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I.
Introduction
a. What has changed: newest guidelines for treatment (2009 DHHS) now
advocate treatment sooner than later.
b. What has changed: life expectancies have lengthened significantly (the
present expectation is a shortening of the typical life expectancy by 10-15
years).
c. What has changed: newer medications and new drug classes
i. Fusion inhibitor – enfuvirtide/Fuzeon
ii. New protease inhibitors with different resistance profiles –
tipranavir/Aptivus, darunavir/Prezista
iii. Chemokine binding inhibitor – maraviroc/Selzentry
iv. Integrase inhibitor – raltegravir/Isentress
d. What has changed: CMV retinitis behaves differently; it is controlled by
restored immunity in successful antiretroviral therapy, and even with
partially successful antiretroviral therapy, it is less rapidly progressive
d. What has not changed: a significant number of patients are unaware of
their infection.
e. What has not changed: a large number of patients diagnosed as HIVpositive either have AIDS at the time of initial diagnosis or progress to
AIDS within 1 year of initial diagnosis.
f. What has not changed: left untreated, HIV infection is a lethal disease and
there remains no cure.
II.
Treatment guidelines
a. Guidelines for treatment have varied over the years. Initially (with the
appearance of zidovudine), every patient was treated (even with high CD4
counts). With the advent of protease inhibitors (1996 and later), the
philosophy was “hit early, hit hard,” echoing what was mandatory in the
treatment of an infectious disease. Then toxicities from protease inhibitors
(diabetes, increased cardiovascular risk, lipodystrophy) manifested,
driving early treatment back to a “wait until 200” stance. Further research
(NA-ACCORD study has noted better survival with a return to earlier
therapy.
b. Current standards urge treatment for the following:
i. Anyone with an AIDS-defining illness
ii. Anyone HIV seropositive woman who is pregnant, any
seropositive individual with HIV nephropathy, any seropositive
individual with hepatitis B infection (possibly hepatitis C also)
iii. Any HIV seropositive patients with CD4 cell counts 350 or lower.
iv. Serious consideration of treatment of all HIV seropositive patients
with CD4 counts between 350 and 500. The DHHS committee’s
latest guidelines, from November 2009, are split 55-45 for this
stance: strong recommendation vs. moderate recommendation.
v. Seriously consider treatment of all HIV seropositive patients with
CD4 counts over 500 (the DHHS committee split 50-50 for
treatment initiation vs. optional).
c. Why the shift to earlier treatment?
i. Medications are simpler to adhere to: once-daily, more
manageable toxicities, and coformulations which reduce the pill
volume.
ii. Better survival is associated with new when-to-treat starting points;
the NA-ACCORD trial, and the subset trial of START both
indicate better survival. There is the suggestion that earlier control
of HIV and reduction of inflammation generally contribute to
better survival.
iii. Pushing against earlier treatment remain the specters of unknown,
long-distant toxicities with long-duration therapy, and likelier
treatment fatigue and non-adherence, with the risk of development
of resistant virus.
d. Treatment guidelines (DHHS 2009):
i. Consistently use a 2-drug ‘backbone’ plus a third drug for
untreated patients; either nucleoside reverse transcriptase inhibitor
(NRTI) or nucleotide reverse transcriptase inhibitor (NtRTI).
1. Tenofovir/emtricitabine (Truvada coformulation)
2. Tenofovir + lamivudine
3. Zidovudine/lamivudine (Combivir coformulation)
4. Zidovudine + emtricitabine
5. Abacavir + lamivudine (Epzicom coformulation)
ii. The choice of critical third drug has changed; it continues to be
either a protease inhibitor (PI) or non-nucleoside reverse
transcriptase inhibitor (NNRTI) for untreated patients.
1. Efavirenz/Sustiva still is the NNRTI of choice – once daily,
and most conveniently coformulated as Atripla (efavirenz,
tenofovir, and emtricitabine).
2. Kaletra (lopinavir/ritonavir) is no longer the first choice PI;
it has dropped off the top tier due to some increased slack
in viral control at 2+ years (consistent with the twice-daily
dosing plus ritonavir boost of 200 mg per dose, which has
definite GI toxicity).
3. Atazanavir/Reyataz (with boosting ritonavir, once daily)
and darunavir/Prezista (with boosting ritonavir, once daily)
are now first choice PIs; tolerance is better, once-daily
treatment is possible, and the boosting level of ritonavir is
lower than with Kaletra.
4. Raltegravir/Isentress has been added to the top tier of
preferred drugs; although a twice daily drug, it has neither
the CNS toxicity of efavirenz or GI upset with ritonavir.
iii. Other drugs from the dark ages are rarely used now
1. NNRTI: delavirdine
2. PI: indinavir, nelfinavir, amprenavir, full-dose ritonavir,
saquinavir
3. NRTI: ddc (d-c’d 2006), didanosine, stavudine; the latter
two are still used but are difficult for either food/diet
requirements or for toxicity issues.
III.
Medications: established classes which have expanded, and new/unique
classes to which treatment-experienced patients are unexposed.
a. There are more than 20 approved antiretroviral drugs in 7 mechanistic
classes for treatment of HIV infection.
b. NRTI (nucleoside reverse transcriptase inhibitors): drugs date from 1987
(introduction of zidovudine/Retrovir) to 2003 (emtricitabine/Emtriva)
c. Nucleotide reverse transcriptase inhibitor: tenofovir/Viread (2001)
d. Protease inhibitors: dating from 1995 (saquinavir/Invirase) to 2006
(darunavir/Prezista)
e. Non-nucleoside reverse transcriptase inhibitors: dating from 1995
(nevirapine/Viramune) to 2008 (etravirine/Intelence)
f. Fusion inhibitor (enfuvirtide/Fuzeon), from 2003
g. Chemokine binding inhibitor (CCR5 inhibitor) maraviroc/Selzentry, 2007
h. Integrase inhibitor (raltegravir/Isentress), 2009
i. New drugs (particularly those introduced since 2005) are better able to
withstand virus resistant to other members within the drug class
(tipranavir/Aptivus for experienced patients, and darunavir/Prezista, both
with ability to manage PI-resistant virus, etravirine/Intelence with ability
to manage NNRTI-resistant virus). New classes of drugs (CCR5 binding
inhibitor, integrase inhibitor) to which patients should be fully susceptible
(since previously unexposed) allow long-term survivors (with multi-drug
resistant virus) who have burned through all the older/standard drug
choices the opportunity to experience some survival benefit. There are
both better drugs to start with as well as better drugs that can be used later.
j. As important as the new drug groups have been changes in coformulations
(Combivir, Epzicom, Trizivir, Kaletra,Truvada, Atripla), once-daily
medication dosing (from either efavirenz, or ritonavir-boosted PIs used
once-daily), and better tolerability (newer PIs use lower boosting doses of
ritonavir, which makes a big difference).
IV.
Ocular manifestations seen with HIV-AIDS
a. CMV retinitis is uncommon at this time. Individuals with successful
cART therapy are able to stop anti-CMV retinitis drugs indefinitely with
the restoration of CMV-specific immunity as they have regained some
degree of immunocompetence. Even individuals with suboptimal
response to cART have CMV retinitis that is less rapidly progressive.
b. Recalling that a significant number of individuals are initially diagnosed
with HIV seropositivity with clinical AIDS (CD4 lower than 200), there
remains the potential for observation of ocular opportunistic infections
reminiscent of the bad old days.
i. HIV retinitis: cotton wool spots, relating possibly to higher viral
load than to CD4 counts (??)
ii. Intraocular manifestations of systemic diseases: tuberculosis,
syphilis, toxoplasmosis, cryptococcosis
c. Ocular opportunistic infections related to systemic infection may occur,
some depending on the CD4 nadir associated with the disease
i. CMV – typically with CD4 very low (usually < 50)
ii. Syphilis – quite variable
iii. Tuberculosis – quite variable
iv. Toxoplasmosis and cryptococcosis – typically with CD4 < 100
V.
What has changed over the past 30 years?
a. HIV is able to be frequently managed as a chronic condition. Patients can
continue to enjoy the benefits initially experienced with the advent of
protease inhibitors in 1996, as frequently inexorable wasting and declining
patients obtained a new lease on life.
b. HIV-infected individuals ultimately succumb less to opportunistic
infections than to conditions rarely seen in the first 15 years of the
epidemic: kidney disease, liver disease, cardiovascular disease, cancers
not specific to HIV. Instead of a ‘death sentence’ that was common in the
80’s, when a diagnosis of AIDS left the patient with two years or less of
life, now patients can actually expect a foreshortened but almost normal
life expectancy. “Old” and “HIV” can be used to describe the same
person and are no longer an oxymoron.
c. Testing procedures have changed dramatically. Oral testing is as
dependable as the blood ELISA test, and results are available that day.
Opt-out testing philosophies have changed the way in which HIV testing
is administered, so that HIV testing is considered to be a (somewhat)
routine blood test.
d. Genotypic resistance testing is mandatory prior to starting therapy in any
patient, as a means of structuring the regimen for optimal success.
e. Survival is vastly different. HIV is no longer a death sentence. But the
deadly seriousness of the epidemic is watered down; 20- and 30somethings have absolutely no knowledge of the immensity of the
epidemic in the decade of the 80’s and 90’s, when one’s peer group was
effectively being decimated, with individuals experiencing loss of
productivity, increasing disability, inexorable decline, and a grim fate.
Given the lack of historical perspective, HIV is unfortunately relegated to
a back burner, with a lack of urgency for advocacy and the still-critical
prevention messages not having the immediacy they once had. Remember
safe sex?
f. Is the cup half full or half empty? Given the expansion of drugs, the cup
is more than half-full for long-term survivors desperately needing a unique
drug class for successful treatment. Given the greater tolerability and ease
of administration of medications, individuals have greater success with
initial treatment and longer durability as well. Given all of this, the
transition has been made from an almost universally fatal disease to a
chronic one – this is indeed good news, but is tempered by the undeniable
fact that the epidemic is not over.
VI.
References
a. Starting therapy and benefits of therapy
i. Sterne JA et al. Timing of initiation of antiretroviral therapy in
AIDS-free HIV-1-infected patients: a collaborative analysis of 18
HIV cohort studies. Lancet 2009; 373:1352-63.
ii. Emery S et al. Major clinical outcomes in antiretroviral therapy
(ART)-naïve participants and in those not receiving ART at
baseline in the SMART study. J Infect Dis 2008; 197:1133-44.
iii. Kitahata MM et al. Effect of early versus deferred antiretroviral
therapy for HIV on survival. N Engl J Med 2009; 360:1815-26.
iv. El-Sadr WM et al. CD4+ count-guided interruption of
antiretroviral treatment. N Engl J Med 2006; 355:2283-96.
v. Hazenberg MD et al. Persistent immune activation in HIV-1
infection is associated with progression to AIDS. AIDS 2003;
17:1881-8.
vi. Willig JH et al. Increased regimen durability in the era of oncedaily fixed-dose combination antiretroviral therapy. AIDS 2008;
22:1951-60.
b. Testing
i. Grigoryan A et al. Late HIV diagnosis and determinants of
progression to AIDS or death after HIV diagnosis among injection
drug users, 33 US States, 1996-2004. PLoS One 2009;
4(2):E4445.
ii. Centers for Disease Control and Prevention (CDC). Late HIV
testing – 34 states, 1996-2005. MMWR Morb Mortal Wkly Rep
2009; 58(24):661-5.
iii. Branson BM et al. Revised recommendations for HIV testing of
adults, adolescents, and pregnant women in health-care settings.
MMWR Recomm Rep 2006; 55(RR-14):1-17.
iv. Granich RM et al. Universal voluntary HIV testing with
immediate antiretroviral therapy as a strategy for elimination of
HIV transmission: a mathematical model. Lancet 2009; 373:48-5
c. Anti-HIV drugs
i. Markowitz M et al. Sustained antiretroviral effect of raltegravir
after 96 weeks of combination therapy in treatment-naïve patients
with HIV-1 infection. J Acquir Immune Defic Syndr 2009;
52:350-6.
ii. Riddler SA et al. Class-sparing regimens for initial treatment of
HIV-1 infection. N Engl J Med 2008; 358:2095-2106.
iii. Malan DR et al. Efficacy and safety of atazanavir, with or without
ritonaivr, as part of once-daily highly active antiretroviral therapy
regimens in antiretroviral-naïve patients. J Acquir Immune Defic
Syndr 2008; 47:161-7.
iv. Mills AM et al. Once-daily darunavir/ritonavir vs.
lopinavir/ritonavir in treatment-naïve, HIV-1-infected patients:
96-week analysis. AIDS 2009; 23:1679-88.
v. Staszewski S et al. Efavirenz plus zidovudine and lamivudine,
efavirenz plus indinavir, and indinavir plus zidovudine and
lamivudine in the treatment of HIV-1 infection in adults. Study
006 Team. N Engl J Med 1999; 341:1865-73.
vi. Yost R et al. Maraviroc: a coreceptor CCR5 antagonist for
management of HIV infection. Am J Health-System Pharm 2009;
66:715-26.
vii. Hicks CB et al. Durable efficacy of tipranavir-ritonavir in
combination with an optimized background regimen of
antiretroviral drugs for treatment-experienced HIV-1-infected
patients at 48 weeks in the Randomized Evaluation of Strategic
Intervention in multi-drug reSistant patients with Tipranavir
(RESIST) studies: an analysis of combined data from two
randomized open-label trials. Lancet 2006; 368:466-75.
d. Eye-related issues and cytomegalovirus retinitis
i. Holland GN et al. Characteristics of untreated AIDS-related
cytomegalovirus retinitis. I. Findings before the era of highly
active antiretroviral therapy (1988 to 1994). Am J Ophthalmol
2008; 145:5-11.
ii. Holland GN et al. Characteristics of untreated AIDS-related
cytomegalovirus retinitis. II. Findings in the era of highly active
antiretroviral therapy (1997 to 2000). Am J Ophthalmology 2008;
145:12-22.
iii. Holland GN. AIDS and ophthalmology: the first quarter century.
Am J Ophthalmol 2008; 145:397-408.
Major guidelines:
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. December 1, 2009; 1-161. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Accessed 2-1-10.
Kaplan JE et al. Guidelines for prevention and treatment of opportunistic infections in
HIV-infected adults and adolescents: recommendations from CDC, the National
Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society
of America. MMWR Recomm Rep 2009; 58(RR-4):1-207.