HIV Infectious Diseases Lesson 11 PDF

Caterina Caserta Esther Ramanathan Infectious diseases lesson 11 Prof. Parisi 23/03/2023 HIV Professor Saverio Parisi presents himself and informs us that he will teach us for about 20 hours. In the case he will not be able to teach the whole 20 hours himself, Professor Basso will give the lessons....

Caterina Caserta Esther Ramanathan Infectious diseases lesson 11 Prof. Parisi 23/03/2023 HIV Professor Saverio Parisi presents himself and informs us that he will teach us for about 20 hours. In the case he will not be able to teach the whole 20 hours himself, Professor Basso will give the lessons. His program will vert on nosocomial infections and about some viral diseases starting with HIV-1 and including HCV, HBV, HHV-8, CMV, Epstein-Barr virus. Later he will discuss infections that can occur during pregnancy and pediatric diseases (as he is also a pediatrician besides being an infectious disease specialist). Natural history of HIV infection (off drugs) This image represents the natural history of HIV infection off drugs. The clinical course of the disease was studied mainly before drugs became available, since nowadays drugs must be provided immediately after diagnosis. After an acute infection, the disease is frequently asymptomatic or mild symptomatic so people don’t understand that they have the disease. During the acute infection, immediately CD4 drop from 1000/1200 to 600-700 (cells/mm), but without symptoms, and plasma viremia starts to increase. Within a few weeks, the plasma viremia drops to a plateau, which in the graph is very low but generally is 1000/100.000 copies and CD4 goes up to 1000, as at the beginning of the disease. For many years the plateau of plasma viremia remains quite stable and predicts the evolution of the infection: higher plateau means faster evolution of the disease; CD4 drop very slowly, within 8-10 years they drop to 200-300 and the AIDS disease develops. AIDS disease is characterized by some symptoms and by opportunistic diseases from agents that are characteristic of the HIV infection or oncologic diseases, and some other syndromes that are characteristic of the late stages of the infection. At this stage, it is possible to talk about AIDS, while before it is HIV infection without AIDS. When a person is diagnosed with HIV with Pneumocystis carinii infection, Candida infection, Cryptococcal infection, toxoplasmosis, they become AIDS patients and they remain AIDS patients for the entire course of the disease. It is possible to treat the patient and lower the HIV plasma viremia and CD4 can go up, but the patient remains classified as AIDS patient. Historical excursus It all began in 1981 when 5 young men in Los Angeles, California presented in different hospitals with a pneumonia-like infection due to Pneumocystis carinii, which was not a frequent infection. Nowadays this infection is observed in other diseases that cause immune-compromission such as transplant patients or patients treated with immunomodulant, rheumatological diseases and oncologic diseases. 40 years ago, this infection was very rare. The clinical picture of these 5 patients was described as a new picture, also characterized by Cytomegalovirus reactivation, by candidiasis, which are all characteristic of immunocompromised patients and were observed mainly in congenital/genetic immunodeficient patients but not in normal people. 1 It was hypothesized that these patients had an infection, but the etiological agent was not yet known, therefore there were no clear diagnostic tests and there were no treatments available for many years. Many labs around the globe tried to understand which the agent was causing this infection, meanwhile quickly the disease started to become very frequent in some ‘kinds’ of patients: homosexual men who had sex with men, drug addicts and people who received blood transfusion. In 1983, one lab in Paris in the Pasteur Institute, run by Luc Montagnier, isolated a virus from the lymph node of a patient and this virus was sent to CDC in Atlanta, USA to identify the virus: it was a retrovirus. In 1983-84 another lab run by Robert Gallo in Bethesda; Maryland discovered a virus from a patient that was very similar to the one found be the Pasteur Institute. Gallo was a very important virologist who studied for many years HTLV-1 and HTLV-2, that are retroviruses as well. The newly discovered virus was then called HTLV-3 but the scientific community stated that Montagnier arrived first in the discovery, and indeed in 2008 he received the Nobel prize together with Barré-Sinoussi for this discovery while Gallo didn’t. The two institutions, NIH, where Gallo worked and Pasteur institute began a debate on who discovered the virus first, above all because a lot of money is behind this game since all companies who want to use this virus for diagnostic test have to pay the researcher who discovered the virus. In the end, it was decided that both institutions could use the virus for the brand. In the meantime, AIDS became the first pathology with only one etiological cause causing death in the world. As a reference, infections of the lower respiratory tract have a pool of etiological agents causing them as well as perinatal diseases or cardiological diseases. The next causes of pathologies with one etiological agent were #8 in the list, malaria and #12 Tuberculosis. HIV classification HIV infection was classified by staging: stage 1, 2, 3 according to CD4 level and to clinical findings. CD4 levels higher than 500 is stage 1 (no symptoms generally) CD4 levels between 200-500: it’s possible to have some disease but not AIDS-defining diseases. CD4 levels under 200: only this parameter allows to define an AIDS patient, or the presence of a disease correlated to AIDS. In Italy these diseases that allowed the identification of the patients were: o Toxoplasmosis o Candidiasis o Cryptococcosis in the CNS o Non-classical mycobacteriosis (caused by Mycobacterium avium or Mycobacterium kansasii) o Cytomegalovirus o Herpes simplex virus o PML (Progressive multifocal leukoencephalopathy) o Kaposi’s sarcoma, which has been known since the beginning of the 20th century but it is not a frequent sarcoma, usually with a slow evolution. In AIDS patient, and also young patients, it has a rapid evolution and it can cause mucocutaneous disease as well as visceral disease; it is very frequent in AIDS patients. [professor then cites the movie “Philadelphia” with Tom Hanks, which is about a lawyer who had many problems in his job related to the lesions on his face caused by Kaposi sarcoma] o Lymphoma The update done in 1985 on the diseases correlated with AIDS also included: o Isopsoriasis 2 o Non-Hodgkin lymphoma o Interstitial pneumonia Later on also other pathologies were included: o Classical tuberculosis (by Mycobacterium tuberculosis) o Some oncological diseases characteristic of older age women. Nowadays one of the main diseases that allows to identify an AIDS patient among young women is invasive cervical cancer. HIV transmission In order to understand the origin of the infection in a patient it’s useful to get the history of the patient, which should also include if he had sex with men. In Italy about 50% of the new diagnosis are in MSM (men having sex with men) and then are heterosexual males (25%) and heterosexual females (17%). Data from the European Union are not very realistic and reliable since 27,7% of diagnosis are detected in unknown source. Data from Italy is more useful, as there is avery good etiological grasp of the data In Italy to this day, after about 40 years since the first cases of HIV infection, there are many late presenters to diagnosis. Late presenters means people with less than 350 CD4 cells/L, which also considering the initial graph means that they have had the infection for 7-10 years. During these years they didn’t know they were infected so they spread the virus in the community, in the family, to the partners or many partners, because they don’t know they are infected and they come to the diagnosis very late in the course of the disease, known as late presenters. In Italy late presenters are 60% of the total diagnoses. Nowadays there are fewer number of diagnoses of infection with respect to the first years of this epidemic: the cases now are way less among drug addicts because today they take pills instead of intravenous injection and the main roads of infection are heterosexual and homosexual unprotected sexual intercourse. The percentage of late presenters is also high in Europe (51%). In the map on the left are reported the number of new HIV diagnosis with CD4 cells count (note that Russia and also eastern Europe countries represent a black hole since the transmission of data is not as reliable). 3 Usually, MSM are diagnosed at higher CD4 count because they take care of their health, they are more aware of this problem. Heterosexuals usually have late diagnoses as they generally don’t think about HIV and don’t even test for HIV, maybe only if they donate blood. The reasons behind this also reside in the fact that general practitioners and gynecologists don’t prescribe tests for HIV but rather for other STIS. This is mostly due to the stigma related to HIV for which HIV infected patients must be drug addicts or MSM, therefore general practitioners are unlikely to test people who aren’t in these demographics. In Italy, for example, the test is provided for free and it is anonymous, although the person is responsible for their disease management especially with regards to spreading it to other people. Below are reported the number and the proportion of new diagnoses, classified based on the reason why people took a HIV test (2020): 37% of people got tested because they had a suspected disease correlated with HIV infection, so late presenters. If they have a correlated disease it’s very late in the course of the infection and it is more difficult to control and treat the diseases. Indeed drugs work better if they are taken at the beginning of the infection, while if taken later they still work well but CD4 reached such a low nadir that the immune response cannot be totally reconstituted. Unprotected sexual intercourse in 17% of cases Screening campaigns (6,5%) Use of drugs, which was a much more common cause during the late 80s/90s in Italy. Now HIV infection is no longer a problem for drug users also because they take drugs in the forms of pills for the most part. Also good testing of drug users has helped to reduce the spread of HIV among drug users The graph on the right reports the proportion of new diagnoses with respect to the reason behind HIV test, comparing 2019 and 2020. 4 Epidemiology and risk factors The maps above report new HIV diagnoses per 100.000 population in heterosexual transmission (left) and MSM (right). Considering the new HIV infection diagnoses for age and gender (2020), most diagnoses were done in the age range 20-30 years, but also in people aged over 60. MSM diagnoses are more frequent in younger people, while in the older age MSM are lower and heterosexual males and females are more frequent. The table below instead reports a comparison between Italians and foreigners. It appears that the number of new diagnoses is way higher in Italians, heterosexuals or homosexuals who are infected by other Italians. Sometimes foreigners come to Italy with HIV infection, sometimes after staying in Italy for many years they are early diagnosed with HIV (so they get HIV in Italy) from other foreigners or from Italians. Therefore it is not just nonItalians who are spreading HIV, but also Italians. 5 Indicative pathologies for AIDS The diseases allowing to make an AIDS diagnosis are: Pneumocystis carinii; if a old man is admitted to the ER with pneumonia, physicians think about bacteria, SARS, TB, fungal infection, and lastly they think about HIV. Kaposi sarcoma, which has an easy diagnosis for the cutaneous lesions that it causes. Candidiasis Wasting syndrome Tuberculosis, which is the leading cause of death in sub-Saharan Africa. When TB and HIV infection are correlated they lead to a serious clinical picture. In Italy it is not so frequent. In over 20 years the percentage goes from 50% to 80% of people who were diagnosed as late presenters. Only 50% had diagnosis of AIDS within 6 months, that became 80% in 2020. These people could spread the virus for over 10 years before diagnosis. This is because nowadays nobody speaks about HIV, and these are the results. Now, we speak about PrEP (Pre-exposure prophylaxis) which is a good solution because people in this case consider the possibility of getting infected by unprotected sexual activity, for example. This of course can still lead to the possibility of getting HCV, syphilis, and many other STIs. 6 Deaths related to AIDS and evolution of demographics affected There are AIDS related deaths in Italy (46.000) from the beginning of HIV history. They are fewer than Covid-related deaths within the last 3 years. This is still a great problem as Covid was a pandemic; however HIV has been a problem for over 40 years that we have not been unable to resolve despite having the PrEP and drugs. In Veneto region out of 30,000 cases only 2,000 were made as new diagnoses (below). MSM cases grew from 16% to 30%; injected drug users drop from 55% to 10%; heterosexual became half of the new diagnoses. Drug discovery timeline The AIDS related deaths peaked in 1994-95-96 as all the people infected at the beginning died within 10 years as they became AIDS patients. After that, there was a drop because in 1996 there was the beginning of administration of good drugs, a 3-drug combination therapy, including zidovudine, a drug previously used for neoplastic disease. The drug company also studied and produced other nucleoside retro-transcriptase inhibitors similar to zidovudine to be used in combination. After they also provided protease inhibitors that worked very well and were very potent with a high genetic barrier to the evolution of the resistant virus. They also provided non-nucleoside reverse transcriptase inhibitors. Therefore after 1996 there were multiple choices to combine different antiretroviral drugs with the so-called HAART (highly active antiretroviral therapy) was also very efficient. When people take these drugs 7 they immediately drop the plasma viremia and their CD4 cell count rises, which prevents the progression to the AIDS stage and prevents those who already had AIDS to die from it in the late 90s. People in those years died due to other diseases and not directly from HIV, including: - liver disease - HCV-related disease - HB- related disease - liver cancer - other neoplasms. Therefore the number of people dying from HIV is way less than 20 years ago. Most patients who die now are patients in a very late stage of the infection. Clinical presentation of acute HIV infection Acute infection is generally asymptomatic or mild symptomatic simil-mononucleosis including symptoms as: Fever Lymphadenopathy (like in mononucleosis) Pharyngitis Rash (which resolves quickly) Myalgia, arthralgia Thrombocytopenia Diarrhea Headache Nausea and vomiting All of these are common symptoms and people don’t understand they have an important acute infection, instead suspecting a respiratory virus or mononucleosis. Therefore the patient doesn’t take care of the infection and the GP doesn’t suspect HIV. The initial disease typically resolves itself and the HIV infection begins to replicate and the patient doesn’t take any care of it. Years later, the patient doesn’t remember the acute phase of the infection, as he didn’t see it as a big problem at the time. [Prof. remembers a case in Verona hospital in 1995 where he made a diagnosis of acute infection in a patient with significant CNS symptoms (acute encephalitis) who tested negative for herpes. They tried to culture HIV from blood and liquor, and HIV was indeed isolated. In 1995 it was only possible to isolate HIV, because plasma viremia could not be tested with molecular methods such as real time PCR. They understood the patient had an acute infection because they were antibody negative, as in the first days there is no IgM or IgG but only the virus]. These are the diagnoses per 100,000 people in Italy with the differences among the regions. 8 The graph reported below on the left indicates the new diagnoses among Italians and foreigners. Italians are more frequently MSM, in foreigners are more frequent heterosexual cases (males and females). The mean age of AIDS (graph on the right) diagnosis has grown by 10 years over the last 20 years. The mean age was less than 40 (in males) and has now became 46. This is because people are careless about HIV hence an increasingly later diagnosis. Treatment and HAART The availability of good drugs allows to cure and control the disease, not to eradicate it. At the beginning of the HIV history, a patient who was diagnosed at 25 years, within 10-15 years he died. The early HAART was characterized with drugs that were potent but with problems such as toxicity and had to be taken multiple times a day, therefore patients didn’t take them properly. Doctors had to frequently change the drugs as the patients didn’t take all the therapies well for a prolonged period of time. The late HAART (highly active anti-viral therapy) was characterized by more efficient drugs, and it usually consisted in taking one pill a day, without any other side effects other than curing the plasma viremia. Therefore many patients were successful in taking the therapy and their life expectancy now is similar to that of the general population (only if they take the drugs immediately after diagnosis or in the early stage of the infection). Look at the line of the infected and uninfected. Comparing the prevalence of HIV and the deaths due to AIDS in the first 10 years of HIV history and after HAART introduction, there was a decline in AIDS diagnoses and in death, which are now related to other diseases such as neoplasms, HCV infections or late diagnoses. In Padova there are about 2000 people being treated with about 150 new patients every year, and no deaths. There are about 7-8000 cases in the Veneto region (similar to other regions in Italy. The south has fewer cases than the north). 9 Strategies and goals for HIV containment There are about 37 million infected people and there are 33 million diagnoses. The goal was to treat 90% of those with a diagnosis. Only 90% of those treated reach complete viral suppression. 90% x 90 x 90 in the end equals 73% (3 out of 4) which is the goal. The graph below shows the current results of this goal. Swiss is 68%, France is 52%, USA is very far down the list (30%) because people who don’t have health insurance have to pay for treatment and often they cannot afford it. Barriers to care and treatment Barriers to treatment are represented by a number of factors: Substance use; Discrimination; Poverty; Stigma; Forgetting to take the pills; Adverse events to medications. Some patients go the hospital regularly, others begin and then disappear, others begin slowly and then go more frequently. These trajectories were studied (also for Covid), to link the patients and to retain them into care, including many different strategies. However, it is important to consider that the greatest number of patients are in Africa, South America, far East. Also due to Covid, an interruption in the HIV surveillance has been translated into at least 1 million AIDS related deaths, more than the normal trajectory estimated in the past. 10 Prevalence of HIV in Europe - The trajectory for the 10 years (2002-2011) in western Europe is stable, not decreasing, with about 7 new cases per 100,000; in the western Europe, the epidemic is sustained by MSM; It is increasing in the near-eastern part of Europe from 1 to 1.5/100,000 however they have a lower starting point than in western Europe. In Russia the increase starts from 7 to 17 per 100,000. The transmission from drug users sustains the heterosexual epidemics in the far East. Diagnosis Now it is not possible to study people in the acute phase of the disease, as there is a very low number of people discovered in this phase of the infection and when it is known that someone has an acute infection, they must be treated immediately and cannot be studied for weeks before providing treatment. Therefore the data used to design this graph is from the early phases of the epidemic. In the past it was possible to study because there was no drug to treat the infection. Studying would occur after an incident, for example those who had a sexual assault or those who had an accident at work (in the hospital or in the lab). In the first 3-5 days, according to the transmission route (blood or sexual route) within a few days, the HIV can be discovered in the blood by RNA testing (plasma viremia). Plasma viremia is immediately very high, and it can be understood that someone has a HIV infection. It is possible to understand it by molecular methods and dose the HIV RNA level in plasma. After a few weeks, it is possible to discover an antigen (P24 antigen) by serological methods, later and at lower levels for a few weeks. When there was no possibility to search for HIV RNA, only the antigen detection was available and therefore only at the later stage. After another couple of weeks, it was possible to see if people were infected via serological methods (IgG and IgM); this stage was called seroconversion and it usually occurs from some weeks to 3-5 months after the exposure. A serological test costs about 5 or 6 euros and it can only discover the antibodies. The first generation of the test in 1985-1987 was not very sensible, so there was a higher titre of IgM and IgG and the diagnostic window was many weeks to a few months. After a few years second generation of tests 11 were more sensitive and also very specific, so the window became shorter; with the third generation it became even shorter. Today a fourth-generation test is available and it is a combined test for the antibodies and the P24 antigen, so even if the antibody is negative, the antigen can be positive. Therefore, the window is much shorter, and the cost is very low (less than 10 euros). Obviously RNA test is the best diagnostic technique, but the cost is much higher. HIV RNA is used when a very short diagnostic window is needed, such as in a transfusion setting. When someone is positive by serological test, there is then a split by making a P24 test and antibody test, to understand which is positive. Also RNA and CD4 tests are performed to understand the stage of the HIV infection. A Western blot is performed after the first serological test to confirm the specificity of the result. Which test- to whom? In Italy testing is free and anonymous and it can be taken by everyone or it is provided: At the beginning of a pregnancy; When referred multiple sexual partners after last test; Partner of seropositive person; Drug addicts; Sex workers. Generally, general practitioners forget all of these issues. In Italy no one can be tested without their written consent. However some hospitals use a strategy where the test is undertaken after notifying the individual that the test will be performed, at this point the person can accept or decline the test. This is known as opt out strategy, and it is inserted together with other blood tests. This strategy allows to test as many people as possible, however there still has to be explicit permission. This choice is important as it is important to prevent people from having a stigma of HIV. In the transfusion setting, when the molecular test became available, in order to test the safety of blood, many millions of tests of HIV, HBV and HCV were performed. Study on safety of transfusions A research paper published in 2008, is about HIV infected people who were diagnosed in the transfusion setting. In the study, 14 people were diagnosed in the transfusion setting, were all antibody negative so they had a very recent infection. It is important to note that 2 people out of 14 were there for the first time donating blood, however 12 people (HIV-antibody negative) were repeating donors so they were donating blood every 6 months or every year but still they didn’t mention a new potential risk (e.g. new sexual partner). They were positive with too much virus in the blood, antibody negative. Many people could have become positive after receiving the blood from these donors. The same study was conducted for HBV and HCV. For HIV they became seropositive after 2 months, so this was the window. 12 [Professor recalls another case from the Verona hospital, in the summer of 2001 where a patient who lost his wife (who died for oncologic problems) remained widowed with a son. He was a blood donor and provided blood every 6 months in the transfusion center. He donated blood in the summer 2001, in in the winter of 2001 he donated. In February 2002 he met a new partner and in June 2002 he donated blood again, and he didn’t’ mention the new partner, because he considered it a normal thing. In June he was positive by RNA testing and Ab negative (this test was provided in Verona for research purposes).. He only mentioned the new partner after the diagnosis. He very recent plasma positive, and even the partner didn’t know she was positive. It was published a paper about this because it is important to test for HIV plasma viremia in the transfusion setting]. Q: What is the difference between HIV-1 and HIV-2? A: In the Veneto area the professor discovered less than 10 people with HIV-2 infection, generally from Africa. Some people can be coinfected with 1 and 2, however HIV-2 is very rare in Italy. In Italy many people 30 years ago were B type, less than 10-15% had non-B type (recombinant virus or C subtype or A subtype). More recently there are many non-B subtype, about 50% of the cases. This is because non-B subtype spread among foreigners, however it is starting to spread also in Italian people, which can still be treated with the same drugs as the B subtype. In HIV-2 some drugs don’t work. The tests are able to distinguish by serological methods like Western blot HIV1 from HIV2, but not by commercial methods. [Prof will discuss more on the serotypes in subsequent lectures] Q: Is it ok to test for HIV on donated blood? A: These people give their default permission for HIV testing by donating the blood. Consent comes with the donation. People diagnosed are referred to the infectious disease ward (if they want). The next lesson will be about the clinical picture of HIV patients. 13