Bioavailability

From Wikipedia, the free encyclopedia

In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.

By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via routes other than intravenous, its bioavailability is generally lower than that of intravenous due to intestinal endothelium absorption and first-pass metabolism. Thereby, mathematically, bioavailability equals the ratio of comparing the area under the plasma drug concentration curve versus time (AUC) for the extravascular formulation to the AUC for the intravascular formulation. AUC is used because AUC is proportional to the dose that has entered the systemic circulation.

Bioavailability of a drug is an average value; to take population variability into account. To ensure that the drug taker who has poor absorption is dosed appropriately, the bottom value of the deviation range is employed to represent real bioavailability and to calculate the drug dose needed for the drug taker to achieve systemic concentrations similar to the intravenous formulation. To dose without knowing the drug taker's absorption rate, the bottom value of the deviation range is used in order to ensure the intended efficacy, unless the drug is associated with a narrow therapeutic window.

For dietary supplements, herbs and other nutrients in which the route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed.

Definitions

In pharmacology

Bioavailability is a term used to describe the percentage of an administered dose of a xenobiotic that reaches the systemic circulation. It is denoted by the letter f (or, if expressed in percent, by F).

In nutritional science

In nutritional science, which covers the intake of nutrients and non-drug dietary ingredients, the concept of bioavailability lacks the well-defined standards associated with the pharmaceutical industry. The pharmacological definition cannot apply to these substances because utilization and absorption is a function of the nutritional status and physiological state of the subject, resulting in even greater differences from individual to individual (inter-individual variation). Therefore, bioavailability for dietary supplements can be defined as the proportion of the administered substance capable of being absorbed and available for use or storage.

In both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve (AUC) of the drug concentration time profile.

In environmental sciences or science

Bioavailability is the measure by which various substances in the environment may enter into living organisms. It is commonly a limiting factor in the production of crops (due to solubility limitation or absorption of plant nutrients to soil colloids) and in the removal of toxic substances from the food chain by microorganisms (due to sorption to or partitioning of otherwise degradable substances into inaccessible phases in the environment). A noteworthy example for agriculture is plant phosphorus deficiency induced by precipitation with iron and aluminum phosphates at low soil pH and precipitation with calcium phosphates at high soil pH. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess. Organic pollutants such as solvents or pesticides may be rendered unavailable to microorganisms and thus persist in the environment when they are adsorbed to soil minerals or partition into hydrophobic organic matter.

Absolute bioavailability

Absolute bioavailability is a ratio of areas under the curves. IV, intravenous; PO, oral route. C is plasma concentration (arbitrary units).

Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non-intravenous administration (i.e., after oral, buccal, ocular, nasal, rectal, transdermal, subcutaneous, or sublingual administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized (e.g., account for different doses or varying weights of the subjects); consequently, the amount absorbed is corrected by dividing the corresponding dose administered.

In pharmacology, in order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and extravascular (non-intravenous, i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. The formula for calculating the absolute bioavailability, F, of a drug administered orally (po) is given below (where D is dose administered).

${\displaystyle F_{\mathrm{a}\mathrm{b}\mathrm{s}}=100\cdot \frac{AU{C}_{\mathrm{p}\mathrm{o}}\cdot D_{\mathrm{i}\mathrm{v}}}{AU{C}_{\mathrm{i}\mathrm{v}}\cdot D_{\mathrm{p}\mathrm{o}}}}$

Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% (f = 1), whereas drugs given by other routes usually have an absolute bioavailability of less than one. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.

Although knowing the true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference; that is, a route of administration that guarantees all of the administered drug reaches systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as potential problems due to solubility limitations. These limitations may be overcome, however, by administering a very low dose (typically a few micrograms) of an isotopically labelled drug concomitantly with a therapeutic non-isotopically labelled oral dose (the isotopically-labelled intravenous dose is sufficiently low so as not to perturb the systemic drug concentrations achieved from the non-labelled oral dose). The intravenous and oral concentrations can then be deconvoluted by virtue of their different isotopic constitution, and can thus be used to determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues with non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology and formulation. The technique was first applied using stable-isotopes such as ¹³C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, ¹⁴C labelled drugs are administered intravenously and accelerator mass spectrometry (AMS) used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug.

There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailability information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously.

Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution (V) and clearance (CL).

Relative bioavailability and bioequivalence

In pharmacology, relative bioavailability measures the bioavailability (estimated as the AUC) of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability (see above).

${\displaystyle F_{\mathrm{r}\mathrm{e}\mathrm{l}}=100\cdot \frac{AU{C}_{\mathrm{A}}\cdot D_{\mathrm{B}}}{AU{C}_{\mathrm{B}}\cdot D_{\mathrm{A}}}}$

Relative bioavailability is one of the measures used to assess bioequivalence (BE) between two drug products. For FDA approval, a generic manufacturer must demonstrate that the 90% confidence interval for the ratio of the mean responses (usually of AUC and the maximum concentration, C_max) of its product to that of the "brand name drug" is within the limits of 80% to 125%. Where AUC refers to the concentration of the drug in the blood over time t = 0 to t = ∞, C_max refers to the maximum concentration of the drug in the blood. When T_max is given, it refers to the time it takes for a drug to reach C_max.

While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown. As a result, in nutritional sciences, relative bioavailability or bioequivalence is the most common measure of bioavailability, comparing the bioavailability of one formulation of the same dietary ingredient to another.

Factors influencing bioavailability

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e., F< 100%). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.

Other factors may include, but are not limited to:

• Physical properties of the drug (hydrophobicity, pKa, solubility)
• The drug formulation (immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release, etc.)
• Whether the formulation is administered in a fed or fasted state
• Gastric emptying rate
• Circadian differences
• Interactions with other drugs/foods:
  • Interactions with other drugs (e.g., antacids, alcohol, nicotine)
  • Interactions with other foods (e.g., grapefruit juice, pomello, cranberry juice, brassica vegetables)
• Transporters: Substrate of efflux transporters (e.g. P-glycoprotein)
• Health of the gastrointestinal tract
• Enzyme induction/inhibition by other drugs/foods:
  • Enzyme induction (increased rate of metabolism), e.g., Phenytoin induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4
  • Enzyme inhibition (decreased rate of metabolism), e.g., grapefruit juice inhibits CYP3A → higher nifedipine concentrations
• Individual variation in metabolic differences
  • Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
  • Phenotypic differences, enterohepatic circulation, diet, gender
• Disease state
  • E.g., hepatic insufficiency, poor renal function

Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.

Bioavailability of drugs versus dietary supplements

In comparison to drugs, there are significant differences in dietary supplements that impact the evaluation of their bioavailability. These differences include the following: the fact that nutritional supplements provide benefits that are variable and often qualitative in nature; the measurement of nutrient absorption lacks the precision; nutritional supplements are consumed for prevention and well-being; nutritional supplements do not exhibit characteristic dose-response curves; and dosing intervals of nutritional supplements, therefore, are not critical in contrast to drug therapy.

In addition, the lack of defined methodology and regulations surrounding the consumption of dietary supplements hinders the application of bioavailability measures in comparison to drugs. In clinical trials with dietary supplements, bioavailability primarily focuses on statistical descriptions of mean or average AUC differences between treatment groups, while often failing to compare or discuss their standard deviations or inter-individual variation. This failure leaves open the question of whether or not an individual in a group is likely to experience the benefits described by the mean-difference comparisons. Further, even if this issue were discussed, it would be difficult to communicate meaning of these inter-subject variances to consumers and/or their physicians.

Nutritional science: reliable and universal bioavailability

One way to resolve this problem is to define "reliable bioavailability" as positive bioavailability results (an absorption meeting a predefined criterion) that include 84% of the trial subjects and "universal bioavailability" as those that include 98% of the trial subjects. This reliable-universal framework would improve communications with physicians and consumers such that, if it were included on products labels for example, make educated choices as to the benefits of a formulation for them directly. In addition, the reliable-universal framework is similar to the construction of confidence intervals, which statisticians have long offered as one potential solution for dealing with small samples, violations of statistical assumptions or large standard deviations.

CCR5 receptor antagonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/CCR5_receptor_antagonist

CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this receptor are entry inhibitors and have potential therapeutic applications in the treatment of HIV infections.

The life cycle of the HIV presents potential targets for drug therapy, one of them being the viral entry pathway. CCR5 and CXCR4 are the main receptors involved in the HIV entry process. These receptors belong to the seven transmembrane G-protein-coupled receptor (GPCR) family and are predominantly expressed on human T-cells, dendritic cells and macrophages, Langerhans cells. They play an important role as co-receptors that HIV type 1 (HIV-1) uses to attach to cells before viral fusion and entry into host cells. HIV isolates can be divided into R5 and X4 strains. R5 strain is when the virus uses the co-receptor CCR5 and X4 strain is when it uses CXCR4. The location of CCR5 receptors at the cell surface, both large and small molecules have the potential to interfere with the CCR5-viral interaction and inhibit viral entry into human cells.

History

Since the discovery of HIV in the 1980s, remarkable progress has been made in the development of novel antiviral drugs. The trigger for the discovery of the CCR5 antagonists was the observation that a small percentage of high-risk populations showed either resistance or delayed development of the disease. This population was found to have a mutation (CCR5-Δ32) in the gene that codes for the CCR5 receptor which results in almost complete resistance against HIV-1 infection and scientists then discovered the key role of the cell surface receptors CCR5 and CXCR4 in successful viral fusion and infection. In 1996, it was demonstrated that CCR5 serves as a co-receptor for the most commonly transmitted HIV-1 strains, R5. This type of virus is predominant during the early stages of infection and remains the dominant form in over 50% of late stage HIV-1 infected patients, however R5 strains can eventually evolve into X4 as the disease progresses. This information led to the development of a new class of HIV drugs called CCR5 antagonists.

Mechanism of action

Figure 1 HIV entry into CD4+ cell via CCR5 co-receptor.

HIV enters host cells in the blood by attaching itself to receptors on the surface of the CD4+ cell. Viral entry to the CD4+ cell begins with attachment of the R5 HIV-1 glycoprotein 120 (gp120) to the CD4+ T-cell receptor, which produces a conformational change in gp120 and allows it to bind to CCR5, thereby triggering glycoprotein 41 (gp41) mediated fusion of the viral envelope with the cell membrane and the nucleocapsid enters the host cell (Figure 1). CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor. Small molecule antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor. They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function.

Drug development

As mentioned, the CCR5 receptor is a G-protein coupled receptor (GPCR). Before the discovery of CCR5's role in HIV infection, many pharmaceutical companies had already built a substantial collection of compounds that target GPCRs. Some of these compounds would prove to be a starting point for CCR5 antagonist medicinal chemistry, but would need optimization to improve CCR5 selectivity and potency, and to improve pharmacokinetic properties. A significant problem was the affinity of available screening hits for the hERG ion channel; inhibition of hERG leads to QT interval prolongation, which can increase the risk of developing fatal ventricular arrhythmias. Many CCR5 antagonists have been studied by pharmaceutical companies, but few of them have actually reached human efficacy studies; for example AstraZeneca, Novartis, Merck, and Takeda have used their GPRC-targeting compound collections to develop a potent CCR5 antagonist, but none of them have reached clinical trials. Three pharmaceutical companies were in competition to be the first to have a small molecule CCR5 antagonist approved: GlaxoSmithKline (GSK) with their compound aplaviroc, Schering-Plough with vicriviroc, and Pfizer with maraviroc. All of the compounds reached clinical trials in humans; only maraviroc has been approved by the U.S. Food and Drug Administration (FDA).

Leronlimab

Leronlimab is a humanized monoclonal antibody targeted against the CCR5 receptor found on T lymphocytes of the human immune system and many types of cancers. It is being investigated as a potential therapy in the treatment of HIV infection, graft versus host disease (NCT02737306) and metastatic cancer (NCT03838367). The United States Food and Drug Administration (FDA) has designated leronlimab for fast-track approval. In February 2008, the drug entered Phase 2 clinical trials and a phase 3 trial was begun in 2015. In February 2018 CytoDyn Inc reported that the primary endpoint has been achieved in the PRO 140 pivotal combination therapy trial in HIV infection.

Leronlimab is being developed by CytoDyn Inc. In May 2007, results from the phase I clinical trial of the drug demonstrated "potent, rapid, prolonged, dose-dependent, highly significant antiviral activity" for leronlimab. Participants in the highest-dosing group received 5 milligrams per kilogram and showed an average viral load decrease of -1.83 log₁₀. On average, reductions of greater than -1 log₁₀ per millilitre were maintained for between two and three weeks, from only a single dose of the drug. The largest individual HIV RNA reductions ranged up to -2.5 log₁₀ among patients receiving both the 2 and 5 mg/kg doses.

Leronlimab is a lab-made antibody that functions as an entry inhibitor. Leronlimab binds to the CCR5 receptor on the CD4 cells, and interferes with HIV's ability to enter the cell. Leronlimab, a humanized form of a PA14 antibody, is a chemokine-receptor CCR5 monoclonal antibody and can inhibit CCR5 tropic HIV-1 at concentrations that do not antagonize the natural activity of CCR5 in vitro. HIV-1 entry is mediated by the HIV-1 envelope glycoproteins gp120 and gp41. The gp120 will bind CD4 and the CCR5co receptor molecule, and this triggers gp41-mediated fusion of the viral and cellular membranes. CCR5 is hence needed for the entry of the virus and this infection of healthy cells. Leronlimab, the anti-CCR5 monoclonal antibody, can stop HIV from entering the cell and stop viral replication. It prevents the virus-cell binding at a distinct site in the CCR5 co-receptor without interfering with its natural activity. Unlike other entry inhibitors, PRO 140 is a monoclonal antibody. The mechanism of inhibition is competitive rather than allosteric. As such, it must be injected to be effective. However, once inside the body, PRO 140 binds to CCR5 for >60 days, which may allow for dosing as infrequently as every other week. Compared to highly-active antiretroviral therapy which has been shown to have treatment-related toxicities for HIV-infected patients, PRO140 has no multi-drug resistance or toxicities.

In February 2018, CytoDyn reported that the primary endpoint has been achieved in the PRO 140 pivotal combination therapy trial in HIV infection and will continue for an additional 24 weeks (end of August 2018) with PRO 140 weekly subcutaneous injections and optimized ART. The report discloses that a single 350 mg subcutaneous injection of PRO 140 resulted in a HIV-1 RNA viral load reduction greater than 0.5log or 68% within one week compared with those who received a placebo. The primary efficacy endpoint results were presented at ASM Microbe 2018. In the pivotal trial of leronlimab in combination with standard anti-retroviral therapies in HIV-infected treatment-experienced patients, 81% of patients completing trial achieved HIV viral load suppression of < 50 cp/mL. Recent approved drugs for this population range from 43% after 24 weeks to 45% after 48 weeks with viral load suppression of < 50 cp/mL. In March 2019, CytoDyn filed with the US FDA the first part of the BLA for leronlimab (PRO140) as a combination therapy with HAART in HIV. In May 2020, the company filed its BLA with potential FDA approval in 4Q'20. CytoDyn is conducting an investigative monotherapy trial of leronlimab (PRO140) for HIV. If successful, once per week self-administered leronlimab would represent a paradigm shift in treatment of HIV.

CytoDyn is investigating the use of leronlimab in various solid tumors. On February 18, 2019, CytoDyn announced it will begin 8 pre-clinical studies on melanoma cancer, pancreatic, breast, prostate, colon, lung, liver, and stomach cancer. This has the potential to lead to 8 phase II clinical studies with leronlimab in the cancer arena. On November 23, 2018, CytoDyn received FDA approval of its IND submission and allowed to initiate a Phase Ib/II clinical trial for metastatic triple-negative breast cancer (mTNBC) patients. On February 20, 2019, CytoDyn announced that leronlimab was able to reduce by more than 98% the incidence of human breast cancer metastasis in a mouse xenograft model for cancer through six weeks with leronlimab. The temporal equivalency of the murine 6 weeks study may be up to 6 years in humans. In May 2019, the U.S. Food and Drug Administration (FDA) granted fast track designation for leronlimab for use in combination with carboplatin for the treatment of patients with CCR5-positive mTNBC. In July 2019, CytoDyn announced the dosing of first mTNBC patient under compassionate use. Simultaneously, the Phase Ib/II trial for treatment-naïve mTNBC patients is active and anticipates top line data in 2020. If successful, the data from treatment-naïve mTNBC patients could serve as the basis for potentially seeking accelerated US FDA approval.

A study demonstrated leronlimab reduced the number and size of new human breast cancer metastasis in a mouse model and reduced the size of established metastasis thereby extending survival.

In May 2019, CytoDyn initiated pre-clinical study of leronlimab to prevent NASH.

Aplaviroc

Figure 2. Molecular structure of aplaviroc and its lead compound

 

Figure 3 Molecular structure of vicriviroc and its lead compounds

Aplaviroc is originated from a class of spirodiketopiperazine derivatives. Figure 2 shows the molecular structure of the lead compound and the final compound aplaviroc. The lead compound showed good potency in blocking CCR5 in a number of R5 HIV strains and against multi-drug resistant strains. The problem with this compound was not its CCR5 selectivity but the oral bioavailability. This led to further development of the molecule and the result was a compound named aplaviroc. Unfortunately, despite the promising preclinical and early clinical results, some severe liver toxicity was observed in the treatment of naïve and treatment-experienced patients that led to the discontinuation in further development of aplaviroc.

Vicriviroc

Schering-Plough identified an active compound during screening. Figure 3 shows the molecular structure of the lead compound, intermediate compound, and the final compound vicriviroc. The lead compound contained a piperazine scaffold and was a potent muscarinic acetylcholine receptor (M₂) antagonist with modest CCR5 activity. The changes that were made on the left hand side of the lead compound and the addition of a methyl group on the piperazine group ((S)-methylpiperazine) resulted in the intermediate compound that had good affinity for CCR5 receptors but very little affinity for muscarinic activity, however, the compound did show affinity for the hERG ion channel. Further reconstruction led to the development of the final compound vicriviroc, when Schering discovered that the pyridyl N-oxide on the intermediate could be replaced by 4,6-dimethylpyrimidine carboxamide. Vicriviroc had an excellent selectivity for CCR5 receptors over muscarinic and hERG affinity was greatly reduced. Phase I clinical trial of vicriviroc gave promising results, so a phase II study in the treatment of naïve patients was initiated. The phase II study was discontinued since there was a viral breakthrough in the vicriviroc group compared to the control group. These results suggested that vicriviroc was not effective in the treatment of treatment-naïve patients compared to current treatments. Another phase II clinical study was performed in treatment-experienced patients. The results were that vicriviroc did have strong antiviral activity but five instances of cancer among the participants were reported, however, the study was continued since there was lack of causal association of the malignancies and vicriviroc. In late 2009, vicriviroc was reported by the company to have entered phase II studies in treatment for naïve patients and phase III studies in treatment-experienced patients.

Maraviroc

Pfizer turned to high-throughput screening in their search for a good starting point for a small molecule CCR5 antagonist. Their screening resulted in a compound that presented weak affinity and no antiviral activity but represented a good starting point for further optimization. Compounds 1–9 in Table 1 show the development of maraviroc in few steps. The chemical structure of the starting molecule (UK-107,543) is presented as compound 1. Their first focus was to minimize CYP2D6 activity of the molecule and to reduce its lipophilicity. They replaced the imidazopyridine with benzimidazole and the benzhydril group was swapped out for a benzamide. The outcome was compound 2. That compound showed good binding potency and the start of an antiviral activity. Further structure–activity relationship (SAR) optimization of the amide region and identifying the enantiomeric preference led to the cyclobutyl amide structure in compound 3. However, the problem with the CYP2D6 activity of the compound was still unacceptable so they had to perform further SAR optimization that determined that the [3.2.1]-azabicycloamine (tropane) could replace the aminopiperidine moiety. This change in the chemical structure led to compound 4. Compound 4 had no CYP2D6 activity while preserving excellent binding affinity and antiviral activity. Although compound 4 showed promising results, it demonstrated 99% inhibition on the hERG ion channel. That inhibition was unacceptable since it can lead to QTc interval prolongation. The research team then did a few modifications to see which part of the molecule played a role in the hERG affinity. Compound 5 shows an analogue that they synthesized which contained an oxygen bridgehead in the tropane ring; however, that reconstruction did not have an effect on the hERG affinity. They then focused on the polar surface area in the molecule to dial out the hERG affinity. These efforts resulted in compound 6. That compound preserved desired antiviral activity and was selective against the hERG inhibition but the problem was its bioavailability. Reduction in the lipophilicity, by replacing the benzimidazol group with a substituted triazole group gave compound 7. Compound 7 had shown a significant reduction in lipophilicity and maintained the antiviral activity but again, with the introduction of a cyclobutyl group, the compound showed hERG inhibition. Changing the ring size in compound 7 from a cyclobutyl unit to a cyclopentyl unit in compound 8 led to a significant increase in antiviral activity and loss of hERG affinity. Further development led to discovery of a 4,4'-difluorocyclohexylamide also known as maraviroc. Maraviroc preserved excellent antiviral activity, whilst demonstrating no significant hERG binding affinity. The lack of hERG binding affinity was predicted to be because of the large size of the cyclohexyl group and the high polarity of the fluoro substituents. In August 2007 the FDA approved the first CCR5 antagonist, maraviroc, discovered and developed by Pfizer.

Table 1 represents the molecular structures in the development of maraviroc.
Blue indicates differences from the previous step

Compound 1	Compound 2	Compound 3
Compound 4	Compound 5	Compound 6
Compound 7	Compound 8	Compound 9 (maraviroc)

Pharmacophore

Figure 4 Predictive pharmacophore model for piperidine- and piperazine-based CCR5 antagonists

The predictive pharmacophore model was developed for a large series of piperidine- and piperazine-based CCR5 antagonists by Schering-Plough Research Institute. Their hypothesis consisted of mostly five features, two hydrogen bond acceptors, marked C and D in figure 4 and three hydrophobic groups, A, B and E in figure 4. Part B usually has a basic nitrogen group. The model was validated using diverse set of six CCR5 antagonists from five different pharmaceutical companies. The best model correctly predicted these compounds as being highly active. It is possible to use the model as a tool in virtual screening for new small molecular CCR5 antagonists and also to predict biological activities of compounds prior to undertaking their costly synthesis.

Binding

Figure 5. Putative binding of aplaviroc to the CCR5 receptor

 

Figure 6. Putative binding of maraviroc to the CCR5 receptor

CCR5 is a member of G protein-coupled, seven transmembrane segment receptors. The structure of the receptor comprises seven-helix bundle in the transmembrane region, these regions are labeled I–VII in figures 5 and 6. The CCR5 antagonists are predicted to bind to a putative binding pocket which is buried inside the transmembrane domain, enclosed by the seven transmembrane helices. The binding pocket is very hydrophobic with multiple aromatic residues lining the pocket. The key residues are tryptophan 86 and 248 (Trp86, Trp248), tyrosine 108 and 251 (Tyr108, Tyr251), phenylalanine 109 (Phe109), threonine 195 (Thr195), isoleucine 198 (Ile198), glutamic acid 283 (Glu283). CCR5 antagonists are very different in shape and electrostatic potential although they all share the same binding pocket. The interesting thing about the binding of these molecules is that they exhibit significantly different binding modes, although they all establish an extensive interaction network with CCR5.

Aplaviroc

The putative binding mode for aplaviroc is shown in figure 5. The key saltbridge interaction between aplaviroc and Glu283 is predicted to be quite weak compared to other CCR5 antagonists. The hydroxyl group on aplaviroc forms a strong hydrogen bond to the polar residue Thr195. This H-bond interaction is the strongest with aplaviroc compared to other CCR5 antagonists. The cyclohexyl group in the aplaviroc structure is predicted to interact with the receptor in a hydrophobic pocket formed by Ile198, Thr195 and Phe109 and is thought to show quite strong hydrophobic interactions. The researchers predict that the butyl group of aplaviroc is buried within the helical bundle through strong hydrophobic interaction with multiple aromatic residues of the CCR5 receptor. Aplaviroc has a unique feature of preserving two of the natural chemokine protein ligands binding to CCR5 and subsequent activation, whereas maraviroc and the other antagonists almost fully block chemokine-CCR5 interactions. This kind of interference is so far considered to be safe, and individuals that naturally lack CCR5 do not show any obvious health problems. However, to limit the toxicity and side effects of CCR5 antagonists it would be ideal to be able to preserve the chemokine receptor function. Consequently, it should be of interest to design inhibitors that specifically disrupt CCR5–gp120 binding but do not affect the CCR5 chemokine activation.

Maraviroc

The putative binding mode for maraviroc is shown in figure 6. The strongest interaction is estimated to be between maraviroc and glutamic acid (Glu283) through a strong salt bridge interaction. The interaction between tryptophan (Trp86) and maraviroc involves T-shaped π-π stacking while the interaction with phenylalanine (Phe109) is predicted to be hydrophobic. Tyrosine (Tyr108) is thought to interact with the phenyl group on maraviroc through a parallel displaced interaction. The interaction between maraviroc and isoleucine (Ile198) is predicted to be mostly hydrophobic in nature and the interaction between maraviroc and tyrosine (Tyr251) is very limited.

Other CCR5 antagonists

Figure 7. Molecular structure of compound A

Development of new CCR5 antagonists continues, both for their antiviral effects and also for potential utility in a variety of autoimmune indications. Researchers at Roche Palo Alto discovered a novel series of potent CCR5 small-molecule antagonists. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Combination of the spiropiperidine template with pharmacophore elements from both aplaviroc, and Schering's CCR5 antagonist program, led to the initial lead compound in this series. Further development of that lead compound led to the discovery of compound A in figure 7 — a compound that possesses a good selectivity and pharmacokinetic properties.

The CCR5 antagonist INCB009471 has nanomolar activity against HIV-1 in vitro. This compound demonstrated potent and prolonged antiviral activity against R5-tropic HIV-1 when given 200 mg once daily dose for 14 days. These findings supported further clinical development of INCB009471 and they have since progressed to phase IIb clinical trials. As of 2009 the study of this compound is inactive and no further studies are planned at this time.

Not only small molecules but also proteins delivered by gene therapy have been suggested to ablate CCR5 function, an approach that has also been employed for other HIV targets.

HIV/AIDS research

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/HIV/AIDS_research

Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte

 

Diagram of HIV

HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.

Transmission

See also: Circumcision and HIV

A body of scientific evidence has shown that men who are circumcised are less likely to contract HIV than men who are uncircumcised. Research published in 2014 concludes that the sex hormones estrogen and progesterone selectively impact HIV transmission.

Pre- and post-exposure prophylaxis

Main articles: Pre-exposure prophylaxis and Post-exposure prophylaxis

"Pre-exposure prophylaxis" refers to the practice of taking some drugs before being exposed to HIV infection, and having a decreased chance of contracting HIV as a result of taking that drug. Post-exposure prophylaxis refers to taking some drugs quickly after being exposed to HIV, while the virus is in a person's body but before the virus has established itself. In both cases, the drugs would be the same as those used to treat persons with HIV, and the intent of taking the drugs would be to eradicate the virus before the person becomes irreversibly infected.

Post-exposure prophylaxis is recommended in anticipated cases of HIV exposure, such as if a nurse somehow has blood-to-blood contact with a patient in the course of work, or if someone without HIV requests the drugs immediately after having unprotected sex with a person who might have HIV. Pre-exposure prophylaxis is sometimes an option for HIV-negative persons who feel that they are at increased risk of HIV infection, such as an HIV-negative person in a serodiscordant relationship with an HIV-positive partner.

Current research in these agents include drug development, efficacy testing, and practice recommendations for using drugs for HIV prevention.

Progression of HIV

The progression of HIV infection is analyzed by measuring the concentration of  HIV virions (or viral load) and the concentration of CD4 T cells in the patient's bloodstream and lymphoid tissues. An untreated infection will progress in the following phases: Acute phase, chronic phase, and AIDs phase. In the Acute phase, the virions invade the host body and replicate expeditiously. The concentration of the virions increase vastly, while the concentration of CD4 T cells declines. After a spiked replication of HIV, the  viral load and CD4 T cell count drops back down. Symptoms of acute HIV infection include fever, chills, rash, night sweats, muscle aches, and swollen lymph nodes. Acute symptoms occur usually 2–4 weeks after initial HIV infection and can last between a few days and several weeks.

During the chronic phase, HIV will continue to replicate, but the concentration of virions tend to stabilize for a period of time before rising again. The CD4 T cell count continues to fall. Individuals in the chronic phase may not experience any symptoms. Left untreated, the chronic stage can last between 10 and 15 years. However, some individuals can move through this stage quickly to the AIDS phase.

An untreated HIV infection ultimately progresses to AIDS (acquired immunodeficiency syndrome). In the AIDS phase, the CD4 T-cell count significantly drops to below 200 cells per cubic millimeter. Individuals with AIDS become immunocompromised due to irreversible  damage to the immune system and lymph nodes. The immune system does not have the ability to generate new T cells. Opportunistic infections, that a robust immune system could fight off, now are capable of causing severe symptoms and illnesses. Without a comprehensive anti-HIV drug therapy, an individual diagnosed with AIDS is expected to have less than three years to live.

Immune System Response to HIV

Once the retrovirus invades the body, the immune system mobilizes to fight against HIV infection. The first line of defense for the immune system utilizes dendritic cells. These cells actively patrol vulnerable tissue (i.e. lining of the digestive and reproductive tracts). Once a dendritic cell apprehends the virion invader, it will transport the virus to lymphoid tissue and introduce parts of the virus's proteins to Naive helper T cells (which are specialized white blood cells). The transported viral protein binds to the naive helper T cell's receptor, and the T cell activates. As the helper T cells grow and divide, they produce effecter helper T cells (which help coordinate the immune system response to HIV). The effector T cells utilize cytokines to mobilize other immune cells to join the combat against HIV. The cytokines promote the maturation of B cells into plasma cells. Then the plasma cells secrete antibodies that will bind to the HIV virions and target them for destruction. Finally, activated killer T-cells come in to eradicate the infected host cells.

Within-host dynamics

The within-host dynamics of HIV infection include the spread of the virus in vivo, the establishment of latency, the effects of immune response on the virus, etc. Early studies used simple models and only considered the cell-free spreading of HIV, in which virus particles bud from an infected T cell, enter the blood/extracellular fluid, and then infect another T cell. A 2015 study proposes a more realistic model of HIV dynamics that also incorporates the viral cell-to-cell spreading mechanism, where the virus is directly transited from one cell to another, as well as the T cell activation, the cellular immune response, and the immune exhaustion as the infection progresses.

Virus characteristics

See also: Structure and genome of HIV and Subtypes of HIV

HIV binds to immune cell surface receptors, including CD 4 and CXCR4 or CD4 and CCR5. The binding causes conformation changes and results in the membrane fusion between HIV and cell membrane. Active infection occurs in most cells, while latent infection occurs in much fewer cells 1, 2 and at very early stages of HIV infection. 9, 35 In active infection, HIV pro virus is active and HIV virus particles are actively replicated; and the infected cells continuously release viral progeny; while in latent infection, HIV pro virus is transcriptionally silenced and no viral progeny is produced.

Management of HIV/AIDS

Main article: Management of HIV/AIDS

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining better sequences of regimens to manage drug resistance. There are variations in the health community in recommendations on what treatment doctors should recommend for people with HIV. One question, for example, is determining when a doctor should recommend that a patient take antiretroviral drugs and what drugs a doctor may recommend. This field also includes the development of antiretroviral drugs.

Age acceleration effects due to HIV-1 infection

Infection with the Human Immunodeficiency Virus-1 (HIV) is associated with clinical symptoms of accelerated aging, as evidenced by increased incidence and diversity of age-related illnesses at relatively young ages. A significant age acceleration effect could be detected in brain (7.4 years) and blood (5.2 years) tissue due to HIV-1 infection with the help of a biomarker of aging, which is known as epigenetic clock.

Long-term nonprogressor

A long-term nonprogressor is a person who is infected with HIV, but whose body, for whatever reason, naturally controls the virus so that the infection does not progress to the AIDS stage. Such persons are of great interest to researchers, who feel that a study of their physiologies could provide a deeper understanding of the virus and disease. There are also two cases where HIV was apparently entirely cleared by a person's immune system without a therapy.

HIV vaccine

Main article: HIV vaccine

An HIV vaccine is a vaccine that would be given to a person who does not have HIV, in order to confer protection against subsequent exposures to HIV, thus reducing the likelihood that the person would become infected by HIV. Currently, no effective HIV vaccine exists. Various HIV vaccines have been tested in clinical trials almost since the discovery of HIV.

Only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.

In 2003 a clinical trial in Thailand tested an HIV vaccine called RV 144. In 2009, the researchers reported that this vaccine showed some efficacy in protecting recipients from HIV infection (31% efficiency). Results of this trial give the first supporting evidence of any vaccine being effective in lowering the risk of contracting HIV. Other vaccine trials continue worldwide including a mosaic vaccine using an adenovirus 26 vector as well as a newer formulation of RV144 called HVTN 702.

One recent trial was conducted by scientists at The Scripps Research Institute (TSRI) who found a way to attach HIV-fighting antibodies to immune cells, creating a HIV-resistant cell population.

HIV cure

Three people have been reported cured of AIDS. In 2019, the NIH and Bill & Melinda Gates Foundation announced making $200 million available for broad-based, multi-prong scientific efforts focused on developing a global cure for AIDS as well as for sickle cell disease, with NIH Director Francis S. Collins saying, "We aim to go big or we go home." In 2020, Tony Fauci's division at NIH, NIAID, issued its first solicitation exclusively focused on methods to cure HIV infection. These announcements from NIH are not limited to stem cell therapies.

Excision is a biotechnology company with a first-in-human CRISPR-based one-time gene therapy to be evaluated in individuals with HIV. Research Foundation to Cure AIDS is the first 501(c)(3) non-for-profit organization with a royalty-free license to research, develop and commercialize a cell engineering technology in the field of curing AIDS on a pro bono basis.

Microbicides for sexually transmitted diseases

Main article: microbicides for sexually transmitted diseases

A microbicide for sexually transmitted diseases is a gel which would be applied to the skin – perhaps a rectal microbicide for persons who engage in anal sex or a vaginal microbicide for persons who engage in vaginal sex – and if infected body fluid such as blood or semen were to touch the gel, then HIV in that fluid would be destroyed and the people having sex would be less likely to spread infection between themselves.

On March 7, 2013, the Washington University in St. Louis website published a report by Julia Evangelou Strait, in which it was reported that ongoing nanoparticle research showed that nanoparticles loaded with various compounds could be used to target infectious agents whilst leaving healthy cells unaffected. In the study detailed by this report, it was found that nanoparticles loaded with Mellitin, a compound found in Bee venom, could deliver the agent to the HIV, causing the breakdown of the outer protein envelope of the virus. This, they say, could lead to the production of a vaginal gel which could help prevent infection by disabling the virus. Dr Joshua Hood goes on to explain that beyond preventive measures in the form of a topical gel, he sees "potential for using nanoparticles with melittin as therapy for existing HIV infections, especially those that are drug-resistant. The nanoparticles could be injected intravenously and, in theory, would be able to clear HIV from the blood stream."

Initial stem cell cures of HIV/AIDS

In 2007, Timothy Ray Brown, a 40-year-old HIV-positive man, also known as "the Berlin Patient", was given a stem cell transplant as part of his treatment for acute myeloid leukemia (AML). A second transplant was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being homozygous for a CCR5-Δ32 mutation that confers resistance to HIV infection. After 20 months without antiretroviral drug treatment, it was reported that HIV levels in Brown's blood, bone marrow, and bowel were below the limit of detection. The virus remained undetectable over three years after the first transplant. Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues such as the brain (which acts as a viral reservoir). Stem cell treatment remains investigational because of its anecdotal nature, the disease and mortality risk associated with stem cell transplants, and the difficulty of finding suitable donors. As of 2022, there have been four patients cured by stem cell transplant.

Strategies to develop broadly-applicable cures

Scientists have been using different approaches of stem cell based gene therapy in an attempt to develop a cure as well as to propose an alternative to the conventional antiretroviral therapy (ART). Specifically, advances had been made with a cure to HIV.

A cellular receptor, generally CCR5 or CXCR4 is required in order for HIV entry into CD4 cells. Cells of individuals homozygous for the CCR5 gene variant Δ32 (CCR5Δ32/Δ32) lack the CCR5 cell-surface expression, meaning that they are naturally resistant to infection with CCR5 tropic HIV strains (R5 HIV). One study done in 2011 achieves successful CD4+ T-cell reconstitution as a result of CCR5Δ32/Δ32 stem cell transplantation at the systemic level and in the gut mucosal immune system in a patient with HIV. Additionally, it provides evidence for the reduction in the size of the potential HIV reservoir over time. The patient in this study even remained HIV free without any evidence of having it for more than 3.5 years.

Other theoretical cures to HIV-1 have been proposed. One supposed cure to HIV-1 involves the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem cells and progenitor cells (GM-HSPC). Though this study does involve several early stage clinical trials that have demonstrated the safety and feasibility of this technique only for HIV-1, none have resulted in improvement of the disease state itself. Therefore, this strategy is intended to go alongside already existing treatment techniques such as drugs and vaccines. However, future technology regarding this approach of single treatment cell therapy could potentially replace current therapy altogether as a functional or sterilizing cure to HIV-1.

An additional study involves the use of genetically engineered CD34+ hematopoietic stem and progenitor cells. Experimental long-term in vivo HIV gene therapy have had huge issues due to both transduction ending in multiple copies of heterologous DNA in target cells as well as low efficacy of cell transduction at the time of transplantation. This study demonstrated the efficacy of a transplantation approach that ultimately allows for an enriched population of HSPCs expressing a single copy of a CCR5 miRNA. Since positive selection of modified cells is likely to be insufficient below the threshold they found of at least 70% of the HIV target cells resulting in gene modification from efficient maintenance of CD34+ T cell and a low viral titer, the findings show evidence that clinical protocols of HIV gene therapy require a selective enrichment of genetically targeted cells.

Immunomodulatory agents

Complementing efforts to control viral replication, immunotherapies that may assist in the recovery of the immune system have been explored in past and ongoing trials, including IL-2 and IL-7.

The failure of vaccine candidates to protect against HIV infection and progression to AIDS has led to a renewed focus on the biological mechanisms responsible for HIV latency. A limited period of therapy combining anti-retrovirals with drugs targeting the latent reservoir may one day allow for total eradication of HIV infection. Researchers have discovered an abzyme that can destroy the protein gp120 CD4 binding site. This protein is common to all HIV variants as it is the attachment point for B lymphocytes and subsequent compromising of the immune system.

New developments

A turning point for HIV research occurred in 2007, following the bone marrow transplant of HIV sufferer Timothy Ray Brown. Brown underwent the procedure after he developed leukaemia and the donor of the bone marrow possessed a rare genetic mutation that caused Brown's cells to become resistant to HIV. Brown attained the title of the "Berlin Patient" in the HIV research field and is the first man to have been cured of the virus. As of April 2013, two primary approaches are being pursued in the search for a HIV cure: The first is gene therapy that aims to develop a HIV-resistant immune system for patients, and the second is being led by Danish scientists, who are conducting clinical trials to strip the HIV from human DNA and have it destroyed permanently by the immune system.

Three more cases with similarities to the Brown case have occurred since the 2007 discovery; however, they differ because the transplanted marrow has not been confirmed as mutated. Two of the cases were publicized in a July 2013 CNN story that relayed the experience of two patients who had taken antiretroviral therapy for years before they developed lymphoma, a cancer of the lymph nodes. They then underwent lymphoma chemotherapy and bone marrow transplantation, while remaining on an antiretroviral regimen; while they retained traces of HIV four months afterwards, six to nine months after the transplant, the two patients had no detectable trace of HIV in their blood. However, the managing clinician Dr. Timothy Heinrich stated at the Malaysian International AIDS Society Conference where the findings were presented:

It's possible, again, that the virus could return in a week, it could return in a month—in fact, some mathematical modeling predicts that virus could even return one to two years after we stop antiretroviral therapy, so we really don't know what the long-term or full effects of stem cell transplantation and viral persistence is.

In 2014, Dr Warner C. Greene and Dr Gilad Doitsh at the Gladstone Institutes identified pyroptosis as the predominant mechanism that causes the two signature pathogenic events in HIV infection––CD4 T-cell depletion and chronic inflammation. Identifying pyroptosis may provide novel therapeutic opportunities targeting caspase-1, which controls the pyroptotic cell death pathway. Specifically, these findings could open the door to an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Recently, pyroptosis and downstream pathways were also identified as promising targets for treatment of severe coronavirus disease 2019–associated diseases.

In March 2016, researchers at Temple University, Philadelphia, reported that they have used genome editing to delete HIV from T cells. According to the researchers, this approach could lead to a dramatic reduction of the viral load in patient cells.

In April 2016, it was announced the publication of a preclinical animal study using SupT1 cells as a decoy target for the HIV virus, aiming to move infection from the patient's cells to the inoculated cells, and therefore to induce the virus to become less aggressive by replicating in such permissive cells.

In March 2019, a patient with Hodgkin's lymphoma was also reported to possibly have been cured using similar treatment to Brown.

In 2022, Moderna announced that the first participants have been vaccinated in a Phase 1 clinical trial of an experimental HIV vaccine that utilizes Moderna's mRNA technology.

HIV/AIDS

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/HIV/AIDS 

 

HIV/AIDS
Other names	HIV disease, HIV infection
The red ribbon is a symbol for solidarity with HIV-positive people and those living with AIDS.
Specialty	Infectious disease, immunology
Symptoms	Early: Flu-like illness Later: Large lymph nodes, fever, weight loss
Complications	Opportunistic infections, tumors
Duration	Lifelong
Causes	Human immunodeficiency virus (HIV)
Risk factors	Unprotected anal or vaginal sex, having another sexually transmitted infection, needle sharing, medical procedures involving unsterile cutting or piercing, and experiencing needlestick injury
Diagnostic method	Blood tests
Prevention	Safe sex, needle exchange, male circumcision, pre-exposure prophylaxis, post-exposure prophylaxis
Treatment	Antiretroviral therapy
Prognosis	Near normal life expectancy with treatment 11 years life expectancy without treatment
Frequency	64.4 million – 113 million total cases 1.5 million new cases (2021) 38.4 million living with HIV (2021)
Deaths	40.1 million total deaths 650,000 (2021)

Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual may not notice any symptoms, or may experience a brief period of influenza-like illness. Typically, this is followed by a prolonged incubation period with no symptoms. If the infection progresses, it interferes more with the immune system, increasing the risk of developing common infections such as tuberculosis, as well as other opportunistic infections, and tumors which are rare in people who have normal immune function. These late symptoms of infection are referred to as acquired immunodeficiency syndrome (AIDS). This stage is often also associated with unintended weight loss.

HIV is spread primarily by unprotected sex (including anal and vaginal sex), contaminated hypodermic needles or blood transfusions, and from mother to child during pregnancy, delivery, or breastfeeding. Some bodily fluids, such as saliva, sweat, and tears, do not transmit the virus. Oral sex has little to no risk of transmitting the virus. Methods of prevention include safe sex, needle exchange programs, treating those who are infected, as well as both pre- and post-exposure prophylaxis. Disease in a baby can often be prevented by giving both the mother and child antiretroviral medication.

Recognized worldwide in the early 1980s, HIV/AIDS has had a large impact on society, both as an illness and as a source of discrimination. The disease also has large economic impacts. There are many misconceptions about HIV/AIDS, such as the belief that it can be transmitted by casual non-sexual contact. The disease has become subject to many controversies involving religion, including the Catholic Church's position not to support condom use as prevention. It has attracted international medical and political attention as well as large-scale funding since it was identified in the 1980s.

HIV made the jump from other primates to humans in west-central Africa in the early-to-mid 20th century. AIDS was first recognized by the U.S. Centers for Disease Control and Prevention (CDC) in 1981 and its cause—HIV infection—was identified in the early part of the decade. Between the first time AIDS was readily identified through 2021, the disease is estimated to have caused at least 40 million deaths worldwide. In 2021, there were 650,000 deaths and about 38 million people worldwide living with HIV. An estimated 20.6 million of these people live in eastern and southern Africa. HIV/AIDS is considered a pandemic—a disease outbreak which is present over a large area and is actively spreading.

The United States' National Institutes of Health (NIH) and the Gates Foundation have pledged $200 million focused on developing a global cure for AIDS. While there is no cure or vaccine, antiretroviral treatment can slow the course of the disease and may lead to a near-normal life expectancy. Treatment is recommended as soon as the diagnosis is made. Without treatment, the average survival time after infection is 11 years.

Signs and symptoms

Main article: Signs and symptoms of HIV/AIDS

There are three main stages of HIV infection: acute infection, clinical latency, and AIDS.

Acute infection

Main symptoms of acute HIV infection

The initial period following the contraction of HIV is called acute HIV, primary HIV or acute retroviral syndrome. Many individuals develop an influenza-like illness or a mononucleosis-like illness 2–4 weeks after exposure while others have no significant symptoms. Symptoms occur in 40–90% of cases and most commonly include fever, large tender lymph nodes, throat inflammation, a rash, headache, tiredness, and/or sores of the mouth and genitals. The rash, which occurs in 20–50% of cases, presents itself on the trunk and is maculopapular, classically. Some people also develop opportunistic infections at this stage. Gastrointestinal symptoms, such as vomiting or diarrhea may occur. Neurological symptoms of peripheral neuropathy or Guillain–Barré syndrome also occur. The duration of the symptoms varies, but is usually one or two weeks.

Owing to their nonspecific character, these symptoms are not often recognized as signs of HIV infection. Even cases that do get seen by a family doctor or a hospital are often misdiagnosed as one of the many common infectious diseases with overlapping symptoms. Thus, it is recommended that HIV be considered in people presenting with an unexplained fever who may have risk factors for the infection.

Clinical latency

The initial symptoms are followed by a stage called clinical latency, asymptomatic HIV, or chronic HIV. Without treatment, this second stage of the natural history of HIV infection can last from about three years to over 20 years (on average, about eight years). While typically there are few or no symptoms at first, near the end of this stage many people experience fever, weight loss, gastrointestinal problems and muscle pains. Between 50% and 70% of people also develop persistent generalized lymphadenopathy, characterized by unexplained, non-painful enlargement of more than one group of lymph nodes (other than in the groin) for over three to six months.

Although most HIV-1 infected individuals have a detectable viral load and in the absence of treatment will eventually progress to AIDS, a small proportion (about 5%) retain high levels of CD4⁺ T cells (T helper cells) without antiretroviral therapy for more than five years. These individuals are classified as "HIV controllers" or long-term nonprogressors (LTNP). Another group consists of those who maintain a low or undetectable viral load without anti-retroviral treatment, known as "elite controllers" or "elite suppressors". They represent approximately 1 in 300 infected persons.

Acquired immunodeficiency syndrome

Main symptoms of AIDS

Acquired immunodeficiency syndrome (AIDS) is defined as an HIV infection with either a CD4⁺ T cell count below 200 cells per µL or the occurrence of specific diseases associated with HIV infection. In the absence of specific treatment, around half of people infected with HIV develop AIDS within ten years. The most common initial conditions that alert to the presence of AIDS are pneumocystis pneumonia (40%), cachexia in the form of HIV wasting syndrome (20%), and esophageal candidiasis. Other common signs include recurrent respiratory tract infections.

Opportunistic infections may be caused by bacteria, viruses, fungi, and parasites that are normally controlled by the immune system. Which infections occur depends partly on what organisms are common in the person's environment. These infections may affect nearly every organ system.

People with AIDS have an increased risk of developing various viral-induced cancers, including Kaposi's sarcoma, Burkitt's lymphoma, primary central nervous system lymphoma, and cervical cancer. Kaposi's sarcoma is the most common cancer, occurring in 10% to 20% of people with HIV. The second-most common cancer is lymphoma, which is the cause of death of nearly 16% of people with AIDS and is the initial sign of AIDS in 3% to 4%. Both these cancers are associated with human herpesvirus 8 (HHV-8). Cervical cancer occurs more frequently in those with AIDS because of its association with human papillomavirus (HPV). Conjunctival cancer (of the layer that lines the inner part of eyelids and the white part of the eye) is also more common in those with HIV.

Additionally, people with AIDS frequently have systemic symptoms such as prolonged fevers, sweats (particularly at night), swollen lymph nodes, chills, weakness, and unintended weight loss. Diarrhea is another common symptom, present in about 90% of people with AIDS. They can also be affected by diverse psychiatric and neurological symptoms independent of opportunistic infections and cancers.

Transmission

Average per act risk of getting HIV
by exposure route to an infected source

Exposure route	Chance of infection
Blood transfusion	90%
Childbirth (to child)	25%
Needle-sharing injection drug use	0.67%
Percutaneous needle stick	0.30%
Receptive anal intercourse*	0.04–3.0%
Insertive anal intercourse*	0.03%
Receptive penile-vaginal intercourse*	0.05–0.30%
Insertive penile-vaginal intercourse*	0.01–0.38%
Receptive oral intercourse*§	0–0.04%
Insertive oral intercourse*§	0–0.005%
* assuming no condom use § source refers to oral intercourse performed on a man

HIV is spread by three main routes: sexual contact, significant exposure to infected body fluids or tissues, and from mother to child during pregnancy, delivery, or breastfeeding (known as vertical transmission).^[13] There is no risk of acquiring HIV if exposed to feces, nasal secretions, saliva, sputum, sweat, tears, urine, or vomit unless these are contaminated with blood.^[52] It is also possible to be co-infected by more than one strain of HIV—a condition known as HIV superinfection.^[53]

Sexual

The most frequent mode of transmission of HIV is through sexual contact with an infected person. However, an HIV-positive person who has an undetectable viral load as a result of long-term treatment has effectively no risk of transmitting HIV sexually. The existence of functionally noncontagious HIV-positive people on antiretroviral therapy was controversially publicized in the 2008 Swiss Statement, and has since become accepted as medically sound.

Globally, the most common mode of HIV transmission is via sexual contacts between people of the opposite sex; however, the pattern of transmission varies among countries. As of 2017, most HIV transmission in the United States occurred among men who had sex with men (82% of new HIV diagnoses among males aged 13 and older and 70% of total new diagnoses). In the US, gay and bisexual men aged 13 to 24 accounted for an estimated 92% of new HIV diagnoses among all men in their age group and 27% of new diagnoses among all gay and bisexual men.

With regard to unprotected heterosexual contacts, estimates of the risk of HIV transmission per sexual act appear to be four to ten times higher in low-income countries than in high-income countries. In low-income countries, the risk of female-to-male transmission is estimated as 0.38% per act, and of male-to-female transmission as 0.30% per act; the equivalent estimates for high-income countries are 0.04% per act for female-to-male transmission, and 0.08% per act for male-to-female transmission. The risk of transmission from anal intercourse is especially high, estimated as 1.4–1.7% per act in both heterosexual and homosexual contacts. While the risk of transmission from oral sex is relatively low, it is still present. The risk from receiving oral sex has been described as "nearly nil"; however, a few cases have been reported. The per-act risk is estimated at 0–0.04% for receptive oral intercourse. In settings involving prostitution in low-income countries, risk of female-to-male transmission has been estimated as 2.4% per act, and of male-to-female transmission as 0.05% per act.

Risk of transmission increases in the presence of many sexually transmitted infections and genital ulcers. Genital ulcers appear to increase the risk approximately fivefold. Other sexually transmitted infections, such as gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, are associated with somewhat smaller increases in risk of transmission.

The viral load of an infected person is an important risk factor in both sexual and mother-to-child transmission. During the first 2.5 months of an HIV infection a person's infectiousness is twelve times higher due to the high viral load associated with acute HIV. If the person is in the late stages of infection, rates of transmission are approximately eightfold greater.

Commercial sex workers (including those in pornography) have an increased likelihood of contracting HIV. Rough sex can be a factor associated with an increased risk of transmission. Sexual assault is also believed to carry an increased risk of HIV transmission as condoms are rarely worn, physical trauma to the vagina or rectum is likely, and there may be a greater risk of concurrent sexually transmitted infections.

Body fluids

CDC poster from 1989 highlighting the threat of AIDS associated with drug use

The second-most frequent mode of HIV transmission is via blood and blood products. Blood-borne transmission can be through needle-sharing during intravenous drug use, needle-stick injury, transfusion of contaminated blood or blood product, or medical injections with unsterilized equipment. The risk from sharing a needle during drug injection is between 0.63% and 2.4% per act, with an average of 0.8%. The risk of acquiring HIV from a needle stick from an HIV-infected person is estimated as 0.3% (about 1 in 333) per act and the risk following mucous membrane exposure to infected blood as 0.09% (about 1 in 1000) per act. This risk may, however, be up to 5% if the introduced blood was from a person with a high viral load and the cut was deep. In the United States, intravenous drug users made up 12% of all new cases of HIV in 2009, and in some areas more than 80% of people who inject drugs are HIV-positive.

HIV is transmitted in about 90% of blood transfusions using infected blood. In developed countries the risk of acquiring HIV from a blood transfusion is extremely low (less than one in half a million) where improved donor selection and HIV screening is performed; for example, in the UK the risk is reported at one in five million and in the United States it was one in 1.5 million in 2008. In low-income countries, only half of transfusions may be appropriately screened (as of 2008), and it is estimated that up to 15% of HIV infections in these areas come from transfusion of infected blood and blood products, representing between 5% and 10% of global infections. It is possible to acquire HIV from organ and tissue transplantation, although this is rare because of screening.

Unsafe medical injections play a role in HIV spread in sub-Saharan Africa. In 2007, between 12% and 17% of infections in this region were attributed to medical syringe use. The World Health Organization estimates the risk of transmission as a result of a medical injection in Africa at 1.2%. Risks are also associated with invasive procedures, assisted delivery, and dental care in this area of the world.

People giving or receiving tattoos, piercings, and scarification are theoretically at risk of infection but no confirmed cases have been documented. It is not possible for mosquitoes or other insects to transmit HIV.

Mother-to-child

Main articles: HIV and pregnancy and HIV and breastfeeding

HIV can be transmitted from mother to child during pregnancy, during delivery, or through breast milk, resulting in the baby also contracting HIV. As of 2008, vertical transmission accounted for about 90% of cases of HIV in children. In the absence of treatment, the risk of transmission before or during birth is around 20%, and in those who also breastfeed 35%. Treatment decreases this risk to less than 5%.

Antiretrovirals when taken by either the mother or the baby decrease the risk of transmission in those who do breastfeed. If blood contaminates food during pre-chewing it may pose a risk of transmission. If a woman is untreated, two years of breastfeeding results in an HIV/AIDS risk in her baby of about 17%. Due to the increased risk of death without breastfeeding in many areas in the developing world, the World Health Organization recommends either exclusive breastfeeding or the provision of safe formula. All women known to be HIV-positive should be taking lifelong antiretroviral therapy.

Virology

Main article: HIV

 

Diagram of a HIV virion structure

 

Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte

HIV is the cause of the spectrum of disease known as HIV/AIDS. HIV is a retrovirus that primarily infects components of the human immune system such as CD4⁺ T cells, macrophages and dendritic cells. It directly and indirectly destroys CD4⁺ T cells.

HIV is a member of the genus Lentivirus, part of the family Retroviridae. Lentiviruses share many morphological and biological characteristics. Many species of mammals are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factors. Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle anew.

HIV is now known to spread between CD4⁺ T cells by two parallel routes: cell-free spread and cell-to-cell spread, i.e. it employs hybrid spreading mechanisms. In the cell-free spread, virus particles bud from an infected T cell, enter the blood/extracellular fluid and then infect another T cell following a chance encounter. HIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread. The hybrid spreading mechanisms of HIV contribute to the virus's ongoing replication against antiretroviral therapies.

Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was originally discovered (and initially referred to also as LAV or HTLV-III). It is more virulent, more infective, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 as compared with HIV-1 implies that fewer people exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.

Pathophysiology

Main article: Pathophysiology of HIV/AIDS

 

HIV replication cycle

After the virus enters the body, there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood. This response is accompanied by a marked drop in the number of circulating CD4⁺ T cells. The acute viremia is almost invariably associated with activation of CD8⁺ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8⁺ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4⁺ T cell counts recover. A good CD8⁺ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.

Ultimately, HIV causes AIDS by depleting CD4⁺ T cells. This weakens the immune system and allows opportunistic infections. T cells are essential to the immune response and without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4⁺ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV-induced cell lysis and killing of infected cells by CD8⁺ T cells accounts for CD4⁺ T cell depletion, although apoptosis may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4⁺ T cell numbers.

Although the symptoms of immune deficiency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4⁺ T cell loss occurs during the first weeks of infection, especially in the intestinal mucosa, which harbors the majority of the lymphocytes found in the body. The reason for the preferential loss of mucosal CD4⁺ T cells is that the majority of mucosal CD4⁺ T cells express the CCR5 protein which HIV uses as a co-receptor to gain access to the cells, whereas only a small fraction of CD4⁺ T cells in the bloodstream do so. A specific genetic change that alters the CCR5 protein when present in both chromosomes very effectively prevents HIV-1 infection.

HIV seeks out and destroys CCR5 expressing CD4⁺ T cells during acute infection. A vigorous immune response eventually controls the infection and initiates the clinically latent phase. CD4⁺ T cells in mucosal tissues remain particularly affected. Continuous HIV replication causes a state of generalized immune activation persisting throughout the chronic phase. Immune activation, which is reflected by the increased activation state of immune cells and release of pro-inflammatory cytokines, results from the activity of several HIV gene products and the immune response to ongoing HIV replication. It is also linked to the breakdown of the immune surveillance system of the gastrointestinal mucosal barrier caused by the depletion of mucosal CD4⁺ T cells during the acute phase of disease.

Diagnosis

Main article: Diagnosis of HIV/AIDS

 

A generalized graph of the relationship between HIV copies (viral load) and CD4⁺ T cell counts over the average course of untreated HIV infection.

  CD4⁺ T Lymphocyte count (cells/mm³)

  HIV RNA copies per mL of plasma

 

Days after exposure needed for the test to be accurate

Blood test	Days
Antibody test (rapid test, ELISA 3rd gen)	23–90
Antibody and p24 antigen test (ELISA 4th gen)	18–45
PCR	10–33

HIV/AIDS is diagnosed via laboratory testing and then staged based on the presence of certain signs or symptoms. HIV screening is recommended by the United States Preventive Services Task Force for all people 15 years to 65 years of age, including all pregnant women. Additionally, testing is recommended for those at high risk, which includes anyone diagnosed with a sexually transmitted illness. In many areas of the world, a third of HIV carriers only discover they are infected at an advanced stage of the disease when AIDS or severe immunodeficiency has become apparent.

HIV testing

HIV rapid test being administered

 

Oraquick

Most people infected with HIV develop specific antibodies (i.e. seroconvert) within three to twelve weeks after the initial infection. Diagnosis of primary HIV before seroconversion is done by measuring HIV-RNA or p24 antigen. Positive results obtained by antibody or PCR testing are confirmed either by a different antibody or by PCR.

Antibody tests in children younger than 18 months are typically inaccurate, due to the continued presence of maternal antibodies. Thus HIV infection can only be diagnosed by PCR testing for HIV RNA or DNA, or via testing for the p24 antigen. Much of the world lacks access to reliable PCR testing, and people in many places simply wait until either symptoms develop or the child is old enough for accurate antibody testing. In sub-Saharan Africa between 2007 and 2009, between 30% and 70% of the population were aware of their HIV status. In 2009, between 3.6% and 42% of men and women in sub-Saharan countries were tested; this represented a significant increase compared to previous years.

Classifications

Two main clinical staging systems are used to classify HIV and HIV-related disease for surveillance purposes: the WHO disease staging system for HIV infection and disease, and the CDC classification system for HIV infection. The CDC's classification system is more frequently adopted in developed countries. Since the WHO's staging system does not require laboratory tests, it is suited to the resource-restricted conditions encountered in developing countries, where it can also be used to help guide clinical management. Despite their differences, the two systems allow a comparison for statistical purposes.

The World Health Organization first proposed a definition for AIDS in 1986. Since then, the WHO classification has been updated and expanded several times, with the most recent version being published in 2007. The WHO system uses the following categories:

• Primary HIV infection: May be either asymptomatic or associated with acute retroviral syndrome
• Stage I: HIV infection is asymptomatic with a CD4⁺ T cell count (also known as CD4 count) greater than 500 per microlitre (µl or cubic mm) of blood. May include generalized lymph node enlargement.
• Stage II: Mild symptoms, which may include minor mucocutaneous manifestations and recurrent upper respiratory tract infections. A CD4 count of less than 500/µl
• Stage III: Advanced symptoms, which may include unexplained chronic diarrhea for longer than a month, severe bacterial infections including tuberculosis of the lung, and a CD4 count of less than 350/µl
• Stage IV or AIDS: severe symptoms, which include toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi, or lungs, and Kaposi's sarcoma. A CD4 count of less than 200/µl

The U.S. Centers for Disease Control and Prevention also created a classification system for HIV, and updated it in 2008 and 2014. This system classifies HIV infections based on CD4 count and clinical symptoms, and describes the infection in five groups. In those greater than six years of age it is:

• Stage 0: the time between a negative or indeterminate HIV test followed less than 180 days by a positive test.
• Stage 1: CD4 count ≥ 500 cells/µl and no AIDS-defining conditions.
• Stage 2: CD4 count 200 to 500 cells/µl and no AIDS-defining conditions.
• Stage 3: CD4 count ≤ 200 cells/µl or AIDS-defining conditions.
• Unknown: if insufficient information is available to make any of the above classifications.

For surveillance purposes, the AIDS diagnosis still stands even if, after treatment, the CD4⁺ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

Prevention

Main article: Prevention of HIV/AIDS

 

AIDS clinic, McLeod Ganj, Himachal Pradesh, India, 2010

Sexual contact

People wearing AIDS awareness signs. On the left: "Facing AIDS a condom and a pill at a time"; on the right: "I am Facing AIDS because people I ♥ are infected"

Consistent condom use reduces the risk of HIV transmission by approximately 80% over the long term. When condoms are used consistently by a couple in which one person is infected, the rate of HIV infection is less than 1% per year. There is some evidence to suggest that female condoms may provide an equivalent level of protection. Application of a vaginal gel containing tenofovir (a reverse transcriptase inhibitor) immediately before sex seems to reduce infection rates by approximately 40% among African women. By contrast, use of the spermicide nonoxynol-9 may increase the risk of transmission due to its tendency to cause vaginal and rectal irritation.

Circumcision in sub-Saharan Africa "reduces the acquisition of HIV by heterosexual men by between 38% and 66% over 24 months". Owing to these studies, both the World Health Organization and UNAIDS recommended male circumcision in 2007 as a method of preventing female-to-male HIV transmission in areas with high rates of HIV. However, whether it protects against male-to-female transmission is disputed, and whether it is of benefit in developed countries and among men who have sex with men is undetermined.

Programs encouraging sexual abstinence do not appear to affect subsequent HIV risk. Evidence of any benefit from peer education is equally poor. Comprehensive sexual education provided at school may decrease high-risk behavior. A substantial minority of young people continues to engage in high-risk practices despite knowing about HIV/AIDS, underestimating their own risk of becoming infected with HIV. Voluntary counseling and testing people for HIV does not affect risky behavior in those who test negative but does increase condom use in those who test positive. Enhanced family planning services appear to increase the likelihood of women with HIV using contraception, compared to basic services. It is not known whether treating other sexually transmitted infections is effective in preventing HIV.

Pre-exposure

Antiretroviral treatment among people with HIV whose CD4 count ≤ 550 cells/µL is a very effective way to prevent HIV infection of their partner (a strategy known as treatment as prevention, or TASP). TASP is associated with a 10- to 20-fold reduction in transmission risk. Pre-exposure prophylaxis (PrEP) with a daily dose of the medications tenofovir, with or without emtricitabine, is effective in people at high risk including men who have sex with men, couples where one is HIV-positive, and young heterosexuals in Africa. It may also be effective in intravenous drug users, with a study finding a decrease in risk of 0.7 to 0.4 per 100 person years. The USPSTF, in 2019, recommended PrEP in those who are at high risk.

Universal precautions within the health care environment are believed to be effective in decreasing the risk of HIV. Intravenous drug use is an important risk factor, and harm reduction strategies such as needle-exchange programs and opioid substitution therapy appear effective in decreasing this risk.

Post-exposure

A course of antiretrovirals administered within 48 to 72 hours after exposure to HIV-positive blood or genital secretions is referred to as post-exposure prophylaxis (PEP). The use of the single agent zidovudine reduces the risk of a HIV infection five-fold following a needle-stick injury. As of 2013, the prevention regimen recommended in the United States consists of three medications—tenofovir, emtricitabine and raltegravir—as this may reduce the risk further.

PEP treatment is recommended after a sexual assault when the perpetrator is known to be HIV-positive, but is controversial when their HIV status is unknown. The duration of treatment is usually four weeks and is frequently associated with adverse effects—where zidovudine is used, about 70% of cases result in adverse effects such as nausea (24%), fatigue (22%), emotional distress (13%) and headaches (9%).

Mother-to-child

Main article: HIV and pregnancy

Programs to prevent the vertical transmission of HIV (from mothers to children) can reduce rates of transmission by 92–99%. This primarily involves the use of a combination of antiviral medications during pregnancy and after birth in the infant, and potentially includes bottle feeding rather than breastfeeding. If replacement feeding is acceptable, feasible, affordable, sustainable and safe, mothers should avoid breastfeeding their infants; however, exclusive breastfeeding is recommended during the first months of life if this is not the case. If exclusive breastfeeding is carried out, the provision of extended antiretroviral prophylaxis to the infant decreases the risk of transmission. In 2015, Cuba became the first country in the world to eradicate mother-to-child transmission of HIV.

Vaccination

Main article: HIV vaccine

Currently there is no licensed vaccine for HIV or AIDS. The most effective vaccine trial to date, RV 144, was published in 2009; it found a partial reduction in the risk of transmission of roughly 30%, stimulating some hope in the research community of developing a truly effective vaccine.

Treatment

Main article: Management of HIV/AIDS

There is currently no cure, nor an effective HIV vaccine. Treatment consists of highly active antiretroviral therapy (HAART), which slows progression of the disease. As of 2010, more than 6.6 million people were receiving HAART in low- and middle-income countries. Treatment also includes preventive and active treatment of opportunistic infections. As of July 2022, four people have been successfully cleared of HIV. Rapid initiation of antiretroviral therapy within one week of diagnosis appear to improve treatment outcomes in low and medium-income settings and is recommend for newly diagnosed HIV patients.

Antiviral therapy

Stribild – a common once-daily ART regime consisting of elvitegravir, emtricitabine, tenofovir and the booster cobicistat

Current HAART options are combinations (or "cocktails") consisting of at least three medications belonging to at least two types, or "classes", of antiretroviral agents. Initially, treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analog reverse transcriptase inhibitors (NRTIs). Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). As of 2019, dolutegravir/lamivudine/tenofovir is listed by the World Health Organization as the first-line treatment for adults, with tenofovir/lamivudine/efavirenz as an alternative. Combinations of agents that include protease inhibitors (PI) are used if the above regimen loses effectiveness.

The World Health Organization and the United States recommend antiretrovirals in people of all ages (including pregnant women) as soon as the diagnosis is made, regardless of CD4 count. Once treatment is begun, it is recommended that it is continued without breaks or "holidays". Many people are diagnosed only after treatment ideally should have begun. The desired outcome of treatment is a long-term plasma HIV-RNA count below 50 copies/mL. Levels to determine if treatment is effective are initially recommended after four weeks and once levels fall below 50 copies/mL checks every three to six months are typically adequate. Inadequate control is deemed to be greater than 400 copies/mL. Based on these criteria treatment is effective in more than 95% of people during the first year.

Benefits of treatment include a decreased risk of progression to AIDS and a decreased risk of death. In the developing world, treatment also improves physical and mental health. With treatment, there is a 70% reduced risk of acquiring tuberculosis. Additional benefits include a decreased risk of transmission of the disease to sexual partners and a decrease in mother-to-child transmission. The effectiveness of treatment depends to a large part on compliance. Reasons for non-adherence to treatment include poor access to medical care, inadequate social supports, mental illness and drug abuse. The complexity of treatment regimens (due to pill numbers and dosing frequency) and adverse effects may reduce adherence. Even though cost is an important issue with some medications, 47% of those who needed them were taking them in low- and middle-income countries as of 2010, and the rate of adherence is similar in low-income and high-income countries.

Specific adverse events are related to the antiretroviral agent taken. Some relatively common adverse events include: lipodystrophy syndrome, dyslipidemia, and diabetes mellitus, especially with protease inhibitors. Other common symptoms include diarrhea, and an increased risk of cardiovascular disease. Newer recommended treatments are associated with fewer adverse effects. Certain medications may be associated with birth defects and therefore may be unsuitable for women hoping to have children.

Treatment recommendations for children are somewhat different from those for adults. The World Health Organization recommends treating all children less than five years of age; children above five are treated like adults. The United States guidelines recommend treating all children less than 12 months of age and all those with HIV RNA counts greater than 100,000 copies/mL between one year and five years of age.

The European Medicines Agency (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection. The two medicines are the first ARVs that come in a long-acting injectable formulation. This means that instead of daily pills, people receive intramuscular injections monthly or every two months.

The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to a certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).

Cabotegravir combined with rilpivirine (Cabenuva) is a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace a current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

Opportunistic infections

Main article: Opportunistic infection § Opportunistic Infection and HIV/AIDS

Measures to prevent opportunistic infections are effective in many people with HIV/AIDS. In addition to improving current disease, treatment with antiretrovirals reduces the risk of developing additional opportunistic infections.

Adults and adolescents who are living with HIV (even on anti-retroviral therapy) with no evidence of active tuberculosis in settings with high tuberculosis burden should receive isoniazid preventive therapy (IPT); the tuberculin skin test can be used to help decide if IPT is needed. Children with HIV may benefit from screening for tuberculosis. Vaccination against hepatitis A and B is advised for all people at risk of HIV before they become infected; however, it may also be given after infection.

Trimethoprim/sulfamethoxazole prophylaxis between four and six weeks of age, and ceasing breastfeeding of infants born to HIV-positive mothers, is recommended in resource-limited settings. It is also recommended to prevent PCP when a person's CD4 count is below 200 cells/uL and in those who have or have previously had PCP. People with substantial immunosuppression are also advised to receive prophylactic therapy for toxoplasmosis and MAC. Appropriate preventive measures reduced the rate of these infections by 50% between 1992 and 1997. Influenza vaccination and pneumococcal polysaccharide vaccine are often recommended in people with HIV/AIDS with some evidence of benefit.

Diet

Main article: Nutrition and HIV/AIDS

The World Health Organization (WHO) has issued recommendations regarding nutrient requirements in HIV/AIDS. A generally healthy diet is promoted. Dietary intake of micronutrients at RDA levels by HIV-infected adults is recommended by the WHO; higher intake of vitamin A, zinc, and iron can produce adverse effects in HIV-positive adults, and is not recommended unless there is documented deficiency. Dietary supplementation for people who are infected with HIV and who have inadequate nutrition or dietary deficiencies may strengthen their immune systems or help them recover from infections; however, evidence indicating an overall benefit in morbidity or reduction in mortality is not consistent.

People with HIV/AIDS are up to four times more likely to develop type 2 diabetes than those who are not tested positive with the virus.

Evidence for supplementation with selenium is mixed with some tentative evidence of benefit. For pregnant and lactating women with HIV, multivitamin supplement improves outcomes for both mothers and children. If the pregnant or lactating mother has been advised to take anti-retroviral medication to prevent mother-to-child HIV transmission, multivitamin supplements should not replace these treatments. There is some evidence that vitamin A supplementation in children with an HIV infection reduces mortality and improves growth.

Alternative medicine

In the US, approximately 60% of people with HIV use various forms of complementary or alternative medicine, whose effectiveness has not been established. There is not enough evidence to support the use of herbal medicines. There is insufficient evidence to recommend or support the use of medical cannabis to try to increase appetite or weight gain.

Prognosis

Deaths due to HIV/AIDS per million people in 2012:

  0

  1–4

  5–12

  13–34

  35–61

  62–134

  135–215

  216–458

  459–1,402

  1,403–5,828

HIV/AIDS has become a chronic rather than an acutely fatal disease in many areas of the world. Prognosis varies between people, and both the CD4 count and viral load are useful for predicted outcomes. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. After the diagnosis of AIDS, if treatment is not available, survival ranges between 6 and 19 months. HAART and appropriate prevention of opportunistic infections reduces the death rate by 80%, and raises the life expectancy for a newly diagnosed young adult to 20–50 years. This is between two thirds and nearly that of the general population. If treatment is started late in the infection, prognosis is not as good: for example, if treatment is begun following the diagnosis of AIDS, life expectancy is ~10–40 years. Half of infants born with HIV die before two years of age without treatment.

Disability-adjusted life year for HIV and AIDS per 100,000 inhabitants as of 2004:

no data   ≤ 10   10–25   25–50   50–100

100–500   500–1000   1,000–2,500   2,500–5,000   5,000–7500

7,500–10,000   10,000–50,000   ≥ 50,000

The primary causes of death from HIV/AIDS are opportunistic infections and cancer, both of which are frequently the result of the progressive failure of the immune system. Risk of cancer appears to increase once the CD4 count is below 500/μL. The rate of clinical disease progression varies widely between individuals and has been shown to be affected by a number of factors such as a person's susceptibility and immune function; their access to health care, the presence of co-infections; and the particular strain (or strains) of the virus involved.

Tuberculosis co-infection is one of the leading causes of sickness and death in those with HIV/AIDS being present in a third of all HIV-infected people and causing 25% of HIV-related deaths. HIV is also one of the most important risk factors for tuberculosis. Hepatitis C is another very common co-infection where each disease increases the progression of the other. The two most common cancers associated with HIV/AIDS are Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphoma. Other cancers that are more frequent include anal cancer, Burkitt's lymphoma, primary central nervous system lymphoma, and cervical cancer.

Even with anti-retroviral treatment, over the long term HIV-infected people may experience neurocognitive disorders, osteoporosis, neuropathy, cancers, nephropathy, and cardiovascular disease. Some conditions, such as lipodystrophy, may be caused both by HIV and its treatment.

Epidemiology

Main article: Epidemiology of HIV/AIDS

Percentage of people with HIV/AIDS

Trends in new cases and deaths per year from HIV/AIDS

Some authors consider HIV/AIDS a global pandemic. As of 2016, approximately 36.7 million people worldwide have HIV, the number of new infections that year being about 1.8 million. This is down from 3.1 million new infections in 2001. Slightly over half the infected population are women and 2.1 million are children. It resulted in about 1 million deaths in 2016, down from a peak of 1.9 million in 2005.

Sub-Saharan Africa is the region most affected. In 2010, an estimated 68% (22.9 million) of all HIV cases and 66% of all deaths (1.2 million) occurred in this region. This means that about 5% of the adult population is infected and it is believed to be the cause of 10% of all deaths in children. Here, in contrast to other regions, women comprise nearly 60% of cases. South Africa has the largest population of people with HIV of any country in the world at 5.9 million. Life expectancy has fallen in the worst-affected countries due to HIV/AIDS; for example, in 2006 it was estimated that it had dropped from 65 to 35 years in Botswana. Mother-to-child transmission in Botswana and South Africa, as of 2013, has decreased to less than 5%, with improvement in many other African nations due to improved access to antiretroviral therapy.

South & South East Asia is the second most affected; in 2010 this region contained an estimated 4 million cases or 12% of all people living with HIV resulting in approximately 250,000 deaths. Approximately 2.4 million of these cases are in India.

During 2008 in the United States approximately 1.2 million people aged ≥13 years were living with HIV, resulting in about 17,500 deaths. The US Centers for Disease Control and Prevention estimated that in that year, 236,400 people or 20% of infected Americans were unaware of their infection. As of 2016 about 675,000 people have died of HIV/AIDS in the US since the beginning of the HIV epidemic. In the United Kingdom as of 2015, there were approximately 101,200 cases which resulted in 594 deaths. In Canada as of 2008, there were about 65,000 cases causing 53 deaths. Between the first recognition of AIDS (in 1981) and 2009, it has led to nearly 30 million deaths. Rates of HIV are lowest in North Africa and the Middle East (0.1% or less), East Asia (0.1%), and Western and Central Europe (0.2%). The worst-affected European countries, in 2009 and 2012 estimates, are Russia, Ukraine, Latvia, Moldova, Portugal and Belarus, in decreasing order of prevalence.

History

Main article: History of HIV/AIDS

For a chronological guide, see Timeline of HIV/AIDS.

Further information: Category:HIV/AIDS by country

Discovery

The Morbidity and Mortality Weekly Report reported in 1981 on what was later to be called "AIDS".

The first news story on the disease appeared on May 18, 1981, in the gay newspaper New York Native. AIDS was first clinically reported on June 5, 1981, with five cases in the United States. The initial cases were a cluster of injecting drug users and gay men with no known cause of impaired immunity who showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to occur in people with very compromised immune systems. Soon thereafter, a large number of homosexual men developed a generally rare skin cancer called Kaposi's sarcoma (KS). Many more cases of PCP and KS emerged, alerting U.S. Centers for Disease Control and Prevention (CDC) and a CDC task force was formed to monitor the outbreak.

In the early days, the CDC did not have an official name for the disease, often referring to it by way of diseases associated with it, such as lymphadenopathy, the disease after which the discoverers of HIV originally named the virus. They also used Kaposi's sarcoma and opportunistic infections, the name by which a task force had been set up in 1981. At one point the CDC referred to it as the "4H disease", as the syndrome seemed to affect heroin users, homosexuals, hemophiliacs, and Haitians. The term GRID, which stood for gay-related immune deficiency, had also been coined. However, after determining that AIDS was not isolated to the gay community, it was realized that the term GRID was misleading, and the term AIDS was introduced at a meeting in July 1982. By September 1982 the CDC started referring to the disease as AIDS.

In 1983, two separate research groups led by Robert Gallo and Luc Montagnier declared that a novel retrovirus may have been infecting people with AIDS, and published their findings in the same issue of the journal Science. Gallo claimed a virus which his group had isolated from a person with AIDS was strikingly similar in shape to other human T-lymphotropic viruses (HTLVs) that his group had been the first to isolate. Gallo's group called their newly isolated virus HTLV-III. At the same time, Montagnier's group isolated a virus from a person presenting with swelling of the lymph nodes of the neck and physical weakness, two characteristic symptoms of AIDS. Contradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I. Montagnier's group named their isolated virus lymphadenopathy-associated virus (LAV). As these two viruses turned out to be the same, in 1986, LAV and HTLV-III were renamed HIV.

Origins

Left to right: the African green monkey source of SIV, the sooty mangabey source of HIV-2, and the chimpanzee source of HIV-1

The origin of HIV / AIDS and the circumstances that led to its emergence remain unsolved.

Both HIV-1 and HIV-2 are believed to have originated in non-human primates in West-central Africa and were transferred to humans in the early 20th century. HIV-1 appears to have originated in southern Cameroon through the evolution of SIV(cpz), a simian immunodeficiency virus (SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes). The closest relative of HIV-2 is SIV (smm), a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey living in coastal West Africa (from southern Senegal to western Ivory Coast). New World monkeys such as the owl monkey are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes. HIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O.

There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV. However, SIV is a weak virus which is typically suppressed by the human immune system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV. Furthermore, due to its relatively low person-to-person transmission rate, SIV can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa before the 20th century.

Specific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout society, depend on the proposed timing of the animal-to-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to c. 1910. Proponents of this dating link the HIV epidemic with the emergence of colonialism and growth of large colonial African cities, leading to social changes, including a higher degree of sexual promiscuity, the spread of prostitution, and the accompanying high frequency of genital ulcer diseases (such as syphilis) in nascent colonial cities. While transmission rates of HIV during vaginal intercourse are low under regular circumstances, they are increased manyfold if one of the partners has a sexually transmitted infection causing genital ulcers. Early 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers, to the degree that, as of 1928, as many as 45% of female residents of eastern Kinshasa were thought to have been prostitutes, and, as of 1933, around 15% of all residents of the same city had syphilis.

An alternative view holds that unsafe medical practices in Africa after World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic and anti-malaria treatment campaigns, were the initial vector that allowed the virus to adapt to humans and spread.

The earliest well-documented case of HIV in a human dates back to 1959 in the Congo. The virus may have been present in the U.S. as early as the mid-to-late 1950s, as a sixteen-year-old male named Robert Rayford presented with symptoms in 1966 and died in 1969. In the 1970s, there were cases of getting parasites and becoming sick with what was called "gay bowel disease", but what is now suspected to have been AIDS.

The earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966, that of Arvid Noe. In July 1960, in the wake of Congo's independence, the United Nations recruited Francophone experts and technicians from all over the world to assist in filling administrative gaps left by Belgium, who did not leave behind an African elite to run the country. By 1962, Haitians made up the second-largest group of well-educated experts (out of the 48 national groups recruited), that totaled around 4500 in the country. Dr. Jacques Pépin, a Canadian author of The Origins of AIDS, stipulates that Haiti was one of HIV's entry points to the U.S. and that a Haitian may have carried HIV back across the Atlantic in the 1960s. Although there was known to have been at least one case of AIDS in the U.S. from 1966, the vast majority of infections occurring outside sub-Saharan Africa (including the U.S.) can be traced back to a single unknown individual who became infected with HIV in Haiti and brought the infection to the U.S. at some time around 1969. The epidemic rapidly spread among high-risk groups (initially, sexually promiscuous men who have sex with men). By 1978, the prevalence of HIV-1 among gay male residents of New York City and San Francisco was estimated at 5%, suggesting that several thousand individuals in the country had been infected.

Society and culture

Stigma

Main article: Discrimination against people with HIV/AIDS

 

Ryan White became a poster child for HIV after being expelled from school because he was infected.

AIDS stigma exists around the world in a variety of ways, including ostracism, rejection, discrimination and avoidance of HIV-infected people; compulsory HIV testing without prior consent or protection of confidentiality; violence against HIV-infected individuals or people who are perceived to be infected with HIV; and the quarantine of HIV-infected individuals. Stigma-related violence or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing treatment, possibly turning what could be a manageable chronic illness into a death sentence and perpetuating the spread of HIV.

AIDS stigma has been further divided into the following three categories:

• Instrumental AIDS stigma—a reflection of the fear and apprehension that are likely to be associated with any deadly and transmissible illness.
• Symbolic AIDS stigma—the use of HIV/AIDS to express attitudes toward the social groups or lifestyles perceived to be associated with the disease.
• Courtesy AIDS stigma—stigmatization of people connected to the issue of HIV/AIDS or HIV-positive people.

Often, AIDS stigma is expressed in conjunction with one or more other stigmas, particularly those associated with homosexuality, bisexuality, promiscuity, prostitution, and intravenous drug use.

In many developed countries, there is an association between AIDS and homosexuality or bisexuality, and this association is correlated with higher levels of sexual prejudice, such as anti-homosexual or anti-bisexual attitudes. There is also a perceived association between AIDS and all male-male sexual behavior, including sex between uninfected men. However, the dominant mode of spread worldwide for HIV remains heterosexual transmission.

In 2003, as part of an overall reform of marriage and population legislation, it became legal for those diagnosed with AIDS to marry in China.

In 2013, the U.S. National Library of Medicine developed a traveling exhibition titled Surviving and Thriving: AIDS, Politics, and Culture; this covered medical research, the U.S. government's response, and personal stories from people with AIDS, caregivers, and activists.

Economic impact

Main articles: Economic impact of HIV/AIDS and Cost of HIV treatment

 

Changes in life expectancy in some African countries, 1960–2012

HIV/AIDS affects the economics of both individuals and countries. The gross domestic product of the most affected countries has decreased due to the lack of human capital. Without proper nutrition, health care and medicine, large numbers of people die from AIDS-related complications. Before death they will not only be unable to work, but will also require significant medical care. It is estimated that as of 2007 there were 12 million AIDS orphans. Many are cared for by elderly grandparents.

Returning to work after beginning treatment for HIV/AIDS is difficult, and affected people often work less than the average worker. Unemployment in people with HIV/AIDS also is associated with suicidal ideation, memory problems, and social isolation. Employment increases self-esteem, sense of dignity, confidence, and quality of life for people with HIV/AIDS. Anti-retroviral treatment may help people with HIV/AIDS work more, and may increase the chance that a person with HIV/AIDS will be employed (low-quality evidence).

By affecting mainly young adults, AIDS reduces the taxable population, in turn reducing the resources available for public expenditures such as education and health services not related to AIDS, resulting in increasing pressure on the state's finances and slower growth of the economy. This causes a slower growth of the tax base, an effect that is reinforced if there are growing expenditures on treating the sick, training (to replace sick workers), sick pay, and caring for AIDS orphans. This is especially true if the sharp increase in adult mortality shifts the responsibility from the family to the government in caring for these orphans.

At the household level, AIDS causes both loss of income and increased spending on healthcare. A study in Côte d'Ivoire showed that households having a person with HIV/AIDS spent twice as much on medical expenses as other households. This additional expenditure also leaves less income to spend on education and other personal or family investment.

Religion and AIDS

Main article: Religion and HIV/AIDS

The topic of religion and AIDS has become highly controversial, primarily because some religious authorities have publicly declared their opposition to the use of condoms. The religious approach to prevent the spread of AIDS, according to a report by American health expert Matthew Hanley titled The Catholic Church and the Global AIDS Crisis, argues that cultural changes are needed, including a re-emphasis on fidelity within marriage and sexual abstinence outside of it.

Some religious organizations have claimed that prayer can cure HIV/AIDS. In 2011, the BBC reported that some churches in London were claiming that prayer would cure AIDS, and the Hackney-based Centre for the Study of Sexual Health and HIV reported that several people stopped taking their medication, sometimes on the direct advice of their pastor, leading to many deaths. The Synagogue Church Of All Nations advertised an "anointing water" to promote God's healing, although the group denies advising people to stop taking medication.

Media portrayal

Main article: Media portrayal of HIV/AIDS

One of the first high-profile cases of AIDS was the American gay actor Rock Hudson. He had been diagnosed during 1984, announced that he had had the virus on July 25, 1985, and died a few months later on October 2, 1985. Another notable British casualty of AIDS that year was Nicholas Eden, a gay politician and son of former prime minister Anthony Eden. On November 24, 1991, the virus claimed the life of British rock star Freddie Mercury, lead singer of the band Queen, who died from an AIDS-related illness having only revealed the diagnosis on the previous day.

One of the first high-profile heterosexual cases of the virus was American tennis player Arthur Ashe. He was diagnosed as HIV-positive on August 31, 1988, having contracted the virus from blood transfusions during heart surgery earlier in the 1980s. Further tests within 24 hours of the initial diagnosis revealed that Ashe had AIDS, but he did not tell the public about his diagnosis until April 1992. He died as a result on February 6, 1993, aged 49.

Therese Frare's photograph of gay activist David Kirby, as he lay dying from AIDS while surrounded by family, was taken in April 1990. Life magazine said the photo became the one image "most powerfully identified with the HIV/AIDS epidemic." The photo was displayed in Life, was the winner of the World Press Photo, and acquired worldwide notoriety after being used in a United Colors of Benetton advertising campaign in 1992.

Many famous artists and AIDS activists such as Larry Kramer, Diamanda Galás and Rosa von Praunheim campaign for AIDS education and the rights of those affected. These artists worked with various media formats.

Criminal transmission

Main article: Criminal transmission of HIV

Criminal transmission of HIV is the intentional or reckless infection of a person with the human immunodeficiency virus (HIV). Some countries or jurisdictions, including some areas of the United States, have laws that criminalize HIV transmission or exposure. Others may charge the accused under laws enacted before the HIV pandemic.

In 1996, Ugandan-born Canadian Johnson Aziga was diagnosed with HIV; he subsequently had unprotected sex with eleven women without disclosing his diagnosis. By 2003, seven had contracted HIV; two died from complications related to AIDS. Aziga was convicted of first-degree murder and sentenced to life imprisonment.

Misconceptions

Main articles: Misconceptions about HIV/AIDS and Discredited HIV/AIDS origins theories

There are many misconceptions about HIV and AIDS. Three misconceptions are that AIDS can spread through casual contact, that sexual intercourse with a virgin will cure AIDS, and that HIV can infect only gay men and drug users. In 2014, some among the British public wrongly thought one could get HIV from kissing (16%), sharing a glass (5%), spitting (16%), a public toilet seat (4%), and coughing or sneezing (5%). Other misconceptions are that any act of anal intercourse between two uninfected gay men can lead to HIV infection, and that open discussion of HIV and homosexuality in schools will lead to increased rates of AIDS.

A small group of individuals continue to dispute the connection between HIV and AIDS, the existence of HIV itself, or the validity of HIV testing and treatment methods. These claims, known as AIDS denialism, have been examined and rejected by the scientific community. However, they have had a significant political impact, particularly in South Africa, where the government's official embrace of AIDS denialism (1999–2005) was responsible for its ineffective response to that country's AIDS epidemic, and has been blamed for hundreds of thousands of avoidable deaths and HIV infections.

Several discredited conspiracy theories have held that HIV was created by scientists, either inadvertently or deliberately. Operation INFEKTION was a worldwide Soviet active measures operation to spread the claim that the United States had created HIV/AIDS. Surveys show that a significant number of people believed—and continue to believe—in such claims.

Research

Main article: HIV/AIDS research

HIV/AIDS research includes all medical research which attempts to prevent, treat, or cure HIV/AIDS, along with fundamental research about the nature of HIV as an infectious agent, and about AIDS as the disease caused by HIV.

Many governments and research institutions participate in HIV/AIDS research. This research includes behavioral health interventions such as sex education, and drug development, such as research into microbicides for sexually transmitted diseases, HIV vaccines, and antiretroviral drugs. Other medical research areas include the topics of pre-exposure prophylaxis, post-exposure prophylaxis, and circumcision and HIV. Public health officials, researchers, and programs can gain a more comprehensive picture of the barriers they face, and the efficacy of current approaches to HIV treatment and prevention, by tracking standard HIV indicators. Use of common indicators is an increasing focus of development organizations and researchers.