Human Immunodeficiency Virus (HIV) Clinical Trials, Diagnosis, and Treatment

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HIV

Human Immunodeficiency Virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Previous names for the virus include human T-lymphotropic virus-III (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS-associated retrovirus (ARV).

Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The three major routes of transmission are unprotected sexual intercourse, contaminated needles, and transmission from an infected mother to her baby at birth, or through breast milk. Screening of blood products for HIV in the developed world has largely eliminated transmission through blood transfusions or infected blood products in these countries.

HIV infection in humans is now pandemic. As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive pandemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of which more than 570,000 were children. It is estimated that about 0.6% of the world's living population is infected with HIV. A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty. According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.

HIV primarily infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages and dendritic cells. HIV infection leads to low levels of CD4+ T cells through three main mechanisms: firstly, direct viral killing of infected cells; secondly, increased rates of apoptosis in infected cells; and thirdly, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. If untreated, eventually most HIV-infected individuals develop AIDS (Acquired Immunodeficiency Syndrome) and die; however about one in ten remain healthy for many years, with no noticeable symptoms. Treatment with anti-retrovirals, where available, increases the life expectancy of people infected with HIV. It is hoped that current and future treatments may allow HIV-infected individuals to achieve a life expectancy approaching that of the general public (see Treatment).

Current Research

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Origin and Discovery

The AIDS epidemic was discovered June 5, 1981, when the U.S. Centers for Disease Control and Prevention reported a cluster of Pneumocystis pneumonia (PCP) caused by a form of Pneumocystis carinii, now recognized as a distinct species Pneumocystis jirovecii, in five homosexual men in Los Angeles. The disease was originally dubbed GRID, or Gay-Related Immune Deficiency, but health authorities soon realized that nearly half of the people identified with the syndrome were not homosexual men. In 1982, the CDC introduced the term AIDS to describe the newly recognized syndrome, though it was still casually referred to as GRID.

In 1983, scientists led by Luc Montagnier at the Pasteur Institute in France first discovered the virus that causes AIDS. They called it lymphadenopathy-associated virus (LAV). A year later a team led by Robert Gallo of the United States confirmed the discovery of the virus, but they renamed it human T lymphotropic virus type III (HTLV-III). The dual discovery led to considerable scientific disagreement, and it was not until President Mitterrand of France and President Reagan of the USA met that the major issues were resolved. In 1986, both the French and the U.S. names for the virus itself were dropped in favour of the new term, human immunodeficiency virus (HIV).

HIV was classified as a member of the genus Lentivirus, part of the family of Retroviridae. Lentiviruses have many common morphologies and biological properties. Many species 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 of the target cell, the viral RNA genome is converted to double-stranded DNA by a virally encoded reverse transcriptase that is present in the virus particle. This viral DNA is then integrated into the cellular DNA by a virally encoded integrase so that the genome can be transcribed. Once the virus has infected the cell, two pathways are possible: either the virus becomes latent and the infected cell continues to function, or the virus becomes active and replicates, and a large number of virus particles are liberated that can then infect other cells.

Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is thought to have originated in southern Cameroon after jumping from wild chimpanzees (Pan troglodytes troglodytes) to humans during the twentieth century. HIV-2 may have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon. HIV-1 is more virulent. It is easily transmitted and is the cause of the majority of HIV infections globally. HIV-2 is less transmittable and is largely confined to West Africa. HIV-1 is the virus that was initially discovered and termed LAV.

Three of the earliest known instances of HIV-1 infection are as follows:

A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of Congo.
HIV found in tissue samples from a 15-year-old African-American teenager who died in St. Louis in 1969.
HIV found in tissue samples from a Norwegian sailor who died around 1976.

Although a variety of theories exist explaining the transfer of HIV to humans, no single hypothesis is unanimously accepted, and the topic remains controversial. The most widely accepted theory is so called 'Hunter' Theory according to which transference from chimp to human most likely occurred when a human was bitten by a chimp or was cut while butchering one, and the human became infected. The London Times published an article in 1987 stating that WHO suspected some kind of connection with its vaccine program and AIDS-epidemic. The story was almost entirely based on statements given by one unnamed WHO advisor. The theory was supported only by weak circumstantial evidence and is now disproven by unraveling the genetic code of the virus and finding out that the virus dates back to the 1930s.

Freelance journalist Tom Curtis discussed one controversial possibility for the origin of HIV/AIDS in a 1992 Rolling Stone magazine article. He put forward what is now known as the OPV AIDS hypothesis, which suggests that AIDS was inadvertently caused in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a polio vaccine. Although subsequently retracted due to libel issues surrounding its claims, the Rolling Stone article motivated another freelance journalist, Edward Hooper, to probe more deeply into this subject. Hooper's research resulted in his publishing a 1999 book, The River, in which he alleged that an experimental oral polio vaccine prepared using chimpanzee kidney tissue was the route through which simian immunodeficiency virus (SIV) crossed into humans to become HIV, thus starting the human AIDS pandemic. This theory is contradicted by an analysis of genetic mutation in primate lentivirus strains that indicates with 95% certainty that the origin of the HIV-1 strain dates to about 1930.

Furthermore in February 2000 one of the original developers of the polio vaccine, Philadelphia based Wistar Institute found from its stores a phial of the original vaccine used in the vaccination program. It was analyzed in April 2001 and no traces of either HIV-1 or SIV were found in the sample. A second analysis showed that only macaque monkey kidney cells, which cannot be infected with SIV or HIV, were used to produce the vaccine. While the analysis was done on only one phial of vaccine, most scientists have concluded that the polio vaccine theory of the origins of HIV is not possible.

Transmission

Estimated Per Act Risk For Acquisition of HIV-1 By Exposure Route
Exposure Route	Estimated Infections Per 10,000 Exposures to an Infected Source
Blood Transfusion	9,000
Childbirth	2,500
Needle-sharing injection drug use	67
Receptive anal intercourse*	50
Percutaneous needle stick	30
Receptive penile-vaginal intercourse*	10
Insertive anal intercourse*	6.5
Insertive penile-vaginal intercourse*	5
Receptive fellatio*	1
Insertive fellatio*	0.5
* Assuming no condom use

Since the beginning of the pandemic, three main transmission routes for HIV have been identified:

Sexual route. The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another.

Blood or blood product route. This transmission route can account for infections in intravenous drug users, hemophiliacs and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. HIV can also be spread through the sharing of leeches. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings, and scarification procedures can also be at risk of infection.

Mother-to-child transmission (MTCT). The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between the mother and child is 25%. However, where drug treatment and Cesarian section are available, this can be reduced to 1%. Breast feeding also presents a risk of infection for the baby.

HIV-2 is transmitted much less frequently by the MTCT and sexual route than HIV-1.

HIV has been found at low concentrations in the saliva, tears and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible. The use of physical barriers such as the latex condom is widely advocated to reduce the sexual transmission of HIV. Spermicide, when used alone or with vaginal contraceptives like a diaphragm, actually increases the male to female transmission rate due to inflammation of the vagina; it should not be considered a barrier to infection. Research is clarifying the relationship between male circumcision and HIV in differing social and cultural contexts, however critics point out that any correlation between circumcision and HIV is likely to come from cultural factors (which govern not only whether someone is circumcised, but also their sexual practices and beliefs). Even though male circumcision may lead to a reduction of infection risk in heterosexual men by up to 60%, UNAIDS believes that it is premature to recommend male circumcision as part of HIV prevention programs. Trials, in which some uncircumcised men were randomly assigned to be circumcised in presumably sterile conditions and others were not circumcised, conducted in Kenya and Uganda found that men who were uncircumcised were twice as likely to contract the human immunodeficiency virus (HIV) compared with circumcised counterparts. South African medical experts are concerned that the repeated use of unsterilized blades in the ritual circumcision of adolescent boys may be spreading HIV.

Structure and Genome

HIV is different in structure from other retroviruses. It is about 120 nm in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.

It is composed of two copies of positive single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24. The single-stranded RNA is tightly bound to nucleocapsid proteins, p7 and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle. This is, in turn, surrounded by the viral envelope which is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle. This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope. This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle. Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.

Of the nine genes that are encoded within the RNA genome, three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles. env, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease. The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells. The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.

Tropism

The term viral tropism refers to which cell types HIV infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with chemokine coreceptors.

Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the β-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4+ T cells. This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus.

T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4, for entry. The α-chemokine, SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed R5, those that only use CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of myeloid dendritic cells, which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels.

Some people are resistant to certain strains of HIV. One example of how this occurs is people with the CCR5-Δ32 mutation; these people are resistant to infection with R5 virus as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target cells.

Heterosexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid which is passed from partner to partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway. How this selective process works is still under investigation, but one model is that spermatozoa may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface and that genital epithelial cells preferentially sequester X4 virus. In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants appear that can infect a variety of T cells through CXCR4. These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS. Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of the SI, and presumably the X4, phenotype.

Replication Cycle

Entry to the Cell

HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

The interactions of the trimeric envelope complex (gp160 spike, discussed above) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4 but others are known to interact) on the cell surface. The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.

Replication and Transcription

Once the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a complementary DNA of 9 kb size. This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause drug resistance. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.

This integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is upregulated when T cells become activated. This means that those cells most likely to be killed by HIV are in fact those currently fighting infection.

In this replication process, the integrated provirus is copied to mRNA which is then spliced into smaller pieces. These small pieces produce the regulatory proteins Tat (which encourages new virus production) and Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing. At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.

HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA whereas HIV-2 will preferentially bind to the mRNA which was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).

Assembly and Release

The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation either occurs in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion. This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.

Genetic Variability

HIV differs from many other viruses as it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 109 to 1010 virions every day, coupled with a high mutation rate of approximately 3 x 10-5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase. This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day. This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes. This recombination is most obvious when it occurs between subtypes.

The closely related simian immunodeficiency virus (SIV) exhibits a somewhat different behavior: in its natural hosts, African green monkeys and sooty mangabeys, the retrovirus is present in high levels in the blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV. By contrast, infection of heterologous hosts (rhesus or cynomologus macaques) with SIV results in the generation of genetic diversity that is on the same order as HIV in infected humans; these heterologous hosts also develop simian AIDS. The relationship, if any, between genetic diversification, immune response, and disease progression is unknown.

Three groups of HIV-1 have been identified on the basis of differences in env: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct. The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.

The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIV than HIV-1.

The Clinical Course of Infection

Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load. The stage of infection can be determined by measuring the patient's CD4+ T cell count, and the level of HIV in the blood.

The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per mL. This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the 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 rebound to around 800 cells per mL (the normal value is 1200 cells per mL ). A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus. During this period most individuals (80 to 90%) develop an influenza-like illness with symptoms of fever, malaise, lymphadenopathy, pharyngitis, headache, myalgia, and sometimes a rash. Because of the nonspecific nature of these illnesses, it is often not recognized as a sign of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. Consequently, these primary symptoms are not used to diagnose HIV infection as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells (FDC) network. The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.

When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibilty to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma, a tumor of endothelial cells that occurs when HIV proteins such as Tat interact with Human Herpesvirus-8. Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.

HIV Test

Many HIV-positive people are unaware that they are infected with the virus. For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results. Again, this proportion is even lower in rural health facilities. Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.

HIV-1 testing consists of initial screening with an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an infected person, or nonspecific reactions in an uninfected person. Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. Generally, a second specimen should be collected more than a month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations. In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection.

Treatment

There is currently no vaccine or cure for HIV or AIDS. The only known method of prevention is avoiding exposure to the virus. However, an antiretroviral treatment, known as post-exposure prophylaxis is believed to reduce the risk of infection if begun directly after exposure. Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART. This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available. Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of anti-retroviral agents. Typically, these classes are two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because AIDS progression in children is more rapid and less predictable than in adults, particularly in young infants, more aggressive treatment is recommended for children than adults. In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the viral load, how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.

HAART allows the stabilisation of the patient’s symptoms and viremia, but it neither cures the patient, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped. Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART. Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated morbidity and mortality in the developed world. A computer based study in 2006 projected that following the 2004 United States treatment guidelines gave an average life expectancy of an HIV infected individual to be 32.1 years from the time of infection if treatment was started when the CD4 count was 350/µL. This study was limited as it did not take into account possible future treatments and the projection has not been confirmed within a clinical cohort setting. In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months. However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART. The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem. The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.

The timing for starting HIV treatment is still debated. There is no question that treatment should be started before the patient's CD4 count falls below 200, and most national guidelines say to start treatment once the CD4 count falls below 350; but there is some evidence from cohort studies that treatment should be started before the CD4 count falls below 350. There is also evidence to say that treatment should be started before CD4 percentage falls below 15%. In those countries where CD4 counts are not available, patients with WHO stage III or IV disease should be offered treatment.

Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS. Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, 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.

Epidemiology

UNAIDS and the WHO estimate that AIDS has killed more than 25 million people since it was first recognized in 1981, making it one of the most destructive pandemics in recorded history. Despite recent improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.

Globally, between 33.4 and 46 million people currently live with HIV. In 2005, between 3.4 and 6.2 million people were newly infected and between 2.4 and 3.3 million people with AIDS died, an increase from 2004 and the highest number since 1981.

Sub-Saharan Africa remains by far the worst-affected region, with an estimated 21.6 to 27.4 million people currently living with HIV. Two million [1.5–3.0 million] of them are children younger than 15 years of age. More than 64% of all people living with HIV are in sub-Saharan Africa, as are more than three quarters of all women living with HIV. In 2005, there were 12.0 million [10.6–13.6 million] AIDS orphans living in sub-Saharan Africa 2005. South & South East Asia are second-worst affected with 15% of the total. AIDS accounts for the deaths of 500,000 children in this region. Two-thirds of HIV/AIDS infections in Asia occur in India, with an estimated 5.7 million infections (estimated 3.4–9.4 million) (0.9% of population), surpassing South Africa's estimated 5.5 million (4.9–6.1 million) (11.9% of population) infections, making India the country with the highest number of HIV infections in the world. In the 35 African nations with the highest prevalence, average life expectancy is 48.3 years—6.5 years less than it would be without the disease.

The latest evaluation report of the World Bank's Operations Evaluation Department assesses the development effectiveness of the World Bank's country-level HIV/AIDS assistance defined as policy dialogue, analytic work, and lending with the explicit objective of reducing the scope or impact of the AIDS epidemic. This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank aims to assist in implementation of national government programmes, their experience provides important insights on how national AIDS programmes can be made more effective.

The development of HAART as effective therapy for HIV infection and AIDS has substantially reduced the death rate from this disease in those areas where these drugs are widely available. This has created the misperception that the disease has vanished. In fact, as the life expectancy of persons with AIDS has increased in countries where HAART is widely used, the number of persons living with AIDS has increased substantially. In the United States, the number of persons with AIDS increased from about 35,000 in 1988 to over 220,000 in 1996.

In Africa, the number of MTCT and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counselling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.

Alternative Hypotheses

A small minority of scientists and activists question the connection between HIV and AIDS, the existence of HIV itself, or the validity of current testing methods. These claims are considered unsupported by most of the scientific community, who accuse the dissenters of selectively ignoring evidence in favor of HIV's role in AIDS and irresponsibly posing a threat to public health by discouraging HIV testing and proven treatments.

AIDS dissidents assert that the current mainstream approach to AIDS, based on HIV causation, has resulted in inaccurate diagnoses, psychological terror, toxic treatments, and a squandering of public funds. Dissident views have been widely rejected, and are considered pseudoscience by the mainstream scientific community.

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/HIV)

Findings From Current Research

The Human Immunodeficiency Virus Epidemic: A Race Against Time for Millions and the Role of Flow Cytometry: A Caribbean and Resource-Constrained Country Perspective.

Authors: Abayomi A.

Department of Internal Medicine, Tygerberg Academic Hospital, Faculty of Medical Sciences, Stellenbosch University, Cape Town, South Africa.

There is a race against time for millions in the world today. Both the technology and the manpower are currently available to deliver the services that are required to meet the needs of the 40 million people currently living with HIV/AIDS, but at what price? The reality is therefore that we are a long shot away from this realization. What are the facts and why have we not achieved even the simplest deadlines set by the World Health Organization (WHO)? Are these objectives realistic? What role does hard science have to play in the search for cost-effective solutions and futuristic effective options? To stem this unrelenting epidemic and convert the natural history of the disorder in those already living with the virus into one of chronicity, rather than one characterized by a dehumanizing and stigmatized death, requires a global commitment at all levels. This discussion examines the reality and offers a snapshot of capacity and experiences in the developing world. Crucially, it looks at the immediate and long term role of flow cytometry in the expanded care and treatment programs for developing nations. (c) 2007 Clinical Cytometry Society.

Journal: Cytometry B Clin Cytom. 2007 Apr 9;
Adapted from PubMed; click here to access full journal article.

Biologic Markers of Ovarian Reserve and Reproductive Aging: Application in a Cohort Study of HIV Infection in Women.

Authors: Seifer DB, Golub ET, Lambert-Messerlian G, Springer G, Holman S, Moxley M, Cejtin H, Nathwani N, Anastos K, Minkoff H, Greenblatt RM.

Maimonides Medical Center, Department of Obstetrics & Gynecology, Brooklyn, New York; Mount Sinai School of Medicine, New York, New York.

OBJECTIVE: To compare Mullerian inhibiting substance (MIS) levels in serum obtained during the early follicular phase to those obtained randomly during the menstrual cycle. To determine whether HIV infection influences early follicular MIS levels, an early marker of ovarian aging. DESIGN: A cross-sectional study. SETTING: Women's Interagency HIV Study, a multicenter prospective study. PATIENT(S): Serum samples obtained from 263 (187 HIV infected and 76 uninfected) participants of the Women's Interagency HIV Study who reported menstrual bleeding during the preceding 6 months and who were not taking exogenous hormones. INTERVENTION(S): Early follicular (cycle days 2-5) MIS samples were compared with serum samples that had been obtained without regard to menstrual cycle phase. Comparison samples were obtained within 6 weeks before or within 3 to 6 months after the early follicular samples. Early follicular FSH, E(2), inhibin B, and MIS levels were also compared between the HIV infected and uninfected women. MAIN OUTCOME MEASURE(S): Correlation between early follicular MIS and prior and subsequent samples. Comparison of serum markers of ovarian reserve between HIV positive and negative women. RESULT(S): The MIS values from early follicular and other random cycle phases were highly correlated with each other (r > 0.93). In multivariate analysis, increased age and FSH level and lower inhibin B levels were associated with lower MIS level; MIS values did not vary by HIV serostatus. CONCLUSION(S): Without regard to cycle phase, MIS was similar during early follicular phase and highly correlated with early follicular FSH and inhibin B in women with and without HIV. Measurement of serum MIS offers a simplified method of determining ovarian reserve using specimens obtained without menstrual phase timing. Furthermore, using biologic measures of reproductive aging, we found no evidence that HIV infection influences ovarian aging.

Journal: Fertil Steril. 2007 Apr 4;
Adapted from PubMed; click here to access full journal article.

Efficacy of Low-Dose Boosted Saquinavir Once Daily Plus Nucleoside Reverse Transcriptase Inhibitors in Pregnant HIV-1-Infected Women With a Therapeutic Drug Monitoring Strategy.

Authors: Lopez-Cortes LF, Ruiz-Valderas R, Rivero A, Camacho A, Marquez-Solero M, Santos J, Garcia-Lazaro M, Viciana P, Rodriguez-Banos J, Ocampo A.

From the daggerInfectious Diseases Service, Hospitales Universitarios Virgen del Rocio, Seville; double daggerInfectious Diseases Unit, Hospital Universitario Reina Sofia, Cordoba; section signInfectious Diseases Unit, Hospital Universitario Virgen de la Victoria, Malaga; paragraph signInfectious Diseases Unit, Hospital Universitario Virgen Macarena, Seville; and parallelHospital Xeral-Cies, Vigo, Spain.

The efficacy of low-dose, ritonavir-boosted saquinavir (SQV/rtv) once daily plus 2 nucleoside retrotranscriptase inhibitors (NRTIs) in pregnant human immunodeficiency virus (HIV)-1-infected women was prospectively evaluated, ensuring a SQV minimum concentration (Cmin) >/=100 ng/mL with a therapeutic drug monitoring strategy. The primary clinical endpoint was the percentage of women with an HIV-RNA viral load (VL) of <50 copies/mL at the time of delivery. Forty-nine pregnancy episodes were included, with a median CD4 count and VL of 441/muL and 3710 copies/mL, respectively. Two patients were lost to follow-up and 1 patient discontinued treatment because of abdominal discomfort. SQV levels were in excess of the target Cmin in 43 of 46 episodes (93.4%) in which the end of pregnancy was reached on 1200/100 mg daily. The dosage was increased to 1600/100 mg in the remaining 3 episodes to achieve the target levels. By an intention-to-treat analysis, VL was undetectable at delivery in 43 episodes (87.7%; 95% confidence interval, 78.5-96.9) after a median of 18 weeks of treatment (range, 3-39). In the 3 episodes remaining, VLs of 110,400 copies/mL and no available data were observed after only 3 weeks of treatment. Mild adverse events attributable to SQV/rtv occurred in 6 of 49 pregnancies (12.2%). No cases of HIV vertical transmission were observed. The pharmacokinetics, efficacy, and tolerability of this regimen suggest that once-daily low-dose boosted SQV may be considered an appropriate option in PI-naive or limited-PI-experienced HIV-infected pregnant women. Nevertheless, therapeutic drug monitoring is advisable to maintain appropriate levels throughout pregnancy.

Journal: Ther Drug Monit. 2007 Apr;29(2):171-176.
Adapted from PubMed; click here to access full journal article.

US and UK Versions of the EQ-5D Preference Weights: Does Choice of Preference Weights Make a Difference?

Authors: Huang IC, Willke RJ, Atkinson MJ, Lenderking WR, Frangakis C, Wu AW.

Department of Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville, FL, USA.

Background Most US studies that estimate EQ-5D index score generally apply the UK preference weights. We compared the validity of a newly-developed US weights to the UK weights for use of EQ-5D as a measure of health-related quality of life. Methods Data were collected from a randomized clinical trial for patients with HIV (n = 1,126) in the US. Convergent validity was examined by comparing Pearson correlations of EQ-5D index scores with the MOS-HIV Health Survey scale scores and Physical and Mental Health Summary (PHS, MHS) scores using the US and UK weights. Known-groups validity of EQ-5D US versus UK index scores was compared using clinical variables (CD4+ cell count and HIV viral load), and the MOS-HIV PHS and MHS. Score changes in the EQ-5D index from baseline to week 50 were examined using effect size (ES) estimates. Results The mean EQ-5D index scores was slightly higher using US weights than UK weights (0.87 vs. 0.84, respectively). The correlation coefficient for EQ-5D utilities using the US and UK weights was 0.98. The correlations of EQ-5D index scores with the MOS-HIV scores were moderate and similar using the US and UK weights. The EQ-5D index scores discriminated equally well for both versions between levels of CD4+ count, HIV viral load, and PHS and MHS scores (P < 0.05), suggesting equivalent known-groups validity. The changes in EQ-5D index scores from baseline to week 50 were similar for both versions (ES: 0.21 vs. 0.22 for US and UK, respectively), suggesting equivalent responsiveness to score changes. Conclusions EQ-5D index scores generated using UK and US preference weights showed equivalent psychometric properties. For assessing treatment benefit in a single population, the use of either the UK or US weights as a measure of HRQOL will not change inferences. However, for comparisons across US and UK populations, the choice between these two weights should be based on their relevance to the study population.

Journal: Qual Life Res. 2007 Apr 6;
Adapted from PubMed; click here to access full journal article.

Responding to the Threat of HIV Among Persons with Mental Illness and Substance Abuse.

Authors: Parry CD, Blank MB, Pithey AL.

aAlcohol and Drug Abuse Research Unit, Medical Research Council, Tygerberg bDepartment of Psychiatry, Stellenbosch University, Stellenbosch, South Africa cDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PURPOSE OF REVIEW: This article discusses current knowledge regarding the threat of HIV among persons with mental illness and substance abuse, and strategies for reducing this threat. It contains a review of the prevalence and consequences of dual/triple diagnosis, HIV risk behaviour and current HIV risk-reduction interventions among persons with dual diagnosis and interventions for triply diagnosed individuals. RECENT FINDINGS: Many persons with dual diagnosis remain undetected and there is a high prevalence of sexual risk behaviours among persons with dual diagnosis. Case management and supportive housing programmes are feasible options for the delivery of HIV risk-reduction interventions among such patients, and the adaptation of integrated behavioural treatment interventions can improve behavioural and healthcare utilization outcomes. SUMMARY: The developing world continues to see an escalation in HIV incidence. A more complete understanding of mental health, substance use and HIV serostatus interactions is needed to serve vulnerable populations. Mental health status not only mediates HIV risk behaviours, but positive serostatus has various effects on mental health. Co-morbid substance abuse is common among HIV-positive individuals with mental illness, resulting in serious adverse effects. Separate services for individuals with co-occurring substance abuse are less effecttive than integrated treatment programmes.

Journal: Curr Opin Psychiatry. 2007 May;20(3):235-41.
Adapted from PubMed; click here to access full journal article.

Highly Efficient HIV Transmission to Young Women in South Africa.

Authors: Pettifor AE, Hudgens MG, Levandowski BA, Rees HV, Cohen MS.

From the aDivision of Infectious Diseases, School of Medicine, USA bDepartments of Epidemiology, USA cBiostatistics, University of North Carolina, Chapel Hill, North Carolina, USA dReproductive Health and HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.

BACKGROUND: Young women in sub-Saharan Africa are at very high risk of HIV acquisition, and high prevalence levels have been observed among women reporting one lifetime partner and few sexual contacts. Such findings have led to hypotheses that the probability of HIV transmission from men to women must be far higher than previously appreciated. METHODS: We used the data from a cross-sectional national household survey of HIV among South African women aged 15-24 years to estimate the per-partnership transmission probability from men to women. Estimates were obtained using maximum likelihood methods and a transmission probability model allowing for random error in the self-reported number of lifetime partners. Sensitivity analyses were employed to assess the robustness of the per-partnership transmission probability estimates to the assumed HIV prevalence in male partners. RESULTS: HIV prevalence in women was 21.2% (95% confidence interval 17.9-24.5). The mean reported number of lifetime partners was 2.3. A significant increase in prevalence was observed with increasing lifetime partner numbers (P = 0.02). For a range of plausible values of the partner prevalence, the estimated per-partnership transmission probability varied from 0.74 to 1.00 with 95% confidence intervals ranging from 0.56 to 1.00. DISCUSSION: The per-partnership probability of HIV transmission from men to women in this population was very high. Before this, the majority of studies examining per-partnership transmission probabilities estimated values below 50%. Identifying the factors that may drive the efficient spread of HIV in sub-Saharan Africa is essential for the development of effective prevention interventions.

Journal: AIDS. 2007 Apr 23;21(7):861-865.
Adapted from PubMed; click here to access full journal article.

Factors Affecting Reproductive Hormones in HIV-Infected, Substance-Using Middle-Aged Women.

Authors: Santoro N, Lo Y, Moskaleva G, Arnsten JH, Floris-Moore M, Howard AA, Adel G, Zeitlian G, Schoenbaum EE.

From the 1Department of Obstetrics, Gynecology, and Women's Health, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY; and Departments of 2Epidemiology and Population Health and 3Medicine, Montefiore Medical Center, Bronx, NY.

OBJECTIVE: To determine whether reproductive hormone levels are affected by human immunodeficiency virus (HIV) and drug use. DESIGN: HIV-infected and uninfected women (N = 429), median age 45, were interviewed on menstrual frequency, demographic and psychosocial characteristics, and drug use behaviors. Serum was obtained on cycle days 1 to 5 in women reporting regular menses. Premenopausal-, early menopausal, and late menopausal transition and postmenopausal stages were assigned based on menstrual history. Serum was assayed for follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH), prolactin, thyroid-stimulating hormone, and inhibin B. Body mass index, HIV serostatus, and CD4+ counts were measured. Factors associated with hormone concentrations were assessed using uni- and multivariable analyses. Hormone concentrations were compared within menstrual status categories using nonparametric comparisons of means. RESULTS: In this cross-sectional analysis, LH and FSH increased, and E2 and inhibin B were significantly lower in women of older age and more advanced menopausal status. Increased body mass index was strongly associated with decreased LH. Opiate use was significantly associated with lower inhibin B and E2 and increased prolactin. Poorer self-rated health was statistically significantly associated with lower LH and FSH, but increased education was associated with higher LH and FSH. Among HIV-seropositive women, opiate users had detectably lower FSH and LH than nonusers, and use of highly active antiretroviral therapy was significantly related to higher LH, FSH, and E2, whereas cocaine use was associated with lower E2. CONCLUSIONS: Age and menopausal status are strongly related to reproductive hormones. Body mass index and use of opiates, cocaine, and highly active antiretroviral therapy as well as educational attainment and perceived health can significantly modify reproductive hormones during the menopausal transition and need to be considered when interpreting hormone levels in middle-aged women.

Journal: Menopause. 2007 Mar 30;
Adapted from PubMed; click here to access full journal article.

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