HIV/AIDS FOR THE GENERAL INTERNIST
| UPDATE ON HIV MEDICINE IN PRIMARY CARE: THE MACRO LEVEL —Meg D. Newman, MD, Associate Professor
of Medicine and Director, HIV Clinical Scholars, University of California, San Francisco, School of Medicine
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| Epidemiology: international—≈14,000 new infections daily, largely in low- and middle-income countries; ≈2000 of
these in children <15 yr of age; ≈12,000 in people 15 to 49 yr of age, and, of these, ≈50% in 15- to 24-yr age group,
and ≈50% women; affected age group comprises infrastructure of most low- and middle-income countries; ≈10 million
people need antiretroviral therapy, but only 15% of needs met; national—estimated prevalence rates for adults
and adolescents in United States (HIV infection in 2004) from 35 states (California and Pacific Northwest omitted);
high rates along Eastern seaboard, 238 per 100,000 in New York and New Jersey; high-risk heterosexual contact accounts
for ≈40% of new cases; infections from injection drug use decreased since 2001; 4% to 5% due to male-to-male
sexual contact plus injection drug use; 78% of women infected through high-risk heterosexual contact (do not perceive
themselves as at risk and their partners as having risk factors); when research done, partners often “on the down low”
(having sexual contact with men or using injection drugs); 16% of men infected through high-risk heterosexual sex;
either partner may not know of other’s risk factors
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| Case 1: laboratory technician 31 yr of age had needlestick and asks whether he should take HIV postexposure prophylaxis
(PEP); risk for transmission after percutaneous needlestick 0.3% (determined by pooled analysis of prospective
studies on health care workers with occupational exposures); key risk factors for seroconversion—deep injury, visibly
bloody device, needle in artery or vein, and terminally ill source patient; if individual takes zidovudine (AZT) as
PEP, odds ratio of seroconversion extremely low; majority of needlesticks relatively low risk; infectivity of fluids—
spinal fluid, pleural fluid, pus, and blood potentially infectious; sweat, saliva, feces, and urine not infectious, unless
contaminated by blood and visibly bloody
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| Timing and duration of PEP: animal studies suggest PEP substantially less effective if given 24 to 36 hr after exposure;
case control study of humans given PEP within 4 hr showed good results; analysis of PEP failures suggests no
clear cutoff; after 72 hr, no utility in giving PEP; in animal models, 28 days of PEP more effective than 10 or 3 days;
28 days recommended by Centers for Disease Control and Prevention (CDC) guidelines; in general, 2 drugs often adequate;
if exposure less severe and patient HIV class 1 (undetectable viral load or <1000 copies/mL of blood or on antiretrovirals),
2 drugs adequate; if patient class 2 (high viral load, not on antiretrovirals, or low CD4 count), expanded
3-drug PEP recommended; if patient has unknown HIV status, PEP not warranted; if patient in methadone clinic
where 20% of patients HIV-positive, look at individual case and make best decision; if individual finds needle and
gets stuck outside hospital, PEP not warranted; if in hospital, consider 2-drug PEP; no instance of seroconversion by
individual stuck by needle outside of hospital; with more severe needlesticks, expanded 3-drug regimen recommended;
cuts on hand or splashes to eye have lower risk, and 3-drug regimen given only if source patient more sick,
HIV class 2, or large-volume (>10 mL) exposure to mucous membranes
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| Nonoccupational PEP (nPEP): case 1 continued—laboratory technician failed to mention that he had high-risk sex and
really calling for prophylaxis for that; exposure risks—receptive anal intercourse 1% to 2% on average per episode involving
HIV-infected source patient; receptive vaginal intercourse and receptive oral intercouse (male) lower risk; needle sharing in injection
drug use low risk; studies—Brazilian nonrandomized trial of PEP after sexual assault found rate of HIV transmission
≈3% in control subjects and 0% in those who received PEP; Buenos Aires study involving men who have sex with men (MSM)
found HIV transmission occurred in 4.2% of 131 men who did not receive PEP, compared to <1% in 66 men who received
PEP; more data needed; PEP always should be coupled with counseling; case 1 continued—nPEP offered but prescription
never filled, and patient developed acute HIV infection; fever, lymphadenopathy, and rash most common symptoms; most specific
findings aphthous ulcers and weight loss of 5 to 10 lb; patient sick for ≈2 wk, then felt better; 7 yr later, patient interested in
getting HIV care and wants to know when he should start medications and about possible problems in future; at 7 yr, good likelihood
patient will not need to start therapy
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| Natural history of HIV: how quickly HIV proceeds and puts person at risk for opportunistic infections (OIs) different
for each individual; antiretroviral drugs improve quality of life of patients but should not be started unless absolutely
necessary; time from seroconversion to diagnosis of AIDS variable; 50% of infected people go 10 yr before
developing clinical illness; average progressor needs medication in 10 to 12 yr; rapid progressor diagnosed with AIDS
in 2 yr, slow progressor at 14 to 16 yr, long-term nonprogressor, 24 yr
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| AIDS in 2006: most people have higher quality of life with antiretroviral therapy (ART) than without it; rare to
find patient responding to ART developing OI or wasting; difficult to eliminate lymphoma; pill burden of
highly potent regimens better today, but side effects still problematic, eg, loss of extremity and facial fat, truncal
fat accumulation, hip and breast fat accumulation (particularly in women), dorsocervical fat pads; etiology
unknown (problems existed before introduction of protease inhibitors and ART); nucleoside reverse transcriptase
inhibitors (NRTIs)—AZT, stavudine (d4T), dideoxyinosine (ddI), lamivudine (3TC), and abacavir
have great affinity for and can damage human mitochondria; play significant role in body habitus changes (disfiguring
and disturbing; patients feel changes identify them as someone with HIV); age plays role; metabolic
side effects—include insulin resistance, particularly from ritonavir, lopinavir, and indinavir; abnormal lipids
(increased triglycerides and total cholesterol with ritonavir, indinavir, saquinavir, lopinavir, nelfinavir, and
efavirenz); ritonavir has this side effect even when used just as booster; atazanavir exception; nelfinavir increases
low-density lipoprotein (LDL) and triglycerides; nelfinavir and saquinavir also decrease high-density
lipoprotein (HDL); skin rashes—associated with newer antiretrovirals; even nevirapine and efavirenz cause
rash; abacavir hypersensitivity may include rash, fever, and other constitutional symptoms; nevirapine rash 11
times more common in women; hyperpigmentation from emtricitabine in dark-complected individuals; mitochondrial
toxicity— can cause lactic acidosis and hepatic steatosis; onset insidious; patients can present with
anorexia, weight loss, and malaise weeks to months before diagnosis; drugs inhibit mitochondrial DNA gamma
polymerase, decreasing mitochondrial DNA; osteopenia, osteoporosis, and avascular necrosis—appear to have
less to do with drugs used to treat HIV and more to do with cohort effect; anyone who has had 2-wk course at
risk for osteopenia and osteoporosis; as cohort, patients smoke more often, have had low body weight and trauma
more often, and often used more alcohol (more at risk in general); end-organ cardiovascular or neurologic sequelae—
vascular intima thickened at much higher rate in patients on protease inhibitors; screen and treat patients aggressively for coronary
artery disease and other problems; harm vs benefit for average HIV patient—issue whether patient should take
drugs
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| Case 2: HIV-positive man, 39 yr of age, not injection drug user; before ART, viral load ≈70,000 copies/mL and CD4
count 220/mm3 ; after ART, CD4 count improved to 380/mm3 and viral load undetectable after 6 mo; patient smoker
with total cholesterol of 220 mg/dL; not diabetic; if patient does not take ART, 40% chance of developing AIDS at 10
yr; if he takes ART with any outcome (good or poor adherence), 6.1% chance of developing AIDS; if virus below
level of detection, chance drops dramatically to ≈2.4%; 10-yr cardiovascular risk—with no intervention, significant
cardiovascular disease at 10 yr; if patient takes fibrate, 8% to 9% chance of having disease; statin, 7%; protease inhibitor
(abacavir or atazanavir), 6%; if patient stops smoking, 2%; immune reconstitution disease—can develop on
ART; also seen with tuberculosis (TB), recent infection with Pneumocystis, Mycobacterium avium complex (MAC),
cytomegalovirus (CMV), and Cryptococcus; if patient on ART and has had OI in past, likely to have exuberant response
to self-antigen or some byproduct of antigen; usually develops 1 to 6 wk after starting ART; risk factors for
pulmonary or extrapulmonary TB include low CD4 count when going on ART, viral load >100,000 copies/mL, and
starting ART simultaneously with TB treatment or without waiting ≥2 wk (true waiting period unknown)
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| Case 3: woman 65 yr of age with low CD4 count (10/mm3 ) and viral load of 95,000 copies/mL presented with confusion,
somnolence, far lateral nystagmus, and ataxia; patient on phenytoin; phenytoin level normal 6 days ago but
efavirenz (3TC), and tenofovir (MPA) started ≈5 days ago; phenytoin big problem for patients on HIV medication;
careful drug interaction evaluation necessary before starting medication; phenytoin both inhibited and induced by
efavirenz in same patient at different times; once CD4 cells >50/mm3 , rare for CMV retinitis to develop; take-home
points—always consider PEP and nPEP; ART essential in most patients and use recommended when benefits exceed
risks; watch for medication side effects and interactions; watch for abacavir hypersensitivity; think of lactic acidosis
when patient has undetectable viral load but still sick
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| UPDATE ON HIV MEDICINE IN PRIMARY CARE: THE MICRO LEVEL —Steven Deeks, MD, Assistant Professor
of Medicine, University of California, San Francisco, School of Medicine
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| Four types of drugs: nucleoside analogues; nonnucleoside analogues (exceedingly potent; anchor of first-line regimens);
protease inhibitors; fusion inhibitors
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| Biology of HIV: retrovirus; contains 2 strands of RNA; diverse and encapsulated in sugar that protects virus from immune
system; virus binds to CD4 receptor, leading to conformational change that allows virus to react with CCR5 receptor;
1% to 10% of individuals born with defect in CCR5 receptor and immune to infection with HIV (drug
companies attempting to develop drugs that bind to CCR5 receptor and prevent viral entry); virus enters cell and RNA
released; virus goes from RNA to DNA (by reverse transcriptase); reverse transcriptase inaccurate (makes mutation
every 10,000 nucleotides); 10 billion viruses produced daily; because of capacity of virus to mutate, single dose of
nevirapine to prevent maternal-fetal transmission often results in drug resistance; DNA taken into chromosome by integrase;
cell now contains genetic information for virus as long as cell survives (memory T cells designed to survive
for decades); virus undergoes further processing, with generation of large polypeptide chains; ≈10,000 viruses leave
cell; HIV protease allows virus to mature by cutting up proteins (where protease inhibitors work); point mutations can
arise several thousand times per day; on single viral genome, 3 mutations causing resistance to 3 drugs do not occur;
early 1990s study by Merck of 1-, 2-, and 3-drug regimens found those who got 3 drugs had undetectable viral loads; cohort
of 30 patients followed for 10 to 12 yr and found completely aviremic
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| When to start ART: based on expert opinion; no randomized clinical trials looking at early vs deferred therapy (not
perceived as practical); observational studies show that waiting until CD4 count <200/mm3 leads to dramatic increase
in risk for AIDS and death; guidelines state treat anyone who is symptomatic; in asymptomatic patients, do not allow
CD4 count to drop below 200/mm3 ; as drugs become less toxic and easier to take, pendulum swinging to treating earlier
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| Starting therapy: first-line regimen 2 nucleoside analogues and one “anchor drug” (because nucleoside analogues developed
first); almost any 3-drug regimen likely works; main differences potency, pill burden, short- and long-term toxicity,
drug interactions, need for refrigeration, and pregnancy issues; present development of drugs geared to once-daily
dosing; if 2 nucleoside analogues combined with efavirenz (Sustiva), 80% of patients have undetectable viral loads for
2 yr; drug resistance negligible; different drug options, depending on patient, eg, efavirenz not used in women who may
become pregnant (associated with birth defects) or in patients with psychiatric disease (central nervous system side effects)
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| When to stop therapy: reasons for stopping therapy—pill fatigue; low-level toxicity; acceleration of end-organ
disease by drugs; Strategies for Management of Anti-Retroviral Therapy (SMART) study—by National Institutes of
Health; ≈6000 patients with CD4 counts >350/mm3 randomized to standard of care (treat and keep viral load undetectable)
vs episodic therapy (treat to increase T cells, then stop, and when T cells decrease, treat again); study stopped
when clear that those on intermittent therapy did much worse, as measured by time to disease progression or death; interrupting
therapy and allowing virus to replicate in uncontrolled manner associated with accelerated disease; events
mainly cardiovascular; patients for whom drugs so toxic should stop; if necessary to stop regimen and regimen nonnucleoside-based
(efavirenz and nevirapine), because those drugs associated with low threshold for developing resistance
and have long half-life, should be stopped only by expert
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| Drug toxicities: nucleoside analogues—work by being incorporated into DNA of HIV where they terminate DNA
synthesis; mitochondrial DNA synthesized differently; now dealing with long-term complications of nucleoside analogues
due to mitochondrial dysfunction, including lipoatrophy and fat redistribution; all nucleoside analogues
associated with lactic acidosis and severe hepatomegaly (black box warning); only treatment discontinuing drug; abacavir
hypersensitivity—abacavir comes as single pill (Ziagen), combination pill (Epzicom), and as triple-drug regimen
(Trizivir); 1 in 20 people, particularly those expressing HLA-B5701, within 2 to 6 wk of starting abacavir,
develop low-grade fever, malaise, abdominal pain, with or without rash; if abacavir stopped due to toxicity, cannot resume;
if stopped for other reason, complicated decision to resume; tenofovir—can cause Fanconi syndrome; protease
inhibitors—cornerstone of second- and third-line regimens; cause malaise and diarrhea; ritonavir particularly associated
with insulin resistance and accelerated atherosclerosis; common drug interactions—atazanavir level decreased
by proton pump inhibitors, leading to viral rebound; level of non-NRTIs reduced by anti-TB drugs, with emergence of
drug resistance; immune reconstitution syndrome—patients typically have advanced disease and usually present
within ≈4 wk of starting ART; viral load decreased and CD4 count increased; odd presentations; thought to reflect
rapid expansion and dysregulation of antigen-specific T cell responses in patients for whom OI existing as subclinical
disease; treat condition and continue ART
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| Questions and answers: how often to check CD4 count—controversial; speaker recommends every 3 mo; diurnal
variation (lower in morning); with acute intercurrent illness, count artificially low; screen for TB every 6 mo or annually;
data clear that AZT and d4T cause lipoatrophy
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Suggested Reading
Chou R et al: Initial highly-active antiretroviral therapy with a protease inhibitor versus a non-nucleoside reverse transcriptase
inhibitor: discrepancies between direct and indirect meta-analyses. Lancet 368:1503, 2006; El-Sadr WM et al:
CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355:2283, 2006; Espinoza L et al: Characteristics
of persons with heterosexually acquired HIV infection, United States 1999-2004. Am J Public Health 97:144, 2007;
Gross R et al: A simple, dynamic measure of antiretroviral therapy adherence predicts failure to maintain HIV-1 suppression.
J Infect Dis 194:1108, 2006; Hallfors DD et al: Sexual and drug behavior patterns and HIV and STD racial disparities:
the need for new directions. Am J Public Health 97:125, 2007; Hankins C: From a vicious circle to a virtuous circle:
reinforcing strategies of risk, vulnerability, and impact reduction for HIV prevention. Lancet 364:1915, 2004; MacArthur
RD et al: A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase
inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy
(CPCRA 058 FIRST Study): a long-term randomised trial. Lancet 368:2125, 2006; Marston C et al: Factors that shape
young people's sexual behaviour: a systematic review. Lancet 368:1581, 2006; Morse CG et al: Metabolic and skeletal
complications of HIV infection: the price of success. JAMA 296:844, 2006; Paltiel AD et al: Expanded HIV screening in
the United States: effect on clinical outcomes, HIV transmission, and costs. Ann Intern Med 145:797, 2006; Piot P: AIDS:
from crisis management to sustained strategic response. Lancet 368:526, 2006; Prati D: Non-sterile injections, contaminated
blood, and the spread of HIV. Lancet 368:1064, 2006; Rodriguez B et al: Predictive value of plasma HIV RNA
level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 296:1498, 2006; Simon V et al: HIV/AIDS epidemiology,
pathogenesis, prevention, and treatment. Lancet 368:489, 2006; Torres GW et al: Rapid HIV testing. Hosp Health
Netw 80:80, 2006; Toulson AR et al: Treatment interruption of highly active antiretroviral therapy in patients with nadir
CD4 cell counts >200 cells/mm3 . J Infect Dis 192:1787, 2005; Epub 2005 Oct 5. Vaughn A: Substance abuse, medications,
HIV, and the community. Nurs Clin North Am 41:355, 2006; Voelker R: Women shoulder growing HIV/AIDS burden.
JAMA 293:281, 2005; Weinstock HS et al: The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-
infected persons in 10 US cities. J Infect Dis 189:2174, 2004; Epub 2004 May 21. Yue FY et al: Preferential apoptosis of
HIV-1-specific CD4+ T cells. J Immunol 174:2196, 2005
Educational Objectives
| The goal of this program is to improve the management of HIV infection. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Determine when to prescribe postexposure prophylaxis.
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| 2. Discuss the side effects of antiretroviral therapy (ART).
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| 3. Recognize immune reconstitution disease.
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| 4. Determine when to start ART.
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| 5. Discuss toxicities and drug interactions of common drugs used in treatment of HIV.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Drs. Newman and Deeks were recorded at the University of California, San Francisco, School of Medicineís 34th Annual
Advances in Internal Medicine, held June 19-23, 2006 in San Francisco, CA, and sponsored by the University of
California, San Francisco, School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsor for
their cooperation in the production of this program.
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