HIV/AIDS

Overview

HIV/AIDs is caused by the retrovirus Human Immunodeficiency Virus (HIV-1 and HIV-2). Most patients with acute HIV infection are asymptomatic but some may present with a flu-like illness in the weeks following exposure.

• Characteristics of Human Immunodeficiency Virus
  • Retroviridae
  • Baltmiore class VI (positive ssRNA Reverse Transcriptase viruse)
  • HIV-1 and HIV-2 subtypes
    • Groups M, N, O and P
    • Clades A, B, C, D, F, G, H, J, and K within group M
    • A circulating recombinant form (CRF01_AE) exists
• Replication cycle of Human Immunodeficiency Virus
  • Attachment → Penetration → Uncoating → Reverse transcription → Integration → Transcription of gag, pol, env and regulaitng genes → Translation → Assembly → Viral release
• HIV genome and the roles of genes
  • Genes essential to viral replication:tat and rev
    • ***tat: “***transactivator for transcription” enhances transcription
    • rev: regulates and promotes transport of viral mRNA into the cytoplasm, splicing and post-transcriptional modifications
  • Structural genes:gag pol and env
    • gag: group-specific antigen codes for core and capsid proteins (p24, p17, p7, p6, p2, p1)
    • pol: encodes for reverse transcriptase, a protease and integrase
    • env: envelope glycoproteins (gp 120 and gp41)
  • Genes not essential for viral replication:vif nef vpr vpu and vpx
    • vif: virus infectious factor, makes the virus more infectious
    • nef: “Negative factor” inhibits or activates viral transctiption as required, influences T-cell activation, reduces CD4 expression. Essential for progression to AIDS
    • vpr: transport of cDNA into nucleus
    • vpu: only in HIV 1, contributes to viral release, increases CD4 turnover
    • vpx: by HIV-2 only, others above are by HIV-1

Transmission

HIV is spread parentally via infected body fluids (sexual contact or IV drug use). It can also be spread vertically (mother-to-fetus).

• Common HIV transmission modes
  • Heterosexual contact (73%; more heterosexual males with HIV that have gotten infected via vertical transmission)
  • Other modes (9%)
  • Injecting drug users (8%)
  • Blood transfusion (7%)
  • Spouse infection (1%)
  • Men having sex with men (<1%)
  • Blood product infusion (<1)

HIV testing

HIV is diagnosed using HIV-1/-2 antigen and antibody immunoassays (4th gen antibody and antigen immunoassay). If the original test returns positive a HIV-1/HIV-2 antibody differentiation immunoassay is obtained. If differentiation is indeterminate negative a HIV NAT test is obtained.

• Who should get tested for HIV?
  • Anyone who asks
  • Patients who have engaged in unprotected vaginal or anal sex with partners of unknown HIV status
  • Men who have sex with men (MSM; unprotected anal sex is very efficient at transmission)
  • HIV-negative partner in a serodiscordant relationship
  • Patients who use or have used IV drugs and needles
  • Patients who have been recently diagnosed with an STD
  • Pregnant women (as part of the ANC profile)
  • Patients with symptoms consistent with acute HIV syndrome

HIV natural progression

Natural progression from the onset of symptoms to death is usually about 7 to 10 years. The CD4 count and viral load kind of have an inverse relationship, whereby a decrease in CD4 count is associated with an increase in viral load (and vice versa)

Prognosis is based on CD4 count

Infectivity is based on Viral load

• Natural progression
  • Acute infection: Initial infection is associated with CD4+ depletion and elevated viral load. Host immune response develops. The patient may present with Acute Retroviral Syndrome (mononucleosis like illness – lymphadenopathy, diarrhea, rash, etc.)
  • Latent (chronic) infection: Associated with a stable viral load for 7-10 years. The virus replicates at the spleen, lymph nodes ,brain, and GIT. Some mechanisms contributing towards latency include: loss of cell mediated immunity, antigenic drift, heavy glycosylation, direct cell-cell spread, and down regulation of MHC molecules
  • AIDS: Associated with a CD4+ of less 200 cells/mm3, marked viraemia, presence of p24 antigens, HANDS, opportunistic infections, and malignancies

Epidemiology

Up to 2 million new HIV infections occur worldwide. Kenya has the fifth-largest number of persons living with HIV in the world.

• Top 5 high-prevalence counties in Kenya
  • Homa Bay
  • Kisumu
  • Siaya
  • Migori
  • Busia

Acute HIV Syndrome (Acute Retroviral Syndrome – ARS)

ARS occurs soon after infection. It is difficult to diagnose. It corresponds with a rapid increase in viral load and a mild drop in CD4 count. Patients can be asymptomatic or subclinical. Important to get a sexual history (recent unprotected sex) to rule out HIV in patients who present with mononucleosis/flu-like symptoms. Patients are particularly infectious during acute HIV infection because

• Signs and symptoms
  • Fever
  • Malaise
  • Generalized lymphadenopathy
  • Maculopapular rash
• Investigations
  • HIV-1/-2 antigen and antibody immunoassay (Provider Initiated Testing and Counselling)
• Treatment
  • HAART if HIV+

WHO Clinical Staging of HIV/AIDS

WHO Clinical Stage	Feautres
Stage 1 (Asymptomatic)	Asymptomatic, persistent generalized lymphadenopathy (PGL)
Stage 2 (Mild illness)	Hepatosplenomagaly, maculopapular pruritic eruptions, seborrhoeic dermatitis, fungal nail infections, extensive warts, molluscum infection, herpes zoster, angular cheilitis, linear gingival erythema, recurrent oral ulcerations, parotid enlargment, recurrent or chronic URTI (including otitis media)
Stage 3 (Moderately severe illness)	Unexplained moderate malnutrition, unexplained persistent diarrhoea (> 14 days), unexplained fever (> 4 months), severe pneumonia, pulmonary tuberculosis, oral candidiasis, oral hairy leukoplakia, acute necrotizing ulcerative gingivitis, chronic HIV-associated lung disease (bronchiectasis, LIP), unexplained anaemia, neutropenia or thrombocytopaenia
Stage 4	AIDS-indicator conditions. For HIV-positive infants < 18 months: oral candidiasis, severe pneumonia or severe sepsis can be used for a presumptive diagnosis

AIDS-indicator conditions: these signify progression to AIDS in individuals with HIV

Classification	Conditions
Opportunistic fungal infection	Candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis
Opportunistic bacterial infection	Tuberculosis, MAC, recurrent pneumonia (≥ 2 episodes in 12 months), recurrent salmonella septicaemia
Opportunistic parasitic infection	Toxoplasmosis of the brain, cryptosporidiosis, isosporiasis
Opportunistic viral infection	CMV retinitis, HSV, Progressive multifocal leukoencephalopathy
Cancers	Kaposi’s sarcoma, Non-hodkin lymphoma, primary CNS lymphoma, cervical cancer
Neurological and wasting conditions	AIDS dementia complex, HIV wasting syndrome

Treating a Patient with HIV

Begin HAART upon diagnosis. Make sure patient gets their vaccinations and follow-up every 3-6 months.

• Investigations for newly diagnosed HIV patients
  • CD4 count
  • HIV Viral Load
  • HIV viral genotyping (resistance and susceptibility to meds)
  • Testing for TB, CMV, other STDs, and Toxoplasma antibodies
  • Pap smear (HIV increases the risk of cervical dysplasia)
  • CBC, BMP, TFTs, LFTs, Fasting lipid profile (HAART drugs can cause metabolic disturbances, some patients may have Hepatitis, so make sure kidneys and livers are functioning properly)
  • Ophthalmologic exam

Anti-retroviral therapy (ARVs)

Anti-retrovirals are the mainstay therapy in HIV. Treatment with ARVs can get very complicated. Before starting get HIV viral genotyping to determine the most effective drugs.

Zidovudine was the first ARV medication, first approved in 1986. 6 classes of ARVs exist.

Anti-retrovirals

Class	Examples
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)	Zidovudine (AZT), Tenofovir (TDF), Lamivudine (3TC), Emtricitabine, Abacavir (ABC), Didanosine, Zalcitabine, Stavudine
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)	Delavirdine, Nevirapine (NVP), Efavirenz (EFV)
Protease Inhibitors (PIs)	Indinavir, Saquinavir, Ritonavir, Lopinavir/Ritonavir, Nelfinavir, Amprenavir, Atazanavir
Integrae strand trasnfer inhibitors (INSTIs)	Raltegravir (RAL), Doultegravir (DTG), Elvitegravir
Fusion inhibitors	Enfuviritide
CCR5 antagonist	Maraviroc

• Indications for changing ARVs (severe toxicity)
  • Severe GI intolerance (vomiting and diarrhoea)
  • Severe rash e.g. SJS/TEN
  • Jaundice or ALT/AST > 5 times normal
  • Anaemia < 7.5 g/dL
  • Platelets < 50,000 per mm3
  • Neutrophils < 500 per mm3
  • Lactate > 5 times normal or symptomatic lactic acidosis

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs block reverse transcriptase by competing for nucleotide binding. All NRTIs include lactic acidosis as a potential adverse effect

NRTIs and their adverse effects

NRTI	Side effects
Zidovudine (AZT – most commonly used)	Myelosuppression (anaemia and neutropenia), GI upset
Tenofovir (TDF)	Few side effects, can cause renal failure (avoid in patients with renal impairment)
Abacavir (ABC)	Hypersensitivity reaction (get HLAB*5701), shortness of breath, myalgia
Lamivudine (3TC)	Few severe adverse effects. Well tolerated.
Emtricitabine	Few severe adverse effects. Well tolerated.
Didanosine	Peripheral neuropathy, Pancreatitis (linked to length of use)
Zalcitabine	Peripheral neuropathy, Pancreatitis (linked to legngth of use)
Stavudine	Peripheral neuropathy

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Block reverse transcriptase allosterically (allosteric inhibitors).

Some NNRTIs and their adverse effects

NNRTI	Adverse effects
Efavirenz (EFV – most commonly used)	Avoid in pregnancy (women should get a pregnancy determining test and birth control if taking efavirenz). CNS toxicity – depression, nightmares, ocular impairment. Gynaecomastia. Fatigue
Nevirapine (NVP)	Rash, hepatotoxicity
Delaviridine	Rash, hepatotoxicity

Protease Inhibitors

Blocks protease (which is responsible for maturing the HIV virion). The general adverse effect is lipodystrophy (liporedistribution is worse than other ARVs), lipid disturbances and GI upset. Ritonavir can be used to boost the potency of other protease inhibitors.

Protease inhibitor	Adverse effects
Lopinavir (LPV/r)	Nausea, diarrhoea, vomiting, lipodystrophy, glucose intolerance
Atazanavir (ATV/r)	Hyperbilirubinaemia

Integrase Strand Transfer Inhibitor (INSTIs)

Blocks HIV integrase (integrates HIV DNA into the genome of the host CD cell). Has fewer adverse effects than other antivirals.

• Dolutegravir (DTG)
  • First line ARV in combination with two others for adolescents and adults with HIV
  • Well-tolerated and is less likely to develop resistance. Also has fewer drug-drug interactions
  • Adverse effects: headache, nausea, diarrhoea, or insomnia (reduced by taking DTF in the morning and with a low-fat meal or empty stomach)
  • Increase DTG levels to 50 mg twice daily for patient taking Rifampicin (since Rifampicin lowers DTG levels)

Highly Active Antiretroviral Therapy (HAART)

Once HAART is initiated, the viral load should be cut in half in the first month and should ideally drop to undetectable within a couple of months. CD4 count should also rise. Monitor patient on HAART for HIV metabolic syndrome.

Viral Load Supression: Viral load supression is defined as having < 1,000 viral copies per mL of plasma. It is a key indicator of treatment success in HIV-opositve persons. Patients with Viral Load Supression have a very low risk fo tranmitting the virus.

• Antiretroviral regimen: Two NRTIs plus something else
  • Two NRTIs and an NNRTI
  • Two NRTIs and a PI
  • Two NRTIS and an INSTI

First-Line Regiments according to Age

Age	Preferred Regimen
Birth – 4 weeks	AZT + 3TC + RAL/NVP
4 weeks – 3 years	ABC + 3TC + LPV/r
3 – 15 years (< 35 kg)	ABC + 3TC + EFV/DTG
≥ 15 years	TDF + 3TC + DTG8 or TDF + 3TC + EFV

HIV in Pregnancy and Preventing Mother to Child Transmission (PMTCT)

HAART is recommended to be started or continued in ALL HIV positive pregnant women as soon as they become pregnant (May continue their current regimen). Viral load should be undetectable in all pregnant women. Because of lowered immunity, patients can get recurrent infections (including UTI) that interfere with pregnancy. Pregnancy can also increase HIV disease progression.

The risk of transmission of HIV during pregnancy is 5 – 10% since the virus can cross over to the fetus through the placent. Risk of transmission is highest during labour (10-20%) due to injuries to the birth canal of the mother, high viral content of vaginal secretions, and mixing of fetal and maternal blood. Breastfeeding for the first 18 – 24 months carries a 10 – 15% risk of transmission. Pregnancy + labour + breastfeeding carries a 25 – 45% risk of transmission.

Risk factors for mother-to-child tranmission

Classification	Risk factors
Maternal factors	High viral load, low CD4 count, micronutrient deficiency, vitamin A, anaemia, STDs (genital ulcer disease), multiple sexual partners, malaria, new infections
Obstetric factors	Vaginal delivery, PROM > 4 hours, assisted delivery, AROM, episiotomies, frequent vaginal examinations, chorioamnionitis, laceration, cord milking, delayed clamping and prolonged labor
Fetal factors	Prematurity, low birth weight, genetic defects, multiple births (1st twin), trauma in birth canal
Breastfeeding factors	Prolong breast feeding, mixed feeding, breast disease (abscess, mastitis), infant oral thrush, mothers having AIDS, high maternal viral load

• PMTCT interventions
  • Family planning (primary HIV prevention)
  • HAART
  • Safe obstetric practices
  • Safe infant feeding practices in HIV context
  • Postnatal care for the baby, mother and partner
• Efavirenz
  • Efavirenz is contraindicated during pregnancy (particularly in the first trimester)
  • Women on efavirenz should be on birth control
• Nevirapine
  • Nevirapine can be given 4 hours before surgery (effective at least 2 hours before surgery) for women are were not on HAART
• When is vaginal delivery safe and recommended for HIV positive women?
  • Viral load less than 1000 (provided no OB/GYN contraindications)
  • Viral load undetectable is preferred
• What prophylaxis is given to HIV-exposed infants (HEI) after birth?
  • Zidovudine (AZT) for at least 4-6 weeks and Nevirapine (NVP) until 6 weeks after stopping breastfeeding
  • HAART can be started if viral load >1000/mL OR mother was not taking ARVs
  • Test HIV DNA q6mos until complete sessation of breastfeeding
• Which HAART regimen is initiated for HIV positive infants?
  • Neonates: AZT +3TC + RAL/NVP
  • Infants > 4 weeks old: ABC + 3TC + LPV/r
    • Tenofovir alafenamide is preferred over Abacavir for children > 20 kg
    • Dolutegravir is preferred over Lopinavir/Ritonavir for children > 20 kg

Post-exposure prophylaxis (PEP)

PEP is recommended when there is exposure of mucous membranes or non-intact skin to high-risk body fluids of an HIV+ person. It must be commenced within 72 hours of exposure.

PEP involves HAART therapy for 4 weeks

Preferred regimen: tenofovir/emtricitabine along with an INSTI (raltegravir, dolutegravir)

• Criteria for post-exposure prophylaxis
  • Fluid must be exposed to non-intact skin or mucous membrane
  • It should be high-risk body fluid (eg. blood, semen, breast milk)
  • Should be from HIV positive person
• Which patient groups are regimens including Zidovudine reserved for?
  • Patients with renal dysfunction (eGFR <60) (cannot tolerate tenofovir)
  • Children < 2 years
• When to do HIV testing after post-exposure prophylaxis
  • 4-6 weeks
  • Again after 3 months
  • Whenever there are symptoms of acute HIV infection
• Additional investigations to get for the exposed patients
  • Investigations based on occupational and sexual exposure
    • HBV
    • HCV
  • Investigations for other STDs
    • VDRL
    • NAAT for gonorrhea and Chlamydia
  • Pregnancy test

Pre-exposure prophylaxis (PrEP)

PrEP is an FDA-approved, evidence-based means to prevent new infections among those a risk (reduces the risk of HIV transmission by up to 90%). Strict adherence is necessary for maximal effect.

Tenofovir/emtricitabine (Truvada) 300mg/200mg PO taken once daily

• Who is a candidate for PrEP?
  • HIV-negative patients in a sexually active serodiscordant relationship
  • Men who have sex with men (MSM) and transgender women who:
    • Have had sex without a condom in the past six months
    • Have had any STDs in the past six months
    • Does not regularly use condoms during sex and has sex with people of unknown HIV status who are at risk of contracting HIV
  • Anyone who has injected illicit drugs in the last six months shared recreational drug injection equipment with other drug users in the past six months or has been in treatment for injection drug use in the past six months
• Who is not a candidate for PrEP?
  • HIV+ patients (HIV can become resistant to the NRTIs)
  • Patients with eGFR <60 (IDSA)
• Which patients should you give special consideration when receiving PrEP?
  • HBV+ patients: discontinuing PrEP may result in acute hepatitis flare
  • Pregnant women: possible risk of fetal bone issues and pregnancy loss; breastfeeding is not a contraindication to PrEP

Pre-treatment counseling and workup

Get a detailed history and workup before commencing PrEP. Keep in mind that patients may not volunteer risk factors for HIV (because of stigma)

• Sexual history
  • Sex with men, women, or both
  • Sexual practices (ie. oral, vaginal, anal)
  • HIV serostatus of partner(s) – serodiscordant couple
  • Number of partners
  • STD history
• Drug/Substance history
  • Types of recreational drugs used
  • Sharing needles or equipment
  • Injection into a shooting gallery (shooting gallery = place set up to inject drugs)
  • Use of non-parenteral drugs that decrease condom use
• Investigations
  • HIV-1/-2 antigen and antibody immunoassay
  • Serum creatinine level (U/E/Cs)
  • HBV panel (HBsAG, anti-HBc, anti-HBs)
  • Pregnancy test
• Important information for counseling
  • Drug takes several weeks to achieve optimal serum concentration (condoms necessary for 7 days before anal intercourse, and 21 days before vaginal intercourse)
  • Encourage continued use of safe-sex practices, stressing the role of PrEP as an additional safeguard
  • Educate the patient about the symptoms of acute HIV infection and lactic acidosis.

Treatment

Tenofovir (TDF)/emtricitabin (Truvada) 300mg/200m PO taken OD

• Adverse effects
  • Lactic acidosis (as with all NRTIs)
  • Renal toxicity (AKI, Fanconi syndrome – watch out for patients with risk factors for renal disease DM, Chronic HTN, Older age)
  • Hepatomegaly and steatosis (Rare, but can get jaundice, etc.)
  • Bone Mineral Density Loss (If older women, get a DEXA scan)
  • GI upset (resolves with continued use)

Follow-up

Patients should be seen one month after initiation, then three months, then every three months thereafter

• Every 3 months
  • Monitor adherence to meds (ask about side effects)
  • HIV screening
  • Routine screening for STDs regardless of symptoms
  • Pregnancy test
  • Serum creatinine (for patients with risk factors for renal disease)
• Every 6 months
  • Serum creatinine (all patients)
  • Urinalysis (patients with risk factors for renal disease)