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HIV- WHAT HAS CHANGED IN 30 YEARS?
David C. Bright, O.D.
Professor, Southern California College of Optometry
Chief, Optometry Section, VHA Greater Los Angeles Healthcare System
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. New nonnucleoside reverse transcriptase inhibitor – etravirine/Intelence
iv. Chemokine binding inhibitor – maraviroc/Selzentry
v. 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 only partially successful
antiretroviral therapy, it is less rapidly progressive.
e. What has not changed: a significant number of patients are unaware of their infection.
A large number of patients diagnosed as HIV-positive either have AIDS at the time of
initial diagnosis or progress to AIDS within 1 year of initial diagnosis. Left untreated, HIV
infection is a lethal disease and there remains no definitive 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, North American AIDS Cohort Collaboration on Research and Design) 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 NAACCORD trial, and the subset trial of SMART (Strategies for Management of
Antiretroviral Therapy) 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 nonadherence, with the risk of development of resistant virus, and greater risk of
spreading the infection.
d. Treatment guidelines (DHHS 2009) for combination antiretroviral therapy (cART):
i. Consistently use a 2-drug ‘backbone’ plus a third drug for untreated patients;
the backbone is either 2 nucleoside reverse transcriptase inhibitors (NRTI) or
nucleotide reverse transcriptase inhibitor (NtRTI) plus NRTI.
1. Tenofovir/emtricitabine (Truvada coformulation)
2. Tenofovir + lamivudine
3. Zidovudine/lamivudine (Combivir coformulation)
4. Zidovudine + emtricitabine
5. Abacavir + lamivudine (Epzicom coformulation)
ii. The choices of critical third drug have changed; that drug continues to be either
a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor
(NNRTI) for untreated patients (a new integrase inhibitor may be used).
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 have
appeared 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 frequently able to be managed as a chronic condition. Patients can continue to
enjoy the benefits initially experienced with the advent of protease inhibitors in 1996, as
frequently inexorably 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. Vaccine research has been stymied repeatedly, since the days of HHS Secretary
Margaret Heckler promising, in 1984, an AIDS vaccine “within two years.” That clearly
has not happened; HIV vaccine research has hit numerous roadblocks. The most recent
was the failure of Merck’s V520 vaccine; testing was terminated in 2007, after
discoveries that the vaccine may have increased risks of infection. Two good news items
have surfaced recently: a sort-of good news came from Vaxgen’s RV144 testing in
Thailand, noting a 30% reduction in infection rates with the vaccine; better news has
been released (August 2010) from the Vaccine Research Center (Bethesda) of isolation
of broadly neutralizing monoclonal antibodies of HIV, the best candidate being VRC01.
e. Genotypic resistance testing is mandatory prior to starting therapy in any patient, as a
means of structuring the regimen for optimal success.
f. Survival is vastly different. HIV is no longer a death sentence. But the deadly
seriousness of the epidemic is watered down; 20- and 30-somethings 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?
g. 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-1infected patients: a collaborative analysis of 18 HIV cohort studies. When to
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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, 19962004. PLoS One 2009; 4(2):E4445.
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c. Anti-HIV drugs
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of combination therapy in treatment-naïve patients with HIV-1 infection. J
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v. Staszewski S et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus
indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV1 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 treatmentexperienced 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.
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randomized, double-blind, placebo-controlled trial. Lancet 2007; 370:39-48.
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inhibitor for managing human immunodeficiency virus infection. Am J HealthSyst Pharm 2010; 67:193-205.
x. Este JA, Telenti A. HIV entry inhibitors. Lancet 2007; 370:81-88.
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.
e. Life expectancy, mortality, and vaccines
i. Buchacz K et al. AIDS-defining opportunistic illnesses in US patients, 19942007: a cohort study. AIDS 2010; 24:1549-59.
ii. Life expectancy of individuals on combination antiretroviral therapy in highincome countries: a collaborative analysis of 14 cohort studies. Lancet 2008;
372:293-99.
iii. Van Sighem A et al. Life expectancy of recently diagnosed asymptomatic HIVinfected patients approaches that of uninfected individuals. AIDS 2010;
24:1527-35.
iv. Hill A, Pozniak A. A normal life expectancy, despite HIV infection? AIDS 2010;
24:1583-84.
v. Neuhaus J et al. Risk of all-cause mortality associated with nonfatal AIDs and
serious non-AIDS events among adults infected with HIV. AIDS 2010; 24:697706.
vi. McElrath MJ et al. HIV-1 vaccine-induced immunity in the test-of-concept Step
Study: a case-cohort analysis. Lancet 2008; 372:1894-905.
vii. Buchbinder SP et al. Efficacy assessment of a cell-mediated immunity HIV-1
vacine (the Step Study): a double-blind, randomized, placebo-controlled, testof-concept trial. Lancet 2008; 372:1881-93.
viii. Rerks-Ngarm S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1
infection in Thailand. N Engl J Med 2009; 361:2209-2220.
ix. Burton DR, Weiss RA. A boost for HIV vaccine design. Science 2010; 329:77073.
x. Wu X et al. Rational design of envelope identifies broadly neutralizing human
monoclonal antibodies to HIV-1. Science 2010; 329:856-61.
xi. Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by
antibody VRC01. Science 2010; 329:811-17.
xii. El-Sadr WM et al. AIDS in America – forgotten but not gone. N Engl J Med 2010;
362:967-970.
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 9-10-10.
Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the
use of antiretroviral agents in pediatric HIV infection. August 16, 2010; 1-219. National Institutes of
Health. Available at http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. Accessed 9-10-10.
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(RR4):1-207.