Definition: HIV type 1 is a retrovirus that infects predominantly lymphocytes that bear CD4 surface protein as well as coreceptors belonging to the chemokine receptor family (CCR5 or CXCR4) and causes acquired immunodeficiency syndrome (AIDS).
Subtype B is common in North America, Europe, and Australia, while the subtype C is common worldwide.
M group: A, B, C, D, E, F, G, H, J, K, and CRFs (circulating recombinant forms -infection of an individual with 2 subtypes)
Characteristics: The genome consists of two identical subunits of (ss) RNA (diploid linear), surrounded by a conical truncated capsid. These components are surrounded by an envelope which is plasma membrane derived of host-cell origin, formed when the capsid buds out from the host cells. It is an icosahedral shape.
(ss) RNA: Tightly bound to the nucleocapsid proteins and enzymes, such as reverse transcriptase (RT), integrase, and protease.
The main matrix protein p17 surrounds the capsid (p24-capsid protein) and maintains the integrity of the virion particle.
The envelope includes glycoproteins gp120 and gp41.
The HIV genome is very complex and includes several major genes coding for structural proteins (expressed in all retroviruses), and several regulator genes, unique to HIV.
Structural genes:
Gag (group-specific antigen); encodes p24; p6, p7, and p9; p17.
The core nucleocapsid proteins p6, p7, and p9 are associated with the genomic RNA, thus preventing its digestion by nucleases.
Pol - encodes RT; integrase; protease
Env - encodes gp120; gp41.
Regulatory genes:
Tat - encodes transactivator proteins.
Rev - encodes regulatory virion proteins.
Nef - encodes negative factor.
Pathogenesis: Transmission of HIV may occurs secondary to sexual contact (semen, vaginal secretions), blood transfusions, IV drug use, and contact with other infected bodily fluids (plasma, CSF). HIV can also be transmitted through the placenta (intrauterine transmission), perinatally, and through breast milk.
HIV primarily infects macrophages and CD4+ T cells. Macrophages are thought to play a key role in primary HIV-1 infection. Infection of and replication in monocytes/macrophages results in the spread of HIV to other tissues.
Viral entry to CD4+ T cells and macrophages is initiated through interaction of the envelope glycoproteins (gp120) with CD4 molecules of target cells.
Fusion of target cells is further facilitated through their own chemokine receptors (CCR5 or CXCR4).
Mutations in CCR5 can lead either to immunity (homozygous) or to slower progression to AIDS (heterozygous).
Mutations in CXCR4 lead to rapid progression to AIDS.
HIV invades CD4+ T cells, impairing both the humoral and cell-mediated arms of the immune system.
Presentation: The hallmarks of initial infection with HIV are an abrupt drop in CD4+ T-cell count and rapid viral replication (increase viral load).
Primary infection; acute HIV syndrome (CDC category A): Patients may experience infectious mononucleosis-like syndrome, which usually occurs 4 - 5 weeks after initial infection. Major symptoms include, but are not limited to, fever, generalized LAD, HA, myalgia, and pharyngitis.
Although 40% - 70% of infected patients experience symptoms in the acute stage, the symptoms are rather nonspecific; most HIV cases are not detected this time.
Clinical latency stage: CD4+ T-cell count rebounds, and most symptoms of acute infection subside. However, LAD can be present throughout the entire course of an HIV infection. Clinical latency is an extremely variable stage, which can last from a few weeks to over 20 years, depending on the patient. Median latency is 10 years.
Disease progression: Determined by the number of CD4 T-cells that are viable. They decline over time, however, and patients have an increased risk of acquiring common and not so common infections (CDC category B).
Constitutional symptoms: Moderate, unexplained weight loss, fever (38.5°C last > 1 month), chronic diarrhea.
Infectious conditions: Oropharyngeal and persistent vulvovaginal candidiasis, herpes zoster (shingles), frequent respiratory infections, PID.
Precancer/cancer lesions: Most common are oral hairy leukoplakia and cervical dysplasia/cervical carcinoma in situ.
Other: Peripheral neuropathy may develop.
Later stages of AIDS, CDC category C: Broad spectrum of clinical entities (AIDS-defining) conditions. Patients may also suffer neurological complications (HIV/AIDS encephalopathy and AIDS dementia). Complications of these severe opportunistic infections may result in death.
Fungal infections: Candidiasis of oral cavity, esophagus, trachea, bronchi, or lungs. Coccidioidomycosis, disseminated or extrapulmonary. Cryptococcosis (extrapulmonary), histoplasmosis, disseminated or extrapulmonary, P. jiroveci (carinii)
Carcinomas: Invasive cervical carcinoma, Kaposi's sarcoma, Burkitt's lymphoma, Immunoblastic lymphoma, primary CNS lymphoma.
Viral infection: CMV retinitis or disease, herpes simplex (ulcers, bronchitis, pneumonitis, or esophagitis), progressive multifocal leukoencephalopathy, wasting syndrome (due to HIV).
Parasitic infections: Cryptosporidiosis, isosporiasis, toxoplasmosis of the brain.
Bacterial infection: Mycobacterium tuberculosis, MAC, recurrent Salmonella septicemia.
Classification: CDC classification is based on CD4 count and the presence of AIDS-associated conditions. Diagnosis of AIDS is made on the basis of CD4 cell count <200/μL (regardless of the presence of sx or OI), CD4 percentage <14%, or development of one of the 25 AIDS-defining conditions.
The system is based on three ranges of CD4+ T lymphocyte counts and three clinical categories. Using this system, once individuals have, say, condition B, their disease classification cannot be reverted back to category A, even if the condition resolves.
1993 revised classification system for HIV infection and expanded AIDS surveillance case definition for adolescents and adults
NNRTI
Clinical conditions of HIV infection
Category A: consists one or more of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection. Conditions listed in categories B and C must not have occurred.
Asymptomatic HIV infection
Persistent generalized lymphadenopathy
Acute (primary) HIV infection with accompanying illness or history of acute HIV infection
Category B: consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical categories C and that meet at least one of the following criteria:
The conditions are attributed to HIV infection or are indicative of the defect in cell-mediated immunity; or
The conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples include, but are not limited to, the following:
Bacillary angiomatosis
Candidiasis, oropharyngeal (thrush)
Candidiasis, vulvovaginal; persistent; frequent, or poorly responsive to therapy
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month
Hairy leukoplakia, oral
Herpes zoster (shingles), involving atleast two distinct episodes or more than one dermatome
ITP
Listeriosis
PID, particularly if complicated by TOA
Peripheral neuropathy
Protease Inhibitors
Category C: conditions listed in the AIDS surveillance case definition
Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month’s duration)
CMV (other than liver, spleen, or nodes)
CMV retinitis (with loss of vision)
Encephalopathy, HIV-related
HSV: chronic ulcer(s) (>1 month’s duration); or bronchitis, pneumonia, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month’s duration)
Kaposi’s sarcoma
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, primary, of brain
MAC or M. kansasii, disseminated or extrapulmonary
MTB any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV
Epidemiology: 33 million affected worldwide. Mostly in Sub-Saharan Africa
http://www.who.int/hiv/data/en/index.html
1.2 million in U.S affected. 50% of new cases of HIV in U.S is accounted for by African Americans. Women comprise 30% - 35% of all cases. 50,000 infections occur annually in the US.
History: Detailed history with emphasis on previous OIs, viral coninfections, and other complications. Pschosocial and psychiatric history (depression and substance use). Family and social support assessment. Insight, and knowledge regarding the disease.
Physical Examination:
Oral findings: hairy leukoplakia, aphthous ulcers, thrush.
Lymhatic system: generalized LAD.
Skin: molluscum contagiosum, cryptococcus, psoriasis, eosinophilic folliculitis, Kaposi's sarcoma.
Abdominal exam: evidence of hepatosplenomegaly.
Genital exam: presence of ulcers, genital warts, vaginal discharge, and rectal discharge.
Neurologic exam: presence of sensory deficits and cognitive testing.
Diagnosis:
CDC recommends that all persons aged 13 to 64 be offerred HIV testing in all health care settings using an opt-out format (assent is inferred unless the patient declines testing).
Significant individuals health benefits if HAART is initiated early in the course of illness.
Significant public health benefits with the knowledge of HIV status leading to changes in risk behavirors.
Availability of inexpensive, reliable, and rapid testing technology.
Persons at high risk who need screening annually:
IVDA, homosexual and bisexual men, hemophiliacs, sexual partners of a known HIV patient, or homsexual or bisexual men. Sex traders and their partners, person with h/o STIs, persons who received blood products between 1977 - 1985. Multiple sexual partners engaging in unprotected intercourse
Others: pregnant women (opt-out screening), TB, donors of blood, semen, and organs, health care workers who perform invasive procedures, occupational exposures ( needlestick injury).
ELISA test for initial screening: HIV-1/HIV-2 enzyme immunoassay. Target HIV antigens p24, p17, gp120, and gp41.
p24 is detectable shortly after initial infection, so it is often used as an early signs of HIV infection.
Western blot: Done if ELISA is positive. HIV infection is confirmed if antibodies to at least two HIV antigens (p24, gp41, gp120/160) are positive.
An isolated positive ELISA result should not be reported to the patient until this result is confirmed by a Western blot.
An indeterminate test is one for which the ELISA is positive but the criteria for a positive Western blot are not fulfilled. Repeat testing should be considered for these patients to confirm whether they have a false-positive ELISA or have a recent/acute HIV infection.
HIV DNA-PCR: Used to determine viral load and monitor the effects of the treatment. Also used to screen for HIV infection in newborns of HIV positive mothers.
CD4+ T-cell count: Assess treatment progress.
Labs:
CBC, CMP, LFTs, UA, CD4 cell count (nl: 600 - 1500 cells/mm3), CD4 percentage.
CD4 count should be periodically checked 3 - 4 times a year to assess immune status of the patient and to determine the need for OI prophylaxis.
Virologic markers: Plasma HIV RNA is used for monitoring of HAART efficacy. Reverse transcriptase PCR assay is the most widely used with a lower limit of detection of 40 - 50 copies/mL. The goal is to achieve maximal viral suppression by reducing viral load to undetectable levels.
Tuberculin skin test
RPR test
Toxoplasma immunoglobulin (IgG) and hepatitis A, B (HBsAg, HBsAb, HBcAb) and C serologies.
PAP smear
G & C urine probe
HIV resistance testing at baseline, with treatment failure, and particularly for pregnant women.
HLA B5701 for patients in who one is considering the use of abacavir.
Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B5701 is associated with an extreme sensitivity to abacavir. This drug is a treatment for HIV-1 that slows the spread of the virus in the body. People with abacavir hypersensitivity often develop a fever, chills, rash, upset stomach, and other symptoms when treated with this drug.
CCR5 Tropism testing for patients in whom one is considering the use of maraviroc.
Treatment:
Immunizations
Pneumococcal vaccine is given in HIV infection. Some recommend giving the vaccine when the CD4 counts are >200 cell/mm3, as response is poor when vaccination occurs with low CD4 counts. Revaccinate after 5 years.
Hep A and B virus vaccination is recommended.
Influneza is recommended annually.
Varicella vaccine which is a live attenuated can be safely given to persons with CD4 counts >200 cell/mm3 but is contraindicated for persons with CD4 counts <200 cells/mm3.
MMR is given safely to persons with CD4 cell counts >200 cell/mm3, but C/I when CD4 counts <200 cells/mm3.
TdaP. All adults should receive Td booster every 10 years with one-time substitution with TdaP.
HPV vaccine. Studies to determine efficacy and safety is ongoing.
Medications:
Treatment decision is based on patient's readiness, compliance, adherence issues, drug interactions, drug toxicities, comorbidities, and the level of risk indicated by CD4 T-cell count.
Maximal and durable suppression of HIV replication is the goal of therapy once it is initiated.
Reductions in plasma viremia correlate with increased CD4 counts and prolonged AIDS-free survival.
Viral rebound should trigger an evaluation of adherence, drug interactions, and viral resistance.
Pregnant women should receive optimal antiretroviral therapy (ART) to reduce vertical transmission.
Current recommendations from the IAS/USA (http://www.iasusa.org/guidelines) for the initiation of ART include the following:
All patients with clinical AIDS or immunologic AIDs (CD4 count <200 cells/mm3) to prevent progression of disease and incident or recurrent OIs.
Patients who are symptomatic HIV disease, regardless of CD4 cell count.
Patients with CD4 cell count <350 cells/mm3 with asymptomatic disease.
HIV-associated nephropathy,hepatitis B virus coinfection, and pregnancy.
CD4 count > 350 cells/mm3 in an asymptomatic patient needs decision making regarding treatment initiation, on a case-by-case basis.
Antiretroviral drugs: Grouped in 5 categories. Expert recommend 3 active drugs from two different classes to maximally and durably suppress HIV viremia.
NRTIs stop HIV replication by incorporating into the elongating strand of DNA, causing chain termination. All nucleoside analogs have been associated with lactic acidosis, presumably related to mitochondrial toxicity. Includes: Abacavir (ABC), didanosine (ddI), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T), zidovudine (ZDV, AZT), tenofovir (TDF). Zalcitabine (ddC) is rarely used in clinical practice.
NNRTIs inhibit HIV by binding noncompetitively to the reverse transcriptase. Side effects of NNRTIs include rash, hepatotoxicity, and Stevens-Johnson syndrome (more likely with nevirapine). CNS side effects are commonly experienced with the use of efavirenz. Includes: Efavirenz (EFV), nevirapine (NVP), etravirine (ETV)
Protease inhibitors (PIs) block the action of viral protease required for protein processing late in the viral cycle. GI intolerance is one of the most commonly encountered adverse effects. All PIs can produce increased bleeding in hemophiliacs. Glucose intolerance, increased cholesterol and triglycerides, and body fat redistribution. They are metabolized via cytochrome P-450 which they both induce as well as inhibit, and have important drug interactions. Boosting with ritonavir is a common practice to achieve better therapeutic concentrations. Includes: Fosamprenavir (fAPV), atazanavir (ATV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), tipranavir (TPV), darunavir (DRV).
HIV entry inhibitors (fusion inhibitor) target different stage of HIV entry process. T-20 (enfuvirtide), 90 mg sc bid is a fusion inhibitor that prevents the fusion of virus into the host cell. Maraviroc is a CCR5 receptor blocker. Initiation of CCR5 inhibitor requires baseline determination of HIV coreceptor tropism (CCR5 or CXCR4).
CCR5-tropic HIV-1: a virus strain that can only use the CCR5 co-receptor to infect CD4 cells.
CXCR4-tropic HIV-1: a virus strain that can only use the CXCR4 co-receptor to infect CD4 cells.
Dual-tropic HIV-1: a virus strain that can use either the CCR5 or CXCR4 co-receptor to infect CD4 cells.
Integrase inhibitors are new class of antiretroviral agents that target DNA strand transfer and integration into a human genome. Raltegravir is the only drug available.
Potential initial ART generally consists of a combination of 2 NRTIs + 1 or 2 PI, or an NNRTI + NRTI + PIs, or 2 NNRTI + PIs, or 2 NNRTI + 1 NRTI. Experts currently recommend using three active drugs from two different classes to maximally and durably suppress HIV viremia.
Treatment monitoring: Viral load should be checked at 4 - 6 weeks after initiation of HAART. An expected 10-fold reduction (1.0 log10) and suppression to <50 copies/mL by 24 weeks of therapy. If not adequate, regimen should be reassessed. When the HIV RNA becomes undetectable and the patient is on stable regimen, monitoring can be done every 3 months.
Treatment failure is defined:
Less than a log (10-fold) reduction of the viral load 4 - 6 weeks after starting a new antiretroviral regimen
Failure to reach an undetectable viral load after 6 months of treatment
Detection of virus after initial complete suppression of viral load, which suggests development of resistance.
Persistent decline in CD4 cell count or clinical deterioration.
Confirmed treatment failure should prompt changes in HAART based on results of genotype testing. In this instance at least two of the drugs should be administered with other drugs that have no expected cross-resistance.
Complications of ART:
Lipodystrophy syndrome: body fat maldistribution. Accumulation of visceral fat in the abdomen, neck (buffalo hump), and pelvic areas, and/or the depletion of subcutaneous fat, causing facial or peripheral wasting. Seen especially in PI and NRTIs uses. Lifestyle modificaitons, exercise may help. Rosiglitazone and cosmetic surgery are under inv.
HLP: ▲ TG associated mainly with PIs (ritonavir). Improvements have been with atorvastatin, pravastatin, and/or gemfibrozil.
Peripheral insulin resistance, impaired glucose tolerance, and hyperglycemia have been associated with the use of PI-based regimens, including indinavir and ritonavir.
Lactic acidosis with liver steatosis is rare but fatal complication associated with NRTIs. High rates reported with stavudine and ddI. Mechanism appears to be part of mitochondrial toxicity.
Osteopenia and osteoporosis are well described HIV-infected individuals. The pathogenic mechanism of this problem is likely related to the inflammatory milleu of HIV itself.
Osteonecrosis, particularly of the hip, has been increasingly associated with HIV disease.
Monitoring/Follow-up:
Plasma HIV RNA is used for monitoring of ART efficacy. Goal is to reduce the viral load to undetectable levels.
CD4 cell count should be checked periodically (3 - 4 times a year) to determine the immune status of the patient and the need for OI prophylaxis.
After starting or changing ART, check viral load at 4 - 6 weeks.
HIV resistance testing is done using two different types of assays: genotypic (in which the reverse transcriptase and the polymerase genes are sequenced using different techniques) and phenotypic (in which the HIV replication in vitro in the presence of antiretroviral drug is examined). Results of resistance testing should be used to guide ART.
Opportunistic Infections and other associated conditions in HIV
Opportunistic Infection Prophylaxis
Entry Inhibitors
Integrase Inhibitors
ART and interactions with other medications
Protease inhibitors: PI when given with other drugs:
PI both induce and inhibit the P-450 system and interacts:
P-450 inhibitors: macrolides (erythromycin, clarithromycin), antifungals (ketoconazole, itraconazole)
P-450 inducers: rifamycins (rifampin, rifabutin) and anticonvulsants (phenobarbital, phenytoin, carbamazepine).
Drugs with narrow therapeutic indices that should be avoided or used with extreme caution:
Antihistamines (loratadine is safe), antiarrhythmics (flecainide, encainide, quinidine), long-acting opiates (fentanyl, meperidine), long acting benzodiazepines (midazolam, triazolam), warfarin, HMG-CoA reductase inhibitors (pravastatin is the safest), and oral contraceptives.
Sildenafil concentrations are ▲.
Methadone and theophylline concentrations are ▼.
Grapefruit juice can ▲ levels of saquinavir and ▼ levels of indinavir.
Simvastatin, lovastatin levels are ▲ can cause myopathy and rhabdomyolysis. Atorvastatin and pravastatin can be administered with PIs with close monitoring.
Rifampin and rifapentine are ▼ plasma conc.
St. John's Wort should not be used with any PIs: ▼ PI plasma concentration.
Lopinavir/ritonavir inhibit P-450 system. Fluticasone use (Advair) can result in suppressed adrenal function. Decrease rifabutin to 150 mg qod or 3ice a week.
Atazanavir (ATV): ▼ clarithromycin dose by 50%. PPIs ▼ ATV conc, should not be coadminstered. H2 blockers must be given 12 hours apart. Levels of antiarrhythmics usually ▲. Decrease rifabutin to 150 mg qod or 3ice a week. Monitor anticonvulsant levels.
Nelfinavir (NFV): monitor anticonvulsant levels. Decrease rifabutin to 150 mg qod or 3ice a week.
Tipranavir (TPV): inhibits P-450 system. Fluticasone use (Advair) can result in suppressed adrenal function. Do not coadminster with amiodarone, quinidine, flecainaide, OCPs. Decrease rifabutin to 150 mg qod or 3ice a week.
Darunavir (DRV). Use the lowest dose of pravastatin with close monitoring.
NNRTIs:
St. John's Wort should not be used as it results in suboptimal levels of NNRTIs.
Decreased levels of OCPs when coadministered
Efavirenz (EFV) induces/inhibits the P-450 system. Do not administer with voriconazole: decreases voriconazole levels. Decreases methadone levels, can cause opiate withdrawal.
Nevirapine (NVP) induces P-450 system. Rifabutin ▼ NVP levels, so do not coadminister with rifampin. ▼ methadone levels, can result in opiate withdrawal.
NRTIs:
Tenofovir (TDF): coadminister with cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir may ▲ serum conc. of either tenofovir or the coadministered drug.
Didanosine (ddI): Do not coadminister with allopurinol (decreased ddI conc), ribavirin (hepatic failure). Monitor for ddI toxicity when coadministered with ganciclovir or valganciclovir.
Zidovudine (AZT): Avoid concomitant ribavirin and interferon use. Increased hematologic toxicity with ganciclovir, valganciclovir, cidofovir.
ATRIPLA contains three HIV medicines in one pill: SUSTIVA® (efavirenz), EMTRIVA® (emtricitabine) and VIREAD® (tenofovir disoproxil fumarate). This combination works to help lower the amount of HIV in the blood (called viral load) by interfering with the way HIV makes copies of itself (called viral replication). Lowering the amount of HIV in the blood may also help increase the number of T-cells (also called CD4+ cells). CD4+ cells are an important part of your immune system because they help the body fight infections.
For many patients, ATRIPLA may be a complete regimen, with three medicines from two different classes, or types of drug, in one pill. For some patients, ATRIPLA may be taken with other medicines to treat HIV-1. ATRIPLA contains two NRTIs (emtricitabine and tenofovir disoproxil fumarate) and one NNRTI (efavirenz). Regimens that combine HIV medicines from different classes are effective because they help to slow HIV multiplication during several stages of the process.
Prophylaxis for OIs: primary and secondary prophylaxis
Primary prophylaxis before an episode of OI occurs.
Not routinely recommended for: recurrent bacterial pneumonia, mucosal candidiasis, CMV retinitis, cryptococcosis, and endemic fungal infections such as histoplasmosis and coccidiodomycosis.
Secondary prophylaxis is instituted after an episode of infection is adequately established.
Withdrawal of prophylaxis. Recommendations suggest when sustained immunologic recovery has occurred (CD4 cell counts consistently above 150 - 200 cells/mm3)
Immune reconstitution syndrome (IRIS), generally presents as local inflammatory reactions. Examples include paradoxical reactions with TB reactivation, localized MAC adenitis, and CMV vitreitis immediately after initiation of potent ART. Hepatitis virus infections can be aggravated with the immune reconstitution associated with ART. Of patients with PML associated with HIV, 19% may develop IRIS after initiating antiretroviral therapy. It is caused by immune attack of the PML lesions by the newly reconstituted immune system in the setting of antiretroviral therapy. Diagnosing IRIS in patients with PML may be tricky because many of the focal symptoms in the two conditions are similar. Gadolinium enhancement of the lesions is not typical in PML and is more characteristic of IRIS, although it is not invariably present. PML-associated IRIS usually develops within 4 to 8 weeks after initiation of antiretroviral therapy.