Diagnosis

Many HIV-positive people are unaware that they are infected with the virus.^[98] 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.^[98] Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.^[98] Again, this proportion is even lower in rural health facilities.^[98] 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.^[99]

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.^[100] 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.^[101] 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.^[100] 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.

Modern HIV testing is extremely accurate. The chance of a false-positive result in the two-step testing protocol is estimated to be 0.0004% to 0.0007% in the general U.S. population.^{[102][103][104][105]}

Treatment

See also Antiretroviral drug

Abacavir - a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)

There is currently no publicly available vaccine or cure for HIV or AIDS.^[106][107] However, a vaccine that is a combination of two previously unsuccessful vaccine candidates was reported in September 2009 to have resulted in a 30% reduction in infections in a trial conducted in Thailand.^[108] Additionally, a course of antiretroviral treatment administered immediately after exposure, referred to as post-exposure prophylaxis, is believed to reduce the risk of infection if begun as quickly as possible.^[109] However, due to the incomplete protection provided by the vaccine and/or post-exposure prophylaxis, the avoidance of exposure to the virus is expected to remain the only reliable way to escape infection for some time yet. Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.^[110] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.^[111] Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral 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). New classes of drugs such as Entry Inhibitors provide treatment options for patients who are infected with viruses already resistant to common therapies, although they are not widely available and not typically accessible in resource-limited settings. 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.^[112] 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.^[113]

HAART neither cures the patient nor does it uniformly remove all symptoms; high levels of HIV-1, often HAART resistant, return if treatment is stopped.^[114][115] Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.^[116] 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.^{[111][117][118]} One study suggests the average life expectancy of an HIV infected individual is 32 years from the time of infection if treatment is started when the CD4 count is 350/µL.^[119] 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.^[9] 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.^[120] 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.^{[121][122][123]} The side effects include lipodystrophy, dyslipidemia, insulin resistance, an increase in cardiovascular risks, and birth defects.^[124][125]

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.^[117][126] In those countries where CD4 counts are not available, patients with WHO stage III or IV disease^[127] 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.^[128] 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.^[128] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.^[128]

Treatments in development

Media reports in 2008 and a publication in the New England Journal of Medicine in 2009 described the anecdotal case of an HIV-positive patient of a Berlin doctor, Gero Hütter. The patient, who had both acute myelogenous leukemia (AML) and HIV infection, was said by some to be "functionally cured" of his HIV following a bone marrow transplant for AML. The bone marrow donor had been selected as homozygous for a CCR5-Δ32 mutation (which confers resistance to "almost all strains of HIV").^[129][130] After 600 days without antiretroviral drug treatment, HIV levels in the patient's blood, bone marrow and bowel were below the limit of detection, although the authors note that the virus is likely present in other tissues. Researchers cautioned that it would be premature to consider this treatment a possible cure because of its anecdotal nature, the mortality risk associated with bone marrow transplants and other concerns.^[131][132]

HIV latent reservoir

Despite the success of highly active antiretroviral therapy (HAART) in controlling HIV infection and reducing HIV-associated mortality, current drug regimens are unable to completely eradicate HIV infection. Many people on HAART achieve suppression of HIV to levels below the limit of detection of standard clinical assays for many years. However, upon withdrawal of HAART, HIV viral loads rebound quickly with a concomitant decline in CD4+ T-Cells, which, in most cases, absent a resumption of treatment, leads to AIDS.

To successfully reproduce itself, HIV must convert its RNA genome to DNA, which is then imported into the host cell's nucleus and inserted into the host genome through the action of HIV integrase. Because HIV's primary cellular target, CD4+ T-Cells, function as the memory cells of the immune system, integrated HIV can remain dormant for the duration of these cell's lifetime. Memory T-Cells may survive for many years and possibly for decades. The latent HIV reservoir can be measured by co-culturing CD4+ T-Cells from infected patients with CD4+ T-Cells from uninfected donors and measuring HIV protein or RNA.^[133]

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.^[134]

Prognosis

Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,^[135] and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.^[136] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly diagnosed HIV-infected person to 20–50 years.^[137][138]

As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year after the individual progresses to AIDS.^[9] Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.^[5] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function^{[66][139][140]} health care and co-infections,^[5][9] as well as which particular strain of the virus is involved.^{[141][142][143]}

Epidemiology

Main article: AIDS pandemic

Estimated prevalence of HIV among young adults (15-49) per country at the end of 2005.

Disability-adjusted life year for HIV and AIDS per 100,000 inhabitants.

no data ≤ 10 10-25 25-50 50-100 100-500 500-1000 1000-2500 2500-5000 5000-7500 7500-10000 10000-50000 ≥ 50000

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.^[1]

In 2007, between 30.6 and 36.1 million people were believed to live with HIV, and it killed an estimated 2.1 million people that year, including 330,000 children; there were 2.5 million new infections.^[135]

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.^[1] 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. South Africa has the largest number of HIV patients in the world followed by Nigeria.^[144] India has an estimated 2.5 million infections (0.23% of population), making India the country with the third largest population of HIV patients. 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.^[145]

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.^[146] 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 has substantially reduced the death rate from this disease in those areas where these drugs are widely available.^[111] As the life expectancy of persons with HIV has increased in countries where HAART is widely used, the continuing spread of the disease has caused the number of persons living with HIV to increase substantially.

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.

History

Origins

Main article: Origin of AIDS

See History of known cases and spread for early cases of HIV / AIDS

HIV is thought to have originated in non-human primates in sub-Saharan Africa and transferred to humans early in the 20th century.^[147] The first paper recognizing a pattern of opportunistic infections was published on June 4, 1981.^[148]

Both types of the virus are believed to have originated in West-Central Africa and jumped species (zoonosis) from a non-human primate to humans. HIV-1 is thought to have originated in southern Cameroon after jumping from wild chimpanzees (Pan troglodytes troglodytes) to humans during the twentieth century.^[149][150] It evolved from a Simian Immunodeficiency Virus (SIV_cpz).^[151] HIV-2, on the other hand, may have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.^[15]

New World Monkeys are an interesting exception to the transmission of HIV. Their immunity is believed to be caused by retrotransposition of the Cyclophilin gene into an intron of TRIM5. The result is fusion gene that provides the owl monkey with resistance to HIV-1 infection.^[152]

Discovery

AIDS was first clinically observed between late 1980 and early 1981. A group of five men showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare oppourtinistic infection that was known to present itself in people with very compromised immune systems. Soon thereafter, another set of men developed a rare skin cancer called Kaposi’s sarcoma (KP). Many more cases of PCP and KP quickly emerged, alerting U.S. Centers for Disease Control and Prevention (CDC). A CDC task force was formed to monitored the outbreak. After recognizing a pattern of anomalous symptoms presenting themselves in patients, the task force named the condition acquired immune deficiency syndrome (AIDS).^[153]

In 1983, two separate research groups lead by Robert Gallo and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal Science.^[154][155] Gallo claimed that a virus his group had isolated from an AIDS patient was strikingly similar in shape to other human T-lymphotropic viruses (HLTVs) his group had been the first to isolate. Gallo's group called their newly isolated virus HLTV-III. At the same time, Montagnier's group isolated a virus from a patient presenting lymphadenopathy (swelling of the lymph nodes) of the neck and physical weakness, two classic 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).^[153]

Whether Gallo or Montagnier deserve more credit for the discovery of the virus that causes AIDS has been a matter of considerable controversy. Together with his colleague Françoise Barré-Sinoussi, Montagnier was awarded one half of the 2008 Nobel Prize in Physiology or Medicine for his "discovery of human immunodeficiency virus".^[156] Harald zur Hausen also shared the Prize for his discovery that human papilloma virus leads to cervical cancer, but Gallo was left out.^[157] Gallo said that it was "a disappointment" that he was not named a co-recipient.^[158] Montagnier said he was "surprised" Gallo was not recognized by the Nobel Committee: "It was important to prove that HIV was the cause of AIDS, and Gallo had a very important role in that. I'm very sorry for Robert Gallo."^[157]

2009 strain

A new strain of HIV was discovered in a 62-year-old woman from Cameroon in 2009.^{[159][160][161]} She was diagnosed with HIV in 2004, but as of August 2009 showed no signs of AIDS. The new strain, designated HIV-1 group P and derived from gorillas, is most similar to a strain of simian immunodeficiency virus known as SIVgor that was first isolated from western lowland gorillas in 2006.^[159] The discovery of the new strain has been taken as evidence that gorillas, and not only chimpanzees, are likely sources for HIV.^[159]

AIDS denialism

Main article: AIDS denialism

Some individuals, including some scientists who are not recognized experts on HIV,^[162] question the connection between HIV and AIDS,^[163] the existence of HIV itself, or the validity of HIV testing and treatment methods.^[162][164] These claims, known as AIDS denialism, have been examined and rejected by the worldwide scientific community,^[165] although they have had a political impact, particularly in South Africa, where the government's official promotion of AIDS denialism was responsible for its ineffective response to that country's AIDS epidemic.^{[166][167][168]}