Fernando Alvarez BOGNAR
The HIV landscape has changed. Some of the HIV infected individuals who caught the virus during their teens or twenties are entering middle age. Now we are faced with an aging population carrying a chronic infection. Because of antiretroviral treatment and its positive impact on outcome, it is important we now concentrate our efforts in assuring that this new aging group is managed according to standard practice appropriate for the patient's age and sex regardless of HIV status.1 The HIV care model is naturally evolving. While highly active antiretroviral therapy (HAART) is normally prescribed by specialist HIV physicians, a whole range of associated medical conditions are emerging, which require the support of professionals from family physicians to other medical specialists. This chapter is devoted to HIV management with a primary care perspective. By primary care, we refer to our attention to:
(a) Health maintenance in people living with HIV/AIDS;
(b) Management of health problems not specific to people living with HIV/AIDS but the general population;
(c) Prevention and early detection of complications in people living with HIV/AIDS.
This chapter is divided into two main sections: Firstly, the spectrum of primary care problems faced by people living with HIV/AIDS is described. This is followed by the second part that focuses on screening and prophylactic measures for reducing health risks.
In 1987, the Centers for Disease Control and Prevention (CDC) included HIV-associated wasting as an AIDS Defining Condition. Wasting was defined as an involuntary weight loss of >10% of baseline body weight plus either diarrhoea, fever, or weakness for >30 days in the absence of a concurrent illness.2 Although >10% weight loss is the cut-off used in this definition, data showed that as little as 5% weight loss was associated with increased morbidity and mortality. Today involuntary weight loss continues to be associated with lower CD4 cell counts, disease progression and death, even where access to antiretroviral treatments is not limited.3
Nutritional assessment should include: history, height, weight, body mass index, waist circumference, hip circumference, waist-hip ratio, serum albumin, vitamin B12, serum free testosterone, fasting glucose and lipid profile. In some settings bioimpedance analysis or dual energy X-ray absorptiometry (DEXA) may also be employed. Any significant change in patient's weight reflecting involuntary weight loss should be evaluated. Causes of weight loss that can be treated need to be explored in detail and excluded.
Some of the interventions studied for wasting and proven to be efficacious are: nutritional supplements plus dietary education, strength training, and different pharmacologic approaches.4 Drugs studied for wasting in HIV includes: Megestrol acetate, testosterone, anabolic steroids, growth hormone and thalidomide.
In Hong Kong, mortality attributed to diseases of the heart for 2005 was the second most common cause of death (87 cases per 100,000 population). The observation is also of relevance in HIV management. In the era of HAART, clinicians started to notice an increase of cardiovascular events in association with the use of antiretroviral drugs.5 Studies revealed that the average carotid artery IMT (intima-media-thickness) was larger in HIV patients compared to control group. An increased progression rate in HIV infected individuals was also reported.6 Administrative data reviews and prospective studies confirmed an excess risk of cardiovascular disease in HIV infected patients with diagnosis at a younger age compared with the general population.7 HIV infected patients presenting with acute coronary syndrome generally have single vessel disease at time of presentation and have been found to have higher rates of restenosis after percutaneous coronary intervention.8 Other reports suggested a higher risk for coronary heart disease in association with the use of antiretroviral therapy, with some studies pointing specifically at protease inhibitors (PI) for which a temporal correlation was shown.9,10
A yearly cardiovascular risk evaluation is recommended for patients living with HIV as part of their routine care. The Framinghan equation is still useful, but we should keep in mind that it may underestimate risk since HIV status and antiretroviral therapy are not taken into consideration. Risk assessment should include: age, tobacco smoking, dyslipidaemia, diabetes mellitus, hypertension, prior history of cardiovascular disease, family history for cardiovascular disease, and history of antiretroviral therapy. Fasting blood testing and routine blood pressure monitoring should accompany history and physical examination. Risk management should follow our assessment if a risk can be modified with the ultimate goal to decrease the estimated cardiovascular risk and by doing so reduce future cardiovascular events. It is known that tobacco cessation is one of the most cost effective interventions.
Dyslipidaemia, diabetes mellitus and hypertension may be conditions under-diagnosed and sometimes under-treated. In patients infected with HIV there is a higher incidence of diabetes when compared to the general population. On the other hand it is well known that many antiretroviral drugs cause lipid abnormalities. These metabolic abnormalities do play a role in the predisposition to coronary heart disease in the HIV infected population demanding special attention at the time of evaluating each patient.
Abnormalities of the lipid profile had been documented in HIV infected patients before HAART became available in 1996.11 Patients with HIV infection have an increase in serum triglycerides and a decrease in total and high-density lipoprotein cholesterol in correlation with disease progression. With the use of antiretroviral therapy clinicians started to experience an increased incidence of dyslipidaemia among HIV infected patients.12
In the assessment of an HIV infected patient, a fasting lipid profile should be requested at baseline. At this point of time assessment should include careful risk stratification. Fasting serum testing to include fasting lipid profile should be repeated at 3 and 6 months after the initiation of HAART and then yearly.
The US National Cholesterol Education Program Adult Treatment Panel III guidelines is a starting point for patient assessment, from which we can determinate the ideal target cholesterol for a patient based on risk stratification (Box 17.1). For the calculation of a patient's 10-year risk for cardiovascular disease we can access a risk calculator.
A strong association has been documented between the use of PI and hyperlipidaemia. Ritonavir and the combination lopinavir/ritonavir are the PIs most likely to cause lipid abnormalities. The newer PI atazanavir has been found not to be associated with dyslipidaemia. Lipid abnormalities can be detected within 2 to 3 weeks after PI is started. The association between NRTI (nucleoside reverse transcriptase inhibitor)'s and dyslipidaemia is less clear. It is known that NNRTI (non-nucleoside reverse transcriptase inhibitor)'s have less effect on lipids.
The first step in dyslipidaemia management is lifestyle modification, which involves: dietary counselling, reduction in alcohol intake, smoking cessation and recommendation to increase aerobic exercise. Unfortunately only few patients are able to comply with such recommendations to get their cholesterol on target. The second step is to consider a pharmacological intervention. For the HIV specialist, a change of the antiretroviral treatment could be considered to ameliorate adverse effects from a prescribing drug. The other option is the addition of a lipid-lowering agent if necessary.
Switching antiretroviral therapy should be left to the attending HIV physician of individual patient. If a patient is on a PI-based regimen the physician could switch within the group by selecting a PI known to have little effect on lipids (e.g. atazanavir). Another option would be to switch this patient to a non-PI regimen.
To correct cholesterol abnormalities, statins work by inhibiting the last regulated step in cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Many statins are metabolised by the cytochrome P450 enzyme system and notably the CYP3A4 isoform. Most PIs inhibit CYP3A4, ritonavir being the one that has the most potent effect. Pravastatin, fluvastatin and rosuvastatin are not metabolised by the CYP3A4 system, so pravastatin is the statin of choice followed by fluvastatin and rosuvastatin. Patients should always be started with the lowest dose and have liver enzymes closely monitored.
When treating hypertriglyceridaemia a pharmacological approach is recommended after lifestyle modifications. Triglyceride levels above 5.6 mmol/L carry an increased risk for pancreatitis. Drug therapy should be considered for these patients. Whether to make a switch in the antiretroviral regimen or to add a fibrate to bring the triglyceride level to target are the approaches to be considered.13
Abnormalities of glucose metabolism in HIV infected population were first reported in the late 1990's. A link was discovered between the use of PIs and the development of insulin resistance. The prevalence of diabetes mellitus in the HIV infected population on antiretroviral therapy is 2 to 4 folds higher that in the general population.14 On the other hand, insulin resistance has been reported to affect 30% to 90% of HIV infected patients on a PI containing regimen.
Diabetes mellitus can be diagnosed with two tests confirming a fasting glucose >7.0 mmol/L, or symptoms of diabetes in combination with a random plasma glucose >11 mmol/L. Impaired glucose tolerance is confirmed when fasting blood glucose level is between 5.5-7 mmol/L. Two hours fasting glucose tolerance test can be used for confirmation of either condition. Further testing if indicated could include the measurement of fasting insulin levels.
For HIV positive patients it is recommended to check fasting glucose at baseline, prior to antiretroviral therapy and then every 3 and 6 months, followed by yearly testing if normal. If diagnosis of diabetes is confirmed a haemoglobin A1c (HbA1c) should be checked at time of diagnosis. Follow-up HbA1c every three months is recommended to assess response to treatment and diabetes control with the goal to maintain the level below 7%.
As routine care, patients with diabetes should receive yearly eye examination, yearly foot examination, yearly measurement of microalbumin and microalbumin/creatinine ratio, blood pressure monitoring at each office visit. Routine vaccination and tobacco cessation programmes should be also offered. Preventive interventions to be considered are aspirin and the use of angiotensin-converting enzyme inhibitors according to medical indications.
If HIV infected individual is found to have glucose abnormalities we need to review current antiretroviral regimen and question if there is need to make a switch of any current antiretroviral drugs. Diabetes education is advised, and when possible this should be accomplished by providing a referral to a diabetes educator.
Lifestyle modifications with changes in diet and exercise are vital interventions in treating glucose abnormalities. As first line agents metformin or thiazolidinediones should be considered. Insulin at small doses can be added to the regimen if indicated. For patients whose diabetes is difficult to control, referral to specialist endocrinologist shall be discussed.
Changes in body fat distribution in HIV infected individuals is associated with deleterious changes in blood lipids and insulin resistance. Body fat changes are often identified in advanced HIV disease but it has also been reported in early infection. In general lipodystrophy has the following components occurring either singly or in various combinations:
(a) Lipodystrophy affecting the face and the extremities.
(b) Lipohypertrophy affecting visceral abdominal fat, neck (buffalo hump) and breast.
(c) Hypercholesterolaemia and hypertriglyceridaemia.
(d) Insulin resistance and occasionally diabetes mellitus.
There are few data available on incidence of lipodystrophy. A local study reported 20% of patients being diagnosed with lipodystrophy after 8 months of a PI containing HAART.15 With the currently available data no standard recommendations can be issued on the management of lipodystrophy. There are some data on the evaluation of different treatment approaches: the role of human growth hormone, androgens, metformin and thiazolidinediones. Diet and exercise should be included in the treatment. Careful review of the HAART regimens shall be considered and a switch be made if indicated. Potential loss on viral suppression is the main weakness of such strategy.
Osteoporosis is defined as a reduction of bone mass in association with bone architectural structure deterioration, leading to increased risk of fractures. The World Health Organization defined osteoporosis as a bone density that falls 2.5 standard deviations (SDs) below the mean for young healthy adults of the same sex and gender (T-score of -2.5 SDs). Osteopaenia is defined as a T-score between -2.5 and -1 SDs, and patients are considered to be at increased risk of osteoporosis. Validated risk factors for osteoporosis fracture are: low bone mineral density at the femoral neck, previous history of low trauma fracture, low body mass index, current smoking, steroid exposure, alcohol use, family history, older age, recurrent falls, low calcium intake and estrogen deficiency.
Osteopaenia and osteoporosis have been described in HIV-infected patients. Underlying mechanisms leading to these complications are thought to be multifactorial. A recent cohort study reported that 54.3% of the analysed HIV positive group had osteopaenia and 25.4% osteoporosis.16 HIV patients with significant risk factors for fragility fracture should be screened by DEXA and considered for treatment. Until studies are completed that address the treatment of low bone mineral density (BMD) in the HIV infected patients, it seems reasonable to pursue osteoporosis treatment strategies that have been proven to be effective in the general population. First of all, calcium and vitamin D intake should be optimised. Recommended intake for calcium is 1500 mg/day and Vitamin D 400-1000 IU/day. Studies have confirmed the safety and efficacy of bisphosphonates in the treatment of osteopaenia and osteoporosis in patients with HIV infection.17
Osteonecrosis, also known as avascular necrosis was increasingly reported in HIV patients in the 1990s, with a possible association with the use of antiretroviral therapy. In a recent study an incidence rate of 4.5/10,000 person-years was reported in the HIV infected population. Involvement of the hip accounted for 79.8% followed by the knee.18 Patients with monoarthralgia should be evaluated for the possible occurrence of avascular necrosis, especially if the hip is involved. Diagnosis can be confirmed by magnetic resonance imaging and/or scintigraphy and/or surgery. Treatment involves not bearing weight in the affected limb, pain management and orthopaedic consultation since surgery is usually needed.
In HIV/AIDS patients psychiatric disorders are prevalent and range from mood disorders, substance abuse, and personality disorders to anxiety and depression. A comprehensive psychiatric evaluation is recommended at baseline with yearly reassessment sessions, where appropriate. Mental health care should be a collaborative endeavor involving patients, primary care practitioners, psychiatrists, psychologists and social workers. All medical personnel involved in the care of HIV infected individuals should recognise and address these mental conditions in a timely manner.
Data from the Hong Kong Cancer Registry revealed that for the general population malignant neoplasms have been the number one cause of death since 1991. Screening is one of the potential effective strategies in cancer prevention and early treatment.
Cervical cancer was the fourth commonest cancer among females in Hong Kong in 2003. It accounted for about 4% of all new cancers in females for that year. Recommendation for HIV positive female is covered in Chapter 34.
Anal cancer - Overseas incidence figures of anal cancer range from 13-35 cases per 100,000 in HIV negative men having sex with men (MSM), compared to that of 23-65 per 100,000 in those HIV positive. There is a direct risk association between anal cancer and HPV. Abnormal anal cytology in women is associated with HIV status, lower CD4 cell counts, history of anal intercourse, anal HPV infection and abnormal cervical pathology.
Anal dysplasia is prevalent in the HIV positive population and the incidence of anal cancer is increasing among HIV positive patients. Anal cytology testing could be considered as a screening test. Abnormal cytology will require high resolution anoscopy with biopsy if indicated. Further prospective data are needed to recommend for or against standardised screening in the HIV positive population.
A whole range of cancers common in the general population may also occur in people living with HIV/AIDS. Breast cancer has surpassed lung cancer as the commonest cancer among females in Hong Kong since the early 1990's. Recommendations on breast cancer screening are the same as that for the general population. Cancer of colon or colorectal cancer is the second commonest cancer in Hong Kong. It accounted for about 15% of all cancer new cases in 2003. The incidence is higher among patients 50 years old and older. Prostate cancer showed the largest increase in men in the general population of Hong Kong. Screening and diagnostic tools are prostate digital rectal examination, prostate specific antigen assay (PSA). Lung cancer is the commonest cancer in men and the third commonest in women, after breast cancer and colorectal cancer in Hong Kong. Tobacco cessation and a healthy diet are highly recommended as general means of prevention. There is insufficient data to support routine screening of cancer of colon, prostate and lung in the general population. Neither is such recommendation available to HIV patients.
Sexual transmitted infections
Sexual transmitted infections are commonly found in the HIV positive population as co-infection. For this reason there is a need to establish a protocol for routine screening. In many cases testing is needed on a case by case basis based on patient own risk behaviour. Screening for HIV patients is recommended on yearly basis but it should be considered every 3 to 6 months for patients at high risk.
Syphilis. Screening for syphilis in the HIV infected patient is recommended at baseline and annually due to the high rates of co-infection - refer to Chapter 39.
N. gonorrhoeae & C. trachomatis. Urine screening, if available, (first 10-30 mL AM void) for nucleic acid amplification test (NAT) offers a convenient means for regular assessment. Other options are urethral culture (men) and cervical culture (women). Collection of anal swab and pharyngeal swab is to be considered based on patient's risk behaviour. Access to quality laboratory services is paramount in considering the introduction of screening.
Trichomonas. Wet mount screening could be collected for HIV positive women on yearly basis at time of Pap smear.
Latent tuberculosis
Routine Tuberculin Skin Test (TST), by the administration of (1-TU) RT23 purified protein derivative (PPD) using the Mantoux method is recommended for all HIV infected patients. Screening is not needed for patient with prior history of tuberculosis or prior history of positive TST. Patients with negative TST should be screened on yearly basis. A TST is considered positive when it creates an induration of 5 mm or more at 48 to 72 hours. A course of antituberculosis treatment is recommended in such cases. Appropriate treatment can reduce the chance of progression to active TB (see Chapter 27).
Prophylaxis against opportunistic infections (refer to Box 17.2)
Pneumocystis pneumonia (PCP) occurs in the immunocompromised patients and is a common AIDS defining condition in Hong Kong, typically occurring in those who are unaware of their HIV infection. In the Multicenter AIDS Cohort Study, the risk of PCP was greatly increased in HIV patients with CD4 counts of less than 200/μL, thrush or unexplained fever >2 weeks. Primary PCP prophylaxis is indicated when one's CD4 falls below 200/μL.
Toxoplasmosis. There are two levels of primary prevention of toxoplasmosis: prevention of disease acquisition and prevention of clinical disease in latently infected individuals. The route of contracting T. gondii is often via contacting infected animals or eating contaminated undercooked meats that harbor the pathogen. Behavioural prophylactic measures are described in the latter part of this chapter. All HIV positive patients should have a baseline check for IgG antibody to toxoplasma. For subjects who test negative, repeat screening might be performed yearly to look for seroconversion. The risk of developing toxoplasmosis increases in those patients with CD4 cell counts <100/μL. Primary prophylaxis against PCP provides protective effects in preventing from toxoplasmosis.
Disseminated MAC. Chemoprophylaxis against MAC is recommended for patients with CD4 count <50/μL. Before starting prophylaxis underlying MAC needs to be excluded by requesting blood cultures. The dose of azithromycin 1000 mg per week has been employed in Hong Kong. By using this dose there has been no reported breakthrough disseminated MAC infection.
Vaccination as a means of prophylaxis
Vaccination of HIV infected patients has shown to be more efficacious when administered while CD4 cells are not depleted. In order for a patient to be capable of mounting an adequate immune response, vaccination is advised while CD4 cell counts are at least above 200/μL. CD4 cell counts above 500/μL are optimal. Undetectable HIV viral load has been found to also correlate with a good immune response after vaccination.
Hepatitis B is endemic in Hong Kong. Vaccination is recommended for all HIV infected individuals with negative screening serology.
Hepatitis A (HAV) vaccination should be considered for all HIV infected patients with negative screening serology. In Hong Kong the prevalence of anti-HAV antibodies can be up to 50% in individuals 39 years old and younger; and around 94% in individuals age 50 and older. Pre-vaccination screening shall be considered as appropriate.
Because of the underlying immunodeficiency, protection from influenza is beneficial in HIV/AIDS patients. Influenza vaccination annually is indicated, in line with recommendations for other people in Hong Kong who should be receiving the vaccine.
As a live vaccine, varicella zoster (VZV) virus vaccine is not recommended for HIV infected adults. Patients who are susceptible to VZV should avoid contact with persons with chickenpox or shingles. VZIG could be administered within 96 hours of exposure to prevent infection.
The 23-valent polysaccharide pneumococcal vaccine is not routinely recommended for HIV infected patients in Hong Kong. Unlike other parts of the world, HIV associated Streptococcus pneumoniae infection is relatively uncommon locally. One randomised placebo-controlled trial in Africa reported increase in no. of cases of pneumonia among the vaccinated group. Data from the US has not shown this trend, where vaccination is a low priority recommendation for patients with CD4 cell count above 200/μL
Behavioural prophylaxis refers to the adoption of healthy behaviours conducive to a reduction of risks associated with complications which are relatively commoner in people living with HIV/AIDS. While this is beneficial to individual patient, the strategy also carries positive public health consequences by minimising similar risk to the community.
Sexual behaviour. A risk behavioural assessment is to be performed at each clinic visit. This task can be completed by using a standardised questionnaire, nurse assessment or by the clinician as part of the consultation. The goal is to educate by modifying persons' knowledge, attitudes and behaviours in order to diminish their health risks and their risk of transmitting HIV to others.
Injection drug use. HIV patients who inject drug, notably heroin, should be counselled on giving up the addiction habit. If abstinence cannot be achieved, it is important to refer for harm reduction practices (e.g. avoid needle sharing, use of clean needles). Participation in methadone maintenance is one means of reduction of risk exposure.
Pets. Cat ownership carries the risks of toxoplasmosis and other infections. A cat that is >1 year of age, in good health, kept indoors, not allowed to hunt and feed with cooked meat, carriers lower the risks. Litter boxes should be cleaned daily by an HIV-negative non-pregnant person. On the other hand, contact with reptiles should be avoided to reduce the risk of salmonellosis. Gloves should be used during the cleaning of fish tanks to reduce the risk of infection with Mycobacterium marinum. Contact with exotic pets is not recommended.
Food and water. Raw or undercooked eggs, meats, seafood and unpasteurised dairy products may contain enteric pathogens. Produce should be washed thoroughly. Cross-contamination of foods should be avoided Patients should not drink water from lakes or rivers because of the risk of protozoan infections. As a general advice, boiling of water for 1 minute will eliminate the risk of cryptosporidiosis.
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