According to the classification system used by the World Health Organization, there are four hierarchical clinical stages of HIV infections, ranging from stage 1 (asymptomatic) to stage 4 (AIDS). Patients showing at least one symptom attributed to a higher stage are assigned this higher stage. Also, they cannot be re-assigned a lower stage if symptoms are relieved by adequate treatment. This classification is to be understood as a one-way street and includes the following stages [1] [2]:

• Stage 1. Patients are asymptomatic or may have persistent generalized lymphadenopathy. They may remain in this stage for many years.
• Stage 2. This stage is also referred to as the mildly symptomatic stage. Patients tend to lose weight, although weight loss doesn't exceed 10% of their body weight. They may present with recurrent infections of the respiratory tract, including otitis media, tonsillitis, sinusitis, pharyngitis, and bronchitis. Dermatological conditions such as herpes zoster flares, papular eruptions on the skin, seborrheic dermatitis, and fungal infections of the nails may be reported. Angular cheilitis may occur repeatedly and may be accompanied by oral ulcerations.
• Stage 3. During this moderately symptomatic stage, HIV patients contract more severe infections. Systemic bacterial infections may affect the respiratory tract, the gastrointestinal and urogenital systems, muscles, joints, and bones, and possibly the central nervous system. They result in fever and diarrhea persisting for more than a month, and weight loss, which now exceeds 10% of the patient's body weight. The concurrent and recurrent development of mucocutaneous conditions such as oral candidiasis, hairy leukoplakia, acute necrotizing ulcerative stomatitis, gingivitis, and periodontitis may suggest an immune disorder and increasingly reduce the patient's quality of life. Laboratory analyses of blood samples may reveal anemia, leukopenia, and/or thrombocytopenia.
• Stage 4. Progression to this stage is associated with the development of AIDS. It may be referred to as severely symptomatic stage and includes about two dozen AIDS-defining illnesses, as follows:
  • Candidiasis of the esophagus, bronchi, trachea, or lungs (but not the mouth)
  • Cervical cancer, invasive
  • Coccidiomycosis, disseminated or extrapulmonary
  • Cryptococcosis, extrapulmonary
  • Cryptosporidiosis, chronic intestinal (lasting more than one month)
  • Cytomegalovirus disease (other than liver, spleen, and nodes)
  • Cytomegalovirus retinitis with loss of vision
  • Encephalopathy, HIV-related
  • Herpes simplex infection, chronic mucocutaneous or bronchitis, pneumonitis, or esophagitis
  • Histoplasmosis, disseminated or extrapulmonary
  • Isosporiasis, chronic intestinal (lasting more than one month)
  • Kaposi sarcoma
  • Lymphoma, Burkitt's
  • Lymphoma, immunoblastic
  • Lymphoma, primary of brain
  • Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
  • Mycobacterium tuberculosis
  • Mycobacterium, other or unspecified species, disseminated or extrapulmonary
  • Pneumocystis jiroveci pneumonia
  • Pneumonia, recurrent
  • Progressive multifocal leukoencephalopathy
  • Salmonella septicemia, recurrent
  • Toxoplasmosis of brain
  • Wasting syndrome due to HIV

Of note, the clinical stages defined for children infected with HIV differ from those described above [2]. Additional symptoms commonly observed in pediatric patients comprise persistent hepatosplenomegaly, extensive molluscum contagiosum, extensive wart virus infection, and linear gingival erythema during stage 2 of an HIV infection, as well symptomatic lymphoid interstitial pneumonitis and chronic HIV-associated lung disease, including bronchiectasis, during stage 3. Besides the majority of the aforementioned conditions, AIDS-defining illnesses to be observed in children include unexplained severe wasting, stunting, or severe malnutrition that don't respond to standard therapy. Recurrent severe bacterial infections, which are attributed to stage 3 in adult patients, are considered AIDS-defining in children.

In some cases, the aforedescribed classical course of HIV infections may be preceded by symptoms of acute HIV infection [3]. During the first 6 to 12 weeks after primary exposure to the pathogen, the virus aggressively replicates in the lymphoid tissues. This is associated with high viral loads and declining lymphocyte counts. Non-specific, constitutional symptoms may manifest before the beginning of clinical latency. They may be described as flu- or mononucleosis-like symptoms [4].

Both direct and indirect assays may be used to confirm HIV infection, and they primarily differ in their window periods [4]:

• Viral RNA may be detected as early as 1-2 weeks after the infection, with viral loads frequently exceeding 10 million copies per milliliter during acute HIV infection [3].
• Viral antigen p24 becomes detectable shortly thereafter.
• The production of antibodies may not be confirmed until >3 weeks after primary exposure.

Currently, diagnosis of HIV infection is performed with fourth generation immunoassays. These are designed to detect HIV antigen p24 as well as IgG and IgM antibodies against HIV-1 and HIV-2, and their specificity and sensitivity are >99.5%. In order to differentiate between HIV-1 and HIV-2, the presence of antibodies directed against one or the other agent needs to be proven. In case of contradictory results, HIV nucleic acids may be amplified and identified using nucleic acid amplification tests [4].

The confirmation of HIV infection entails an extensive laboratory workup to assess the patient's immune status, and to check for co-infections. This workup includes [5]:

• Quantification of HIV loads
• HIV genotyping and test for drug-resistance, if feasible
• Complete blood count and chemistry panel, including CD4+ T-cell counts with percentage
• Fasting lipid profile
• Baseline urinalysis and calculated creatinine clearance or estimated glomerular filtration rate
• Screening for glucose-6-phosphate dehydrogenase deficiency
• HLA B*5701 screening
• Test for infections with Mycobacterium tuberculosis, hepatitis B virus, hepatitis C virus, Toxoplasma gondii
• Test for other sexually transmitted diseases like syphilis and Chlamydia infection

Adequate treatment should be provided as soon as HIV infection is diagnosed, irrespective of the presence of symptoms. This applies to both genders and all ages, including pregnant women. Preferred first-line regimens of antiretroviral therapy (ART) are as follows [2]:

• Adults: tenofovir disoproxil fumarate, lamivudine/emtricitabine, and efavirenz. Alternative regimens replace tenofovir disoproxil fumarate with azidothymidine, or efavirenz with dolutegravir or nevirapine.
• Pregnant women: tenofovir disoproxil fumarate, lamivudine/emtricitabine, and efavirenz. Alternative regimens replace tenofovir disoproxil fumarate with azidothymidine, or efavirenz with nevirapine.
• Adolescents: tenofovir disoproxil fumarate, lamivudine/emtricitabine, and efavirenz. Alternative regimens replace tenofovir disoproxil fumarate with azidothymidine or abacavir, or efavirenz with dolutegravir or nevirapine.
• Children aged <10 years: abacavir, lamivudine, and efavirenz. Alternative regimens replace abacavir with azidothymidine or tenofovir disoproxil fumarate, or efavirenz with nevirapine.
• Children aged <3 years: abacavir/azidothymidine, lamivudine, and lopinavir plus low-dose ritonavir. In an alternative regimen, lopinavir plus low-dose ritonavir is replaced by nevirapine.

Drug resistance and toxicity are the principal reasons for the choice of alternative regimens, but interactions with any agents employed to treat co-infections and comorbidities should also be considered [2]. In general, fixed-dose combinations and once-daily regimens are preferred to improve adherence to therapeutic recommendations. Lifelong treatment is required, and patients should be monitored for their response to ART. Six and twelve months after the initiation of ART, and annually thereafter, HIV loads should be measured, and CD4+ T-cell counts should be evaluated to assess the patient's immune status. These tests may be complemented by standard analyses of blood samples to detect potential signs of organ failure.

Of note, post-exposure prophylaxis of HIV infection should be provided within 72 hours after the potential acquisition of the virus [2]. In this context, combination regimens comprising tenofovir disoproxil fumarate, lamivudine/emtricitabine, and lopinavir or amprenavir plus low-dose ritonavir are recommended for adolescents and adults.

The use of ART may significantly diminish the risk of progression to AIDS and of premature mortality. On a global scale, the expansion of access to ART has been associated with a 30% decrease in mortality. Increasingly fewer patients develop AIDS-defining illnesses and die of the disease [6]. With regard to survival, it has been estimated that a 25-year old person with HIV and without hepatitis C virus had a mean life expectancy of 64 years, which is about a decade less than the matched general population [7].

HIV infection is caused by two related, yet distinct viruses, by HIV-1 and HIV-2. HIV-1 accounts for the majority of infections and severely interferes with T-cell immunity, whereas infections with HIV-2 allow for the establishment of a more effective and sustained immune response against [8].

HIV is mainly transmitted via the sexual route. Furthermore, contact with blood, blood products, and body fluids of HIV patients may lead to an infection. Intravenous drug abuse and needle sharing are the most important risk factors to this end, while the transmission of HIV during the transfusion or transplantation of blood and organs, respectively, has become increasingly rare after the introduction of screenings.

HIV may also be transmitted from the pregnant mother to her unborn child, and from the nursing mother to the infant [9] [10]. The risk of transmission is particularly high in case of incident HIV infections during pregnancy or the postpartum period, and it's precisely these cases that remain undetected in the absence of repeat HIV testing. It may amount to 58%, as has been shown for Rwanda, but is more commonly estimated at about 20% [9]. In general, the risk of transmission may be significantly reduced with ART.

In 2012, an estimated 35 million people were living with HIV. Both the incidence and prevalence of HIV infections have been declining for about two decades: About 3.7 million people became infected in 1997, approximately 2.3 million new infections occurred in 2012, and an estimated 1.8 million patients contracted the disease in 2016. This development corresponds to an overall reduction by >50%, and it is mainly attributed to the expansion of ART [11].

By far the highest incidence and prevalence rates are reported in Sub-Saharan Africa. In 2012, almost three-fourths of HIV patients worldwide were living in this region. Similarly, the vast majority of children infected with HIV comes from this part of Africa. While mortality related to HIV and AIDS diminished on a global scale, this does not necessarily apply to resource-limited settings as encountered in developing countries [6]. Poverty remains a major barrier to access to education, healthcare, and ART, and large parts of the Sub-Saharan Africa population live below the poverty line [12]. In sum, about 1 million people died of AIDS in 2016 - about 800.000 of them in the African region.

The detrimental consequences of HIV infection are due to the gradual loss of CD4+ T-cells and imbalance in CD4+ T-cell homeostasis, resulting in progressive immunodeficiency and ultimately death. CD4+ T-cells are implicated in cellular and humoral immune responses against infections, and they are selectively infected by HIV. The virus binds to CD4 and enters the target cell. Inside the lymphocyte, the viral genome and enzymes are released and the reverse transcription of viral RNA is initiated. This process is mediated by viral reverse transcriptase and precedes the integration of viral DNA into the host genome by HIV integrase. Transcription factors are required for the subsequent transcription of the viral genome, and the resulting RNA serves as a template for protein biosynthesis at the host's ribosomes. Posttranslational modifications are realized by HIV proteases before virion buds form from viral proteins and RNA. These virion buds undergo a maturation process and are eventually able to infect other cells. They may be released during the lysis of the initial host cell, but they may also reach other cells upon the fusion of infected and uninfected lymphocytes. In any case, the spread of the infection is associated with decreasing quantities of CD4+ T-cells and a reduction in the number of functional cells [8].

Because HIV infection is essentially a sexually transmitted disease, information campaigns and sex education are the pillars of prophylaxis. From adolescence onward, boys and girls should be encouraged to practice safer sex. The correct and consistent use of condoms largely reduces the risk of infection, as does the reduction of the number of sexual partners. Before abstaining from condoms, both partners should get tested for HIV.

Distinct measures may dam the spread of the virus at a higher level [2]:

• In order to comply with the aforementioned recommendation of safer sex, condoms may be provided to those who are unable or unlikely to purchase them.
• The implementation of needle and syringe programs may save the life of drug addicts.
• Voluntary medical male circumcision should be offered in high-risk settings and may be associated with an approximately 60% reduction in the risk of female-to-male sexual transmission.
• Each and every unit of blood, tissues, and organs to be transplanted to another person should be screened for the presence of HIV, among others.

Additionally, people at very high risk of exposure to HIV may be provided pre-exposure prophylaxis containing tenofovir disoproxil fumarate [2]. This may apply to serodiscordant couples, heterosexual men and women, men who have sex with men, transgender people, sex workers, people who inject drugs, and those in prisons and other closed settings.

At the same time, researches worldwide are working intensively on the development of a vaccine against HIV infections [13] [14].

HIV infection constitutes a pandemia. Incidence and prevalence peaked in the 1990s, but could significantly be reduced by the introduction of highly active antiretroviral therapies. Today, HIV patients who are diagnosed before the progression to advanced-stage disease and provided ART, have a near-to-normal life expectancy [7]. This may give the misleading impression of HIV no longer being a serious threat to health, and it may motivate to neglect safety measures to prevent an infection. Because the vast majority of patients acquires HIV during sexual intercourse, safer sex remains the most important of those prophylactic measures.

Additionally, the global fight against HIV and AIDS is hindered by limited access to medical care and effective treatment in developing countries. Current epidemiological data clearly show a concentration of infections in Sub-Saharan Africa, where people may not be able to afford ART or even HIV testing, so many infections remain undetected and/or untreated. The improvement of accessibility is a major challenge on the way towards the eradication of HIV, as is the continuous education about the prevention of sexually transmitted diseases.

Human immunodeficiency virus (HIV) infection is possibly the most widely known sexually transmitted disease. It follows a progressive course and is associated with a gradual impairment of the immune system, eventually leading to life-threatening acquired immunodeficiency syndrome (AIDS) and death. The development of effective therapies made HIV infections lose some of its dreadfulness, but it currently remains incurable. What's more, HIV infection interferes with the patient's quality of life and constitutes a substantial health and economic burden, so every possible effort should be made to avoid the exposure to the virus:

• The consistent and correct use of condoms is the most important preventive measure and applies to both genders and all ages.
• Intravenous drug users should not share needles and syringes, and strive for overcoming their addiction.
• Medical personnel and everyone else possibly exposed to infected blood, blood products or body fluids should apply appropriate safety measures. In high-risk settings, these may include the prophylactic administration of antiretroviral drugs.

In any case, treatment should be started as early as possible to assure an optimum outcome, so people who have reasons to assume they may have contracted the disease should seek medical assistance and check their HIV status. If antiretroviral treatment is initiated within 72 hours after the initial exposure, HIV infection may possibly be avoided.

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