HIV Infection and AIDS Question and Answers

HIV Infection and AIDS

Global Hiv And Aids Statistics:

• There were approximately 38 million people across the globe with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) in 2019.
• An estimated 1.7 million individuals worldwide acquired HIV in 2019, marking a 23% decline in new HIV infections since 2075.7 million people have become infected with HIV since the start of the epidemic (end 2019).
• As of the end of June 2020, 26.0 million people were accessing antiretroviral therapy (ART).

Read And Learn More: General Medicine Question And Answers

• India has the third largest HIV epidemic in the world. India had 2.35 million people living with HIV. Of this 1.345 million were receiving ART. There were 69,220 new HIV infections and 58,960 AIDS related deaths reported in India in 2019.
• The 90–90–90 targets by UN AIDS envision that, by 2020, 90% of people living with HIV will know their HIV status, 90% of people who know their HIV-positive status will be accessing treatment, and 90% of people on treatment will have suppressed viral loads. In India, 79% of people living with HIV knew their status, 56% of people living with HIV were on treatment and viral load data is not available.

Characteristic Features Of Human Immunodeficiency Virus:

• The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS)
• Former names of the virus include: human T-cell lymphotropic virus (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS associated retrovirus (ARV).
• Discovered independently by Dr Luc Montagnier, Dr Anthony Gallo, and Dr Jay Levy in 1983–84.
• It is an ribonucleic acid (RNA) virus belonging to the Lentivirus genus of the Retroviridae family
• HIV occurs in two genetically different but related main forms—HIV-1 and HIV-2.
• HIV-1:
  • Most common type
  • Four distinct groups of HIV-1, each arising from a different zoonotic transmission event. These include:
  • Group M (“Major”)—Majority.
    • Has nine distinct subtypes/clades [A-D, F-H, J-K] and
    • More than 90 known circulating recombinant forms (CRFs)
      • CRF01_AE: Is common in southeast Asia
      • CRF02_AG: Is common in west and central Africa.
  • Group O (“Outlier”)—in West Africa
  • Group N (“nonmajor and nonoutlier”)—in Cameroon
  • Group P—in Cameroon
    Group P was transmitted from a gorilla, while group M, N, and O were transmitted from a chimpanzee.
• HIV-2:
• Endemic in West Africa; Prevalence is also higher in France, Spain, Portugal, Brazil, Angola, Mozambique, and parts of India
• Coinfection with HIV-1 and HIV-2 can occur
• HIV-2 is inherently resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Structure Of HIV:

• Each mature virion comprises of:
  • Electron-dense and cone-shaped core
  • Membrane-associated matrix protein
  • Lipid bilayer envelope with surface glycoproteins, gp120 and gp41.
• About 90–120 nm in diameter
• Spherical in shape
• Viral core:
  • Major capsid protein p24:
    • Most abundant viral antigen
    • Can be detected early in infection before the development of antibodies
    • Antibodies against p24 antigen are also important serologic markers of infection.
• Nucleocapsid protein p7/p9
  • Diploid genome: Two single-stranded, positive-sense RNA molecules
  • Three viral enzymes:
    • Reverse transcriptase [RNA-dependent deoxyribonucleic acid (DNA) polymerase] Synthesizes DNA by using the genome RNA as a template
    • Integrase: Integrates the viral DNA into the host cell DNA
    • Protease: Cleaves the various viral precursor proteins.
• Membrane associated matrix protein: p17
  • Surrounds the viral core
• Lipid envelope
  • Lipid bilayer is derived from the host cell membrane
  • Two envelope proteins, gp120 and gp41, are embedded in it
    • gp120:
      • Projects from the surface as knob-like spikes
      • Interacts with the CD4 receptor and a chemokine receptor (CCR5 or CXCR4) and helps in attachment
    • gp41: Mediates the fusion of the viral envelope with the host cell membrane at the time of infection and facilitates entry.
• HIV genome consists of:
  • Structural genes:
    • gag—encodes the structural proteins—p24, p7, and p17
    • pol—codes for reverse transcriptase, integrase, and protease
    • env—codes for envelope glycoproteins gp120 and gp41.
• Six regulatory genes
  • • Required for replication
    • tat—activation of transcription of viral genes
    • rev—transport of unspliced messenger RNAs (mRNAs) from nucleus to cytoplasm.
  • Accessory genes—not required for replication
    • nef—decreases CD4 proteins and class I MHC proteins on surface of infected cells
    • vif—enhances viral infectivity
    • vpr—facilitates entry of viral core from cytoplasm into nucleus in nondividing cells
    • vpu—enhances virus assembly and release. Note that HIV-2 encodes Vpx instead of Vpu.

Transmission Of Hiv:

Question 1. List the modes modes of transmission of HIV infection and high-risk groups.
Answer:

• Transmission of HIV occurs when there is an exchange of blood or body fluids containing the virus or virus-infected cells.
• The risk of contracting HIV after exposure depends on:
  • Exposure route
  • The integrity of the exposed site
  • Type and volume of fluid
  • Viral load.
• Exposure route and percentage of transmission of HIV is presented in Table.

Transmission Of Hiv Major routes of transmission include:

Sexual transmission:

• Main route of transmission, accounting for more than 75% of cases of HIV.
• HIV is present in vaginal secretions and cervical cells (in women) and semen (in men).
• Although majority of the cases worldwide are transmitted\ via heterosexual route, HIV transmission is higher among men who have sex with men (MSM).
• Unprotected anal intercourse conveys the greatest risk of sexual transmission of HIV.
• Risk of sexual transmission of HIV is increased when there is coexisting sexually transmitted diseases, especially those associated with genital ulceration (e.g., syphilis, chancroid, and herpes).
• Other risk factors include vaginal/rectal laceration, menstruation, and uncircumcised male partner. Risk of HIV acquisition is decreased with circumcision in heterosexual men. Male circumcision decreases the risk of female-to-male sexual transmission of HIV by 50% to 60%.

Parenteral transmission:

• Intravenous drug users (IDU):
  • Transmission occurs by sharing of needles and syringes contaminated with HIV-containing blood.
  • Risk factors that determine transmission in this subgroup include the duration of IDU, frequency of needle sharing, number of needle-sharing partners, number of injections, and prevalence of HIV infection among the users.
• Transfusion of blood or blood components:
  • Recipients of blood transfusion of HIV-infected whole blood or components (e.g., platelets and plasma) was one of the modes of transmission prior to 1985.
  • Screening of donor blood and plasma for antibodies to HIV-1 and HIV-2, as well as determination of the presence of HIV nucleic acid has reduced the risk of this mode of transmission.
  • However, since a recently infected individual may be antibody-negative (window-period), there is a small risk (1 in 1.4–1.8 million units) of acquiring AIDS through transfusion of blood.
  • Note that the likelihood of a person becoming infected with HIV after receiving a single-donor blood product from an HIV-positive patient approaches 100% due to the large volume of transfusion.
• Hemophiliacs:
  • Mainly those who received large amounts of factor VIII and factor IX concentrates before 1985.
  • Increasing use of recombinant-clotting factors has eliminated this mode of transmission.
• Splash of body fluids on the mucosa (For Example, nose, mouth, and eyes)
• Spread through organ transplantation from HIV-infected donors has been reported.
• Perinatal transmission (mother-to-infant transmission):
• Major mode of transmission of AIDS in children.
• Can occur during gestation (in utero), at the time of delivery (intrapartum), or postpartum through breastfeeding
  • In utero vertical transmission from mother to fetus:
  • Transplacental spread
    • Mechanism: Microtransfusions of maternal blood containing the virus to the fetus across the placenta; facilitated by the disruption in the integrity of the placenta
    • Genital tract infections and chorioamnionitis can increase in utero HIV transmission.
  • Intrapartum spread:
    • Due to contact of infant mucosal membranes with infected maternal blood and cervicovaginal fluids during
      the birth process
    • Microtransfusions across the placenta during labor contractions also contribute to the increased risk of transmission
    • Prolonged rupture of membranes, greater than 4 hours, is associated with increased risk of transmission.
  • Postpartum:
    • Via breastfeeding
    • More likely due to HIV-infected cells within breast milk than cell-free virus
    • The portal of entry is likely to be via intestinal or tonsillar tissues, with breaches in epithelial integrity facilitating transmission.
• Transmission of HIV infection to healthcare workers:
  • Via percutaneous, mucous membrane, and cutaneous exposure to blood-contaminated body fluids
  • Percutaneous injury, usually by a needle-stick injury, is the most common mechanism of occupational HIV transmission
• The risk of transmission of HIV to healthcare workers increases when:
  • The device causing the injury is visibly contaminated with blood
  • The device was used for insertion into an artery or a vein
  • The device caused a deep injury or
  • The source patient died within 2 months after the exposure.
• Routes by which HIV is not transmitted are mentioned in Box.

The Role of Viral Load in Transmission of HIV:

• Viral load is the strongest predictor of transmission
• Higher the plasma viral load, the more likely HIV transmission will occur
• “Undetectable equals Untransmittable (U = U)” concept negligible risk of sexual transmission of HIV when the HIVinfected sex partner has persistently suppressed viral replication on ART.

Routes by which HIV is not transmitted:

• Casual nonsexual contact
• By vectors such as mosquitoes
• Respiratory droplet spread

Pathogenesis Of Hiv Infection And Aids:

• The interaction between HIV and the host immune system is the basis of the pathogenesis of HIV disease.
• From the site of initial mucosal exposure, virus enters the blood or tissues of an individual.
• HIV is transported by dendritic cells from mucosal surfaces to regional lymph nodes where it establishes a permanent
  infection.
  • Note that HIV has selective affinity for host cells bearing the CD4 receptor, such as CD4+ T cells (T-helper lymphocytes)
    which are present in the mucosal lymphoid tissue (largest reservoir of T cells and where majority of memory cells are
    lodged), monocytes/macrophages, dendritic cells, and microglial cells in the central nervous system.
• This is followed by viremia and dissemination to lymphoid organs, which are the main sites of viral replication.
• As a result, plasma levels of HIV-1 peak within 2 weeks of infection, and patients develop the acute retroviral syndrome.
  This is associated with significant declines in peripheral CD4+ T-cell counts.
• Within several weeks, there is development of an HIV-specific immune response.
  • This involves both a humoral immune response, with the development of antibodies to various antigens, as well a cell-mediated immune response.
  • The cell-mediated immune response involves the expansion of HIV-specific CD8 cytotoxic T lymphocytes, resulting in a CD8 lymphocytosis and reversal of the usual CD4:CD8 ratio.
  • CD8 cytotoxic T lymphocytes kill CD4 cells that are actively replicating the virus, but not latently infected CD4 cells.
  • Despite this robust immune response, HIV escapes destruction, because the highly conserved gp120 and gp41 regions needed for viral attachment and entry are protected by highly variable glycoprotein loops that vary over time as a result of mutations caused by the error-prone reverse transcription process.
• The initial peak of viremia in primary infection settles to a plateau phase of persistent chronic viremia.
• With time, there is gradual reduction of the CD4+ T-helper lymphocyte population.
• This makes the patient susceptible to opportunistic diseases.
• This is summarized

Read And Learn More: General Medicine Question And Answers

Life Cycle Of Hiv:

Question 2. Discuss the life cycle of HIV.
Answer:

Life cycle of HIV consists of the following steps:

Natural History Of Hiv Infection:

Question 3. Discuss the natural history of HIV infection. (or) Discuss acute HIV syndrome.
Answer:

The clinical picture of HIV infection can be divided into three stages:

• Acute infection
• Latent stage
• Immunodeficiency stage.

Natural History Of Hiv Infection Acute Phase:

• There is an initial infection with HIV through sexual/ parenteral/perinatal transmission.
• This is followed by a window period.
  • About 2–6 weeks immediately following infection
  • This period is silent both clinically and serologically
• This is followed by acute HIV syndrome
  • Nonspecific flu-like illness
  • Symptoms include fever, sore throat, lymphadenopathy, maculopapular rash, diarrhea, malaise, mucosal ulcers, arthralgia, myalgia, weight loss, and hepatosplenomegaly
  • Patients may also present with neurologic symptoms, such as meningitis, encephalitis, peripheral neuropathy, and myelopathy
  • Opportunistic infections have also been reported at this stage, due to the presence of high level viremia combined with reduced numbers of CD4+ T cells
  • However, may be asymptomatic in up to 60% of the patients
• During this period, uncontrolled viral replication occurs and results in high viral loads. The patient is also unaware of his HIV status. Thus, the patient is highly infectious.
• CD4 cell count can drop transiently.
• Presence of a prolonged symptomatic illness (>14 days) during early infection appears to correlate with more rapid progression to AIDS
• Early diagnosis at this stage may be achieved by
  • HIV RNA by polymerase chain reaction (PCR)
  • p24 antigen positivity.
• Seroconversion, i.e., the appearance of HIV-specific antibodies occurs 2 weeks—3 months after the development of symptoms.
• Establishment of the viral set point:
  • By approximately 6 months of infection, plasma viremia reaches a steady-state level, known as the viral set point.
  • The viral set point level is closely associated with the rate of disease progression in the absence of ART, i.e., higher viral set point results in faster progression to AIDS.
  • Fiebig staging, typically used for research purposes, can be used to characterize viral and immunologic dynamics following HIV transmission

Natural History Of Hiv Infection Clinical Latency Period:

• It is predominantly characterized by asymptomatic infection
  • HIV reproduces at relatively lower levels during this phase, with relative stability of the viral load.
  • Although CD4+ T-cell destruction is ongoing, their levels are sufficiently high enough such that the patient may remain asymptomatic and without any opportunistic infection.
• Persistent generalized lymphadenopathy (PGL):
  • Development of persistent generalized lymphadenopathy (PGL) is common.
  • PGL is defined as lymphadenopathy greater than 1 cm at 2 or more extrainguinal sites for more than 3 months in the absence of causes other than HIV infection.
  • Biopsy reveals nonspecific lymphoid hyperplasia.
  • The lymph nodes are usually symmetrical, firm, mobile, and nontender.
  • Nodes may disappear as the disease progresses.
• Progressive decrease of CD4+ T cells:
  • The key mechanism of T-cell depletion is via the direct killing of T cells by the virus.
  • In the early stages of disease, the loss of CD4+ T cells may be replaced by new T cells. Over the years, however, the persistent cycle of viral infection and death of T cells leads to a steady decrease in the number of CD4+ T cells, both in lymphoid tissue and in peripheral blood.
• In the absence of ART, the average time from acquisition of HIV to a CD4 cell count <200 cells/µL is approximately 8–10 years.

Immunodefiiency Stage:

• Minor HIV-associated disorders
  • Increasing signs and symptoms due to worsening immunity
  • Includes diseases in CDC category B or WHO stage 2 and 3 (See below)
• AIDS
  • It is final phase of HIV infection
  • AIDS is defined as a CD4 cell count <200 cells/µL or the presence of any AIDS-defining condition regardless of the CD4 cell count.
  • This stage is characterized by numerous opportunistic infections and malignancies.
  • Without treatment, individuals with AIDS have a life expectancy of 1–3 years.

Patterns Of Hiv Progression:

• Noncontroller: HIV-infected individuals with plasma HIV-RNA >10,000 copies/mL without ART.
• Rapid progressors: HIV infected with CD4+ T-cell counts of <300 cells/μL within 3 years after the last HIV-seronegative test.
• Slow progressors: Seropositive asymptomatic individuals infected for 8 or more years with a CD4+ T-cell count above 500 cells/μL in the absence of ART.
• Long-term nonprogressors: Asymptomatic and ART-naive for 10 years during follow-up with all CD4+ cell counts above 500 cells/μL during this period.
• Elite controllers are HIV-infected individuals who have viral loads below 50 copies/mL without ART and maintain normal CD4+ counts.
• Viremic controller: Infected with HIV and maintaining viral loads of <2,000 RNA copies/mL without ART.

Hiv Clinical Staging And Classification:

Question 4. Write short essay/note on clinical staging and classification of HIV.
Answer:

• Two clinical staging systems, namely the World Health Organization (WHO) and the Centers for Disease Control (CDC), are in use and are listed below.
• Note that the World Health Organization clinical stage is used in low- and middle-income countries while the CDC clinical categories are used in high-income countries.

 WHO clinical staging classification of HIV infection:

CDC clinical staging classification of HIV infection:

Important Infections And Presenting Problems In Aids:

AIDS-defiing conditions:

Question 5. List of important opportunistic infections in AIDS. (Or) Write short essay/note on AIDS-defining diseases and opportunistic infections in HIV
Answer:

Relation between CD4+ cell count and common illness in HIV patients is presented.

Hiv And Organ System Involvement:

Respiratory System:

Question 6. Enumerate upper/lower respiratory tract infections and pulmonary complications in AIDS. (or) Write short essay/note on Pneumocystis jirovecii pneumonia (PJP), its treatment, and prophylaxis.
Answer:

Pulmonary manifestations of HIV:

Gastrointestinal Disease:

Question 7. Write short essay/note on gastrointestinal manifestations of AIDS. (or) List the causes of esophagitis in HIV
Answer:

Diarrhea In Patients With Hiv:

Question 8. List the causes and management of diarrhea in a HIV patient.
Answer:

• Diarrhea is an important cause of morbidity in patients with HIV and is a predictor of increased mortality.
• Some of the important causes of diarrhea in patients with HIV are described in Table.
• History and physical examination should determine:
  • Small bowel diarrhea versus colonic diarrhea
  • Duration of symptoms
  • Other abdominal or constitutional symptoms:
    • Fever
    • Weight loss
    • Hepatosplenomegaly
  • Status of HIV disease, including CD4 count
  • Medication history and recent changes in medications
  • Exposures: Travel, exposure to antibiotics.
• Investigations include
  • For all patients:
    • Stool culture for enteric pathogens
    • Stool for ova and parasites × 3
    • Stool for Clostridium difficile toxin.
  • For patients with suspicion of colitis
    • Colonoscopy and biopsy
  • For patient with no suspicion of colitis
    • Upper gastrointestinal (GI) endoscopy and biopsy
  • For patients with diarrhea and concomitant significant abdominal pain
    • Abdominal computed tomography (CT) using oral and intravenous contrast
      • Imaging may show evidence of:
        • Colitis—CMV, herpes simplex virus (HSV), and Clostridium difficile
        • Abdominal adenopathy or hepatosplenomegaly—MAC, tuberculosis, histoplasmosis, and lymphoma
        • Biliary tract disease

Diarrhea In Patients With Hiv Treatment:

• Treatment of the underlying cause
• Empiric therapy is not recommended
• Substitution of an alternative medicine: If a particular antiretroviral medication is the culprit (e.g., ritonavir)
• If chronic diarrhea continues without a diagnosis, symptomatic therapy with an antimotility drug (e.g., loperamide or diphenoxylate with atropine can be attempted.

Crofelemer:

• 125 mg orally twice daily
• Blocks chloride secretion and accompanying high-volume water loss in diarrhea
• Approved by Food and Drug Administration (FDA) for noninfectious diarrhea in HIV-infected patients receiving antiretroviral therapy

Hepatobiliary Manifestations Of Hiv:

Question 9. Add a note on hepatobiliary manifestations in HIV
Answer:

Mucocutaneous Manifestations Of Hiv/Aids:

Question 10. List the mucocutaneous manifestations of HIV/AIDS.
Answer:

Neurological Manifestations Of Aids:

Question 11. Discuss the neurological manifestations of AIDS. (or) Discuss the clinical features and management of cryptococcal meningitis.
Answer:

Neurological manifestations in patients with HIV/AIDS:

Cardiovascular Manifestations Of Hiv:

Question 12. Enumerate the cardiovascular manifestations seen in HIV/AIDS
Answer:

Cardiovascular manifestations of HIV:

Diseases Of Kidney And Genitourinary System In Hiv:

Question 13. Write a short note on HIVAN
Answer:

HIV-associated nephropathy:

• Classic glomerulopathy of HIV
• Etiopathogenesis:
• Infection of kidney epithelial cells by HIV and the expression of HIV genes within infected kidney cells
  • Higher viral loads, lower CD4 count—favor infection
  • HIV genes, especially Nef and Vpr are specifically involved
• Host factors
  • Africans > Europeans, Asians
  • Single nucleotide polymorphisms in APOL1 gene on Chr 22 → associated with increased risk
• Proposed mechanism: Endolysosomal dysfunction, mitochondrial dysfunction, and activation of stress kinases due to altered transcellular cation flux
• Clinical features:
  • Advanced HIV infection—usually; may also present in acute HIV infection
  • Proteinuria—usually nephrotic range
  • Edema
  • Rapid decline in renal function
  • Hematuria and hypertension may also be seen
• Diagnosis:
  • Urinalysis, including quantification of proteinuria
  • Urea, creatinine, electrolytes, and random blood sugar (RBS)
  • USG abdomen—increased kidney size, increased echogenicity
  • Kidney biopsy
    • Pathology:
      • Characterized by the collapsing form of FSGS
      • Light microscopy →
        • Glomeruli: Proliferation and dysregulation of podocytes, glomerular collapse, and pseudocrescent formation
        • Dilated tubules
        • Interstitial inflammation
      • Electron microscopy: Tubuloreticular inclusions

Kidney And Genitourinary Treatment:

• ART
• ACE-inhibitor/ARB for proteinuria
• Routine CKD care—Target BP: 130/80, management of anemia, mineral-bone disease, avoiding nephrotoxic drug, hemodialysis, and renal transplant
• Renal transplant—Risk of recurrence of HIVAN present

Other renal and genitourinary manifestations in patients with HIV:

Hematological Manifestations Of Hiv:

Question 14. List the hematological manifestations of HIV:
Answer:

• Hematological manifestations in patients with HIV include
  • Anemia
  • Leukopenia
    • Causes:
      • Decrease in endogenous granulocytic colony-stimulating factor
      • Medications: Zidovudine, TMP-SMX, and ganciclovir

Hematological Manifestations Management:

• ART
• Stop offending agents
• G-CSF and GM-CSF: In patients who have profound neutropenia despite removal of the offending agent

Thrombocytopenia:

• Any stage of HIV infection; however, it is more commonly seen with advanced disease
• Mechanisms:
  • Immune thrombocytopenia: Development of cross-reactive antibodies between the HIV envelope glycoprotein
    gp120 and the platelet glycoprotein IIb/IIIa; seen in early-stage HIV
  • Direct infection of megakaryocytes: In late-stage HIV
  • Drug-induced immune thrombocytopenia: TMP-SMX, and rifampicin
  • HCV infection: Due to direct effects on platelet production or hypersplenism

Hematological Manifestations Management:

• Virologic suppression with ART
• For those individuals who do not respond to this, corticosteroids, IVIG, or anti-D immune globulin (Rh-positive patient who has not undergone splenectomy) have been used.
• Surgical splenectomy and splenic irradiation—for refractory cases
• Eltrombopag and romiplostim—recently being tried for refractory HIV-related thrombocytopenia

Thrombotic microangiopathy:

Causes of anemia in patients with HIV:

Aids And Malignancy:

Question 15. Discuss common cancers in HIV/AIDS
Answer:

Aids And Malignancy Cancers in HIV:

Investigations In Patients With Hiv/Aids:

Question 16. Write short note on laboratory tests for the diagnosis HIV infection.
Answer:

Indications for Testing:

• Symptoms of HIV infection
• Possible HIV exposure
• Individuals who seek screening/treatment for sexually transmitted infections
• Patients with tuberculosis and hepatitis B/C
• Patients who are considering pre-exposure antiretroviral prophylaxis as an HIV prevention strategy
• High-risk groups
  • MSM
  • Commercial sex workers
  • Injection-drug users
  • Sex partners of persons who are HIV-infected, bisexual, or inject drugs
• Routine screening in pregnant women
• In areas of high and extremely high prevalence: All patients not previously diagnosed with HIV who register with a general practice or undergo blood testing for any reason.

Patients With Hiv/Aids Goals of Testing:

1. Confirmation of the diagnosis
2. Assess degree of immunosuppression
3. To prepare for treatment
4. To evaluate for coinfections and prior exposures
5. To monitor response to treatment and evaluate for side effects
6. Screening/preventive care

Patients With Hiv/Aids Confimation of Diagnosis:

• CDC 2014 recommends a three-3 step algorithm for diagnosis of HIV involving two immunoassays and a confirmatory nucleic acid amplification test
• Step 1: Screen with fourth generation HIV-1/HIV-2/p24 antigen-antibody combination assay.
  • If negative: Chances of an established HIV-1 or HIV-2 infection are low. No further testing is required.
  • If positive, proceed to step 2
• Step 2: Test the samples with HIV-1/HIV-2 antibody differentiation assay
  • If HIV-1 reactive and HIV-2 nonreactive: HIV-1 antibodies detected
  • If HIV-1 nonreactive and HIV-2 reactive: HIV-2 antibodies detected
  • If HIV-1 reactive and HIV-2 reactive: HIV antibodies detected
  • If HIV-1 nonreactive or indeterminate and HIV-2 nonreactive: proceed to step 3
• Step 3: Specimens with screening test positive and negative/indeterminate test on HIV-1/HIV-2 antibody differentiation assay test should be confirmed by HIV-1 nucleic acid amplification test (NAAT). (HIV-1-RNA testing)
  • If HIV-1 NAT is positive: Acute HIV-1 infection
  • If HIV-1 NAT is negative: Negative for HIV-1 infection
• Inconsistent or conflicting results should be investigated with follow-up testing on a newly collected specimen
• Step 1: Screening test with HIV-1/2 enzyme immunoassay (EIA) (third-generation assay)
  • If nonreactive: HIV-negative; retest after 3–6 months if clinically indicated
  • If reactive, proceed to step 2

• Step 2: HIV-1 Western blot
  • If positive, report as HIV-1 positive
  • If inconclusive or nonreactive, proceed to step 3
• Step 3: HIV-2 enzyme immunoassay
  • If Western blot is nonreactive and HIV-2 EIA nonreactive: HIV-negative
  • If Western blot is inconclusive and HIV-2 EIA nonreactive: Inconclusive and request follow-up specimen after 4–6 weeks
  • If HIV-2 EIA reactive: proceed to step 4
• Step 4: HIV-2 supplemental test
  • If the supplemental test is inconclusive or negative: A follow-up specimen
  • If the supplemental test is positive: HIV-2 positive

The sequence of appearance of laboratory markers of HIV-1 infection:

Question 17. Write a short note on Western blot testing in HIV.
Answer:

Western blot:

• Previously used confirmatory test
• Procedure:
  • Virions are electrophoresed in a polyacrylamide gel
  • The antigens get separated on the basis of molecular weight
  • This is then transferred onto nitrocellulose and then incubated with the patient’s serum
  • Antibodies to each component can be detected as discrete bands on the Western blot
• Results:
  • Negative Western blot: No bands are present at molecular weights corresponding to HIV gene products
  • Positive Western blot: If antibodies exist to two of the three HIV proteins, i.e., p24, gp41, and gp120/160
• Indeterminate: If the results do not fall into the positive or negative categories.
• This may be due to:
  • Antibodies that cross-react with one of the proteins of HIV
  • The individual is infected with HIV and is in the process of developing an antibody response
  • In both scenarios, the Western blot should be repeated after 1 month to determine if the indeterminate pattern is a pattern in evolution
• Time to positivity:
  • 35–50 days—indeterminate
  • 45–60 days—positive
• Disadvantages:
  • High cost
  • Delayed results
  • Can take up to 2 months after HIV acquisition for the test to turn fully positive
  • Do not reliably detect subtype O virus
  • If HIV-2 is being considered, a special HIV-2 Western blot must be requested

Assessing Degree of Immunosuppression:

Question 18. Write short note on CD4 cell count.
Answer:

CD4 Cell Count:

• Usually determined by flow cytometry
• Most useful indicator of the degree of immunosuppression in patients with active HIV
• The normal CD4 count is over 500 cells/μL. Patients with CD4 counts <200 cells/μL are at increased risk for opportunistic infections, with the greatest risk in patients with CD4 counts <50 cells/μL.
• Helps clinicians choose prophylactic therapy and vaccine administration (See subsequent section on prophylaxis against opportunistic infections).
• Can help estimate the duration of infection:
  • After a transient drop at the time of acute infection, the CD4 cell count typically returns near to baseline and declines steadily at a mean rate between 20 and 50 cells/μL per year in patients not on ART.
• Disadvantage of measuring absolute CD4 count:
  • The CD4 count is transiently reduced by inter-current infections.
  • Due to this variability, major therapeutic decisions should not be taken on the basis of a single count.
• CD4 lymphocyte percentage:
  • May be more reliable than CD4 count, especially in the settings of transient lymphopenia due to intercurrent infection or pregnancy.
  • Risk of AIDS-related opportunistic infection or malignancy is high in patients with CD4 lymphocyte percentage less than 14% in the absence of treatment.
• Follow up: Monitoring of CD4 counts
  • For patients with a CD4 cell count less than 200 cells/μL, serial testing every 1–3 months is recommended to track immune reconstitution and to guide the need for ongoing prophylactic medications
  • Once patients have achieved a stable CD4 cell count greater than 300 cells/μL, less frequent monitoring (every 3–6 months) is done.
  • Mild variation in the CD4 cell count does not warrant changes in ART as long viral suppression is maintained.
• To Prepare for Treatment:
  • To characterize the health status of the patient—“safety laboratory tests”
  • Complete blood count: May show anemia, leukopenia, and/or thrombocytopenia
  • Urea, creatinine, electrolytes, and urinalysis: Presence of chronic kidney disease or proteinuria alters the choice of ART. Renal function must be monitored while on therapy, especially for patients on regimens that include tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)
  • Liver function tests: May be deranged in viral hepatitis coinfection. LFTs should be monitored on therapy to look for drug-induced liver injury
  • Pregnancy testing: Pregnancy may alter the choice of ART
• Human immunodeficiency virus resistance testing:
  • Timing:
    • At the time of diagnosis
    • When changing antiretroviral regimens
    • When patient has suboptimal viral response
  • Genotypic resistance testing is preferred over phenotypic resistance testing
  • Standard genotypic resistance testing involves testing for mutations in reverse transcriptase and protease genes
  • Resistance testing for integrase inhibitors (integrase strand transfer inhibitor, INSTI) is only recommended if INSTI resistance is a concern
  • Testing may not be successful in patients with HIV RNA levels <500–1,000 copies/mL
  • ART initiation should not be delayed while awaiting resistance testing results in patients with acute or recent HIV infection or pregnancy
• HLA B*5701: Presence is associated with a high risk for hypersensitivity to abacavir
• Glucose-6-phosphate dehydrogenase deficiency: Before starting the patient on dapsone, primaquine, or sulfonamides
• CCR5/CXCR4 tropism assay: For patients who are being considered for treatment with maraviroc (not routinely used)

To Evaluate for Coinfections and Prior Exposures:

• Testing for sexually transmitted infections:
  • Nucleic acid amplification tests from vaginal and cervical swabs—for gonorrhea and chlamydia
  • VDRL/RPR, followed by confirmatory treponemal test—syphilis
• Hepatitis B and C testing:
• Testing for latent TB: Tuberculin skin test (TST) or interferon-γ release assay (IGRA)
• Toxoplasma IgG: Seropositive patients are at risk of reactivation disease if severely immunosuppressed (CD4 counts <100), and need primary prophylaxis until they respond to ART
• Cryptococcus antigen if CD4 ≤100 cells/µL
• Other investigations: As per clinical presentation

To Monitor Response to Treatment and Evaluate for Side Effcts:

• Viral load:
  • Pretreatment viral load = patient’s “baseline.”
  • Viral load declines rapidly after initiation of ART
  • Repeat a viral load 4–6 weeks after initiation of therapy and then every 1–3 months until viral suppression is achieved
  • Once patients are stable on therapy, the viral load should be monitored every 6 months, or more frequently after any change in regimen
• CD 4 count: See section on CD4 counts.
• Safety laboratory tests:
  • All patients should be monitored with complete blood count, RFT and electrolytes, and LFTs to track abnormalities
  • due to HIV infection and assess for medication side effects
  • About 4–6 weeks after treatment initiation or change in ART Every 6 months, if stable on therapy
  • Urinalysis should also be obtained for patients on tenofovir-based therapy

Screening/Preventive Care:

• Cervical cancer screening:
  • Rationale: Risk of abnormal cervical cytology secondary to human papilloma virus (HPV) infection is 10 times higher in HIV-infected women as compared to the general population
    • Timing: Cervical pap smears every 1–3 years. More intensive follow-up if abnormal results are identified
    • Anal cancer screening:
    • Rationale: HIV-infected individuals who practice receptive anal intercourse are at increased risk for HPV-related anal
      dysplasia
    • Timing: Anal pap smears every 1–3 years
  • HbA1c:
    • Rationale: Increased prevalence of diabetes in patients with HIV.
    • Timing: At entry to care and repeated yearly in patients at high risk for diabetes
  • Lipid panel:
    • Rationale: Cardiovascular disease is now becoming the leading cause of morbidity and mortality, due to increased inflammation and immune activation
    • Timing: At entry to care and repeated yearly
  • Bone density (DEXA) scan:
    • Rationale: HIV and its treatment (especially tenofovir-containing regimens) reduce bone density
    • Timing: All patients should undergo evaluation of bone density at age 50 years.

Management Of A Patients With Hiv/Aids:

Question 19. List indications for starting antiretroviral therapy.
Answer:

Indications of Antiretroviral therapy:

Treatment is recommended for all HIV-positive patients irrespective of the CD4 count

• Conditions favoring early initiation of therapy:
  • Acute or recent HIV infection
  • AIDS-defining conditions
  • Pregnancy
  • HIV-associated nephropathy
  • Lower CD4 counts (<200 cells/µL)
  • CD4 decline >100 cells/µL/year
  • HIV RNA >100,000 copies/mL
  • Hepatitis B coinfection and hepatitis C coinfection
• In patients with an AIDS-defining condition or an opportunistic infection: ART should be initiated within 2 weeks of starting treatment for intercurrent conditions.
• Exceptions:
  • Cryptococcal meningitis: ART should be initiated 5 weeks after starting treatment for cryptococcal infection, as earlier initiation increases the risk of death
  • Tuberculosis: ART should be initiated 2–8 weeks after starting ATTs (except if the CD4 count is < 50 cells/µL). This is because earlier initiation increases the risk of IRIS. See section on HIV-TB co-infection.

Patients With Hiv/Aids Advantages of initiating antiretroviral therapy:

• Reduction in overall mortality
• Reduction in cardiovascular and renal morbidity
• Decreased risk of opportunistic infections and malignancies
• Decreased risk of transmitting HIV to others

Principles of antiretroviral therapy:

• Goals of treatment: Reduction of plasma viral load to less than 50 copies/mL.
  • Other goals:
    • Improve the CD4 count to over 200 cells/L
    • Improve the quantity and quality of life
    • Reduce transmission of HIV
• “Hit hard and hit early” approach: All patients should be treated with combination of preferably three antiretroviral drugs as soon as possible.
• “First chance = Best chance”:
  • The choice of medications during the first treatment course determines remaining options when a different treatment regimen becomes necessary.
  • Chances for success are better initially; later on, alternatives are limited by development of resistant mutants.
• Use of fixed dose combinations: Antiretroviral therapy is complex because of various drug interactions and adverse effects.
• Hence, initial therapy with single pill fixed-dose combinations has become the standard of care.
• Antiretroviral resistance:
  • HIV resistance occurs due to the high rate of HIV replication, as well as the error-prone nature of antiretroviral drugs Antiretroviral drugs differ in their ability to select for resistant mutations.
  • Some drugs (e.g., emtricitabine, lamivudine, and efavirenz) have a low genetic barrier to resistance, rapidly selecting for a single mutation conferring high-level resistance.
  • On the other hand, drugs, such as PIs and some NRTIs (e.g., zidovudine) select for resistance mutations slowly, and multiple resistant mutations often need to accumulate before the drug’s efficacy is lost.
• Treatment adherence is key:
  • Current antiretroviral regimens do not eradicate HIV Viral rebound occurs rapidly after treatment discontinuation, followed by CD4 decline, with potential for disease progression
  • Therapy should be regularly monitored.

Categories of anti-retroviral drugs:

Question 20. Discuss and describe the principles of cART, the classes of antiretrovirals used, adverse reactions and interactions. (or) Write a note on integrase inhibitors. (or) Write a note on protease inhibitors. (or) Write a note on HIV entry inhibitors. (or) Write a note on ibalizumab
Answer:

Important antiretroviral therapy agents (alphabetical order within class):

Question 21. What antiretroviral regimen to choose for initial therapy?
Answer:

• Factors to consider when selecting an ART regimen include
  • Patient-specific factors
    • Pretreatment viral load and CD4 count
    • Results of HIV genotypic drug resistance testing
    • HLA-B*5701 status if considering abacavir
    • Patient preferences and adherence potential
    • Comorbid conditions and coinfections
    • Pregnancy or child-bearing potential
  • Drug-specific factors
    • Genetic barrier to drug resistance
    • Adverse effects
    • Drug-drug interactions
    • Convenience: Pill burden, dosing frequency, and food requirements
    • Cost and access
• Preferred regimens, as per DHHS and WHO are mentioned.

Special considerations (DHHS 2019):

Cardiovascular disease:

• If a patient requires a PI: Atazanavir is preferred over other boosted PIs
• Avoid abacavir in patients with/at risk for cardiovascular disease

Preferred regimens—United States Department of Health and Human Services (DHHS):

• Hepatitis B coinfection:
  • Tenofovir (tenofovir alafenamide or tenofovir disoproxil fumarate)-emtricitabine is the preferred NRTI combination
    for patients with HIV/HBV coinfection
  • Emtricitabine and lamivudine should not be used as monotherapy for the treatment of HBV
• Kidney disease:
  • Avoid tenofovir disoproxil fumarate in patients with an eGFR <60 mL/min/1.73 m2
  • Avoid TDF with cobicistat, in patients with eGFR <70 mL/min/1.73 m2
  • Avoid tenofovir alafenamide in patients with acute kidney injury or eGFR <30 mL/min/1.73 m2
• Osteoporosis: Avoid tenofovir disoproxil fumarate
• Persons of childbearing potential/pregnancy: (Also see section on HIV-pregnancy below)
  • 2 NRTIs + integrase inhibitor or protease inhibitors preferred
  • NRTIs:
  • Abacavir + lamivudine or
  • Tenofovir disoproxil fumarate + emtricitabine or
  • Tenofovir disoproxil fumarate + lamivudine
  • Integrase inhibitor: Raltegravir is preferred
  • Protease inhibitor: A ritonavir-boosted PI is acceptable
  • Also see World Health Organization (WHO) 2016 Recommendations
• Baseline resistance testing not available:
  • Regimen containing dolutegravir, bictegravir, or pharmacologically boosted darunavir should be initiated.

Predictors of long-term virologic success in HIV therapy:

• Low baseline viral load
• High baseline CD4 count
• Rapid reduction of viral load to undetectable levels
• Patient adherence to prescribed therapy

Changing ART regimen:

• Treatment failure
• Adverse events
• Drug interactions
• Pregnancy
• Cost

Treatment Failure In Hiv:

Question 22. Discuss treatment failure in HIV.
Answer:

Important defiitions:

• Virologic failure:
  • Inability to achieve or maintain suppression of viral replication to HIV-1 RNA levels <200 copies/mL
  • May be either
    • Incomplete virologic response: Two consecutive plasma HIV RNA levels ≥200 copies/mL after 24 weeks on ART in patients without previous documented virologic suppression on regimen
    • Virologic rebound: Confirmed detectable HIV RNA levels ≥200 copies/mL after achieving virologic suppression.
• Virologic failure:
  • Plasma viral load >1,000 copies/mL based on two consecutive viral load measurements after 3 months
• Clinical failure:
  • New or recurrent clinical event indicating severe immunodeficiency after 6 months of effective treatment
  • Clinical event refers to WHO clinical stage 4 conditions and some WHO clinical stage 3 conditions, such as pulmonary TB and severe bacterial infections
  • The condition must be differentiated from IRIS occurring after initiating ART
• Immunological failure:
  • CD4 count ≤ baseline or
  • Persistent CD4 levels <100 cells/µL.

Risk factors for treatment failure:

• HIV-related factors
  • Transmitted or acquired drug resistance
  • Prior treatment failure
  • Innate resistance to antiretroviral drugs
  • Higher pretreatment HIV RNA level
• Patient and regimen-related factors
  • Poor adherence
  • Drug side effects and toxicities
  • Variable absorption
  • Drug interactions
  • Low genetic barrier to resistance
  • Previous exposure to suboptimal regimens
  • Prescription errors

Management of treatment failure:

New antiretroviral regimen should contain at least two, and preferably three, fully active drugs based on

• Patient’s treatment history
• Drug resistance testing

Outlines the treatment strategies for management of treatment failure with first-line ARTs:

Treatment in cases of failure of fist-line regimen:

Hiv Resistance:

Question 23. Add a note on HIV resistance.
Answer:

• Important cause of treatment failure in HIV
• Factors favoring drug resistance:
  • Drug related
    • Differing genetic barrier to resistance
      • Emtricitabine, lamivudine, and efavirenhave a low genetic barrier to resistance
      • PIs and some NRTIs (e.g., zidovudine) select for resistance mutations slowly, and multiple resistant mutations often need to accumulate before the drug’s efficacy is lost
  • Cross-resistance within drug classes
  • Potency of the drug: Low potency leads to subtherapeutic suppression of viral load, favoring resistance
• Virus related
  • High rate of HIV-1 replication
  • Error-prone nature of reverse transcriptase
• This leads to mutations which:
  • Alter the coreceptor used for entry into the host cell
  • Increase the removal of a bound drug
  • Change the conformation of a viral enzyme, thus, preventing drug binding
  • Increase the efficiency of a viral enzyme, thus, overcoming drug-based inhibition of that enzyme
• Transmitted drug resistance:
  • Occurs when primary HIV infection is caused by a drug resistance mutation-bearing virus
  • Hence, HIV resistance testing is advised at the time of patient’s initial diagnosis
• Acquired drug resistance:
  • Seen in patients with virological failure
• HIV resistance testing has been described earlier

Treatment is as described in the above sections, taking into consideration patient’s treatment history and results of drug resistance testing.

Special Considerations In Patients With Hiv:

HIV-TB Coinfection:

Question 24. Add a note on HIV-TB coinfection. (or) Add a note on latent TB infection in patients with HIV.
Answer:

Active Tuberculosis in Patients with HIV:

• TB is the leading cause of death in patients with HIV. Most common opportunistic infection and can occur at any CD4 level.
• HIV infection is the most important risk factor for TB. Patients have an increased risk of acquiring new TB disease as well as have an increased risk of developing active TB from reactivated latent infection.
• Clinical manifestations of TB in patients with HIV varies based on the degree of immunosuppression and sites of TB
• Pulmonary TB is the most common presentation
• Extrapulmonary TB is more common in patients with HIV than patients without HIV.
  • In patients with extrapulmonary TB, common presentations include genitourinary tuberculosis, central nervous system TB, abdominal TB, TB lymphadenitis, cutaneous TB, and pleural TB
• Tuberculosis progresses more rapidly, with a subacute or even acute presentation in those with advanced immunosuppression. The diagnosis therefore needs to be made and therapy commenced promptly.
• Diagnosis of tuberculosis (TB) in patients with HIV
  • Sputum smears:
    • Negative in more than half of patients
    • This is mainly due to the absence of pulmonary cavities
  • Nucleic acid amplification testing
    • Use of NAAT in patients with HIV is recommended
    • Advantages include rapid results, increased sensitivity as compared to smear microscopy, and distinction between tuberculosis and nontuberculous mycobacterial infections.
• Radiologic presentation of chest X-ray varies with state of immunodeficiency.
  • In patients with CD4 T-cell count >350 cells/µL, presentation is similar to that of non-HIV patients, and includes upper lobe infiltrates, cavitation, and pleural disease.
  • In patients with lower CD4 counts, cavitation is less common.
  • They present more often with lower or middle lobe infiltrates, interstitial nodules, miliary infiltrates, mediastinal lymphadenopathy, pleural effusion or sometimes, a normal X-ray.

• Testing of extrapulmonary tuberculosis depends on the site of the disease,
  • For example, for patients with suspected TB lymphadenitis, needle aspiration or biopsy for histopathology, acid fast bacilli, smear, and culture
  • Other samples, depending on the involvement, may include pleural fluid, pericardial fluid, ascites, or cerebrospinal fluid (CSF).

Management of tuberculosis (TB) in patients with HIV:

• Recommendations for antituberculosis treatment regimens in adults with HIV infection follow the same principles as for adults without HIV infection
  • Initiation phase: 2 months of isoniazid, rifampin (or rifabutin), pyrazinamide, and ethambutol
  • Continuation phase: 4 months of isoniazid, rifampin (or rifabutin), and ethambutol daily for drug-susceptible TB (longer duration for CNS TB/TB involving the bone/more severe disease)
  • Corticosteroids are recommended for patients with CNS or pericardial disease
• All patients should be given antiretroviral therapy (ART)
  • The preferred cotreatment regimen includes rifampin-based TB therapy plus 2 NRTIs + efavirenz
  • Alternative regimens include:
    • 2 NRTIs plus raltegravir 400–800 mg twice daily with standard rifampin dosing or
    • 2 NRTIs plus ritonavir-boosted protease inhibitor with rifabutin-based TB therapy.
• Recommendations for timing of ART vary by CD4 T-cell count and clinical disease.
  • CD4 T-cell count <50 cells/µL: ART should be started within 2 weeks of starting ATT
  • CD4 T-cell count ≥50 cells/µL and severe clinical disease: ART should be started within 2–4 weeks of starting ATT
  • For patients with CD4 T-cell count ≥50 cells/µL and not severe clinical disease: ART can be delayed beyond 2–4 weeks of starting TB therapy, but should be started within 8–12 weeks.
• TB-IRIS in patients with HIV
  • Patients with HIV infection and TB are at risk of developing immune reconstitution inflammatory syndrome (IRIS) with worsening of signs and symptoms after beginning antiretroviral therapy.
  • Risk of IRIS is higher in those who start ART within 2 weeks of starting ATT compared to those who start at 8–12 weeks of starting ATT.
  • Most IRIS is self-limited and can be managed with anti-inflammatory agents
  • Corticosteroids may rarely be needed to control symptoms.

Latent Tuberculosis in Patients with HIV:

• Patients with HIV may often be detected to have latent tuberculosis infection (LTBI), i.e., presence of a Mycobacterium tuberculosis-specific immune response in the absence of clinical and radiological disease.
• Guidelines recommend that all persons with HIV should undergo testing for latent tuberculosis infection (LTBI)
• Options for testing include
• Tuberculin skin test (TST):
  • Assesses for a delayed hypersensitivity response to an intradermally injected Mycobacterium tuberculosis purified protein derivative (PPD)
  • It is read at 48–72 hours following the injection
  • For HIV-positive patients: Positive TST is defined as induration ≥5 mm
  • Advanced HIV infection is associated with reduced TST reactivity and decreased sensitivity of the test.
• Interferon-gamma release assays (IGRAs):
  • Preferred if patient has received prior BCG vaccination, or if patients are unlikely to return after 48–72 hours for TST reporting.
  • Note that a negative TST or IGRA does not definitively exclude a diagnosis of TB
  • All patients with a positive testing for LTBI should undergo testing for active tuberculosis.

HIV-TB coinfection Management of latent TB in HIV [TB prophylaxis in HIV]:

• Indications:
  • Positive diagnostic test for LTBI,
  • No evidence of active tuberculosis (TB) disease and
  • No prior history of treatment for active or latent TB
  • Patient is a close contact of persons with infectious pulmonary TB, regardless of LTBI status.
• Rule out active TB prior to initiating treatment for LTBI, as treatment of active disease with regimens to treat LTBI can lead to development of drug-resistant TB
• Recommended treatment regimens:
  • Preferred regimen is isoniazid (INH) and pyridoxine for 9 months as either:
    • INH 300 mg orally once daily plus pyridoxine 25–50 mg orally once daily
    • INH 900 mg orally twice weekly by directly observed therapy (DOT) plus pyridoxine 25–50 mg orally once daily.
  • Alternative regimens include:
    • Rifampin 600 mg/day orally for 4 months
    • Rifabutin for 4 months, with dose adjusted based on concomitant antiretroviral therapy (ART)
    • Rifapentine plus isoniazid plus pyridoxine for 12 weeks (for patients having ART regimens containing efavirenor raltegravir)
• ART should be given in addition to LTBI treatment to reduce the risk of TB disease
• Treatment for LTBI reduces the risk of developing active TB by about 60%.

Immune Reconstitution Inflmmatory Syndrome (IRIS):

Question 25. What do you mean by IRIS? List the types and management.
Answer:

Treatment of HIV infection with combination antiretroviral therapy (ART) results in a rapid improvement in cell immunity. However, restoring the immune response may also lead to a paradoxical worsening of the existing opportunistic disease or to unmasking a new infection. This is referred to as immune reconstitution inflammatory syndrome (IRIS).

• Usually develops within the first 3 months of ART but occasionally develops later.
• Risk factors: Lower CD4 cell counts and high HIV viral load at the time of initiation of ART.
• Types:
  • Paradoxical IRIS:
    • Worsening or atypical manifestation (or both) of an established opportunistic infection after ART is initiated
    • Due to the immune response against residual antigens of the pathogen or the dying organism.
  • Unmasking IRIS:
    • Disease that occurs for the first time after ART is commenced
    • Due to an immune response against a subclinical infection by an opportunistic pathogen or a missed diagnosis of an opportunistic infection
    • Manifests with accelerated or exaggerated inflammatory presentations of the infection.
  • Immune reconstitution disease (IRD): Patients with HIV infection who are receiving ART also have an increased susceptibility to some autoimmune diseases, such as Graves’ disease, and sarcoidosis. This is also referred to as a type of IRIS by some authors.
• Examples and features of immune reconstitution inflammatory syndrome are given in Table.
• Fever is the most common clinical manifestation
• Diagnosis: Most or all of the following features should be present
  • Presence of AIDS with a low pretreatment CD4 count (<200 cells µL)
  • A positive virologic and immunological response to ART
  • The presence of clinical manifestations consistent with an inflammatory condition
  • A temporal association between ART initiation and the onset of clinical features of illness

Examples of IRIS:

• Absence of evidence of bacterial superinfection, drug-resistant infection, adverse drug reactions, reduced drug levels or patient noncompliance.

Immune Reconstitution Inflmmatory Syndrome Management:

• Continue antiretroviral therapy. Temporary discontinuation of ART should be considered only in patients with life-threatening disease when all other measures have failed
• Unmasking IRIS: Treat the underlying opportunistic infection
• Paradoxical IRIS: Continue treatment of underlying opportunistic infection
• Anti-inflammatory therapy: Reserved for patients with severe inflammation, particularly when it is life-threatening, or causing significant symptoms
  • NSAIDs
  • Glucocorticoids—e.g., prednisone 1.5 mg/kg/day for 2 weeks, then 0.75 mg/kg/day for 2 weeks.
• Prevention:
  • Delay initiation of ART to 5 weeks after starting treatment for cryptococcal infection
  • Delay initiation of ART 2–8 weeks after starting ATTs in cases of tuberculosis. See section on HIV-TB coinfection.

HIV and Pregnancy:

Question 26. Write a note on pregnancy considerations in patients with HIV.
Answer:

• Mother-to-child transmission (MTCT) accounts for >90% of HIV infection in children.
• Screening:
  • All pregnant women should be screened for HIV infection at entry to antenatal care
  • Testing should be repeated in the third trimester for women at high risk
• Antiretroviral therapy:
  • Start ARTs as early as possible for all pregnant women with HIV infection regardless of CD4 T-cell count or viral load.
  • ART should be continued even after delivery
  • Starting antiretroviral therapy early in pregnancy is associated with decreased viral loads at time of delivery
  • 2 NRTIs + integrase inhibitor or protease inhibitors preferred
  • NRTIs:
    • Abacavir + lamivudine or
    • Tenofovir disoproxil fumarate + emtricitabine or
    • Tenofovir disoproxil fumarate + lamivudine
  • Integrase inhibitor: Raltegravir is preferred
  • Protease inhibitor: A ritonavir-boosted PI is acceptable
• World Health Organization (WHO) recommendations. The antiretroviral drugs dolutegravir and emtricitabine/ tenofovir alafenamide fumarate (DTG + FTC/TAF) may comprise the safest and most effective HIV treatment regimen currently available during pregnancy (March 2020)
  • Preferred first-line regimen: Tenofovir disoproxil fumarate + lamivudine (or emtricitabine) + efavirenz
  • Alternative first-line regimen
    • Zidovudine + lamivudine + efaviren(or nevirapine)
    • Tenofovir disoproxil fumarate + lamivudine (or emtricitabine) + nevirapine
• Labor and delivery considerations:
  • Mode of delivery:
    • Cesarean delivery at 38 weeks of gestation is recommended for women with viral loads >1,000 copies/mL or unknown viral loads near time of delivery.
    • Scheduled cesarean delivery is not routinely recommended in women with HIV RNA levels ≤1,000 copies/mL
    • Avoid invasive labor procedures, such as an artificial rupture of membranes in the setting of viremia, the use of fetal scalp electrodes, and the use of forceps or vacuum extractor when possible. This is to reduce fetal exposure to bodily fluids.
• Role of IV zidovudine
  • For women with HIV viral loads >1,000 copies/mL, start zidovudine 2 mg/kg IV over 1 hour at labor onset and then 1 mg/kg/hour IV until delivery.
  • For women with HIV infection receiving combination ART during pregnancy and HIV RNA ≤1,000 copies/mL near delivery, intrapartum zidovudine is not required.
• Following delivery:
  • Give postpartum antiretroviral drugs to all HIV-exposed infants to reduce perinatal transmission
  • Antiretroviral regimens (at gestational age-appropriate doses) should be given preferably within 6–12 hours of birth
  • Antiretroviral prophylaxis
  • To prevent HIV infection in infants with low risk of transmission
• Options:
  • Single drug regimen: Zidovudine alone for 4 weeks for infants born to mother on regular ART with viral load <50 copies/mL
  • Two-drug regimen: Zidovudine for 6 weeks plus three doses of nevirapine during first week of life for infants at higher risk of transmission but in whom presumptive HIV therapy is not needed.
• Presumptive HIV therapy:
  • For infants with higher risk of HIV acquisition, such as those born to mothers who
    • Did not have antepartum or intrapartum antiretroviral drugs
    • Only had intrapartum antiretroviral drugs
    • Had antepartum antiretroviral drugs but did not achieve viral suppression near delivery
    • Acquired HIV infection during pregnancy or breastfeeding.
  • Options include
    • Zidovudine for 6 weeks plus emtricitabine and nevirapine for 2–6 weeks
    • Zidovudine for 6 weeks plus emtricitabine and raltegravir for 2–6 weeks
• HIV therapy:
  • To newborns with confirmed infection
  • Administration of three-drug regimen at treatment doses.
• Breastfeeding recommendations:
  • Breastfeeding is not recommended in resource-rich settings due to the availability of safe alternatives
  • However, in resource-limited situations, breastfeeding may be acceptable till safe and adequate diet can be provided.
• Other concerns:
  • Prevention of secondary transmission to partner
  • Family planning
  • Prophylaxis against opportunistic infection: Similar to nonpregnant adults.

Prevention Of Opportunistic Infections:

Question 27. Enumerate the indications and discuss prophylactic drugs used to prevent HIV-related opportunistic infections
Answer:

Prophylaxis for prevention of opportunistic infections (decreasing order of CD4 count):

Vaccination In Patients With Hiv:

Question 28. List the vaccine that should be given to patients with HIV.
Answer:

Considerations with vaccination:

• Poor immune response
  • Patients with CD4 count <200 cells/µL, develop poor immune responses to immunization. Thus, it is preferable to wait until the CD4 count increases to >200 cells/µL on ART prior to immunization.
• Live vaccines:
  • Vaccination with live organisms is contraindicated in patients with severe immune suppression, as this may result in disease from the attenuated organisms.
  • Live attenuated vaccines should not be given to patients with CD4 counts of <200 cells/µL, and should be used with caution in those with CD4 counts of <350 cells/µL.

Postexposure Prophylaxis For Hiv:

Question 29. Discuss and describe the principles and regimens used inn postexposure prophylaxis for HIV. (or) Write a short note on postexposure prophylaxis for hepatitis B.
Answer:

• What is considered an exposure:
  • Exposure is defined as contact between blood, tissue, or body fluids (semen, vaginal secretions, breast milk, amniotic fluid, CSF, and pleural/peritoneal/pericardial/synovial fluid) from a source patient and blood, broken skin, or mucosa of exposed patient.
  • Note that contact of a potentially infectious fluid/substance with intact or unbroken skin is not considered a possible exposure.
• Types of exposure:
  • Occupational exposures: Healthcare worker
    • Percutaneous exposure: Needlesticks with hollow bore or solid bore needles
      • Visible contamination of needle with blood, insertion of the needle into an artery or a vein, deep injury caused by the device-associated with increased risk of transmission
    • Mucosal exposures: Splashing of blood or body fluids from source into eyes, nose, or mouth of the exposed person
  • Nonoccupational exposures:
    • Sexual exposures (including victims of rape)
    • Injection drug use
    • Biting: Has a theoretical risk of transmission, especially if source patient’s saliva contains blood
• Risk of transmission:
  • Risk based on source patient:
    • Highest risk: Those with HIV infection and high viral load
    • Risk increases if source is member of group with high risk for HIV acquisition: Men who have sex with men (MSM), injection drug user, commercial sex worker, person from country with ≥1% HIV seroprevalence, and sexual partner of a member of above groups
  • Blood transfusion (very rare): Highest rate of transmission
• Patient evaluation:
  • Exposed patient:
    • HIV testing at time of exposure or within 3 days of exposure to determine baseline HIV status
      • Fourth generation HIV-1/HIV-2/p24 antigen-antibody combination assay
      • Positive result on Ag/Ab test must be followed by further antibody testing and/or RNA testing to determine whether patient has acute or chronic infection
    • Baseline testing to assess for undiagnosed conditions prior to starting PEP include complete blood count, renal function tests and electrolytes, liver function tests, hepatitis B and C serology, and pregnancy test for women
    • For sexual exposures, screen for gonorrhea and chlamydia using nucleic acid amplification testing and syphilis using VDRL/RPR.
• Source patient:
  • If HIV status unknown, test for HIV infection
  • If source patient known to be HIV-positive
  • Results of any previous resistance testing and treatment history should be obtained
  • Viral load should be determined, as should HIV drug resistance testing, if status unknown
  • Also test source patient for coinfections including hepatitis B and C.

Postexposure Prophylaxis Treatment:

• Decontamination:
  • Wash the area with soap and water.
  • Avoid squeezing or milking the wound.
  • Do not use caustic agents (e.g., bleach).
• Indications for PEP:
  • PEP should be provided following exposure of nonintact skin or mucous membranes to potentially infected body fluid from source that is HIV-positive or has unknown HIV status.
• Exposures for which PEP not indicated:
  • Preexisting HIV infection in exposed patient based on baseline blood tests
  • Consistent pre-exposure prophylaxis use by exposed patient
  • Chronic ongoing exposure
  • Exposure to intact skin
  • Exposure to noninfectious bodily materials such as feces, urine, saliva, and sweat
  • Exposure to bodily fluids from a person known to be HIV-negative (unless person at high risk for recent infection within previous 3 months)
  • Certain types of close contact in the absence of blood or ulcers: Kissing, mouth-to-mouth CPR, human bites without visible blood, and exposure to solid bore needles or sharps without recent contact with blood.
• When to start:
  • Start antiretroviral PEP as soon as possible after an exposure
  • Initiation of PEP ≥72 hours after exposure generally not recommended.
• What drugs to give:
  • Three-drug regimen recommended—two NRTIs plus a third drug [preferably an integrase strand transfer inhibitor (INSTI), or a ritonavir-boosted protease inhibitor (PI)]
  • Preferred regimen (NACO June 2021):
    • Tenofovir 300 mg plus Lamuvidine 300 mg PO OD plus Dolutegravir 50 mg orally once daily or raltegravir 400 mg orally twice daily
  • Alternative regimen (NACO June 2021):
    • Tenofovir plus emtricitabine (or lamivudine) plus
    • Third drug:
      • Lopinavir/ritonavir or atazanavir/ritonavir preferred
      • Raltegravir, darunavir/ritonavir, or efavirenalternative options
    • Antiretroviral agents generally not recommended in PEP:
      • Abacavir: Need for early initiation of PEP does not allow time for testing for HLA-B*5701 allele)
      • Didanosine: Rrisk of mitochondrial toxicity
      • Nelfiavir
      • Tipranavir
    • Medications contraindicated as PEP:
      • Nevirapine: Risk of fatal hepatotoxicity (rare)
      • Efavirenfor pregnant women
      • Tenofovir for persons with estimated creatinine clearance <60 mL/min
  • Duration of therapy:
    • 28-day course after exposure
    • If patient tests positive for HIV at baseline, refer for evaluation and treatment of new diagnosis of HIV infection
    • If source patient confirmed HIV-negative, PEP regimen may be discontinued
  • Other management:
  • Treatment of other blood-borne or sexually transmitted infections (hepatitis B, hepatitis C, gonorrhea, and chlamydia)
• Monitoring:
  • Monitor for adverse effects of the antiretroviral drugs.
  • Complete blood counts, urea, creatinine, electrolytes, and liver function tests 2 weeks after initiating PEP
  • Repeat testing for HIV, hepatitis B, and hepatitis C infections: At 6 weeks, 12 weeks, and 6 months postexposure.

Postexposure Prophylaxis for Hepatitis B Infection

• PEP for hepatitis B infection is summarized in Table.
  • HBV—
    • If source patient is positive for both HBsAg and HBeAg—37–62%;
    • If source patient is positive for HBsAg but is HBeAg negative—23–37%
  • HCV—1.8%.

Pre-Exposure Prophylaxis In Hiv:

Question 30. Discuss pre-exposure prophylaxis in HIV.
Answer:

Pre-exposure prophylaxis (PrEP) refers to the use of antiretroviral agents by HIV-uninfected but at-risk individuals in order to prevent the acquisition of HIV infection.

• Indications:
  • HIV-negative patients or patients with indeterminant testing and no signs or symptoms of acute HIV infection in prior 4 weeks and
  • In the following populations:
    • Sexually active adult men who have sex with men (MSM) at substantial risk for acquiring HIV
    • Heterosexually active adult men and women at substantial risk for acquiring HIV
    • Adult injection drug users at substantial risk for acquiring HIV.
• Evaluation before starting PrEP:
  • Exclude acute or chronic HIV infection before starting PrEP
    • Patients with positive testing are not eligible for PrEP and should be initiated on HIV treatment
    • Patients with negative or indeterminant test who have signs or symptoms of acute HIV in prior 4 weeks should be
      advised confirmatory HIV or viral load testing
  • Baseline renal function:
    • PrEP is not recommended for patients with a eGFR <30 mL/minute/1.73 m2.
    • Individuals with an eGFR <60 mL/min/1.73 m2 are not candidates for PrEP with TDF-FTC.
  • Pregnancy testing
  • Screening for other infections: Hepatitis B, hepatitis C, and other sexually transmitted infections
  • DEXA scan in patients with, or at high risk for, osteoporosis.
• PrEP options:
  • Preferred regimen:
    • 2 NRTIs: Tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC).
  • Alternative:
    • Tenofovir alafenamide plus emtricitabine (TAF/FTC) PO OD
    • Preferred for MSM and transgender women with bone and renal issues (eGFR <60 mL/min/1,73 m2) who are not eligible for TDF-FTC
• Duration of therapy for the above regimen:
  • As long as the risk of infection persists
  • PrEP should be continued for one month after the last high-risk exposure
  • However, not more than a 90-day supply should be prescribed
  • Prescription may be renewed only after HIV testing confirms that patient remains HIV uninfected.
• Alternative regimen:
  • On demand dosing (also known as event-based dosing or “2-1-1″ PrEP):
  • PrEP is taken only when sex is anticipated
  • Has been shown to be effective for MSM having anal sex
  • Not recommended in transgender women and heterosexual males and females
  • Should not be used in patients with chronic hepatitis B virus infection.
• Patient monitoring:
  • Frequency of follow-up:
    • At 1 month and 3 months after starting treatment, and then every 3 months thereafter
    • More frequent follow-up for:
      • Patients who have been exposed to and/or have symptoms of a sexually transmitted infection (STI)
      • Patients with evidence of renal dysfunction.
• Tests to be done include 3 monthly HIV testing with a fourth-generation antigen/antibody test, screening for STIs, creatinine, and urinalysis, pregnancy testing, and hepatitis C virus screening every 6 to 12 months.

Hiv Vaccine:

Question 31. Add a short note on HIV-vaccine.
Answer:

• Challenges:
  • HIV mutates rapidly; HIV mutates in one day as much as influenza viruses do in a year
  • Can be transmitted by cell-free or cell-associated virus

• HIV provirus integrates itself into the genome of the target cell and remains in a latent form, unexposed to the immune system
• The virus has developed multiple mechanisms to evade the body’s defenses.
  • Targets the cells (CD4) that coordinate the immune response to viral infections.
  • Broadly neutralizing antibodies usually appear between 2 and 4 years but by that time the antibodies cannot save them because they are overwhelmed by the mutating virus.
• Vaccines:
  • Currently, there is no safe and effective vaccine that is approved for the prevention of HIV infection
  • More than 50 HIV-1 vaccine candidates have been studied since 1987
  • Some of the important vaccine trials are described in Table
  • Research on broadly neutralizing antibodies against certain epitopes on the HIV envelope are underway.

Hiv Vaccine Mississippi Baby:

The “Mississippi baby” was born to an HIV-positive mother who had not received any treatment during pregnancy. Doctors began treating the child by the time she was 30 hours old, but the family stopped antiretroviral therapy at 18 months.

She remained off the drugs for the next 27 months with no signs of the virus in her blood. She was monitored closely. However, at 4 years of age, the CD4 cells dropped and in a few weeks the HIV virus levels were detectable. She is presently on treatment.

Hiv Vaccine Berlin Patient:

Timothy Ray Brown had HIV for 12 years before he became the first person in the world to be cured of the infection following a stem cell transplant in 200The stem cell donor had a specific genetic mutation called CCR5 Delta 32 that protects a person against HIV infection. After the stem cell transplant, Brown was able to stop all antiretroviral treatment and the HIV has not returned till now.