HIV Infection: What Does the General Doctor Need to Know?

Howard Libman, M.D. Beth Israel Deaconess Medical Center Harvard Medical School

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

Acute HIV Syndrome

800

10,000,000

1,000,000

500

100,000

10,000

200

1,000

HIV Disease/AIDS

100

100

50

(copies/ mL)

Months | Years

10

0

HIV-infected/Infectious

(cells/ mm3)

Seropositive

Acute HIV Syndrome

Clinical Latency

HIV Disease/AIDS

Spectrum of HIV Infection

• CD4 cell count > 500/mm3

Most patients asymptomatic Bacterial infections, TB, shingles

• CD4 cell count 500-200/mm3 Many patients asymptomatic Generalized lymphadenopathy, KS, thrush

PCP, cryptococcosis, toxoplasmosis

• CD4 cell count < 200/mm3

• CD4 cell count < 50/mm3 CMV and MAC infections Increased risk of lymphoma Mortality highest

Reported Cumulative Cases of HIV, AIDS, and Deaths in Vietnam by Year

Vietnam MoH, 2010.

Distribution of HIV Infection in Vietnam by Age

VAAC/Vietnam MoH, 2010.

Distribution of HIV Infection in Vietnam by Gender

VAAC, 2010.

Distribution of HIV Cases in Vietnam by Risk Behaviors

VAAC/Vietnam MoH, 2010.

• Over 50% from injection-drug use • 40% likely from sexual transmission (heterosexual and homosexual) • 5% of cases unknown risk behavior

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

Traditional Historical Indications for HIV Antibody Testing

• Men who have sex with men • Persons with multiple sexual partners • Current or past injection drug users • Recipients of blood products between 1978 • Persons with current or past STD's • Commercial sex workers and their contacts • Pregnant women and women of child-bearing age • Children born to HIV-infected mothers • Sexual partners of those at risk for HIV infection • Donors of blood products, semen, or organs • Persons who consider themselves at risk

and 1985

or request testing

Traditional Clinical Indications for HIV Antibody Testing

Tuberculosis Syphilis

Encephalopathy Thrombocytopenia

vaginal candidiasis

• • • Recurrent shingles • Chronic constitutional symptoms • Chronic generalized adenopathy • Chronic diarrhea or wasting • • • Unexplained thrush or chronic/recurrent • HIV-associated opportunistic diseases

CDC Recommendations for “Routine” HIV Antibody Testing

Screen all healthy patients after notification that an HIV test will be performed unless they decline (“opt-out” testing)

Specific informed consent is unnecessary Persons at high risk for HIV infection should be

• • • •

screened at least annually

Prevention counseling should be not required as part of routine HIV testing, but it is strongly encouraged for persons at high risk

WHO Recommendations for HIV Antibody Testing

• HIV screening should be voluntary,

confidential, and undertaken with consent

• Recommended in all patients presenting for care in countries with a generalized HIV epidemic

epidemics, recommended in patients presenting for care in antenatal, tuberculosis, and sexual health clinics • Specific HIV screening policies vary by

• In countries with concentrated or low-level

country

Diagnostic Tests for HIV Infection

•

•

•

•

• WB results are occasionally described as

In the US, HIV antibody testing is performed by using enzyme-linked immunosorbent assay (ELISA), which is highly sensitive If result is negative, the test is reported as negative If result is positive, a Western blot (WB) assay is performed for confirmation If WB assay result is positive, the test is reported as positive

indeterminate; supplemental testing may be recommended

MOH Testing Strategies

SERODIA, rapid test

• One positive screening test is sufficient to

reject blood for safe transfusion

Testing Strategy I: At the blood banks • Positive test with one of these test: ELISA,

Testing Strategy II: Routine screening in

high prevalence areas • Two different ELISA tests • Positive result if both ELISAs are positive

• Three different ELISA tests • Positive result if all three tests are positive

Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

Testing Strategy III: HIV diagnosis

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

History

• Risk behaviors

Emotional response

•

Knowledge of HIV infection •

Employment/insurance status

•

Family/social situation •

Syphilis, other STDs, TB, hepatitis

•

• General health issues

Physical Examination

•

Integument: seborrhea, psoriasis, EF, onychomycosis, HSV, VZV, KS, generalized adenopathy

• HEENT: CMV retinitis, CWS,

• Pulmonary: PCP

thrush, OHL, ANUG

• Gastrointestinal: organomegaly

• Genitourinary: vaginitis, PID, HPV,

• Neurological: mental status,

cervical and anal dysplasia/carcinoma

focal central/peripheral findings

Pulmonary Tuberculosis

Extrapulmonary Tuberculosis

Pneumocystis Pneumonia

Penicillium Infection

Cytomegalovirus Retinitis

Baseline Laboratory Evaluation in US

•

CBC, differential count

•

BUN/creatinine, LFTs

•

glucose, lipid profile

•

CD4 cell count

•

HIV viral load

•

HIV genotype test

•

RPR

•

hepatitis A, B, and C serologies

•

toxoplasmosis serology

•

PPD (or TB IFN-gamma test)

•

Pap smear in women

•

Chlamydia and GC tests in persons at risk

•

Consider anal Pap smear in persons at risk

CD4 Cell Count

• Normal value > 350/mm3

• Surrogate marker for HIV disease progression

•

Intercurrent illnesses may affect value

Average decline of 50-100 per year Variability between patients

• Main clinical uses are to determine need for

• Care in comparing values from different labs

antiretroviral therapy and prophylaxis against opportunistic pathogens

Viral Load Testing

• Measurement of viral RNA by PCR or bDNA

•

Level correlates with CD4 cell count decline and clinical progression; the lower, the better

• Normal variability of 0.3 log (3- to 5-fold)

•

Intercurrent illnesses and immunizations may affect value

• Main clinical use is to assess effectiveness

of antiretroviral therapy

Baseline Laboratory Evaluation in Vietnam

• All patients:

- HIV antibody test (for confirmation) - CBC - CD4 cell count (if available) - If any suspicion of TB: CXR, sputum AFB, other tests for diagnosis of extrapulmonary disease • If available:

- ALT, AST, HBsAg, HBsAb, anti-HCV,

RPR/VDRL

- Creatinine, glucose, lipid profile - Pregnancy testing, Pap smear (in women)

Syphilis in HIV Infection

• Unusual clinical presentations, disease progression, serologic results, and response to therapy have been described

• False-positive RPR/VDRL in drug users

•

Indications for lumbar puncture? CDC: Evidence of neurologic disease Some authorities are more aggressive

CDC recommendations: Unchanged

• What is appropriate therapy?

• Follow clinically and serologically

Viral Hepatitis in HIV Infection

• Hepatitis B is very common in patients with HIV

disease; majority show evidence of prior infection

• Clinical course may be accelerated

• Exacerbation of chronic hepatitis B infection may occur with initiation of combination antiretroviral therapy or discontinuation of 3TC, FTC, or TDF

• Hepatitis C is common in IDUs; the majority have

chronic infection

• HCV progression is accelerated in patients with

HIV disease

• Treatment of chronic hepatitis C infection in the

context of HIV disease is less likely to be effective

• Hepatitis A is common in MSM

PPD Interpretation in HIV Infection

• Positive PPD is defined as > 5 mm induration

• Use of control panel is no longer recommended

• Frequency of anergy is high is patients with

•

Isoniazid treatment of latent TB is indicated in HIV- infected patients with +PPD regardless of age; it is not recommended in anergic, high- risk patients

CD4 cell count < 200/mm3

if clinical evidence of hepatitis

• Hold INH if transaminases > 5 times normal or

• Total duration of prophylaxis is 9 months

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

Antiretroviral Drugs Available in Vietnam

• Nucleoside RT inhibitors (NRTIs)

* zidovudine (ZDV) * didanosine (ddI) * stavudine (d4T) * lamivudine (3TC) * abacavir (ABC)

* tenofovir (TDF) [nucleotide]

• Non-nucleoside RT inhibitors (NNRTIs)

* nevirapine (NVP) * efavirenz (EFV)

• Protease inhibitors (PIs)

* lopinavir/ritonavir (LPV/rtv)

DHHS Recommended Regimens for Antiretroviral Therapy-Naïve Patients in US

NNRTI-based

TDF/FTC/EFV

PI-based

TDF/FTC + ATV/r TDF/FTC + DRV/r (qd)

II-based

TDF/FTC + RAL

Pregnant women

ZDV/3TC + LPV/r (bid)

EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 3TC can be used in place of FTC and vice versa.

First-line ARV Regimens in Vietnam

AZT

or

+ 3TC

+

TDF

NVP or EFV

d4T is no longer recommended

Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. Modification and Supplement, November, 2011.

Antiretroviral Therapy: General Usage Guidelines

•

Potent combination therapy is necessary, and effect is durable in majority of patients

Initial options include NRTI x 2 plus NNRTI,

boosted PI, or II

•

•

Indications for initiation of treatment: * AIDS-defining diagnosis * CD4 cell count < 500/mm3 * pregnancy * HIV-associated nephropathy * coinfection with HBV (where Rx indicated)

About three-quarters of patients achieve virologic suppression with first regimen

• •

Indications for modification of regimen: * increase in viral load

* drug toxicity

When to Start Antiretroviral Therapy in Vietnam

• Patients with CD4 cell count < 350 cells/mm3

• Patients with WHO clinical stage 3 or 4

regardless of clinical stage

Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. Modification and Supplement, November, 2011.

regardless of CD4 cell count

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

Long Term Treatment Complications

Lipid metabolism

increased triglycerides increased cholesterol, LDL, cholesterol/HDL ratio decreased HDL

Fat atrophy

Fat accumulation increase visceral fat buffalo hump lipomatosis gynecomastia

face, extremities, buttocks

insulin resistance glucose intolerance diabetes mellitus

Lactic acidemia/acidosis Osteopenia/osteoporosis Avascular necrosis of hips Peripheral neuropathy

Glucose metabolism

Facial Lipoatrophy

Management of Lipodystrophy Syndrome

Hyperlipidemia, insulin resistance

Visceral fat accumulation

Subcutaneous fat wasting

Diet and exercise Switch therapy

Diet and exercise Switch therapy PI  NNRTI

PI  NNRTI or ATV

Switch therapy PI  NNRTI d4T TDF or ABC

Growth hormone Cosmetic surgery

Statins/fibrates Insulin-sensitizing drugs

Insulin-sensitizing drugs Local injection Rx (polylactic acid, calcium hydroxylapatite)

Hyperlactatemia: Clinical Syndromes

Normal

Range

Lactate (mmol/L)

1

2

3

4

5

6

Compensated or asymptomatic hyperlactatemia

Decompensated or symptomatic lactic acidosis/hepatic steatosis

•Chronic •Stable over time •HCO3  20 mmol/L •Common •Risk factors-NRTIs (d4T>ZDV)

•Rapidly progressive •Life-threatening •HCO3 <20 mmol/L •Rare •Risks: women, HCV/HBV, liver disease, pregnancy

Lactic Acidemia and Acidosis • Lactic acidemia is common in patients on NRTIs,

but symptomatic acidosis is not

• Related to mitrochondrial toxicity from interference

with DNA polymerase-gamma

• Clinical manifestations are variable and

nonspecific

• Management consists of discontinuation of NRTI drugs in symptomatic patients with high lactate level

• Routine lactate monitoring in the absence of

symptoms is unlikely to be helpful

• However, if symptoms are present and an

increased lactate level is confirmed, modification of ARV regimen is warranted

Peripheral Neuropathy

• HIV infection itself and certain ARV drugs

• Manifests with sensory symptoms

(ddI, d4T, ddC) are likely responsible

involving the lower extremities • Diagnosis is made clinically after

excluding other common causes of peripheral neuropathy

• Management consists of discontinuation of the offending drug and control of HIV infection

antidepressants and /or anticonvulsants can be used for chronic pain management

• If necessary, analgesics and

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

OI Prophylaxis in HIV Infection in US Stratified by CD4 Cell Count

Infection

> 200

200-50

< 50

Isoniazid

Same

Same

TB *

PCP

None

Cotrimoxazole

Same

Toxo **

None

Cotrimoxazole (100) Same

MAC

None

None

Azithromycin

CMV

None

None

(Ganciclovir)

Fungal

None

Fluconazole

Same

HSV

None

Acyclovir

Same

Red font indicates secondary prophylaxis only. * In patients with positive PPD ** Alternative Rx: dapsone/pyrimethamine

Primary Prophylaxis for Select OIs in Vietnam

Disease/Agent

Indication

When to Stop?

Pneumocystis jiroveci

Primary Prophylaxis Cotrimoxazole (960 mg tab) once daily

CD4 < 350 cells/mm3 * or WHO Stage III or IV disease

WHO Stage IV or

Toxoplasma gondii

Cotrimoxazole (960 mg tab) once daily

CD4 < 100 cells/mm3

CD4 > 200 cells/mm3 for more than 6 months CD4 > 200 cells/mm3 for more than 6 months

Mycobacterium tuberculosis

INH 300 mg daily x 9 months

After treatment course

All HIV+ patients without evidence of active TB

* CD4 count of 200 cells/mm3 is used as threshold for PJP; it was increased to 350 cells/mm3 for prevention of infectious diarrhea and malaria.

Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

Outline

• Overview and epidemiology • HIV diagnostic testing • Initial evaluation of new patient • General principles of antiretroviral therapy • Long term treatment complications • Prophylaxis of opportunistic infections • Health care maintenance issues

HIV Routine Health Care Maintenance in US

Issue

Intake

Semiannually

Annually

Pneumococcal vaccine

X

Hepatitis B vaccine *

X

Hepatitis A vaccine **

X

Influenza vaccine ***

X

RPR

X

X

Chlamydia/GC

X

X

Pap smear +

X

X

PPD ++

X

X

* In HBV-seronegative patients; ** In at risk patients and those with chronic hepatitis; *** Especially in patients at risk for exposure to or morbidity from influenza; + Annually after first year; ++ In PPD-negative patients.