HIV and Diabetes

Introduction

Metabolically neutral vs. metabolically unsafe drugs

Risk factors for development of diabetes in HIV+ patients

Classification of HIV in patients with diabetes

Mechanisms of diabetes in HIV infected individuals

Screening

Diagnosis of diabetes in HIV

Evaluation of patient

Monitoring of diabetes control on patients with HIV infection

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SEMDSA 2017 Recommendations

Both HIV and diabetes are increasing epidemics and each condition influences the other

HIV itself, and the treatment of the condition, both increase the risk for the development of diabetes

The criteria for the diagnosis of diabetes in HIV-infected individuals is not different. However, HbA1C measurements may be influenced by co-morbidities and drugs, and is therefore not optimal for diagnosis.  A glucose tolerance test is preferred for diagnosis. HbA1C is suitable for diabetes monitoring

Metabolically neutral anti-retroviral drugs are preferred in patients with diabetes

Metfomin, pioglitazone, sulphonylureas and insulin are all effective in the treatment of diabetes in patients infected with HIV infection, although caution is needed with specific co-morbidities

South Africa, with a population of just over 50 million people (2017), has an HIV prevalence of 12.7%, equating to about 7.03 million people living with HIV, which is the highest in the world, and equally has the largest state funded Anti HIV Roll out programme, with approximately 3.4 million patients receiving treatment. 

This has translated into a reduction in acute complications of HIV infection and increased longevity, with lifespan increases from 52 years in males in 2002 to 60.6 years in 2016 and 56.4 years to 64.3 years for females for the same period.
This has led to an increase in the chronic metabolic complications of both HIV and highly active anti-retroviral therapy (HAART) which amongst others include dyslipidaemia, accelerated atherosclerosis, osteoporosis, insulin resistance and diabetes mellitus.

In patients treated with HAART, the prevalence of new onset diabetes mellitus is approximately 5% and that of pre diabetes up to 15%, especially in patients on protease inhibitors (PI) and certain nucleoside reverse transcriptase inhibitors (NRTI).

METABOLICALLY NEUTRAL VS. METABOLICALLY UNSAFE DRUGS

Since the last type 2 diabetes guidelines were published in 2012, the South African HIV Society has adopted new treatment guidelines in line with international guidelines. The biggest change is the so-called “test to treat” strategy whereby every HIV positive patient is initiated on HAART irrespective of their CD4 cell count or clinical condition. This means that more patients are becoming eligible for treatment. However, an even bigger positive step is the introduction of newer, safer, metabolically neutral antiretroviral drugs as illustrated below (Table I).

The newer classes which include entry inhibitors (enfurvirtide), and integrase inhibitors (raltegravir) and CCR5 inhibitors (maraviroc) are considered metabolically neutral. Therefore it is likely that more patients will live longer with safer drugs.

Table I: Classification of drug classes by metabolic profile

Metabolically neutral NRTIs	Metabolically unsafe NRTIs	Metabolically unsafe Protease Inhibitors	Metabolically neutral Protease Inhibitors
Abacavir Tenofivir Emtricitabine Lamivudine	Stavudine Didanosine Zidovudine	Indinavir Ritonavir Saquinavir Lopinavir Ritonavir	Darunavir Atazanvir

 

RISK FACTORS FOR DEVELOPMENT OF DIABETES IN HIV+ PATIENTS 

There are many factors that predispose HIV positive patients on HAART to developing diabetes. The same traditional risk factors that apply to non-HIV positive patients must still be considered.

Traditional risk factors

• Family history
• Ethnicity
• Obesity (BMI ≥25 kg/m²)
• Physical inactivity
• Previous gestational diabetes or big baby (>4 kg)
• Cardiovascular disease
• Low birth weight
• Polycystic ovary syndrome or acanthosis nigricans
• Dyslipidaemia
• Age > 45 years

HIV related risk factors

• HIV virus, viral load, CD4 count, duration of HIV infection
• Rapid weight gain after the catabolic phase (return to health phenomenon)
• Co-infection with hepatitis
• Dyslipidaemia with lipotoxicity
• Lipodystrophy
• Latrogenic

 

CLASSIFICATION OF HIV IN PATIENTS WITH DIABETES 

Three subgroups of patients with HIV and diabetes can be identified:

1. Patients with pre-existing diabetes who IV
2. Those who are diagnosed with both HIV and diabetes mellitus at the same time
3. Those who develop hyperglycaemia post-HAART initiation

 

MECHANISMS OF DIABETES IN HIV INFECTED INDIVIDUALS 

HIV viral infection: through various inflammatory mediators and cytokines, can induce a state of insulin resistance. Most cases of HIV-associated diabetes are type 2 diabetes. Auto-immune ß cell destruction has also been described.

Co–infection with hepatitis C: (HCV) has been shown to cause dysglycaemia by increasing intrahepatic tumour necrosis factor and causing hepatic steatosis. Hepatitis C positive patients above the age of 40 years are three times more likely to develop DM than those without.

Return to health phenomenon: as a patient’s general health improves, there is a rapid increase of body fat (visceral fat) instead of lean muscle mass that they would have lost during the catabolic phase of the disease. This can overwhelm the β cell secretory capacity leading to β cell failure.

Drugs (iatrogenic)

NRTI’s: These drugs can cause mitochondrial toxicity with subsequent lipoatrophy and therefore reduced uptake of triglyceride and glucose in affected tissues. Stavudine has the highest onset of diabetes relative risk per year of exposure followed by zidovudine and didanosine. This class may also cause pancreatitis.

NNRTI’s: Have not directly been implicated in the pathogenesis of diabetes. They might however induce dyslipidaemia in the form of raised triglycerides.

Protease Inhibitors: Are the biggest diabetogenic culprits, inducing hyperglycaemia by different mechanisms which include but are not limited to:

1. Reducing insulin production by between 25-50% by the β cells
2. Impairing GLUT-4 translocation to the surface of the cell membrane and therefore preventing entry of glucose into cells
3. Inhibiting PPARy receptors ane preventing adipocyte differentiation with resultant release of free fatty acids
4. Inducing lipodystrophy – the exact mechanism of lipodystrophy remains unknown with some theories implicating mitochondrial dysfunction with increased fat cell apoptosis, and others suggesting inhibition of SREBP–I activation of RXR-PPARy heterodimers in adipocytes. Clearly not one mechanism can explain its pathogenesis

 

SCREENING

1. All HIV positive patients with traditional diabetes risk factors should be screened as in non-HIV positive patients
2. HIV positive patients should be screened before initiating HAART or when changing ARV’s
3. Every 3-6 months for patients with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
4. Annually if initial glucose levels were normal at the initial screen
5. Fasting plasma glucose is preferred but standard 75 g OGTT is preferred in those with IGT or IFG with additional risk factors

 

DIAGNOSIS OF DIABETES IN HIV

The same diagnostic criteria apply as in non-HIV positive patients. Caution is advised when using HbA1C for diagnosis as it might be affected by multiple variables which include drugs (AZT), presence of anaemia, and opportunistic infections involving the bone marrow. 

Most authorities do not recommend the use of HbA_1C for diagnosis in people with HIV infection but it remains the gold standard for monitoring. The target for HbA_1C should be individualised based on the patient’s general condition.

 

EVALUATION OF A PATIENT

Initial evaluation of a patient with both HIV and diabetes mellitus includes a detailed history which amongst others includes a detailed search for infections which are common in both conditions and that includes search for tuberculosis, fungaemia,
sexually transmitted infections, urinary tract infections and presence of hypertension, renal impairment and any form of dyslipidaemia, as these need to be aggressively managed and will also influence the choice of anti HIV drugs.

Initial investigations should include:

1. Full blood count
2. Urea and creatinine with estimated GFR
3. Liver function with hepatitis screen
4. CD4 count
5. Viral load
6. HbA_1C
7. Serum lipids

Depending on the initial examination, the treating practitioner will decide on the need for further investigations, such as chest radiograph, blood or urine cultures, or any other imaging techniques.

 

MONITORING OF DIABETES CONTROL IN PATIENTS WITH HIV INFECTION

Glycaemic control in patients with both diabetes and HIV infection is no different from non-HIV infected patients; however, caution is needed in the interpretation of HbA_1C as a number of HIV-specific factors may influence this value (See: Screening and diagnosis of type 2 diabetes and Use of HbA1C for the diagnosis of type 2 diabetes).

TREATMENT OF DIABETES IN HIV INFECTED INDIVIDUALS

General Measures

1. Appropriate treatment of opportunistic infections
2. Lifestyle modification, which includes physical exercise, smoking and alcohol cessation and where available, dietary advice, taking account of BMI, desired weight and comorbidities
3. Psychosocial support and both family and community involvement where feasible
4. Reinforce compliance at every visit
5. Treatment of other cardiovascular risk factors:

• Dyslipidaemia – general measures and targets apply; the only major exception is that simvastatin is contraindicated in patients using protease inhibitors as it competes for the same Cytochrome P450 Isoenzyme. Fluvastatin and pravastatin are safer
• Hypertension – ACE Inhibitors and ARB’s (Angiotensin Receptor Blockers) need to be used with caution: captopril has been associated with the development of Kaposi’s sarcoma and enalapril may cause myalgias and diarrhoea. In addition, ARB’s may compete with other drugs that are metabolised by cytochrome P450 Isoenzymes

Glucose lowering drugs

a. Insulin sensitisers: Pioglitazone

Thiazolidinedione’s (TZDs) – Pioglitazone has a mechanism of action that is favourable in patients with HIV and diabetes. Pioglitazone may be a drug of choice in patients with lipoatrophy as it has been showed to cause fat redistribution from abdominal fat to subcutaneous fat in lipoatrophic areas. Pioglitazone should not be used with tenofovir as the risk of osteoporotic fractures increases

b. Biguanides

Metformin still remains the drug of choice for most patients with HIV. It should, however, be used with caution in patients with HIV associated enteropathy as the gastrointestinal side effects of metformin will be exaggerated. It is contraindicated in patients with HIV associated nephropathy (HIVAN), liver disease, cachectic patients and tuberculosis as the risk of lactic acidosis is markedly increased. It should not be used in conjunction with thymidine-based NRTI’s (Stavudine, didanosine) as the risk of lactic acidosis is increased due to mitochondrial toxicity. Extended release metformin is the preferred formulation of the drug

c. Insulin secretagogues

Sulphonylureas
The general principles apply as in non-HIV patients, but, caution has to be exercised in patients with cachexia who might have depleted glycogen stores and who are at increased risk of hypoglycaemia. Where possible, modified release formulations should be used

Glinides
Because of their short acting profile and lower risk of hypoglycaemia, they are suitable drugs, but are not commonly used in South Africa

d. Incretins
There is currently no data available regarding the newer classes of drugs in HIV patients with diabetes, including DPP-4 inhibitors and incretin receptor analogues

e. Insulin
Insulin remains the drug of choice for most patients with HIV and diabetes and ultimately most, if not all patients, will require insulin because of the progressive nature of the disease. Insulin has anabolic effects, reduces inflammatory markers, has no interactions with antiretroviral drugs and can be used safely in patients with renal failure (with proper titration).

Refer to general guidelines on insulin initiation and titration.
It is important to note that insulin requirements might initially be high and will later fall as glucotoxicity is reversed and infections are controlled.

CHANGING HAART

A patient who develops diabetes while on HAART with drugs that are potentially diabetogenic especially the protease inhibitors should be changed to anti-retroviral agents that are metabolically neutral See Table I above).

Author: Duma Khutsoane
Editors: Fraser J Pirie and Aslam Amod

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