HIV
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What is HIV?
HIV is a virus that gradually attacks the immune system, which is our body’s natural defence against illness. If a person becomes infected with HIV, they will find it harder to fight off infections and diseases. The virus destroys a type of white blood cell called a T-helper cell and makes copies of itself inside them. T-helper cells are also referred to as CD4 cells.1
There are many different strains of HIV – someone who is infected may carry various different strains in their body. These are classified into types, with lots of groups and subtypes. The two main types are:
- HIV-1: the most common type found worldwide
- HIV-2: this is found mainly in Western Africa, with some cases in India and Europe.
Basic facts about HIV
- HIV stands for human immunodeficiency virus.
- If left untreated, it can take around 10 to 15 years for AIDS to develop, which is when HIV has severely damaged the immune system.
- With early diagnosis and effective antiretroviral treatment, people with HIV can live a normal, healthy life.
- HIV is found in the following body fluids of an infected person: semen, blood, vaginal and anal fluids and breast milk.
- HIV cannot be transmitted through sweat, saliva or urine.
- According to UK statistics, the most common way for someone to become infected with HIV is by having anal or vaginal sex without a condom.2
- You can also risk infection by using infected needles, syringes or other drug-taking equipment (blood transmission), or from mother-to-child during pregnancy, birth or breastfeeding.3
What is AIDS?
AIDS is a syndrome caused by the HIV virus.4 It is when a person’s immune system is too weak to fight off many infections, and develops when the HIV infection is very advanced. This is the last stage of HIV infection where the body can no longer defend itself and may develop various diseases, infections and if left untreated, death.
There is currently no cure for HIV or AIDS. However, with the right treatment and support, people can live long and healthy lives with HIV. To do this, it is especially important to take treatment correctly and deal with any possible side-effects.
Basic facts about AIDS
- AIDS stands for acquired immune deficiency syndrome.
- AIDS is also referred to as advanced HIV infection or late-stage HIV.
- Someone with AIDS may develop a wide range of other health conditionsincluding: pneumonia, thrush, fungal infections, TB, toxoplasmosis and cytomegalovirus.
- There is also an increased risk of developing other life-limiting conditions, including cancer and brain illnesses.
- CD4 count refers to the number of T-helper cells in a cubic millilitre of blood. When a person’s CD4 count drops below 200 cells per millilitre of blood, they are said to have AIDS
Human Immunodeficiency Virus (HIV) InfectionHuman immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain infections and cancers. Initial infection may cause nonspecific febrile illness. Risk of subsequent manifestations—related to immunodeficiency—is proportional to the level of CD4+ lymphocytes. HIV can directly damage the brain, gonads, kidneys, and heart, causing cognitive impairment, hypogonadism, renal insufficiency, and cardiomyopathy. Manifestations range from asymptomatic carriage to AIDS, which is defined by serious opportunistic infections or cancers or a CD4 count of < 200/?L. HIV infection can be diagnosed by antibody, nucleic acid (HIV RNA), or antigen (p24) testing. Screening should be routinely offered to all adults and adolescents. Treatment aims to suppress HIV replication by using combinations of ? 3 drugs that inhibit HIV enzymes; treatment can restore immune function in most patients if suppression of replication is sustained.
Retroviruses are enveloped RNA viruses defined by their mechanism of replication via reverse transcription to produce DNA copies that integrate in the host cell genome. Several retroviruses, including 2 types of HIV and 2 types of human T-lymphotropic virus (HTLV—see HTLV Infections), cause serious disorders in people.
HIV-1 causes most HIV infections worldwide, but HIV-2 causes a substantial proportion of infections in parts of West Africa. In some areas of West Africa, both viruses are prevalent and may coinfect patients. HIV-2 appears to be less virulent than HIV-1.
HIV-1 originated in Central Africa in the first half of the 20th century, when a closely related chimpanzee virus first infected humans. Epidemic global spread began in the late 1970s, and AIDS was recognized in 1981.
In 2015, about 36.9 million people, including 2.6 million children, were living with HIV worldwide, according to the World Health Organization (WHO [ 1]). Almost half do not know they are infected. In 2014, 1.2 million died, and 2 million were newly infected. Most new infections (95%) occur in the developing world, > 1/2 are in women, and 1/7 are in children <15 yr. In many sub-Saharan African countries, incidence is declining markedly from the very high rates of a decade before.
In the US in 2012, 1.2 million people aged ? 13 yr were estimated to be living with HIV infection; HIV was undiagnosed in about 12.8% of them. About 50,000 new cases are estimated to occur each year in the US. In 2010 (the most recent year for these data), there were 47,500 new cases. Almost two thirds of new infections occurred in gay and bisexual men, and 8 times as many cases occurred in black/African Americans as in whites
Symptoms and Signs
Initial HIV infection
Initially, primary HIV infection may be asymptomatic or cause transient nonspecific symptoms (acute retroviral syndrome).
Acute retroviral syndrome usually begins within 1 to 4 wk of infection and usually lasts 3 to 14 days. Symptoms and signs are often mistaken for infectious mononucleosis or benign, nonspecific viral syndromes and may include fever, malaise, fatigue, several types of dermatitis, sore throat, arthralgias, generalized lymphadenopathy, and septic meningitis.
After the first symptoms disappear, most patients, even without treatment, have no symptoms or only a few mild, intermittent, nonspecific symptoms for a highly variable time period (2 to 15 yr).
Symptoms during this relatively asymptomatic period may result from HIV directly or from opportunistic infections. The following are most common:
Asymptomatic, mild-to-moderate cytopenias (eg, leukopenia, anemia, thrombocytopenia) are also common. Some patients experience progressive wasting (which may be related to anorexia and increased catabolism due to infections) and low-grade fevers or diarrhea.
Worsening HIV infection
When the CD4 count drops to < 200/?L, nonspecific symptoms may worsen and a succession of AIDS-defining illnesses develop (see AIDS-Defining Illnesses).
Evaluation may detect infections that do not typically occur in the general population, such as Mycobacterium sp, P. jirovecii, Cryptococcus neoformans, or other fungal infections.
Infections that also occur in the general population but suggest AIDS if they are unusually severe or frequently recur include herpes zoster, herpes simplex, vaginal candidiasis, and Salmonella septicemia.
In patients with HIV infection, certain syndromes are common and may require different considerations (see Table: Common Manifestations of HIV Infection by Organ System). Some patients present with cancers (eg, Kaposi sarcoma, B-cell lymphomas) that occur more frequently, are unusually severe, or have unique features in patients with HIV infection (see Cancers Common in HIV-Infected Patients). In other patients, neurologic dysfunction may occur.
Diagnosis
HIV infection is suspected in patients with persistent, unexplained, generalized adenopathy or any of the AIDS-defining illnesses (see AIDS-Defining Illnesses). It may also be suspected in high-risk patients with symptoms that could represent acute primary HIV infection.
Diagnostic tests
Detection of antibodies to HIV is sensitive and specific except during the first few weeks after infection. Enzyme-linked immunosorbent assay (ELISA) to detect HIV antibodies is highly sensitive, but rarely, results are false-positive. Positive ELISA results are therefore confirmed with a more specific test such as Western blot. However, these tests have drawbacks:
Newer point-of-care tests using blood or saliva (eg, particle agglutination, immunoconcentration, immunochromatography) can be done quickly (in 15 min) and simply, allowing testing in a variety of settings and immediate reporting to patients. Positive results of these rapid tests should be confirmed by standard blood tests (eg, ELISA with or without Western blot) in developed countries and repetition with one or more other rapid tests in developing countries. Negative tests need not be confirmed.
If HIV infection is suspected despite negative antibody test results (eg, during the first few weeks after infection), the plasma HIV RNA level may be measured. The nucleic acid amplification assays used are highly sensitive and specific. HIV RNA assays require advanced technology, such as reverse transcription–PCR (RT-PCR), which is sensitive to extremely low HIV RNA levels. Measuring p24 HIV antigen (p24 is a core protein of the virus) by ELISA is less sensitive and less specific than directly detecting HIV RNA in blood.
Monitoring
When HIV is diagnosed, the following should be determined:
Both are useful for determining prognosis and monitoring treatment.
The CD4 count is calculated as the product of the following:
Using the numbers above, the CD4 count (4000 x 0.3 x 0.2) is 240 cells/mL, or about 1/3 of the normal CD4 count in adults, which is about 750 ±250/?L.
Plasma HIV RNA level (viral load) reflects HIV replication rates. The higher the set point (the relatively stable virus levels that occur after primary infection), the more quickly the CD4 count decreases and the greater the risk of opportunistic infection, even in patients without symptoms.
Staging
HIV-related conditions
Diagnosis of the various opportunistic infections, cancers, and other syndromes that occur in HIV-infected patients is discussed elsewhere in TheManual. Many have aspects unique to HIV infection.
Hematologic disorders (eg, cytopenias, lymphomas, cancers) are common and may be usefully evaluated with bone marrow aspiration and biopsy. This procedure can also help diagnose disseminated infections with MAC, M. tuberculosis, Cryptococcus, Histoplasma, human parvovirus B19, P. jirovecii, and Leishmania. Most patients have normocellular or hypercellular marrow despite peripheral cytopenia, reflecting peripheral destruction. Iron stores are usually normal or increased, reflecting anemia of chronic disease (an iron-reutilization defect). Mild to moderate plasmacytosis, lymphoid aggregates, increased numbers of histiocytes, and dysplastic changes in hematopoietic cells are common.
HIV-associated neurologic syndromes can be differentiated via lumbar puncture with CSF analysis and contrast-enhanced CT or MRI (see Table:Common Manifestations of HIV Infection by Organ System and elsewhere in The Manual).
Screening for HIV
Screening antibody tests should be offered routinely to adults and adolescents, particularly pregnant women, regardless of their perceived risk. For people at highest risk, especially sexually active people who have multiple partners and who do not practice safe sex, testing should be repeated every 6 to 12 mo. Such testing is confidential and available, often free of charge, in many public and private facilities throughout the world.
Prognosis-Risk of AIDS, death, or both is predicted by the
For every 3-fold (0.5 log10) increase in viral load, mortality over the next 2 to 3 yr increases about 50%. HIV-associated morbidity and mortality vary by the CD4 count, with the most deaths from HIV-related causes occurring at counts of < 50/?L. However, with effective treatment, the HIV RNA level decreases to undetectable levels, CD4 counts often increase dramatically, and risk of illness and death falls but remains higher than that for age-matched populations not infected with HIV.
Another, less well-understood prognostic factor is the level of immune activation as determined by evaluating the expression of activation markers on CD4 and CD8 lymphocytes. Activation, which may be caused by leakage of bacteria across the HIV-damaged colonic mucosa, is a strong prognostic predictor but is not used clinically because this test is not widely available and antiretroviral therapy changes the prognosis, making this test less important.
A subgroup of HIV-infected people (termed long-term nonprogressors) remains asymptomatic with high CD4 counts and low HIV levels in the blood without antiretroviral treatment. These people usually have vigorous cellular and humoral immune responses to their infecting HIV strain as measured by assays in vitro. The specificity of this effective response is shown by the following: When these people acquire a superinfection with a second strain of HIV to which their immune response is not as effective, they convert to a more typical pattern of progression. Thus, their unusually effective response to the first strain does not apply to the second strain. These cases provide a rationale for counseling HIV-infected people that they still need to avoid exposure to possible HIV superinfection through unsafe sex or needle sharing.
Cure of HIV infection has not been thought possible, and thus lifelong drug treatment is considered necessary. However, several recent cases of HIV-infected infants who were treated briefly with antiretroviral therapy after diagnosis and who have remained HIV-negative for many months after stopping treatment suggests that cure is possible in this setting.
Control
Prevention
Key Points
- HIV infects CD4+ lymphocytes and thus interferes with cell-mediated and, to a lesser extent, humoral immunity.
- HIV is spread mainly by sexual contact, parenteral exposure to contaminated blood, and prenatal and perinatal maternal transmission.
- Frequent viral mutations combined with immune system damage significantly impair the body’s ability to clear the HIV infection.
- Various opportunistic infections and cancers can develop and are the usual cause of death in untreated patients.
- Diagnose using antibody tests, and monitor by measuring viral load and CD4 count.
- Treat with a combination of antiretroviral drugs, which can restore immune function to nearly normal in most patients if they take the drugs consistently.
- Use postexposure and preexposure antiretroviral prophylaxis when indicated.
- Give primary prophylaxis against opportunistic infections based on the CD4 count.
Treatment
- Combinations of antiretroviral drugs (antiretroviral therapy [ART], sometimes called highly active ART [HAART] or combined ART [cART])
- Chemoprophylaxis for opportunistic infections in patients at high risk
Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic drugs have been developed, treatment with ART is now recommended for nearly all patients. A few exceptional patients can control their HIV strain without treatment, maintaining very low blood levels of HIV and normal CD4 counts for long periods. These patients may not require ART, but studies to determine whether treating them is helpful have not been done and would be difficult because there are few of these patients and they would likely do well not taking ART for long periods.
Antiretroviral therapy: General principles
ART aims to
- Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL)
- Restore the CD4 count to a normal level (immune restoration or reconstitution)
A poor CD4 count response is more likely if the CD4 count at initiation of treatment is low (especially if < 50/?L) and/or the HIV RNA level is high. However, marked improvement is likely even in patients with advanced immunosuppression. An increased CD4 count correlates with markedly decreased risk of opportunistic infections, other complications, and death. With immune restoration, patients, even those with complications that have no specific treatment (eg, HIV-induced cognitive dysfunction) or that were previously considered untreatable (eg, progressive multifocal leukoencephalopathy), may improve. Outcomes are also improved for patients with cancers (eg, lymphoma, Kaposi sarcoma) and most opportunistic infections.
ART can usually achieve its goals if patients take their drugs > 95% of the time. However, maintaining this degree of adherence is difficult. Partial suppression (failure to lower plasma levels to undetectable levels) may select for single or multiple accumulated mutations in HIV that make viruses partially or completely resistant to a single drug or entire classes of drugs. Unless subsequent treatment uses drugs of other classes to which HIV remains sensitive, treatment is more likely to fail.
Patients with most acute opportunistic infections benefit from early ART (initiated during the management of the opportunistic infection). However, for some opportunistic infections, such as tuberculous meningitis or cryptococcal meningitis, the evidence suggests that ART should be delayed until the first phase of antimicrobial therapy for these infections is finished.
The success of ART is assessed by measuring plasma HIV RNA levels every 8 to 12 wk for the first 4 to 6 mo or until HIV levels are undetectable and every 3 to 6 mo thereafter. Increasing HIV levels are the earliest evidence of treatment failure and may precede a decreasing CD4 count by months. Maintaining patients on failing drug regimens selects for HIV mutants that are more drug-resistant. However, compared with wild-type HIV, these mutants appear less able to reduce the CD4 count, and failing drug regimens are often continued when no fully suppressive regimen can be found.
If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available drugs. Genotypic and phenotypic assays are available and can help clinicians select a new regimen that should contain at least 2 and preferably 3 drugs to which the HIV strain is more susceptible. The dominant HIV strain in the blood of patients who are taken off antiretroviral therapy may revert over months to years to the wild-type (ie, susceptible) strain because the resistant mutants replicate more slowly and are replaced by the wild type. Thus, if patients have not been treated recently, the full extent of resistance may not be apparent through resistance testing, but when treatment resumes, strains with resistance mutations often reemerge from latency and again replace the wild-type HIV strain.
Classes of antiretrovirals
Multiple classes of antiretrovirals are used in ART (see Table: Antiretroviral Drugs). One class inhibits HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.
- Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.
- Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.
- Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.
- Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.
- Integrase inhibitors prevent HIV DNA from being integrated into human DNA.
Some Adverse Effectsb | |||
Entry (fusion) inhibitors | |||
Enfuvirtide | T-20 | 90 mg sc bid | Hypersensitivity reactions, local injection site reactions, peripheral neuropathy, risk of bacterial pneumonia, insomnia, loss of appetite |
Maraviroc(CCR5 inhibitor) | — | 150–600 mg bid, depending on other drugs used | Myocardial ischemia or infarction |
Integrase inhibitors | |||
Dolutegravir | — | 50 mg once/day | Headache, insomnia |
Elvitegravir | — | 150 mg once/day | |
Remedy
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