Knowledge of the natural history of disease ranks alongside causal understanding in importance for disease prevention and control.Understanding the characteristic natural history of a disease enables physicians to anticipate prognosis and to identify opportunities for prevention and control.Understanding the natural history can also tell us roughly the time frame within which we have to intervene to alter the clinical course of diseaseand prevent the development of more serious consequences.One of the major elements of descriptive, analytical epidemiology.
Why it is important to understand the progression of HIV and the clinical stages of HIV infection?Answers:Enables clinicians to identify the appropriate time to start ART.Helps targeted drug development to arrest the infection at various stages.Identifies time to initiate preventive therapy.
This picture shows PYLOGENY of SIV and HV. HIV-1 and HIV-2 are closely related retroviruses of the same genus (Lentiviridae) and share the same modes of transmission. Both types are considered to have arisen from the introduction of simian immunodeficiency virus into the human population, although they derive from different primate simian immunodeficiency viruses: HIV-2 from SIVsm (sooty mangabey) and HIV-1 from SIVcpz (chimpanzee).
1. The first published article related to AIDS was in 1981. The principal author’s name was Michael Gottlieb and it appeared in the Morbidity and Mortality Weekly Report for June 5th. This article reported that there was a random increase in Pneumocystis carinii pneumonia (PCP), a rare lung infection. The Centers for Disease Control and Prevention noticed it when a drug technician named Sandra Ford noticed that there was an unusually high number of requests for the drug that treated PCP."A doctor was treating a gay man in his 20s who had pneumonia. Two weeks later, he called to ask for a refill of a rare drug that I handled. This was unusual - nobody ever asked for a refill. Patients usually were cured in one 10-day treatment or they died."-Sandra Ford for Newsweek2. A short while later, on July 3rd, another article reported eight outbreaks of Kaposi’s Sarcoma (KS) in young homosexual males in New York. This was surprising because Kaposi’s Sarcoma was a rare form of cancer that normally showed up in older people. At this time, the medical community realized that a new disease was probably heading their way.3. In 1982, the term Acquired Immune Deficiency Syndrome is used for the first time. The name was designated by the CDC. That year there were 1600 people diagnosed with the disease and almost seven hundred deaths. The CDC task force on KSOI had traced forty patients suffering from KSOI to a single person, called Patient Zero. Because of this, they realized that the disease was sexually transmitted. The disease also showed up in IV drug users and hemophiliacs. The first case of heterosexual transmission was diagnosed in 1983. “The doctors thought 'AIDS' suitable because people acquired the condition rather than inherited it, because it resulted in a deficiency within the immune system, and because it was a syndrome, with a number of manifestations, rather than a single disease.”
3. In 1982, the term Acquired Immune Deficiency Syndrome is used for the first time. The name was designated by the CDC. That year there were 1600 people diagnosed with the disease and almost seven hundred deaths. The CDC task force on KSOI had traced forty patients suffering from KSOI to a single person, called Patient Zero. Because of this, they realized that the disease was sexually transmitted. The disease also showed up in IV drug users and hemophiliacs. The first case of heterosexual transmission was diagnosed in 1983. “The doctors thought 'AIDS' suitable because people acquired the condition rather than inherited it, because it resulted in a deficiency within the immune system, and because it was a syndrome, with a number of manifestations, rather than a single disease.”4. Although AIDS had a name, no one knew what the causes and tests for AIDS were. The race was on to discover what caused AIDS. In 1983, French scientists Dr.Luc Antoine Montagnier team at the Institute Pasteur found a new virus that they called lymphadenopathy-associated virus or LAV. About a year later, Dr. Robert Gallo, of the National Cancer institute discovered HLTV-III. The first discovery was made in France at the Institute Pasteur, but shared credit is given to Dr. Robert Gallo, the discoverer of AIDS and his French counterparts for discovering HIV on April 23, 1984. In 1985, doctors came up with a test to identify who had AIDS and which donated blood had the AIDS virus. At this time, scientists knew that not only homosexuals got it, but also anyone exposed to the virus from blood or body fluids could get it too, including newborn babies and children.
The first CDC task force, in 1981, called the disease Kaposi’s Sarcoma and Opportunistic Infections (KSOI) The disease was sometimes also referred to as “gay cancer” or Gay-related Immunodeficiency Disease (GRID.) At that time, the medical community had noticed that the people with this disease had deficient immune systems. The early names of the disease showed that it was believed that only homosexuals could get it. There were many theories about what might cause this disease in homosexuals, such as using a drug called amyl and/or butyl nitrite inhalers, also known as “poppers”, various combinations of sexually transmitted diseases (STDs) and exposure to strange tropical illnesses. This was proven wrong when a group of non drug-using heterosexual Haitians were found with the illness. Another group of people with a blood disease called hemophilia, who had to get a lot of blood transfusions, also started to show up with the illness.
HIV-1, HIV-2 and SIV are all thought to share a common ancestor, both HIV-2 and SIV express an extra viral protein that HIV-1 does not. HIV-2 is also less pathogenic than HIV-1. HIV-2 can not be measured by HIV-1 viral load tests.
Virion StructureHIV-1 exhibits all of the structural characteristics of a typical lenti virus retroviridae. It was originally named a retrovirus because of its particle associated reverse transcriptase, a hallmark of the retro viridae family. It is a 100 to 120 µm enveloped virion with 2 single RNA strands and similar morphology to the lenti virus genus confirmed its retrovirus status.The HIV-1 virion uses the host cell membrane to form the viral envelope. This envelope is covered by gp41 and gp120 surface proteins as well as Major histocompatability complex class II (MHC II) proteins inserted into the lipid envelope . Inside the lipid envelope, the matrix formed by Gag protein p17 holding the RNA containing core in place. The cylindrical core not only stores the viral RNA and various proteins, it also contains complementary RNA synthesized by the viral reverse transcriptase. Reservoir of Infection: Cases and carriers.Source of Infection: all the body secretions.
Trainer’s Notes:The next two slides summarize the basic HIV transmission concepts. This information is essential to understanding HIV epidemiology patterns and prevention approaches discussed in this session.Review the bodily fluids that transmit HIV: Semen Vaginal Fluids Blood Breast MilkReview the main modes of HIV transmission:Sexual (vaginal or anal)Injection Drug UseMother to ChildOccupational Exposure Reader’s Notes:How HIV is transmitted:HIV is transmitted from one person to another through the exchange of blood and certain bodily fluids during sexual activity. Vaginal secretions and semen contain HIV. Sexual intercourse (vaginal and anal) is one way in which HIV is transmitted. Sharing needles, syringes and other paraphernalia receiving a blood transfusion, or getting a deep needle stick from a person infected by HIV during an occupational exposure, are ways transmission occurs when blood from an infected person is transmitted to another.Mothers can transmit the virus to their babies during pregnancy, delivery, or during breast feeding. This does not happen all the time - approximately 30-48% of the time as reported in India, but abroad it is less than 30%.
1. Exposure:number of sexual partnersHIV infected primary partner2. Transmission:Viral load of infected personsType of sexual contactCo-existence of untreated STD’SUn-safe sexSource: Annexure #4:Guidelines on the Management of Occupational and Non-Occupational Exposure to HIV, HBV, and HCV and Recommendations for Post-Exposure Prophylaxis, NACO, January 2007.
The risk of HIV transmission would be higher with multiple exposures or if the person who is exposed has an STI or has a weak immune system due to TB, malnutrition or other disease. All transmission risks assume an HIV-infected source partner/patient.Reader’s Notes:Interpretation of data presented in slide:1) Approximately 0.5 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected insertive oral intercourse. 2) Approximately 1 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected receptive oral intercourse. 3) Approximately 5 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected insertive penile-vaginal intercourse. (female to male)4) Approximately 6.5 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected insertive anal intercourse. 5) Approximately 10 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected receptive penile-vaginal intercourse. (male to female)6) Approximately 30 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through occupational percutaneous injury. 7) Approximately 50 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through unprotected receptive anal intercourse.8) Approximately 67 out of 10,000 people will acquire HIV with a single exposure from an HIV-infected source through needle sharing.Sources:1. Rothenberg RB et al. AIDS 1998;12:2095-2105.2. Am J Epidemiology 1999;150:306-11.3. NEJM 336(15):1072-8. (rates in Europe & U.S.)4. Am J Epidemiology 1999;150:306-115. CDC, MMWR 47;RR-17, 1998.6. Bell DM. Am J Med 1997;102(suppl 5B):9—15.7. Am J Epidemiology 1999;150:306-11 and CDC, MMWR 54; RR-2, 2005 (http://www.cdc.gov/mmwr/PDF/rr/rr5402.pdf). 8. CDC, MMWR 47;RR-17, 1998.
Reader’s Notes:HIV transmitted through sexual activity enters the bloodstream via mucous membranes lining the vagina, rectum, and mouth. Macrophages and dendritic cells on the surface of mucous membranes bind virus and shuttle it into the lymph nodes, which contain high concentrations of Helper T cells (CD4+ T cells).Once HIV has entered the body, the immune system initiates anti-HIV antibody and cytotoxic T cell production. However, it can take one to six months for an individual exposed to HIV to produce measurable quantities of antibody. The immune response is weakened as memory T cells (CD4+ CCR5+) are destroyed.HIV enters the body and binds to dendritic cells (orange cells with projections) which carry the virus to CD4+ T cells in lymphoid tissue establishing the infection. Virus replication accelerates producing massive viremia and wide dissemination of virus throughout the body's lymphoid tissues. An immune response against virus causes some protection but a chronic persistent infection is established. The production of cytokines and cell divisions that regulate the immune response for protection also cause HIV replication. There is a rapid turnover of CD4+ T cells that ultimately leads to their destruction and to a change in lymphoid tissues that prevent immune responses.Source: GHTM Fellowship Programme, 2006
Explain the graphic in detail. It shows the normal progression of CD4 count, viral load and clinical course of untreated HIV infection in adults.In close temporal relation with the resulting peak of viraemia (eg, 106 to 107 copies per mL plasma), clinical symptoms can be manifest during primary HIV-1 infection (figure 4).2. A gradual destruction of the naive and memory CD4+ T-lymphocyte populations isthehallmark of HIV-1 infection, with AIDS being the last disease stage (figure 4).
Reader’s Notes:Acute seroconversion:Fever, rash and adenopathyUsually 3-6 weeks after exposureCommon signs and symptoms:¨ fever, fatigue, rash, headache, myalgia, arthralgia, retro-orbital pain,weight loss, depression, nausea, vomiting, or diarrhea, night sweats,lymphadenopathy, pharyngitis, oral / genital ulcers, aseptic meningitis¨ Labs: Thrombocytopenia, leukopenia, ALT / AST¨ The duration of symptoms variable, lasting from a few days to >10 weeksHIV AIDS: U.S. Government site www.AIDS.gov informs: "The timeframe between when you are exposed to HIV to the time you test positive for HIV antibodies can be up to 3-6 months. This period of time is called a “window period” for HIV testing. On average, you may need to wait 2 to 8 weeks from the time of possible exposure to get an accurate test result, because it takes at least that long for the immune system to develop enough HIV antibodies to be detectable.Asymptomatic HIV (clinical latency):Patient often unaware of infection, antibodies detectable.Immune system able to control virus to limited extent and CD4 > 350/cu.mmAble to transmit HIV to othersSymptomatic HIV:Minor to moderately severe symptomsRecurrent symptomsAIDS:Severe immunosuppression associated with opportunistic infections or cancers
Trainer’s Notes:The progression to AIDS among individuals is variable. Following infection with HIV, some people progress rapidly (within 1-2 years) to a low CD4 count, become ill and, without treatment, die. Other people may become infected and remain healthy with relatively normal CD4 counts for many years (>10). Reader’s Notes:Typical progressorshave a drop of 35-50 CD4 cells/year. Rapid progressors("CD4 crash") have a drop of 50 CD4cells per month after seroconversion. Slow Progressors have a CD4 decline that is very slow compared to the typical progressors. Long term non-progressors have CD4 counts that are stable at a baseline for many years.
Natural HISTORY OF HIV/AIDS Kumaravel Ilangovan MPH(first semester) Batch- Fall2012
WHAT?WHY?The natural history of disease refers to adescription of the uninterrupted progression ofa disease in an individual from the moment ofexposure to causal agents until recovery ordeath.Source:http://en.wikipedia.org/wiki/Natural_history_of_disease
Objectives– discovery and Evolution of HIV– Difference between HIV-1/HIV-2– describe HIV transmission routes– describe the pathogenesis and life cycle of HIV– describe the progression of HIV to AIDS– Stage at which the preventive and curative interventions available
Evolution of SIV into HIV• Retroviridae• Lentiviridae• Same modes of transmission.• Introduction of simian immunodeficiency virus into the human population.• primate simian immunodeficiency viruses: HIV-2 from SIVsm (sooty mangabey) and HIV-1 from SIVcpz (chimpanzee).
Discovery of HIV• In 5th june1981first article related to AIDS by MMWR.• Author name was MICHAEL GOTTLIEB.• Pneumocystitis carinii (PCP)• Sandra ford – a drug technician said to news letter “a gay man repeatedly called for refill the rare drug used to treat for PCP”• 3rd July another article reported outbreaks of KAPOSI SARCOMA among Homosexual males in Newyork.
continued• In 1982 the term ACQURED IMMUNO DEFICENCY SYNDROME (AIDS) first time coined by CDC.• KSOI (Kaposi sarcoma and Opportunistic infections) CDC task force identified 40 patients.• 1983 Heterosexual transmission.• AIDS is a suitable name. No cause, No tests.• 23rd April 1984 HIV discovered• 1985 test discovered to identify HIV infected persons.
HIV-1 versus HIV-2Table 1. Key differences between HIV-1 and HIV-2 HIV-1 HIV-2Geographic Distribution Worldwide West AfricaHeterosexual Transmission 3- to 6-fold lowerPerinatal Transmission 15%–45% 0%–5%Time to AIDS 7–10 years 10–25 yearsTreatment NNRTIs* ineffective .
Modes of HIV Transmission Needle Stick Sexual contact Sharing Needles Injury & SyringesThrough Infected Blood During Pregnancy Breast Feeding or Birth NACO-2006
Routes of TransmissionINDIA 2010-2011 Gender variation Source: NACO 2006
Risk of HIV Transmission with Single Unprotected Exposure (Risk per 10,000 exposures) Source: NACO 2006
How HIV Infects the BodyHIV makes contact with cells located within the genital mucosa Virus is carried to regional lymph nodes (1-2 Days) Exponential viral replication Widespread systemic dissemination to the brain, spleen, distant lymph nodes, etc. (5-11 Days)
Clinical course of Infection correlated with Biological Assays
Stages of HIV Infection Viral transmission (2-3 wks) Acute retroviral syndrome (2-3 wks) Seroconversion (2-4 wks) Asymptomatic chronic HIV infection (Avg. 8yrs) Symptomatic HIV infection/AIDS (Avg. 1.3 yrs)
Primary Infection: Lab Diagnosis• ¨ ELISA: NEGATIVE (or only IgM• POSITIVE)• ¨ Western Blot: NON-REACTIVE /• INDETERMINATE• ¨ p24 antigenemia: licensed by US FDA for• diagnosis• ¨ Plasma HIV RNA: detectable and high level
Clinical latency¨Asymptomatic¨Ongoing viral replication¨‘Set-point’ for viral load¨Gradual decline in CD4cells¨Antibody tests remainpositive
Patterns of HIV Progression• Typical progressors (35-50 CD4 cells/year)• Rapid progressors ( >50 cells/month)• Slow progressors (very slow than typical )• Long-term non-progressors (stabilised)
ReferencesSources:1. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment 2006 NIH publication (Lancet).2. Rothenberg RB et al. AIDS 1998;12:2095-2105.3. Am J Epidemiology 1999;150:306-11.4. NEJM 336(15):1072-8. (rates in Europe & U.S.)5. Am J Epidemiology 1999;150:306-116. CDC, MMWR 47;RR-17, 1998.7. Bell DM. Am J Med 1997;102(suppl 5B):9—15.8. Am J Epidemiology 1999;150:306-11 and CDC, MMWR 54; RR-2, 2005 (http://www.cdc.gov/mmwr/PDF/rr/rr5402.pdf).9. CDC, MMWR 47;RR-17, 199810. NACO report 2006, 201111. “AND THE BANDS PLAYED ON” 1993 Documentary film by HBO pictures12. Internet resources: Wikipedia and Encyclopedia