health are necessary.

 ■ References:

 1 Palella FJ Jr, Delaney KM, Moorman AC et al. HIV Outpatient Study Investigators. Declining morbidity and mortality among patients with advanced immunodeficiency virus infection. N Engl J Med 1998;338:853–60. 2 De Wit S, Sabin CA, Weber R et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients. The data collection on adverse events of anti-HIV drugs (D:A:D). Diab Care 2008;31:1224–9. 3 El-Zayadi A, Anis M. Hepatitis C virus induced insulin resistance impairs response to anti-viral therapy. World J Gastroenterol 2012;18:212–24. 4 Stanley TL, Grinspoon SK. GH/GHRH axis in HIV lipodystrophy. Pituitary 2009;12:143–52. 5 Dube MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus. Clin Infect Dis 2000;31:1467–75. 6 Brown TT, Cole SR, Xiuhong Li et al. Anitretroviral therapy and the prevalence and incidence of diabetes in a multicenter AIDS Cohort study. Arch Intern Med 2005;165:1179–84. 7 Hertel J, Struthers H, Horj CB, Hruz PW. A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem 2004;279:55147–52. 8 Lee GA, Rao M, Greenfeld C. The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Respir 2004; 6:471–82. 9 Woerle HJ, Mariuz PR, Meyer C et al. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 2003;52:918–25. 10 Fleishman A, Johnsen S, Systrom DM et al. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab 2007;292:E1666–73. 11 Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active retroviral therapy using International there is no strong argument for using glycated haemoglobin as a screening tool in this situation. Treatment As per guidelines for the management of type 2 diabetes mellitus, there must be robust attempts to modify risk factors for cardiovascular disease (CVD). Dietary measures, exercise, smoking cessation, antihypertensives and lipid-lowering agents are often indicated. Simvastatin is contraindicated because of its interaction with the cytochrome P450 system.13 Rigorous screening and treatment for other concomitant infections (hepatitis C, syphilis, balanitis and vulval candidiasis) are warranted. Ease of access to dietetic, podiatry, retinal screening and diabetes nurse specialist services all argue for a joint HIV/ diabetes service. Drug treatment to allay hyperglycaemia is similar to that used in the non-HIV population with the following caveats. > Metformin: this can reduce insulin resistance in HIV patients.14 The risks of lactic acidosis remain rare but HIV physicians try to avoid HAART combinations that, in theory, could exacerbate this possibility. Diarrhoea and faecal incontinence are well recorded with metformin and so the drug may be inappropriate in HIV patients with coexistent gastrointestinal pathology. > Thiazolidinediones: theoretically these drugs could be of benefi t in those with lipodystrophy, given the known effects that they have on promoting adipocyte differentiation; however, clinical reports have been disappointing.15 Psychological challenge/education Acknowledgement of these twin burdens as a signifi cant challenge for the patient is key to the educational approach. We must not underestimate the psychological impact of a second diagnosis with serious prognostic import. Pill burden can be a signifi cant issue. Depression is common in patients with both conditions and should be treated accordingly

New-onset type 2 diabetes mellitus among patients receiving HIV care at Newlands Clinic, Harare, Zimbabwe: retrospective cohort analysis

Abstract

Objective

To assess the incidence and associated factors of Type 2 Diabetes Mellitus (T2DM) among people living with HIV (PLHIV) in Zimbabwe.

Methods

We analysed data of all HIV-infected patients older than 16 years who attended Newlands Clinic between March 1, 2004 and April 29, 2015. The clinic considers patients whose random blood sugar is higher than 11.1 mmol/l and which is confirmed by a fasting blood sugar higher than 7.0 mmol/l to have T2DM. T2DM is also diagnosed in symptomatic patients who have a RBS >11.0 mmol/l. Risk factors for developing T2DM were identified using Cox proportional hazard models adjusted for confounding. Missing baseline BMI data were multiply imputed. Results are presented as adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI).

Results

Data for 4,110 participants were included: 67.2% were women; median age was 37 (IQR: 31–43) years. Median baseline CD4 count was 197 (IQR: 95–337) cells/mm³. The proportion of participants with hypertension at baseline was 15.5% (n=638). Over a median follow-up time of 4.7 (IQR: 2.1–7.2) years, 57 patients developed T2DM; the overall incidence rate was 2.8 (95% CI: 2.1–3.6) per 1000 person-years of follow-up. Exposure to PIs was associated with T2DM (HR: 1.80, 95% CI: 1.04–3.09). In the multivariable analysis, obesity (BMI>30 kg/m²) (aHR=2.26, 95% CI: 1.17–4.36), age >40 years (aHR=2.16, 95% CI: 1.22–3.83) and male gender, (aHR=2.13, 95% CI: 1.22–3.72) were independently associated with the risk of T2DM. HIV-related factors (baseline CD4 cell count and baseline WHO clinical stage) were not independent risk factors for developing T2DM.

Conclusion

Although the incidence of T2DM in this HIV cohort was lower than that has been observed in others, our results show that risk factors for developing T2DM among HIV-infected people are similar to those of the general population. HIV-infected patients in sub-Saharan Africa need a comprehensive approach to care that includes better health services for prevention, early detection and treatment of chronic diseases especially among the elderly and obese.

  

Active HCV Replication but Not HCV or CMV Seropositive Status Is Associated With Incident and Prevalent Type 2 Diabetes in Persons Living With HIV

De Luca, Andrea MD^*,†; Lorenzini, Patrizia BSc^‡; Castagna, Antonella MD^§; Puoti, Massimo MD^‖; Gianotti, Nicola MD^§; Castelli, Francesco MD, PhD^¶; Mastroianni, Claudio MD^#; Maggiolo, Franco MD^**; Antinori, Andrea MD^††; Guaraldi, Giovanni MD^‡‡; Lichtner, Miriam MD, PhD^§§; d'Arminio Monforte, Antonella MD^‖‖; for the ICONA Foundation Study

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 August 2017 - Volume 75 - Issue 4 - p 465–471

Objective: To analyze the association between chronic hepatitis C virus (HCV) and cytomegalovirus (CMV) infections with type 2 diabetes in HIV-infected patients.

Methods: HIV-1-infected patients enrolled in ICONA, a prospective cohort study involving 42 tertiary care centers in Italy, were selected with the following characteristics: for the diabetes incidence analysis, all patients with available CMV IgG results (first available test = baseline) and without type 2 diabetes were followed until onset of type 2 diabetes, last available clinical follow-up, death or September 30, 2014, whichever occurred first; for the prevalence analysis, all ICONA patients were analyzed at their last follow-up visit. Main outcome measures were the new onset of type 2 diabetes (incidence analysis) and the prevalence of type 2 diabetes at last follow-up.

Results: During 38,062 person-years of follow-up (PYFU) in 6505 individuals, we observed 140 cases of incident type 2 diabetes (Incidence rate 3.7, 95% CI: 3.1 to 4.3, per 1000 PYFU). In a multivariable Poisson regression model, HCV-antibody (Ab)+/HCV RNA+ patients [adjusted relative rate versus HCV-Ab negative 1.73 (95% CI: 1.08 to 2.78)] but not HCV Ab+RNA− or CMV IgG+ patients, had a higher risk of diabetes. Among 12,001 patients, 306 (2.5%) prevalent cases of type 2 diabetes were detected. HCV Ab+RNA+ status was independently associated with prevalent diabetes (adjusted Odds Ratio vs HCV Ab− 2.49; 95% CI: 1.08 to 5.74), whereas HCV-Ab+/HCV RNA− and CMV IgG+ status were not.

Conclusion: In HIV-infected individuals, active HCV replication but not prior HCV exposure or latent CMV infection is associated with incident and prevalent type 2 diabetes.