Primary Care of Patients With HIV Infection

Human immunodeficiency virus (HIV) infection has evolved from a disease that was predictably fatal to a chronic disease that can effectively be managed with contemporary antiretroviral therapy (ART) regimens. As a result of improved HIV care, the life expectancy in persons with HIV infection is similar to that in the general population. ^{[1, 2]} HIV treatment guidelines recommend ART in all HIV-infected individuals, regardless of CD4 cell count. ^{[3, 4]}

Diagnosis of HIV infection soon after infection and early initiation of ART are highly important, as both have been associated with improved CD4 count gains during ART, a reduced risk for acquired immunodeficiency syndrome (AIDS) development, reduced T-cell activation, and greater vaccine responsiveness. ^{[5, 6]}  There are only a few exceptions (such as in cases of cryptococcal meningitis or tuberculosis) in which initiation of ART should be delayed. ^[7]

Primary care providers (PCPs) are experiencing new challenges and opportunities in HIV infection. Understanding HIV risk factors and groups at highest risk is important, as targeted testing by PCPs plays an important role in diagnosing new HIV cases and preventing transmission to others.

In 2020, an estimated 30,635 new HIV infections occurred in the United States. ^[8]  Although this represents a 17% decrease from 2019, in which 36,585 new infections were diagnosed, this likely is due to disruptions in clinical care services, patient hesitancy in accessing clinical services, and shortages of HIV testing reagants/materials in the setting of the COVID-19 pandemic, which raises concerns regarding underdiagnosis. ^[8]  Most (71%) of these occurred in men who have sex with men. Blacks/African Americans and Hispanics/Latinos accounted for 69% of HIV diagnoses, although they comprised only 31% of the US population. ^[8]

In addition to being on the front line for both HIV diagnosis and prevention, PCPs increasingly are involved in the co-management of HIV-infected patients with an HIV specialist. ^[9] PCPs provide expertise in preventive care and management of chronic conditions, such as cardiovascular disease, osteoporosis, and renal disease, which increasingly have become important for aging individuals with HIV infection.

Caring for patients with HIV is challenging, and PCPs need to be mindful of special issues that affect this population, including the medical, psychological, and social challenges involved, along with the stigma associated with the disease. The most important aspect of patient care is education, which should include empowering patients with basic knowledge about HIV infection, methods of transmission, progression, prognosis, and prevention. A multidisciplinary approach that uses the special skills of nurses, pharmacists, nutritionists, social workers, and case managers is desirable. ^{[7, 10]}

HIV infection can manifest in the following 3 main ways:

1. An acute viral illness seen in the initial weeks of infection

2. Immunologically mediated processes related to host responses to chronic viral infection

3. Opportunistic diseases

Acute retroviral syndrome was first described in 1985 by Cooper and colleagues as an acute mononucleosislike syndrome. ^[11]

The incidence is not precisely known. A prospective study of homosexual men showed a 55% incidence in 22 subjects who became antibody-positive compared with 21% in 44 nonconverting control individuals. ^[12] The onset of illness is between 2 and 6 weeks after viral transmission and is believed to correlate with peak viremia, often in excess of 1 million viral copies/mL. Symptoms and associated frequency are as follows:

• Fever: 96%

• Lymphadenopathy: 74%

• Pharyngitis: 70%

• Rash: 70%

• Myalgia or arthralgia: 54%

• Diarrhea: 32%

• Headache: 32%

• Nausea and vomiting: 27%

• Hepatosplenomegaly: 14%

• Weight loss: 13%

• Thrush: 12%

• Neurologic symptoms: 12%

• Oral or genital ulcers: 5%-20% ^[3]

In some cases, HIV infection is initially diagnosed when the patient presents with an AIDS-defining illness. These include the following ^[13] :

• Bacterial infections, multiple or recurrent
• Candidiasis
• Cervical cancer, invasive
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal
• Cytomegalovirus (CMV) disease
• Encephalopathy, HIV related
• Herpes simplex virus (HSV) - Chronic ulcers or bronchitis, pneumonitis, or esophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal
• Kaposi sarcoma
• Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex
• Lymphoma - Burkitt (or equivalent term), immunoblastic (or equivalent term), or primary
• Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or extrapulmonary
• Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary
• Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
• Pneumocystis jiroveci pneumonia (PJP)
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia, recurrent
• Toxoplasmosis of the brain
• Wasting syndrome attributed to HIV

A comprehensive history and physical exam, which includes current and prior medical history, HIV-related history, medication/allergy/social/family history, detailed review of systems, and a complete physical exam, should be performed. ^[7]

Specific HIV-related information should include the date of the first positive HIV test, the date of the most recent HIV care visit, the lowest CD4 count, and the highest viral load. All prior ART regmens, including years of use, prior side effects, and reasons for switching, should be recorded. Immunization status should also be discussed and addressed. 

Patients should be asked about allergies and medication intolerances, including questions about hypersensitivity reactions to antibiotics and ART. All current medications should be addressed, including dietary and herbal supplements, as some have interactions with ART. 

Providers also should ask about partners, sexual practices (including all exposure sites, condom use, and contraceptive use), past sexually transmitted infections (STIs), HIV status of the partner(s), and whether the partner(s) have been informed of the patient's HIV status. Health-related behaviors, such as tobacco abuse, alcohol use, drug use, and diet and exercise, should be discussed and counseled appropriately. 

Reviewing family history of conditions such as malignancies, neurologic disorders, osteoporosis, atherosclerosis, and coronary artery disease is important, especially as patients with HIV are living longer.

A complete physical examination should be performed on the initial visit. The general examination should assess for any signs of wasting or lipodystrophy that may have occurred from prior antiretroviral use. Attention should be given to any rashes and any generalized or localized lymphadenopathy that may be present. Genitourinary and anorectal examinations should focus on the presence of any ulcers, warts, masses, or discharge. Complete cardiopulmonary and neurologic examinations also should be done. 

According to the Department of Health and Human Services (DHHS) HIV treatment guidelines ^[3] and the HIV Medicine Association of the Infectious Diseases Society of America guidelines for primary care of HIV infection, ^[7]  the laboratory tests listed below are useful in monitoring and maintaining the health of patients with HIV infection.

CD4 count and percentage

CD4 count and percentage are important for HIV staging and prognosis. They help guide initiation of ART, indicate risk for opportunistic infections, and guide initiation of prophylaxis.

Guidelines recommend checking the CD4 count upon entry into care and repeating every 3 to 6 months in patients who have not initiated ART. In patients on ART, CD4 count monitoring also should be performed every 3 to 6 months during the first 2 years of ART or if viremia develops while the patient is on ART.

After 2 years on ART with consistently suppressed viral load, the CD4 count can be tested every 12 months in those with a CD4 count between 300 and 500 cells/µL; CD4 count monitoring is optional in those with CD4 count over 500 cells/µL. ^[7]

HIV viral load

HIV RNA viral load is used to monitor efficacy of ART. Viral load has a high sensitivity in the setting of acute HIV infection when antibody results still may be negative. The goal of ART is to suppress virus to undetectable levels, usually less than 20 or 50 copies/mL; however, the threshold for prevention of sexual transmission of HIV is considered to be less than 200 copies/mL. ^[7]  This is the concept of Undetectable = Untransmittable, or U=U. ^[3]

Guidelines recommend evaluating viral load upon entry into care and upon ART initiation or modification.

After initiation of ART, viral load should be rechecked within 1 month, and then again every 4 to 8 weeks until suppression is achieved. Afterwards, the viral load typically is measured every 3 to 4 months to confirm maintanence of suppression. However, in adherent patients with consistently suppressed viral load and stable immunologic status for more than 2 years, monitoring can be extended to every 6 months. ^[7]

HLA B*5701

HLA B*5701 screening should be initiated before beginning abacavir therapy, as patients who are positive for the HLA B*5701 haplotype are at high risk for abacavir hypersensitivity reaction. ^[7]

Complete blood cell count

Perform a complete blood cell (CBC) count upon entry into care and monitor every 3 to 6 months and upon ART initiation or modification.

Complete metabolic profile

Perform a complete metabolic profile upon entry into care and monitor every 3 to 6 months and upon ART initiation or modification.

Urinalysis

Perform a urine analysis for proteinuria and hematuria upon entry into care and at ART initiation or modification and monitor every 12 months (or every 6 months in patients on tenofovir disoproxil fumarate or tenofovir alafenamide). More frequent monitoring may be indicated in patients with evidence of kidney disease. 

Lipid profile

Perform a lipid profile upon entry into care, at ART initiation or modification, and every 6 to 12 months if the prior measurement was abnormal or normal, respectively. ^[7]

Glucose or glycated hemoglobin A1C

Perform glucose (preferably fasting) testing or glycated hemoglobin A1c (HbA1c) upon entry into care and upon ART initiation or modification, and annually thereafterwards. In patients with diabetes mellitus, a HbA1c should be monitored every 6 months. ^[7]

Glucose-6-Phosphate Dehydrogenase (G6PD):

Perform G6PD screening before beginning therapy with oxidant drugs such as dapsone, primaquine, or sulfonamides in patients with a predisposing racial or ethnic background. ^[7]

Hepatitis A virus antibody

Screening for evidence of immunity to hepatitis A virus (HAV) should be obtained with HAV immunoglobulin (IgG). If HAV IgG antibody test is negative, vaccination should be offered to the patient. ^[7]

Hepatitis B virus infection status

The patient’s hepatitis B virus (HBV) infection status should be tested upon entry into care, including measurement of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and antibody to hepatitis B total core antigen (anti-HBc or HBcAb). If HBsAg is positive, HBV viral load should be obtained. Those who are susceptible to infection should be vaccinated against HBV. ^[7]

Hepatitis C virus antibody

Testing for hepatitis C virus (HCV) antibody should be performed upon entry into care and annually thereafter or whenever incident HCV infection is suspected in those at high risk. If positive, confirm result with HCV RNA. ^[3]

Toxoplasma gondii IgG

Testing for ​Toxoplasma gondii IgG should be done shortly after diagnosis with HIV or upon entry into care to screen for latent infection with T. gondii. If T. gondii IgG results are negative, repeat if the patient becomes symptomatic or when the CD4 count is below 100 cells/µL. If the result is positive, initiate prophylaxis when the CD4 count is below 100 cells/µL. ^[13]

Tuberculosis screening

Screen for Mycobacterium tuberculosis upon entry into care via either a tuberculin skin test (TST) or an interferon-gamma release assay (IGRA). Patients with positive test results should be treated for latent tuberculosis (TB) infection after acute TB has been excluded. Patients who are close contacts of persons with infectious TB should be treated for latent M tuberculosis infection regardless of their TST or IGRA results, age, or prior courses of TB treatment after the diagnosis of active TB has been excluded. Repeat testing in patients with advanced HIV disease who initially had negative TST or IGRA results but subsequently experienced an increase in CD4 cell counts to greater than 200 cells/µL on ART, as they may now be able to mount a positive immune reaction. ^[7]  Annual testing for persons with HIV is not recommended unless high risk exists for repeated or continued exposure to persons with active TB disease. ^[13]

Chest radiography

Baseline chest radiographs should be obtained in all patients with a positive TST or IGRA result to rule out active TB disease. A normal chest radiograph along with a negative symptom screen (including absent cough of any duration) usually is sufficient to rule out active TB disease. ^[14]

Cervical and anal cancer screening

Cervical cancer screening in women

Individuals with a uterus aged 21 to < 30 years should have a cervical Papanicolaou test (Pap test) performed within 1 year of the onset of sexual activity or at 21 years of age, whichever comes first. In patients with HIV between 21 and 29 years and who have a uterus, a cervical Pap test should be done at diagnosis, if not done within the last year. In persons with a uterus aged 30 years or older, a cervical Pap test should be performed at diagnosis, either alone or with combination human papillomavirus (HPV) testing. If a cervical Pap test yields normal findings, repeat after 6 months and then annually thereafter. If the findings are abnormal, further evaluation should be performed as indicated with repeat Pap test in 1 year, colposcopy, or biopsy. ^[7]

Anal cancer screening

HIV-infected men and women with HPV infection are at increased risk for anal dysplasia and cancer, particularly men who have sex with men (MSM). Anal cancer is the fourth most common cause of cancer in patients with HIV infection or AIDS. ^[15]  Anal cytologic screening (anal Pap test) is recommended in all persons with a history of receptive anal intercourse, abnormal cervical Pap test results, or genital warts. ^[7]

Anal cytology is a reasonable predictor of anal intraepithelial neoplasia (AIN), but there is poor correlation between cytology and histologic grade. ^[15] Unfortunately, no randomized controlled trials have documented the value of AIN screening to date. Thus, the recommendation to perform anal Papanicolaou tests relies mostly on the histologic similarity between the cervix and the anus, and the significant benefits of cervical cytology screening in reducing the incidence of cervical cancer. If abnormal or atypical cells are noted on anal cytology, high-resolution anoscopy should be performed with biopsy of abnormal areas, and appropriate therapy should be pursued based on biopsy results. 

Serum testosterone

HIV-infected men are at risk for hypogonadism. Obtain a morning serum testosterone level in cisgender male patients with loss of libido, erectile dysfunction, evidence of reduced bone mineral denisty or fragility fractures, hot flashes, or sweats. ^[7]

Syphilis screening

Perform syphilis screening upon entry into care and at least annually in sexually active HIV-infected persons and frequent screening (every 3 to 6 months) in those considered high risk. A lumbar puncture should always be performed in patients with a reactive syphilis serology who have neurologic or ocular symptoms or signs (irrespective of past syphilis treatment) and in those who experience serologic treatment failure (in those whose nontreponemal titers failed to decrease fourfold after appropriate treatment or whose titers increase fourfold if re-infection is ruled out). Screening for syphillis should occur least annually after initial screening, or every 3 to 6 months thereafter in those with multiple partners, a history of condomless intercourse, or a history of sex in conjunction with drug use. ^[7]

Screening for STIs

Anyone who has a vagina or cervix should be screened for trichomoniasis, and those aged 25 years or younger should be screened for gonorrhea and chlamydial infection. People of all genders should be screened for gonorrhea and chlamydia infection at initial presentation and then annually if at risk for infection. Retesting in 3 months is indicated in persons found to be positive for gonorrhea and chlamydial infections and those found to be positive for trichomoniasis on initial screening, owing to high reinfection rates. STIs should be screened for at least annually after initial screening or every 3 to 6 months thereafter, depending on the population, reported behaviors, the presence of other STIs in the patient or their partner(s), and the prevalence of STIs in the community. All persons who have vaginal sex should be screened for trichomonas annually. ^[7]

Herpes viruses

Patients at lower risk for CMV infection should be tested for latent CMV infection with an anti-CMV IgG test upon initiation of care. Patients who do not have evidence of immunity to varicella should receive postexposure prophylaxis with VariZIG as soon as possible (but within 96 hours) after exposure to a person with active varicella or herpes zoster (shingles). Varicella primary vaccination may be considered in HIV-infected, VZV-seronegative persons aged 18 years or above with CD4 cell counts at or above 200 cells/µL. ^[16]

Measles, Mumps, and Rubella

All patients with HIV born in or after 1957 should be tested for immunity against measles, mumps, and rubella (MMR) by measuring antibodies. MMR vacine should be given in this population who have not recieved the vaccine or do not have immunity to MMR. ^[7]

Pregnancy testing

All individuals of child-bearing potential should have a pregnancy test upon initiation or resumption of care. 

Minimizing the risk for vaccine-preventable illnesses is an important component of primary care in HIV-infected individuals. Immunization recommendations in the setting of HIV infection are summarized below.

Haemophilus influenzae type B vaccine

Administer to asplenic patients and those with history of recurrent Haemophilus infections.

Hepatitis A vaccine

Administer to susceptible MSM, as well as others with indications for hepatitis A virus vaccine. Revaccinate in 6 to 12 months for Havrix or 6 to 18 months for Vaqta. The vaccine also is available in combination with the hepatitis B vaccine as Twinrix, administered as 3 or 4 doses. Serologic response should be checked 1 month after completion of series, and nonresponders should be revaccinated.

Hepatitis B vaccine

Administer to patients without evidence of past or present hepatitis B infection. Engerix-B or Recombivax HB is given at 0, 1, and 6 months. The vaccine also is available in combination with the hepatitis A vaccine as Twinrix, administered as 3 or 4 doses. Anti-HBV surface Ab titers should be checked 1 month after completion of vaccine series; if titer is 10 IU/mL or less, then revaccinate. Higher-dose booster or series may be considered in nonresponders. Heplisav, which is a recombinant vaccine approved in November 2017, is approved for those aged 18 years and older. ^[17]

Human papillomavirus vaccine

The quadrivalent HPV vaccination should be given to all persons with HIV between the ages of 9 and 26 years in a 3-dose series. Those with HIV aged 27 to 45 years who were not vaccinated or who were inadequately vaccinated should be offered the vaccination series. ^[7]   

Influenza vaccine

Yearly inactivated influenza vaccine is recommended; do not use live attenuated intranasal vaccine.

Pneumococcal vaccine

All patients with CD4 count above 200 cells/µL should receive a dose of PCV13 (Prevnar 13), followed by a dose of PPV23 (Pneumovax) at least 8 weeks later. If previously vaccinated with PPV23, give PCV13 at least 1 year after PPV23. A second PPV23 dose is recommended 5 years after the first PPV23 dose.

Polio vaccine

Oral polio vaccine (OPV) is contraindicated. Inactivated polio vaccine (IPV) should only be given if indicated. Administer 3 doses over 6 to 12 months for primary immunization.

Tetanus toxoid

Indications are same as for patients without HIV infection. Dose is Td, 0.5 mL IM; Tdap, 0.5-0.75 mL IM as per package insert. Substitute 1-time dose of Tdap vaccine at time of next booster, then Td every 10 years. Precautions should be observed with pregnancy. Td may be administered during the second or third trimester or may be deferred during pregnancy with administration of Tdap postpartum.

Measles, mumps, and rubella

Live vaccine is contraindicated for use in patients with severe immunosuppression (CD4 count < 200 cells/µL). Administer to all nonimmune persons with CD4 counts of 200 cells/µL or more.

Varicella zoster vaccine (VZV)

Live vaccine is contraindicated in patients with severe immunosuppression (CD4 count < 200 cells/µL). Consider for HIV-infected, VZV-seronegative persons with CD4 counts of 200 cells/µL or more. If vaccination results in infection with attenuated virus, treat with acyclovir. Susceptible household contacts of susceptible HIV-infected individuals should be vaccinated. Avoid exposure to VZV. If someone without immunity to VZV is exposed to VZV, administer varicella-zoster immune globulin (VZIG) as soon as possible (but within 96 hours).

Meningococcal conjugate vaccine

The CDC's Advisory Committee on Immunization Practices (ACIP) recommends routine immunization with meningococcal conjugate vaccine (serogroups A, C, W, and Y; Menactra or Menveo) for persons aged 2 months or older with HIV infection. HIV-infected children younger than 2 years should receive the vaccine in accordance with the age-appropriate, licensed, multidose schedule (ie, Menveo at age 2, 4, 6, and 12 months). Persons aged 2 years or older with HIV infection who have not been previously vaccinated should receive a 2-dose primary series of MenACWY conjugate vaccine (Menactra or Menveo). Persons aged 2 years or older with HIV infection who have been previously vaccinated with 1 dose of meningococcal conjugate vaccine should receive a booster dose at the earliest opportunity, provided at least 8 weeks have elapsed since the previous dose, and then continue to receive boosters at the appropriate intervals throughout life. ^[18]

The system-specific infections listed below are of concern when treating patients with HIV.

Central nervous system

A common symptom is headache. Some infectious causes include but are not limited to cryptococcal meningitis, neurosyphilis, tuberculous meningitis, progressive multifocal leukoencephalopathy, toxoplasmic encephalitis, CMV meningoencephalitis, other encephalitis, other meningitis (bacterial, fungal, viral), coccidioidomycosis, and histoplasmosis.

Eyes

Infections that can affect the eye include HSV, herpes zoster virus (HZV), syphilis, CMV retinitis (CD4 count < 100/µL), Toxoplasma retinochoroiditis, and cryptococcal chorioretinitis.

Ears

Unilateral and bilateral sensorineural hearing loss may be caused by HIV infection involving the CNS and syphilis, among others.

Nose and sinus

Sinusitis, allergic rhinitis, nasal lesions, and nasal obstruction are common.

Oral cavity

Most common is oral candidiasis (CD4 cell count < 200/µL). Other causes include angular cheilitis, oral hairy leukoplakia, Kaposi sarcoma, and HSV.

Gastrointestinal

Some common symptoms are dysphagia and odynophagia, infectious causes of which include candidal esophagitis, CMV, HSV, Kaposi sarcoma, MAC, and histoplasmosis. Another presenting symptom is nausea and vomiting, which is a common side effect of many anti-retrovirals (ARVs) but can sometimes be a sign of opportunistic infections.

Diarrhea also is a common symptom. Noninfectious causes such as adverse effects of ARVs, specifically protease inhibitors (PIs), are common. Infectious causes of diarrhea (occurring at any CD4 count) include viruses such as Norwalk virus, viral hepatitis, herpes enteritis, Salmonella, Shigella, Campylobacter, E coli O157:H7, Giardia lamblia, E histolytica, and C difficile. Other infectious causes of chronic diarrhea (occurring at CD4 cell counts < 300 cells/µL) include microsporidia, cryptosporidia, Isospora, MAC, and CMV (at CD4 counts < 50 cells/µL).

Lymphatic system

Causes of lymphadenopathy include HIV infection, persistent generalized lymphadenopathy (PGL), mononucleosis, EBV, MAC, TB, CMV, secondary syphilis, toxoplasmosis, histoplasmosis, other fungal diseases, immune reconstitution inflammatory syndrome (IRIS) involving various infections, and others.

Pulmonary

Infections occurring at any CD4 count include TB and influenza, among others. Infections occurring at CD4 500 cells/µL or less include recurrent bacterial pneumonia, pulmonary Mycobacterium pneumonia (nontuberculous). Those occurring at CD4 200 cells/µL or less include PJP, Cryptococcus neoformans pneumonia or pneumonitis, and disseminated or extrapulmonary TB. At CD4 100 cells/µL or less, pulmonary Kaposi sarcoma and toxoplasma pneumonitis can occur. At CD4 50 cells/µL or less, disseminated histoplasmosis, disseminated coccidioidomycosis, CMV pneumonitis, disseminated MAC, disseminated Mycobacterium (nontuberculous), Aspergillus pneumonia, and Candida pneumonia can occur.

Genitourinary

Vaginitis is a common symptom. Infectious causes include bacterial vaginosis (BV), candidiasis, trichomoniasis, pelvic inflammatory disease (PID), urinary tract infection, condyloma, HSV, chlamydia, and gonorrhea.

Dermatologic

Rash probably is the most common symptom. During routine workup, possible drug-induced rash should be excluded. The 2 main ARVs that cause rash are nevirapine and abacavir. Nevirapine can cause a mild rash; moderate to severe rash with or without hepatitis requires discontinuation. Rash due to abacavir may occur in isolation or as part of the abacavir hypersensitivity reaction. 

The comorbidities listed below may require management.

Abnormalities of body fat distribution

This is a recognized complication of ARVs. Lipohypertrophy has variably been associated with PIs and with nucleoside reverse transcriptase inhibitors (NRTIs). Lipoatrophy most commonly is associated with NRTIs, specifically stavudine, didanosine, and zidovudine. Once body shape changes occur, they cannot be reliably reversed, and switching to an NRTI-sparing regimen can slowly improve limb fat in patients with lipoatrophy, but does not help patients with lipohypertrophy.

Dyslipidemia

Treatment involves a multimodal approach, incorporating diet changes, exercise, lipid-modifying drug therapy, and, potentially, changes to ART. New lipid management guidelines were released by the American College of Cardiology/American Heart Association ^[19] in November 2013, which emphasize global risk assessment rather than treat-to-cholesterol targets.

If pharmacologic intervention is indicated for LDL reduction, HMG-CoA reductase inhibitors are the first-line treatment. Note that significant drug interactions occur between most statins and both PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). PIs increase serum levels of most statins and increase risk for side effects (eg, rhabdomyolysis). Of all statins, pravastatin is least affected. Atorvastatin, if used, should be started at a low dose and titrated upward. Lovastatin and simvastatin are contraindicated; rosuvastatin and fluvastatin have not been as well studied. Most NNRTIs decrease levels of statins, and higher doses may be needed. The other classes of ARVs do not have recognized interactions with statins.

For treating hypertriglyceridemia, fibrates are the first-line drug option.

Other drugs such as niacin can worsen insulin resistance and cause hepatotoxicity; bile acid sequestrants should be avoided because they can interfere with the absorption of other drugs.

Hyperglycemia/ Diabetes mellitus

Patients taking ARVs, especially certain PIs and NRTIs, have an increased risk for hyperglycemia and diabetes mellitus. The incidence of new-onset hyperglycemia among patients with HIV on ART has been reported as about 5%, on average. Criteria for the diagnosis of diabetes mellitus defined by the American Diabetes Association (ADA) include fasting glucose level of ≥ 126 mg/dL, a 2-hour plasma glucose level of ≥ 200 mg/dL during an oral glucose tolerance tested conducted with a standard loading dose of 75 grams, or a HbA1c value of ≥ 6.5%. ^[20]  A lower HbA1c threshold of 5.8% has also been suggested, as this cutoff has been associated with better sensitivity and specificity for patients on ART. ^[21] However, the ADA recommends against the use of HbA1c to diagnose diabetes in persons with HIV on ART, instead preferring the use of the plasma glucose criteria. ^[7]  Patients with HIV and diabetes mellitus should have an HgA1c level monitored every 6 months, with a HbA1c goal of < 7%. ^[7]

Coronary heart disease risk

The incidence is increased up to 2- to 3-fold in individuals with HIV. A number of studies suggest that inflammation and immune activation due to uncontrolled HIV infection likely contribute to atherosclerosis. Clinicians should ask patients about coronary heart disease (CHD), CHD risk equivalents, and CHD risk factors, and address these appropriately.

Renal disease

This can occur either as a primary or as a secondary disease. Some known risk factors include CD4 count less than 200 cells/µL; HIV viremia, particularly RNA levels greater than 4,000 copies/mL; African-American race; family history of kidney disease; and use of nephrotoxins. Kidney function can be abnormal in up to 30% of individuals with untreated HIV, and HIV-associated nephropathy is a common cause of end-stage renal disease in this population. ^[7]  

Screening studies at initial HIV documentation should include urine analysis and serum creatinine. If abnormal values are detected, these should be evaluated further. Of note, selective drugs can cause acute or chronic kidney injury. These include tenofovir (acute tubular necrosis, Fanconi syndrome), indinavir (acute interstitial nephritis [AIN] and crystalluria), atazanavir (AIN and nephrolithiasis), and abacavir (AIN). Special consideration regarding dosing of ARVs should be given to patients who have chronic kidney disease or who are undergoing hemodialysis.

Osteopenia and osteoporosis

HIV infection and use of ART, particularly regimens containing tenofovir, increase the risk for premature bone loss, thereby exacerbating the risk for osteopenia and osteoporosis. ^[3] In addition, some evidence suggests that persons with ovaries who have HIV infection develop premature physiologic menopause. Baseline bone densitometry (DEXA) screening for osteoporosis is recommended in HIV-infected postmenopausal persons and others aged 50 years or older. ^[7]  Other recommendations include counseling patients about risk factors for osteopenia and osteoporosis, such as cigarette smoking and excessive alcohol use, and the importance of regular exercise and adequate intake of calcium and vitamin D.

Drug-drug interactions are a common concern. The issues involved in evaluating drug interactions are complex. This complexity is increased because ARVs, specifically PIs, NNRTIs, and the CCR5 antagonist (Maraviroc), can cause or be affected by alterations in the activity of the cytochrome P450 enzyme system in the liver.

Details on these interactions are available via the topic Common Drug Interactions with Protease Inhibitors and in published guidelines. ^[3] The physician's role is to educate patients that ARVs have a high potential for significant drug interactions. A complete medication list, including any herbal, nutritional, and dietary supplements, should be reviewed at every visit.