AIDS-defining Diseases – Human Immunodeficiency Virus (HIV)

00:01 So, what are those opportunistic infections? And those are called, variably, opportunistic infections, AIDS-defining infections, or in this case, AIDS indicator diseases, and they are many.

00:13 And they correlate with how immunosuppressed the patient is from the attack on the CD4 count.

00:19 We'll start with bacterial infection, and these can be bacterial infections which normally have limited virulence, limited pathogenicity.

00:29 For example, a nontuberculous or an atypical mycobacterium avium-intracellulare complex.

00:37 This is known frequently as MAI or MAC -- Mycobacterium Avium Complex.

00:43 Normally, this causes only rare disease occasionally in children causing chronic lymph nodes.

00:49 But in patients with HIV, it can cause disseminated disease causing lung disease, pneumonia, enteric disease with exaggerated enteric lymph nodes.

00:59 And it is typically seen when the patient is very immunosuppressed.

01:02 Their CD4 count, not percentage, but number of CD4 cells per milliliter of 00:01:11.020 Similarly, these patients can develop normal mycobacterium.

01:13 Tuberculosis, extra pulmonary tuberculosis.

01:16 They develop pneumococcal sepsis, salmonella sepsis, name the bacteria, and they can develop overwhelming disease from any of those.

01:25 Viral infections especially are known to be cytomegalovirus and chronic or disseminated herpes simplex virus.

01:33 So, too, as immune discovery wanes, they can be at risk for escalation or activation of JC virus causing progressive multi-focal leukoencephalopathy.

01:44 Fungal infections, anything and everything.

01:47 So, candidiasis, a very simple yeast.

01:50 Candida which exists everywhere causes thrush in children who are nursing from perhaps a slightly infected breast.

01:59 The candidiasis can be overwhelming, and it goes not just from the mouth, it's not just thrush in a patient with HIV, but it travels all the way down through the GI collecting system.

02:09 Not just the esophagus, but including even intestine to where it can limit absorption.

02:15 There can be pulmonary candidiasis.

02:17 There can be anything and everything.

02:20 Cryptococcal meningitis, that's a classic one.

02:23 Cryptococcus is an environmental mold, which in most immunocompetent people doesn't do anything because we have enough enough immune discovery to limit that, and it's typically addressed by macrophages.

02:37 But in an HIV patient with a CD4 count 00:02:45.460 the ability to stimulate macrophages by interferon -- alpha and interferon gamma is limited, as we just talked about.

02:48 Thus these patients are at risk for cryptococcal meningitis.

02:51 Similarly, histoplasmosis, another fungal mold, pneumocystis jiroveci, which used to be known as pneumocystis carinii, PCP. It's now PJP.

03:01 It causes a diffuse interstitial pneumonia.

03:04 All these are seen in patients who are starting to lose their CD4 count.

03:09 Protozoal infections such as cryptosporidiosis, cerebral toxoplasmosis as the patient gets to a CD4 count.

03:17 And then they can develop cancers because the proliferating cells don't have any control due to an absence of natural killer cell function, CD8 cellular or cytotoxic function.

03:30 And then, unrelated necessarily to the opportunistic infections, but still certainly quite common is HIV wasting syndrome.

03:39 And there is a massive weight of research, pardon the pun, which has been aimed at trying to identify why patients with progressive HIV infection lose so much weight.

03:50 And it's not just fat, but it's fat, muscle, you name it.

03:54 So, how do we diagnose HIV infection? Well, there are many screening tests including fourth generation screening tests, basically all looking for evidence of specific antigens to HIV.

04:07 Diagnostic tests for HIV typically start with an enzyme linked immunosorbent assay or ELISA.

04:14 Originally, one had the third generation ELISA which tested for IgM and IgG antibody.

04:20 This test would become positive.

04:21 20 to 30 days after exposure.

04:24 However, the preferred and currently recommended test is a fourth generation ELISA test, sometimes also known as the combo test.

04:32 This test as well as the third generation test for IgM and IgG antibody, but also the P24 antigen.

04:40 And it can become positive from 15 to 20 days after exposure.

04:45 If the ELISA is positive, a confirmation testing by a rapid HIV one slashes to every two antibody differentiation assay is necessary to distinguish HIV one from HIV two infection.

04:57 HIV two infection is more often endemic in West Africa.

05:01 Western blot is rarely used anymore for confirmation, primarily because it takes too long and is less sensitive.

05:08 The reverse transcriptase PCR or RT-PCR testing is sort of the gold standard at this point, and it is indicated if you're serologic testing via ELISA or possibly western blot is in determinant.

05:23 Also, PCR testing is indicated, if there is suspected acute infection, but the patient is possibly in the window period of HIV seroconversion meaning the time before a fourth generation ELISA might turn positive.

05:37 So within the first really two to three weeks.

05:40 PCR testing also indicated for diagnosis of neonatal HIV infection.

05:45 This makes sense.

05:46 If you remember that mom's HIV positive mothers will transfer IgG of all types across the placenta.

05:55 So doing an ELISA test on a baby will only detect or likely only detect maternal HIV IgG, which is not helpful.

06:04 Instead, we need a specific test for the baby to demonstrate the presence of RNA. PCR testing also then indicated to screen blood donors because it's rapid and very sensitive and a viral load or a quantitative RT-PCR can be used for the management and follow up of HIV one positive patients as well as for diagnosis.

06:26 The viral load, as it's known, is really quite sensitive and in fact there are two quite sensitive assays.

06:34 One has a sensitivity cut off of 50 copies per milliliter.

06:37 That's 50. 5 0 copies per milliliter and detects virus from ten to 15 days after exposure.

06:44 The ultra sensitive cutoff is from one to five copies per milliliter of blood.

06:51 And this detects virus, you know, even as early as five days after exposure.

06:55 That that's incredibly sensitive.

06:58 We'll look at the number and the percentage of CD4-positive T lymphocytes in the peripheral blood.

07:04 Here's an important factor for use clinically Patients may have a low CD4 number if their total number of circulating white blood cells is low as well.

07:15 It kind of makes sense.

07:16 So it's far more sensitive look at the percentage of the lymphocytes which are CD4-positive or the percentage which are not When the percentage drops below 15%, 15%, that is when one is in trouble and can expect to have a specific targeting action on the CD4-positive T lymphocytes.

07:36 Another way which is also quite sensitive is to look at the ratio between CD4-positive and CD8- positive T lymphocytes.

07:44 Normally, in healthy individuals, that ratio is 2 -- 2:1.

07:50 In somebody with active HIV infection or active retroviral attack on the CD4 cell, that ratio typically drops to 0.5 -- 1:2.

08:00 It's a significant difference and it's quite sensitive.

08:04 HIV treatment, ideally and per recommendation treatment should begin as soon as diagnosis is made.

08:10 Some same day of diagnosis treatment should start that day and continue indefinitely without interruption.

08:17 No more does one recommend the HIV treatment holidays or honeymoons as people used to. Drug resistance testing via HIV genome, whether it's it's phenotypic or genotypic, is ordered at the same time, but the therapy is not delayed while waiting for those results.

08:36 One also tests for hepatitis B and C due to the likely cold tracking of these infections with HIV and women of childbearing age also have a pregnancy test.

08:47 The treatment, as stated, is started regardless of viral load or CD4 count or anything else, and one of three regimens is usually recommended initially.

08:57 Each of these regimens includes three HIV medicines from at least two different HIV drug classes.

09:05 An example of a typical initial regimen and a nonpregnant adult who is treatment naive is Dolutegravir, which is an integrase inhibitor and tenofovir, a nucleotide analog reverse transcriptase inhibitor plus either emtricitabine or lamivudine nucleoside reverse transcriptase inhibitors.

09:27 That's just one example.

09:28 Of course, there are many others.

09:30 Treatment is modified then, depending on the patient's characteristics such as pregnancy, age, results of drug resistance testing, viral load testing, especially if the patient does not have or does not demonstrate viral suppression after initiation of their treatment.

09:47 And of course, side effects.

09:49 The Food and Drug Administration in the United States has approved medications in nine different classes to treat HIV infection.

09:56 And these medications exist in 23 distinct drug combinations incorporating at least two HIV medication types in one pill.

10:05 The classes are nucleoside reverse transcriptase inhibitors or NRTIs, non nucleoside reverse transcriptase inhibitors or NNRTIs protease inhibitors, PIs, fusion inhibitors, CCR five antagonists, integrase strand transfer inhibitors or INSTIs attachment inhibitors.

10:29 Post attachment inhibitors and pharmacokinetic enhancers.

10:33 Turning to human t lymph a trove of virus type one or HTLV Type one.

10:38 This is a retrovirus and is known to be associated with two diseases, even though less than 5% of infected individuals develop the disease.

10:47 The two diseases are adult T-cell leukemia, lymphoma or ATLL and HTLV one associated myelopathy/tropical spastic paraparesis or HAM/TSP.

11:03 Clusters of high end immensity of HTLV one infection have been found in southern Japan, the Caribbean, areas of South America and Tropical Africa, as well as specific foci in the Middle East, Australia and Melanesia.

11:18 There are an estimated ten to 20 million HTLV one carriers worldwide, with about nine cases per 100,000 people in the USA.

11:28 Interestingly, it seems to preferentially impact or infect women more than men at a ratio of two to one.

11:35 Nearly all HTLV one infected individuals remain asymptomatic throughout the infection.

11:41 The incidence of adult T-cell leukemia lymphoma ATLL in the USA is about 0.5 cases per 100,000.

11:50 The long term risk of developing ATLL after infection with HTLV one is about two to 5% with onset after 20 to 30 years or more.

12:00 HTLV one associated myelopathy/tropical spastic paraparesis or HAM/TSP has a long term risk after infection of about 2% with an average onset at 3.3 years.

12:13 Although there's a wide range from four to 30 years.

12:17 Note the HTLV two has only rarely been associated with HAM/TSP and has no definite causal association with ATLL or other diseases.

12:30 Looking at transmission HTLV one typically can occur via breastfeeding a non barrier sexual intercourse so no condoms sharing of needles, blood transfusions, especially in resource poor countries and very rarely in intra-uterine transmission.

12:46 The pathogenesis of HTLV one infection occurs after an initial infection of CD4 T lymphocytes as the primary target.

12:55 However, unlike HIV, that infection does not cause death initially of the CD4 T lymphocytes.

13:02 Rather, it causes cell proliferation, genetic instability and then malignant transformation into CD4 lymphocyte clones.

13:11 The exact mechanism of how this occurs is still unknown.

13:14 Apparently the neoplastic transformation is mediated through viral gene products, which interact and interfere with the host proteins.

13:23 There are two major viral proteins identified Tax and HBX. Tax seem to be the one that we know most about, Clinically, ATLLl or adult t cell leukemia lymphoma is diagnosed by demonstrating malignant but mature CD4 positive t lymphocytes with an abnormal convoluted nuclei which appears flower like an on stain and seeing the these abnormal cells in the peripheral blood lymph nodes and even skin.

13:52 Clinically, these patients unfortunately have a very low five year survival rate and they are poorly responsive to chemotherapy, although bone marrow transplant may be successful.

14:02 They may show skin lesions, lytic bone lesions, hepatosplenomegaly and immunosuppression.

14:09 Hypercalcemia is a common presentation because a pair of neoplastic syndrome related to the release of cytokines, including parathyroid hormone related protein PTH-RP, tumor necrosis factor beta and interleukin one and RANKL or receptor activated of nuclear factor kappa Beta ligand.

14:30 HTLV Lymphotropic Virus type one pathogenesis in the setting of the associated myelopathy/tropical spastic paraparesis.

14:39 So have HAM/TSP.

14:40 In this case, HTLV one induces a proinflammatory response through the infected CD4 positive or CCR for positive cells especially if there are high pro viral loads of HTLV one.

14:54 This then induces or provokes a strong virus specific immune response which is associated with detectable high anti Tax antibody levels.

15:04 Elevated levels of pro-inflammatory cytokines and chemokines, and then a chronic vascular lymphocytic and macrophage infiltrate.

15:13 If this occurs or when this occurs in spinal cord and brain, it causes inflammation leading to tissue damage and then axonal myelin and loss, especially in spinal cord.

15:23 In this, that leads to the clinical presentation of H.AM/TSP.

15:28 The clinical aspect of HAM/TSP initially starts with laboratory findings of HTLV one antibodies or even antigens demonstrated in the blood and cerebrospinal fluid. In the CSF one may also see mild increases in lymphocytes as well as mild increases in protein. One then can find lobulated lymphocytes with the flower like nuclei described previously in blood and or spinal fluid.

15:55 Clinically, patients with HAM/TSP or demonstrated slowly progressive weakness and spasticity of one or both legs along with hyperreflexia and ankle clonus extensor planter responses in lumbar pain.

16:10 They may demonstrate Detusor instability presenting as nucturia, urinary frequency and incontinence.

16:16 They may have sensory changes such as paresthesias and loss of vibration sense.

16:21 And of course, they'll have other neurologic manifestations across the whole spectrum.

16:25 Interestingly, however, cognition and upper limbs are usually not affected.

16:31 MRI of the brain and spinal cord may be normal, or it may demonstrate high intensity signal on T2 weighted sequences, which would suggest inflammation and swelling.

16:41 White matter lesions in the subcortical and periventricular regions may actually mimic multiple sclerosis.

16:47 So considering a differential diagnosis of multiple sclerosis, one should also think of HTLV one infection and HAM/TSP.

16:56 The prognosis, unfortunately, is a steadely progressive onset from normal function to wheelchair bound and total loss of neurologic function by a median of 21 years.

17:11 And there is no effective treatment