LOBNA A AL JUFFALI

HIV &Opportunistic Infections

Transmission of HIV

Sexual transmissionParental exposure to blood or blood products

Epidemiology

percentage% Risk Group

47 Homosexual (men)

25 IV drug use

18 Heterosexual

1 Perinatal transmission

2 Other/not reported or identified

United states through December 2006

Epidemiology

People living with HIV/AIDS Geographic Area

2,100,000 North America and western Europe

230,000 Caribbean

1,600,000 Latin/South America

380,000 North Africa and Middle East

22,500,000 Sub-Saharan Africa

4,900,000 Asia

75,000 Oceania

33,200,000 Total cases

37,000,000 Total deaths

Clinical Presentation

SymptomsFever, sore throat, fatigue, weight loss, and myalgiamaculopapular rash usually involving the trunk Diarrhea, nausea, and vomiting Lymphadenopathy, night sweatsAseptic meningitis (fever, headache, photophobia, and

stiff neck) may be present in a one-fourth of presenting cases

OtherHigh viral load (exceeding 50,000 copies/mL in the

adult or 500,000 copies/mL in the child)Persistent decrease in CD4 lymphocytes

HIV Infections

Diagnosis

Enzyme linked immunosorbent Assay ELISA Positive 1-6 months after the infection

Western blot Confirms ELISA

The viral load test quantifies viremia by measuring the amount of viral RNA. For diagnosis and progression RNA: reverse transcriptase-coupled polymerase chain reaction branched DNA nucleic acid sequence-based assay

The number of CD4 lymphocytes (disease progression) The normal adult CD4 lymphocyte count ranges between 500

and 1,600 cells/μL

Goal of Therapy

The central goal of antiretroviral therapy is to decease morbidity and mortality through maximum suppression of HIV replication (HIV RNA level that is undetectable).

Secondary goals include an increase in CD4 lymphocytes.

GENERAL APPROACH TO TREATMENT OF HUMANIMMUNODEFICIENCY VIRUS INFECTION

Measurement of plasma HIV RNA levels and CD4 cell

counts is necessary to determine the risk of disease progression in an HIV infected individual and to determine when to initiate or modify antiretroviral treatment regimens.

Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages.

Women should receive optimal antiretroviral therapy regardless of pregnancy status.

The same principles of antiretroviral therapy apply to both HIV infected children and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations.

GENERAL APPROACH TO TREATMENT OF HUMANIMMUNODEFICIENCY VIRUS INFECTION

HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should be counseled to avoid sexual

and drug-use behaviors that are associated with transmission or acquisition of HIV and other infectious pathogens.

GENERAL APPROACH TO TREATMENT OF HUMANIMMUNODEFICIENCY VIRUS INFECTION

Treatment is recommended for all HIV-infected persons with an AIDS defining event, symptomatic disease or a CD4 lymphocyte count below 200 cells/mm3 Start therapy regardless of CD4 T-cell count in:

pregnant women HIV associated nephropathy Coinfected with HBV

Treatment is generally not recommended in persons with CD4 counts above 350 cells/mm3.

Those between 201 and 350 cells/mm3 should be offered therapy

GENERAL APPROACH TO TREATMENT OF HUMANIMMUNODEFICIENCY VIRUS INFECTION

Antiretroviral Agents

Three primary groups of drugs used:Nucleoside reverse transcriptase

inhibitors (NtRTIs)

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs).

Protease inhibitors (PIs)

Protease Inhibitors PI

Nonnucleoside and nucleotide Reverse Transcriptase Inhibitors (NNRTI)

Nucleoside Reverse Transcriptase Inhibitors(NtRTI)

IndinavirNelfinavirRitonavirSaquinavirFosamprenavirLopinavir/RitonavirAtazanavirTipranavirDarunavir

NevirapineDelaviraneEfavirenzEtravirine

Zidovudine DidanosineStavudineLamivudineEmtricitabineAbacavirTenofovir

Treatment

Current recommendations for treating HIV infection advocate a minimum of three antiretroviral agents.

two NtRTIs

Ritonavir-boosted PI

NNRTI

OR

Treatment

NNRTI Ritonavir-boosted PI

two NtRTIs

EfavirenzNot indicated in pregnant women

Atazanavir Tenofovir Plus Emtricitabine (Coformulated As Truvada)

Ritonavir, Zidovudine Plus Lamivudine (Coformulated As Combivir).

Lopinavir-ritonavir,

Abacavir Plus Lamivudine Is An Alternative

Fosamprenavir-ritonavir.

Drug Interaction

Ritonavir is a potent inhibitor of cytochrome P450 enzyme 3A and is used to reduce clearance of other PIs.

Two NtRTIs, zidovudine and stavudine, antagonize each other’s metabolism and should not be given together.

Rifampin may substantially reduce the concentrations of PIs and is contraindicated with use of most PIs.

Saint John’s wort is a potent inducer of metabolism and is contraindicated with PIs and NNRTIs.

TREATMENT DURING PREGNANCY

In general, pregnant women should be treated similar to nonpregnant adults;

If possible, zidovudine should be used for both mother and infant.

Efavirenz should not be used, particularly in the first trimester, because of the risk of teratogenicity.

POSTEXPOSURE PROPHYLAXIS

Post exposure prophylaxis with a triple-drug regimen consisting of two NtRTIs and a boosted-PI is recommended for percutaneous blood exposure involving significant risk (i.e., large-bore needle or large volume of blood or blood from patients with advanced AIDS).

Two NtRTIs may be offered to healthcare workers with lower risk of exposure such as that involving either the mucous membrane or skin.

Treatment is not necessary if the source of exposure is urine or saliva.

POSTEXPOSURE PROPHYLAXIS

The optimal duration of treatment is unknown, but at least 4 weeks of therapy is advocated.

Ideally, treatment should be initiated within 1 to 2

hours of exposure, but treatment is recommended for up to 72 hours postexposure.

EVALUATION OF THERAPEUTIC OUTCOMES

Following the initiation of therapy, patients are usually monitored at 3-month intervals with immunologic (i.e., CD4 count), virologic (HIV

RNA), and clinical assessments.

There are two general indications to change therapy: significant toxicity or treatment failure.

Therapy should be changed in the following situations

Less than a 1 log10 reduction in HIV RNA 1 to 4 weeks after the initiation of therapy, or a failure to achieve less than 400 copies/mL by24 weeks or less than 50 copies/mL by 48 weeks.

After HIV RNA suppression, repeated detection of HIV-RNA.

Failure to achieve a rise in CD4 of 25 to 50 cells/mm3 by 48 weeks.

Clinical disease progression, usually the development of a new opportunistic infection.

THERAPEUTIC FAILURE

Therapeutic failure may be the result of :nonadherence to medication,Development of drug resistanceIntolerance to one or more medications,Adverse drug–drug interactions Pharmacokinetic-pharmacodynamic

variability.

Opportunistic infection in HIV Patient

Opportunistic infection in HIV Patient

The development of certain opportunistic infections is directly or indirectly related to the level of CD4 lymphocytes.

The most common opportunistic diseases and their frequencies found before death in patients with AIDS between 1990 and 1994 were Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex, and cytomegalovirus disease.

Over view of HIV-associated infections

Principle No. 1: the fungal, Parasitic,and viral infections acquired by people who are infected with HIV are rarely curable . At best , the infection is contollalable during an acute episode but usually requires long term suppressisive therapy

Over view of HIV-associated infections

Principle No.2: Most HIV-associated infections represents endogenous reactivation of previously acquired organisms and do not represent a threat

to others.

Over view of HIV-associated infections

Principle No.3: Concurrent or consecutive infectious with different organisms are a common clinical occurrence in severely immunosuppressed people with HIV infection.

Over view of HIV-associated infections

Principle No.4:infections associated with HIV are severe often disseminated and atypical and characterized by a high density of organisms

Pneumocystis carinii (Pneumocystis jiroveci)

P. jiroveci pneumonia is the most common life-threatening opportunistic infection in patients with AIDS.

The taxonomy of the organism is unclear, having been classified as both protozoan and fungal.

Clinical Presentation

Fever and dyspnea; Tachypnea, with or without rales or rhonchi, nonproductive or mildly productive cough. Chest radiographs may show florid or subtle infiltrates or

may occasionally be normal, although infiltrates are usually interstitial and bilateral.

Arterial blood gases may show minimal hypoxia (pao2 80 to 95 mm hg) but in more advanced disease may be markedly abnormal.

The onset of PCP is often insidious, occurring over a period of weeks.

Treatment

Treatment with parentral trimethoprim–sulfamethoxazole or parenteral pentamidine is associated with a 60% to 100% response rate.

Trimethoprim–sulfamethoxazole is given in doses of 15 to 20 mg/kg/day 3 -4 divided doses

Treatment duration is typically 21 days but must be based on clinical response.

Oral therapy (as oral absorption is high) may suffice in mildly ill and reliable patients or to complete a course of therapy after a response has been achieved with IV administration.

Treatment

The early addition of adjunctive glucocorticoid therapy to anti-PCP regimens has been shown to decrease the risk of respiratory failure and

improve survival in patients with AIDS and moderate to severe PCP (PaO2 ≤70 mm Hg or [alveolar–arterial] gradient ≥35 mm Hg).

Side Effect Of Trimethoprim–sulfamethoxazole

The more common adverse reactions seen with trimethoprim–sulfamethoxazole are rash, fever, leukopenia, elevated serum transaminases, and thrombocytopenia.

Pentamidine Side Effect Of

For pentamidine, side effects include hypotension, tachycardia, nausea, vomiting, severe hypoglycemia or hyperglycemia, pancreatitis, irreversible

diabetes mellitus, elevated transaminases, nephrotoxicity, leukopenia, and cardiac arrhythmias.

M.avium Complex

Sign and symptoms Non specific ;weight loss ,intermittent fever,

chills, night sweats, abdominal pain, diarrhea,chronic malabsorption and progressive weakness

anemia

Treatment

Clarithromycin 500 mg orally twice daily, plus ethambutol 15 mg/kg/day orally

For advanced disease, rifabutin 300 mg/day (dose may need adjustment with ART)

Maintenance therapy can be discontiued after 12 months of therapy if CD4 count is more 100/mm3 for 6 months or longer because of potent combination therapy and if patient is asymptomatic

Adverse effectsClarithromycin a Rash, GI intoleranceRifabutinGI intolerance, optic neuritis, peripheral neuritis Neutropenia,

discolored urine, uveitis

Cytomegalovirus (CMV)

ManifestationsGI ,Pneumonia and Retinitis

Treatment

Cytomegalovirus (retinitis) Ganciclovir intraocular implant plus valganciclovir 900

mg once daily until immune recovery from ART (AI)a

Cytomegalovirus esophagitis or colitisGanciclovir 5 mg/kg IV every 12 hours or foscarnet 180

mg/kg/day in two or three divided doses IV for 21 to 28 days

Neutropenia, thrombocytopeniaNephrotoxicity, hypohypercalcemia, hypophosphatemia,

anemia