Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is a retrovirus that infects and destroys specific lymphocytes (CD4+ T-helper cells), monocytes, and dendritic cells. The virus enters the body through disrupted mucosal barriers and via contact with body fluids. Over time, morbidity and mortality occur due to opportunistic infections and malignancies that result from compromised CD4+ cell-mediated immunity. Worldwide, approximately 38 million people are infected with HIV.
Acquired immunodeficiency syndrome (AIDS) is defined as (1) a CD4+ count of < 200 cells/L (the normal range is > 400 cells/L) in an HIV-infected individual, or (2) the presence of an opportunistic, AIDS-defining illness. An opportunistic illness may be an infection, but other conditions such as malignancy, HIV wasting, and encephalopathy are also AIDS-defining conditions, brought on by severe immunosuppression.
Examples of opportunistic infections include candidiasis of the esophagus; intestinal cryptosporidiosis; cytomegalovirus infections; herpes simplex infections of the esophagus, oropharynx, genitalia, or skin; Mycobacterium avium complex infection; Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii); and toxoplasmosis of the brain. Tuberculosis is the leading cause of death for individuals living with HIV.
HIV transmission occurs by sexual (including oral) intercourse, intravenous drug use with shared needles, vertical transmission through the placenta, breastfeeding, blood products, and open wound-fluid interchange. Perinatal infection can occur if the mother’s viral load is not suppressed, with transmissibility rising in direct proportion to the HIV viral load.
Acute HIV seroconversion is often asymptomatic, although patients may manifest nonspecific symptoms that can be difficult to differentiate from other viral infections. For example, the initial presentation may be a flu-like or mononucleosis-like syndrome (headache, fever, chills, cough, myalgia, adenopathy, sore throat). A generalized rash may appear that typically develops within 48-72 hours of the onset of fevers and lasts 5-8 days. Patients may also have aseptic meningitis that appears to be of viral origin upon examination of spinal fluid. Patients then return to their baseline state of health for 2-10 or more years, while the virus replicates within T cells and the CD4+ cell count declines.
As the number of CD4+ T cells declines, patients become more susceptible to infection and neoplasm. Once the CD4+ cells are sufficiently depleted, patients experience multiple opportunistic infections and malignancies that may affect any organ system. These include:
Pulmonary: Pneumocystis jiroveci pneumonia, tuberculosis, pulmonary Kaposi sarcoma, or fungal pulmonary disease (e.g., coccidioidomycosis, histoplasmosis).
Neurologic: Bell’s palsy, dementia, meningitis (aseptic and cryptococcal), syphilis, histoplasmosis, coccidioidomycosis, cerebritis, spinal cord dysfunction (due to syphilis or viral infections such as cytomegalovirus), or peripheral neuropathy.
Gastrointestinal: Esophagitis due to candidiasis, herpes simplex virus, or aphthous ulcerations; diarrhea due to cytomegalovirus (colitis, proctitis) or parasites, including cryptosporidiosis and Giardia lamblia; liver disease due to hepatitis C coinfection or hepatitis B coinfection, HIV-associated biliary tract disease, or cholangiopathy due to pneumocystis, cryptosporidiosis, cytomegalovirus, or Mycobacterium avium complex.
Dermatologic: Kaposi sarcoma (due to herpesvirus 8), herpetic lesions, molluscum contagiosum caused by the poxvirus.
Hematologic: B-cell lymphomas, thrombocytopenia.
Genitourinary: Human papillomavirus-associated cervical cancer. Human papillomavirus-associated malignancies, including anal cancer in the men who have sex with men (MSM) population, are also AIDS-defining conditions.
High-risk sexual intercourse. This includes both anal and vaginal intercourse. Factors associated with increased risk of transmission include male-male sexual intercourse, lack of circumcision (female-to-male transmission), coinfection with a sexually transmitted infection (particularly those that cause genital ulcers), and sexual intercourse during menses (female-to-male transmission).
Injection drug use. Drug injection is a particularly important source of the HIV epidemics in Eastern Europe, Asia, and the Middle East and accounts for approximately 6% of new HIV diagnoses in the US each year. For this reason, needle exchange programs have been implemented in several countries, resulting in decreased HIV transmission.
Perinatal transmission. Children are at risk in utero, during delivery (especially during vaginal delivery), and during breastfeeding. Prior to the initiation of antiretroviral therapy during pregnancy, transmission rates were as high as 30%, and cesarean sections were recommended. However, through suppression of the HIV viral load with antiretroviral therapy during pregnancy, transmission rates have markedly declined, and elective cesarean deliveries are no longer recommended. When HIV antiretroviral regimens are prescribed through pregnancy and delivery and given to newborns for 4-6 weeks, transmission rates can be less than 1%. Avoidance of breastfeeding in HIV-positive mothers is recommended when replacement feeding is available. When replacement feeding is unavailable, breastfeeding in combination with antiretroviral therapy is preferred.
Occupational exposure. Risk of transmission after splashes of blood or other body fluids to intact skin or mucous membranes is very low. Risk of transmission after an accidental needle stick exposure is less than 1%. Hollow-bore needles have a greater risk of transmitting HIV, compared with solid-bore needles used for suturing, piercing, etc.
Blood transfusion. Since 1985, the screening of blood products has significantly decreased the HIV transmission rate. The risk of transmission due to blood transfusion is now about 1 in 2 million units of blood.
Early diagnosis is important because early antiretroviral treatment enhances immunologic responses to HIV and delays progression to AIDS.
Several tests are available to identify HIV infection:
Rapid HIV-1/2 antibody detection kits provide results within 30 minutes and are most useful as a preliminary screening test in nonclinical settings. Several home testing kits are now available. Supplemental laboratory-based testing using the algorithm below should confirm all positive results of rapid tests.
Step 1. Combination HIV-1/HIV-2 antibody/p24 antigen screening enzyme immunoassay (EIA) ("4th generation immunoassay") is the initial laboratory diagnostic test recommended for detection of HIV and is positive in > 99% of cases within 6 weeks of infection.
Step 2. HIV-1/HIV-2 antibody differentiation immunoassay is performed on all specimens positive by the initial combination screening assay above, in order to differentiate HIV-1 from HIV-2 infection.
Step 3. HIV RNA detection by nucleic acid amplification test is the most sensitive test for identifying primary HIV infection and is used to resolve indeterminate results on the HIV-1/HIV-2 antibody differentiation assay above. It is also used to follow disease progression by detecting the viral load. During acute infection, the viral load can be greater than 500,000 copies/mL, but it then falls significantly.
Western blot or immunofluorescence assays as well as isolated p24 antigen testing are historic assays that are no longer part of the recommended diagnostic algorithm.
CD4+ count is used to monitor the progression of HIV infection: the lower the value, the greater the risk for opportunistic infections. For example, Pneumocystis jiroveci pneumonia is more likely to occur with a CD4+ count of < 200 cells/L, while cytomegalovirus infections occur with CD4+ counts < 75 cells/L. Abnormal complete blood count is common and may reveal leukopenia, lymphocytosis, thrombocytopenia, and/or anemia.
After diagnosis, the CD4+ count and viral load are followed regularly to evaluate the progression of infection and the need for prophylaxis of opportunistic infections. It is important to screen for other sexually transmitted infections, including gonorrhea, chlamydia, syphilis, herpes simplex virus, and hepatitis A, B, and C. Tuberculosis and toxoplasmosis screening are also done at the initial visit.
HIV genotyping and phenotyping should be done to assess drug resistance. Individuals on antiretroviral therapy can still transmit resistant HIV.
Routine follow-up is important, with complete blood count, creatinine, renal function tests, and liver function tests to evaluate for medication side effects. Other diagnostic tests are indicated, as necessary, for diagnosis of opportunistic infections (e.g., chest x-ray, viral titers).
Antiretroviral therapy has significantly improved the prognosis for HIV, reducing progression to AIDS, opportunistic infections, hospitalizations, and death. Most patients will achieve full viral suppression within several months of beginning therapy. Antiretroviral therapy is indicated for all HIV-infected persons, regardless of CD4+ count. Evidence suggests that early initiation of antiretroviral therapy regardless of CD4+ count delays the onset of AIDS and reduces risk of transmission. Physicians and patients may consider enrollment in a clinical trial to take advantage of experimental therapies. Due to the complexity of treatment and the ever-changing landscape of antiretrovirals, HIV-infected individuals should be treated by clinicians with specific expertise in HIV care.
Common classes of antiretroviral agents include:
Nucleoside reverse transcriptase inhibitors (e.g., zidovudine, tenofovir, tenofovir alafenamide, didanosine, lamivudine, emtricitabine, stavudine, abacavir).
Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine, delavirdine, rilpivirine).
Protease inhibitors (e.g., indinavir, lopinavir, atazanavir, fosamprenavir, darunavir).
Pharmacokinetic enhancer ("booster") (e.g., ritonavir, cobicistat).
Integrase strand transfer inhibitor (or "integrase inhibitor") (e.g., dolutegravir, elvitegravir, raltegravir).
Fusion inhibitors (e.g., enfuvirtide).
CCR5 antagonist (e.g., maraviroc).
A regimen combining three antiretroviral medications, known as antiretroviral therapy, is used to avoid or delay drug resistance. Strict adherence is essential to avoid resistance. In an HIV-infected individual who has not previously been treated with antiretroviral therapy, a typical initial regimen would include two nucleoside reverse transcriptase inhibitors along with a third antiretroviral agent such as a non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor, or an integrase inhibitor.
All HIV-infected individuals should undergo HIV genotyping (i.e., antiretroviral resistance testing) following confirmation of diagnosis in order to inform selection of antiretroviral therapy regimen. Once antiviral therapy begins, the CD4+ count and viral load should be assessed regularly, along with medication resistance studies if there is evidence of viral progression.
Pre-exposure prophylaxis is indicated for people who are at high risk of contracting HIV but who are not yet infected. Pre-exposure prophylaxis treatment consists of taking a daily pill (tenofovir and emtricitabine). When taken daily, pre-exposure prophylaxis has shown to be about 92% effective at preventing HIV infection in high-risk individuals.
Post-exposure prophylaxis involves the use of antiretroviral medication within 72 hours or less of an exposure to HIV to prevent seroconversion.
Vaccinations and HIV
Vaccines are important preventive measures for individuals with HIV. Expert recommendations may vary based on the CD4 count, but at minimum, all HIV patients should receive vaccines for influenza, pneumococcal pneumonia, and hepatitis B. Other vaccines may be indicated, such as the tetanus, diphtheria, and acellular pertussis vaccine, as well as the meningococcal, varicella, human papilloma virus, and COVID-19 vaccines. Personalized recommendations should be made in consultation with an HIV specialist.
Regular exercise can reduce some antiretroviral therapy side effects. Aerobic exercise can help reduce total body and visceral fat and normalize lipid profiles in HIV-infected patients. Combinations of aerobic exercise and progressive resistive exercise (done for at least 20 minutes ≥ 3 times per week) may also lead to significant reductions in depressive symptoms and improvements in cardiopulmonary fitness, muscle strength, and quality of life.
Psychological treatment can be helpful. Some evidence suggests that stress reduces resistance to opportunistic infections in HIV-positive persons. In women with HIV, psychosocial stress has been shown to greatly increase the risk of developing progressive, persistent HPV-related squamous intraepithelial neoplasia. Greater stress was also shown to account for about half of the variance in recurrence of genital herpes lesions. Various psychological approaches are significantly associated with decreased viral load, higher CD4+ cell counts, and greater adherence to antiretroviral therapy. HIV-positive men assigned to cognitive-behavioral stress management or active coping interventions were shown to have greater numbers of CD4+ cells.
HIV and COVID-19
The World Health Organization reported in 2021 that HIV positive status was a significant risk factor for severe COVID-19 disease and related mortality. Surveillance data from 37 countries showed mortality rates as high 23% for HIV-positive individuals requiring admission to the hospital with COVID-19. The most common underlying conditions in these individuals were hypertension (33%), diabetes (23%), and obesity (17%).
Nutritional issues in HIV infection relate to macronutrient and energy needs, lipid disorders, and micronutrient adequacy.
Macronutrient and Energy Needs
HIV infection can trigger a chronic inflammatory wasting syndrome with increases in protein turnover and energy requirements. HIV wasting syndrome is defined as an unintentional 10% weight loss accompanied by chronic diarrhea, fever, or weakness.
A grossly undernourished state in HIV-positive patients at the start of antiretroviral therapy (as indicated by a low body mass index [BMI]) is a strong and independent predictor of mortality. In asymptomatic HIV-infected adults, energy requirements are estimated to increase by 10%, and during symptomatic HIV and AIDS, energy needs increase by approximately 20-30%. Increased energy needs are offset to some degree by the reduction in physical movement due to illness. Some degree of wasting is common, despite antiretroviral therapy. Accordingly, patients should not be encouraged to lose significant amounts of weight unless they are obese. Studies have consistently shown that HIV-infected patients with a BMI > 25 have higher CD4+ cell counts, decreased risk of viral progression, and decreased mortality compared with their thinner (BMI < 25) counterparts. This relationship may be explained by the elevated leptin production in heavier persons, which supports CD4+ cell proliferation. Loss of excess weight may be helpful, however, for overweight patients on antiretroviral therapy whose risk factors for heart disease and diabetes have been elevated by these drugs.
Protein intake is associated with lean body mass, loss of which is strongly associated with disease progression and death in HIV-positive persons. A review of available evidence noted that protein requirements of 1-1.4 g per kg of body mass are indicated for maintenance of lean mass, and 1.5-2 g per kg for anabolism. Nevertheless, a Cochrane review concluded that nutritional (i.e., protein-calorie) supplementation did not significantly alter clinical, anthropometric, or immunological outcomes in HIV patients when compared with placebo.
Diet and Lipid Disorders
Diet therapy is recommended for both primary prevention and control of dyslipidemia in HIV patients on antiretroviral therapy. Protease inhibitors exacerbate the effects of HIV infection on lipid metabolism and insulin resistance, leading to lipodystrophy. Medication-related decreases in the catabolism of both apoB and nuclear sterol regulatory element binding proteins in the liver and adipocytes bring about increases in fatty acid and cholesterol biosynthesis, insulin resistance, and lipodystrophy. As a result, 10-50% of patients on protease inhibitors have hypercholesterolemia, and 40-80% of these individuals have hypertriglyceridemia. However, non-nucleoside reverse transcriptase inhibitors, in spite of raising total and low-density lipoprotein cholesterol and triglycerides, also increase high-density lipoprotein by approximately 40%, depending on the specific type.
Antiretroviral therapy has resulted in a significant reduction in HIV-associated cardiomyopathy, due to a reduction in opportunistic infections. On the other hand, exposure to protease inhibitors nearly triples the risk for acute myocardial infarction when compared with individuals not taking these drugs. However, a systematic review indicated a significantly greater risk for myocardial infarction with only certain kinds of nucleoside reverse transcriptase inhibitors (abacavir) and protease inhibitors (lopinavir, indinavir).
A review of cardiovascular risk in HIV patients concluded that a combination of dyslipidemia, insulin resistance, inflammation, and impaired fibrinolysis (and in some persons, diabetes as well) occurs in HIV infection. Nutritional interventions that improve the parameters listed above would therefore seem a prudent measure. Plant-based diets, especially those that include plant sterols, viscous fibers, soy protein, and nuts, have been found to help manage dyslipidemia and prevent or reduce insulin resistance. The high fiber content of these diets can also aid fibrinolysis and reduce inflammation.
Plant-based diets have not been widely tested in HIV patients. A meta-analysis of studies of adult HIV patients using conventional diet therapies (AHA Step I and Step II diets) and treatment with fish oil found significant reductions in triglyceride levels with each treatment compared with control conditions, but no significant reduction in cholesterol levels.
Probiotic supplements. HIV enteropathy causes pronounced CD4+ T-cell loss, increased intestinal permeability, and microbial translocation, which are implicated in disease progression. Controlled trials have demonstrated the ability of probiotics and synbiotics (combinations of pre- and probiotics) to significantly increase CD4+ count.
Preliminary evidence suggests that higher intakes of fruits, vegetables, and juices increase T-cell proliferation or reduce CD38+/CD8+ count, a marker of disease progression. Fruits and vegetables also provide many nutrients that are deficient in persons with HIV and help reduce the oxidative stress that may occur as a side effect of antiretroviral therapy.
Low blood concentrations of many micronutrients are common in HIV-positive individuals, and are associated with disease progression and increased mortality. A meta-analysis found that, in individuals not on antiretroviral therapy, micronutrient supplementation was associated with an almost 40% reduction in disease progression when compared with controls. Clinical trials using multivitamin supplements (combinations of B vitamins and vitamin C, vitamin A, selenium, and zinc; or vitamin A, vitamin D, zinc, N-acetyl cysteine, and other minerals) have demonstrated that these raise CD4 count and reduce morbidity and mortality. In African children, vitamin A supplementation reduced mortality by half.
Selenium appears to be particularly important for HIV patients, given that the selenium-dependent enzyme TrxR1 is a negative regulator of an HIV-encoded (Tat) protein required for viral replication. The ability of selenium to improve the health status of HIV patients who are deficient or low in this mineral has been confirmed. However, questions remain regarding whether the effects seen in clinical trials of selenium supplementation (e.g., reduced frequency of opportunistic infections and increase in CD4 count, with a lack of increase in viral load during the trial period) are the result of optimizing selenium status within the normal range, or the result of a pharmacologic effect.
Vitamin D deficiency is associated with both HIV/AIDS progression and mortality, and increases the risk of mother-to-child transmission by 46% and the risk of death in newborns by 61%. Evidence regarding the ability of vitamin D supplementation to affect immune parameters in HIV patients is limited, and further studies are needed.
A systematic review found that zinc supplementation reduced the incidence of opportunistic infection in HIV patients in general and immunological failure in adults (defined as a drop in CD4 counts to < 200 cells/mm3). However, viral load, mortality, and mother-to-child transmission of HIV and fetal outcomes were not significantly changed.
See Coronary Heart Disease chapter.
Nutrition consultation to assess nutritional requirements.
What to Tell the Family
HIV infection is not currently curable but is manageable with antiretroviral therapy. Progressive immunosuppression and life-threatening, opportunistic infections can be greatly diminished through a combination of medications and a healthful diet. Emotional support from family, friends, and community, plus psychotherapeutic treatments, may provide additional immune benefits for persons with HIV. Family members can encourage healthy lifestyle changes through diet, regular exercise, and abstinence from tobacco and alcohol.
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