Acquired immune deficiency syndrome

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Another disease, from another virus

Until there's more information on ganfyd, try the information about HIV and AIDS at the Health Protection Agency website, or the excellent Wikipedia articles.

AIDS is an advanced stage of the disease caused by the human immunodeficiency virus (HIV). HIV - as its name suggests - causes defects in immunity, chiefly cellular immunity (cf serum immunity), which can lead to infections with organisms that are not usually infectious, and thus to a range of illnesses and symptoms. It is a syndrome, rather than a disease per se.

When HIV and AIDS were first identified, AIDS was a sign of impending death. The treatment and prognosis of AIDS and HIV infection has changed immeasurably from 1995 with the introduction of highly active antiretroviral therapy (HAART), a treatment that involves the usage of several antivirals at once, and had led to a great improvement clinically in patients. Now HIV/AIDS is a virus/syndrome that you live with, rather than die of - at least, if you (or the state you live in) can afford the necessary treatments.

There are those who believe - despite all the evidence - that HIV does not cause AIDS - a form of denialism, similar to climate change denialism, and with many similarities to anti-vaccinationism.

Contents

Aetiology

Info bulb.pngPerverse and devious people spread misinformation about HIV/AIDS for various reasons including religion, politics and personal profit.

Patients may not know or have been persuaded not to believe that

  • HIV is transmitted by heterosexual intercourse
  • condoms provide an effective barrier (though imperfect defence) to transmission

Human immunodeficiency virus (HIV). This is a retro-virus, which must contain reverse transcriptase, an enzyme to reverse the usual direction and make DNA based upon instructions in the RNA template of the virus' genetic material. RNA viruses mutate much more rapidly than DNA ones, because RNA is a less redundant and perhaps less stable information medium than DNA with its double strands and surrounding repair mechanisms.

HIV mutates rapidly mainly due to the fact that there are errors in the replication process using reverse transcriptase. This offers a greater opportunity for variants resistant to any particular drug to evolve by natural selection.

The disease is acquired by sexual transmission by exchange of body fluids or by contamination with body fluids in for instance needle-stick injuries.

HIV-2 (found in West Africa and parts of India) is less aggressive with lower risks of disease progression and transmission.

History

It is assumed that HIV arose from Simian Immunodeficiency Virus (SIV), an analogous virus in our cousins, which crossed the "species barrier" by mixing of human and simian blood while hunting.Genotyping suggests the human disease was first introduced widely into man by the infrastructural developments and social changes in the Belgian Congo in the 1920s around Leopoldville (since 1966 Kinshasa). The virus strain that caused this was probably circulating in man around the turn of the century given the known rate of genetic shift. Retrospective analysis of tissue samples of cases suggestive of AIDS have found genetic material consistent with HIV as early as 1959. Clinical recognition occurred quite late as the disease had established itself in the Caribbean, then jumped to New York city about 1970[1]. It was recognised in 1981 in California[2], recognised to involve patients in New York as well shortly after[3] and formally published by year end[4][5].

Clinical

On initial infection, there may be a seroconversion illness, during which there are non-specific viral symptoms eg fever, lymphadenopathy and high levels of virus are found circulating.

Circulating virus is cleared, but gradually the targeted CD4 T-lymphocytes begin to drop in number. Initially, familiar infections e.g. pneumonia may be seen, but as immunodeficiency progresses more unusual infections (or patterns of infection) begin to be seen. AIDS, also known as Stage IV HIV infection is the final stage.

Staging of HIV infection/AIDS defining illnesses

See Wikipedia article.

CDC uses CD4 count and a clinical staging system. WHO describes 4 clinical stages, with stage 4 being equivalent to category C in the CDC system. The latter system does not rely on CD4 counts and is perhaps more relevant to resource poor settings.

Category B conditions are those attributed to HIV infection (or else a defect in cell-mediated immunity) e.g.:

Category C Conditions (AIDS defining) include:

  • Bacterial pneumonia, recurrent (≥2 episodes in 12 months)
  • Candidiasis, esophageal or of the bronchi, trachea, or lungs
  • Cervical carcinoma, invasive, confirmed by biopsy
  • Cryptococcosis, extrapulmonary
  • Cryptosporidiosis, chronic intestinal (>1-month duration)
  • Cytomegalovirus disease (other than liver, spleen, or nodes)
  • Encephalopathy, HIV-related
  • Kaposi sarcoma
  • Mycobacterium avium complex (MAC) or M kansasii, disseminated or extrapulmonary
  • Mycobacterium tuberculosis, pulmonary or extrapulmonary
  • Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)
  • Progressive multifocal leukoencephalopathy (PML)
  • Toxoplasmosis of brain
  • Wasting syndrome due to HIV (involuntary weight loss >10% of baseline body weight) associated with either chronic diarrhea (≥2 loose stools per day ≥1 month) or chronic weakness and documented fever ≥1 month

Children

Typical presentation (if missed at birth):

  • Parotitis
  • Molluscum contagiosum
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Decreased platelets
  • Shingles
  • Lymphoid interstitial pneumonitis (LIP, where CXR is much worse than clinical picture)

There is bimodal pattern of disease progression: 10% are rapidly progressive and die within a year. The rest appear gradually throughout childhood.

Investigations

Blood tests

A low lymphocyte count may be an initial clue (although it is far from specific). Lymphocyte subsets will show a low CD4 count with a reversed CD4:CD8 ratio (usually 2:1) and otherwise preserved subsets eg B cells (CD19 or CD20), Natural killer (NK, CD56) cells.

Diagnostic tests for HIV

The standard antibody test on serum may not become positive for HIV for 3 months, perhaps even 6. It is also transferred placentally, so is not a reliable marker in the neonate or infant. Therefore it is not reliable to rule out infection until that long has passed since initial infection. More sensitive tests are PCR based, looking for RNA. These can also be quantitative, and have prognostic value. Viral RNA can be found from the initial sero-conversion phase onwards but may disappear in the first 1-2 months post-infection or while on effective antiviral treatment. Normally a specific reason would be required to perform PCR rather than the antibody test.

Children

In babies, early diagnosis is difficult because newborns (especially if on treatment) may not demonstrate DNA even if infected. However, by 3 months sensitivity is 95%+. Ideally a maternal sample should be sent at the same time to confirm that the right primers are being used.

Gold standard is 2 positive DNA results off treatment. Usually tested at 1 day, 6 weeks, 12 weeks - if all negative, the family can be informed. Loss of maternal antibody is usually confirmed at 18 months. If positive despite maternal ART, urgent resistance testing is required. Septrin for PCP prophylaxis is not routinely required as the risk of transmission is so low, but should be considered for high risk cases. BCG should be deferred until diagnosis refuted. Normal CD4 at 6 months is 3000. Moderate disease occurs at 20% of normal count, severe (eg disseminated HSV, atypical mycobacteria) at less than 15%. But younger children are much more likely to progress at any given level than older children/adults so these prognostic indicators are not very meaningful.

Who should be tested for HIV

(This section is closely based on recent (2008) guidance from British HIV Association, British Association for Sexual Health and HIV, and the British Infection Society.)[6]

HIV infection can now be managed; and the outcome is better than for many other conditions for which routine testing is undertaken. Without a good uptake of treatment, it is known that many cases are acquired from people who did not know that they were infected. It is, therefore, important that testing is undertaken without unnecessary barriers. While there is still stigma associated with HIV testing, this can be minimised by following the same principles as would apply when testing for any other medical conditions, as laid down by the GMC.[7]

Universal HIV testing is recommended in the following settings:[8]

  1. GUM or sexual health clinics
  2. Antenatal services
  3. Termination of pregnancy services
  4. Drug dependency programmes
  5. Healthcare services for those diagnosed with tuberculosis, hepatitis B, hepatitis C and lymphoma.

An HIV test should be considered in the following settings where diagnosed HIV prevalence in the local population (PCT/LA) exceeds 2 in 1000 population:

  1. All men and women registering in general practice
  2. All general medical admissions.
LogoKeyPointsBox.pngIndicator diseases (see also Category B above):

HIV testing should be also routinely offered and recommended to the following patients:

  1. All patients presenting for healthcare where HIV, including primary HIV infection, enters the differential diagnosis (see table of indicator diseases and section on primary HIV infection)
  2. All patients diagnosed with a sexually transmitted infection
  3. All sexual partners of men and women known to be HIV positive
  4. All men who have disclosed sexual contact with other men
  5. All female sexual contacts of men who have sex with men
  6. All patients reporting a history of injecting drug use
  7. All men and women known to be from a country of high HIV prevalence (>1%)
  8. All men and women who report sexual contact abroad or in the UK with individuals from countries of high HIV prevalence.

HIV testing should also be routinely performed in the following groups in accordance with existing Department of Health guidance:

  1. Blood donors
  2. Dialysis patients
  3. Organ transplant donors and recipients.

Frequency of testing

Repeat testing should be provided for the following groups:

  1. All individuals who have tested HIV negative but where a possible exposure has occurred within the window period
  2. Men who have sex with men (MSM) – annually or more frequently if clinical symptoms are suggestive of seroconversion or ongoing high risk exposure
  3. Injecting drug users – annually or more frequently if clinical symptoms are suggestive of seroconversion (see section on primary HIV infection)
  4. Antenatal care – women who refuse an HIV test at booking should be re-offered a test, and should they decline again a third offer of a test should be made at 36 weeks. Women presenting to services for the first time in labour should be offered a point of care test (POCT). A POCT test may also be considered for the infant of a woman who refuses testing antenatally. In areas of higher seroprevalence, or where there are other risk factors, women who are HIV negative at booking may be offered a routine second test at 34–36 weeks’ gestation as recommended in the BHIVA pregnancy guidelines.[9]

Counselling relating to HIV tests

See HIV testing, insurance, and mortgage applications.

Radiology

The appearance of Pneumocystis carinii or other atypical pneumonia may be semi-diagnostic of AIDS.

Treatment

Medical

See BHIVA website for treatment guidelines. For drugs and their interactions see Liverpool HIV Pharmacology Group (LHPG) website.

Surgical

Cure by bone marrow transplant was postulated to be possible in 1999 and cure after transplantation with CCR5Δ32/Δ32 stem cells, within the limits of available technological verification, had been reported by 2011[10].

Prevention

The risk of transmission depends on the type of contact, and the level of viraemia in the source (which tends to be low early in the disease, very low while on effective treatment, but progressively higher as disease progresses). The risk is highest in blood transfusion (95% transmission), pregnancy (13-45% transmission) and breast feeding (over a period of months, 10-29%).

In terms of sexual contact, the highest risk is from receptive anal intercourse (0.5-3.2%), then receptive vaginal intercourse (0.05%-0.15%), and lowest with insertive vaginal intercourse (0.03-0.09%). HIV has rarely been transmitted by orogenital sexual exposure, but the risk has not been quantified.

Transmission by human bites has described, but is thought to be extremely rare, even where the bite is contaminated with blood from the source. Saliva appears to inhibit HIV infectivity, the concentration of virus is very low, and there has never been a proven case of household non-sexual HIV transmission (although there have been reports).

Mucosal exposure to blood can transmit infection, but the risk is low (probably <0.1%). Transmission has occurred through damaged skin eg eczema, abrasions but not through intact skin.

Post-exposure Prophylaxis

Post-exposure prophylaxis is effective - with the first zidovudine regimens, there was an 81% reduction in transmission in health care workers. But not 100% effective, especially if the viral load transmitted is very high, so standard precautions are still important (in one series, 2 cases of occupationally acquired HIV were due to needlestick injuries caused by colleagues during resuscitations).[11]

Treatment needs to continue for 28 days, so it is perhaps more accurate to call it early treatment rather than prophylaxis. It makes sense to treat with 3 drugs, but since this increases the risk of side effects some argue that 2 drug regimens are sufficient where the risk is lower. Lamivudine, zidovudine (or stavudine) and nelfinavir (2 NRTIs and a PI) is a standard regimen. Nevirapine has been associated with fatal hepatotoxicity when used as prophylaxis.

Prevention of further exposure is important. Repeated courses of prophylactic treatment should be avoided, not just to avoid toxicity, but also to prevent inducing resistance.

Vertical transmission

The risk of vertical transmission depends on viral load, obstetric factors, and gestation. There is a close association between viral load at delivery and risk, but transmission does still occur (very rarely) at undetectable levels, presumably because virus is still secreted. CD4 and clinical disease stage may be independent factors. Obstetric factors are duration of rupture of membranes and mode of delivery (so avoid instrumentation and invasive monitoring). Delivery before 34/40 increases the risk.

Caesarean section (LSCS) is protective with 100 maternal copies or more on metanalysis, although the benefit is reduced if already in labour or post rupture of membranes. Below that level, there is no data to support LSCS cf SVD, but usually recommended if hepatitis C (HCV) co-infection or on monotherapy.

So the first step in preventing vertical transmission is to suppress viral replication in the mother. There is debate about what to do if there is no clinical indication for treating the mother - monotherapy or short term combination? The latter increases risk to Mum and fetus of side effects and possibly preterm delivery (in 1 study, not in others). Nevirapine monotherapy seems a reasonable choice if viral load <6-10 000, wild type virus and willing to have LSCS - but induces resistance, so HIV genotype/phenotype should be determined at birth.

The transmission risk in combination therapy is around 1%, and approximately half of mothers will achieve undetectable viral loads by delivery (do HIV genotype/phenotype if undetectable viraemia not achieved). Pre-eclampsia risk is increased in combination therapy, esp with PI.

Occasionally a pregnant woman will present with rupture of membranes having not previously had any treatment. If she has AIDS, the risk of transmission increases with each passing hour so give AZT, 3TC (lamivudine) and nevirapine - this combination causes a rapid fall in count and has good placental transfer (Nevirapine persists for a week in baby).

If the diagnosis is only known after birth, post exposure prophylaxis is effective for up to 48 hours. Currently no proven increase in congenital abnormalities has been seen, although there have been mitochondrial cytopathies in 3 out of 1000 deliveries.

Most babies should be given Zidovudine (ZDV) monotherapy for 4 weeks (historically 6 weeks). Alternative monotherapy may be given if maternal therapy did not include ZDV, and should be considered if Mum on stavudine (potential competitive interaction). Triple therapy should be considered if mothers untreated or detectable viraemia at birth. ZDV is the only available intravenous anti-retroviral. The main side effect is bone marrow suppression up to 18 months; mitochondrial toxicity should be suspected in sick infant; no evidence of increased congenital abnormalities overall, but not enough data to comment on any one particular drug.

Occupational health issues

Healthcare workers who believe they may be infected with HIV should consult with their occupational health department. In general it should not limit their ability to work, except that they may be obliged to avoid "exposure-prone" procedures.

Notification

AIDS is NOT one of the statutory notifiable diseases; but systems do exist for surveillance of HIV.

External links

References

  1. Worobey M, Watts TD, McKay RA, Suchard MA, Granade T, Teuwen DE, Koblin BA, Heneine W, Lemey P, Jaffe HW. 1970s and 'Patient 0' HIV-1 genomes illuminate early HIV/AIDS history in North America. Nature. 2016 Nov; 539(7627):98-101.(Print-Electronic) (Link to article – subscription may be required.)
  2. Pneumocystis pneumonia--Los Angeles. MMWR. Morbidity and mortality weekly report. 1981 Jun; 30(21):250-252.(Print)
  3. Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR. Morbidity and mortality weekly report. 1981 Jul; 30(25):305-308.(Print)
  4. Hymes KB, Cheung T, Greene JB, Prose NS, Marcus A, Ballard H, William DC, Laubenstein LJ. Kaposi's sarcoma in homosexual men-a report of eight cases. Lancet (London, England). 1981 Sep; 2(8247):598-600.(Print) (Link to article – subscription may be required.)
  5. Durack DT. Opportunistic infections and Kaposi's sarcoma in homosexual men. The New England journal of medicine. 1981 Dec; 305(24):1465-1467.(Print) (Link to article – subscription may be required.)
  6. British HIV Association, British Association of Sexual Health and HIV, British Infection Society. UK National Guidelines for HIV Testing 2008: British HIV Association, British Association of Sexual Health and HIV, & British Infection Society, 2008 (September)
  7. General Medical Council. Confidentiality: Protecting and Providing Information London: General Medical Council, 2004 (April)
  8. British HIV Association, British Association of Sexual Health and HIV, British Infection Society. UK National Guidelines for HIV Testing 2008: British HIV Association, British Association of Sexual Health and HIV, & British Infection Society, 2008 (September)
  9. de Ruiter A, Mercey D, Anderson J, Chakraborty R, Clayden P, Foster G, Gilling-Smith C, Hawkins D, Low-Beer N, Lyall H, O'Shea S, Penn Z, Short J, Smith R, Sonecha S, Tookey P, Wood C, Taylor G. British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008. HIV medicine. 2008 Aug; 9(7):452-502.(Link to article – subscription may be required.)
  10. Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2011 Mar 10; 117(10):2791-9.(Link to article – subscription may be required.)
  11. Exposure of health care workers to the blood of patients infected with the human immunodeficiency virus. The New England journal of medicine. 1989 May 18; 320(20):1350-1.
  12. British HIV Association, British Association of Sexual Health and HIV, British Infection Society. UK National Guidelines for HIV Testing 2008: British HIV Association, British Association of Sexual Health and HIV, & British Infection Society, 2008 (September)
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