AIDS Presentation Damascus Oct 2004

The Acquired Immunodeficiency Syndrome
Jacques E. Mokhbat, MD
Division of Infectious Diseases
Damascus, October 2004
Human Immunodeficiency Virus
Acquired Immunodeficiency syndrome first described in 1981

HIV-1 isolated in 1984, and HIV-2 in 1986 Belong to the lentivirus subfamily of the retroviridae Enveloped RNA virus, 120nm in diameter HIV-2 shares 40% nucleotide homology with HIV-1 Genome consists of 9200 nucleotides (HIV-1): gag core proteins - p15, p17 and p24
pol - p16 (protease), p31 (integrase/endonuclease)

env - gp160 (gp120:outer membrane part, gp41: transmembrane part) Other regulatory genes ie. tat, rev, vif, nef, vpr and vpu
HIV particles
HIV Genome
Stages of Retrovirus Reproduction
The Human Immunodeficiency Virus (HIV) is an amazingly successful organism devoted to one and only one job: reproduction. Over TEN BILLION new viruses are produced each day in an average HIV-infected person. The average HIV virion has a half-life of about 1.5 days. The production of huge numbers of short-lived viral copies, the virus' extraordinarily high mutation rate and it's very high ratio of infecting virions to resulting viral copies, present major obstacles to successful treatment of HIV infection.
Viral adhesion
Initial interaction of gp-120 with cell surface charged molecules (galactosyl-ceramide, heparan sulfate). Possibility of endocytosis at a neutral pH. Viral retention at the surface of antigen-presenting cells (up to 4 days): important mechanism in mucosal transmission. Role of the DC-SIGN protein on the dendritic cell surface.
Mc Clure et al, 1988; Geijtenbeek et al, 2000
Viral receptors
Role of CD4 receptor: Not necessary and not sufficient: Just an activator of interaction. Presence of chemokine receptor CCR5 or CXCR4 is necessary for viral infection. Interaction of these receptors with gp120 in the presence of CD4. HIV may use one or the other of these receptors:
CCR5 (R5 viruses): tropism to macrophages CXCR4 (X4 viruses): tropism for immortalized cell lines. R5X4 viruses: both tropisms
Moore et al, 1997; Berger et al, 1998
X4 and R5X4 strains emerge at later stages while R5 strains are present throughout. X4 and R5X4 are counter-selected by an efficient immune system: their emergence represent an aggravating factor.
Berger et al, 1999
Conformation changes
Interaction between gp120 and the chemokine receptor. Unmasking of epitopes of gp120 and gp41 (even shedding of gp120).
Moore et al, 1998
Conformation changes
gp41 has three monomers containing 2 helix forming domains each. The six helix bundle of gp41 is dissociated so that the fusion peptide (the amino-terminal of the gp41 monomers) can point toward the target membrane.
Fusion
Merging of the viral and cell membranes. Lipid exchanges and fusion pore formation. Tranlocation of the nucleocapsid inside the cell.
HIV Viral Dynamics

HIV is classified as a retrovirus
-Once HIV enters the host (CD4) cell, it converts its RNA (ribonucleic acid) to DNA (deoxyribonucleic acid) via its enzyme reverse transcriptase.
HIV is completely dependent upon CD4 cells for replication and survival.
HIV Viral Dynamics

Replication and survival of HIV occurs through a number of steps:
HIV gains entry into the CD4 cell by binding onto receptors on the outside of the CD4 cell and fusing with the lipid outer layer of the cell. Once inside the cell, HIV removes its outer coating, exposing its RNA, and releases reverse transcriptase enzyme to convert the HIV RNA to DNA. HIV DNA then enters the nucleus of the CD4 cell and is integrated into the host (CD4) DNA
HIV Viral Dynamics

Replication and survival of HIV (cont)
Once the cellular DNA has been altered in this way, it is known as proviral DNA (part virus/part cell) and begins the process to produce more virus. The CD4 cell is now programmed to be an HIV factory. Long viral protein chains are produced which are then cut into the necessary pieces to produce more HIV. This process is activated by the viral protease enzyme. Each step in this process is a target for antiretroviral therapy (to date, reverse transcriptase, protease inhibitors and fusion inhibitors have been approved)
Normal cellular immune response to HIV

Dendritic cells process and present viral antigens to CD4+ Th1 cells Stimulation of production of interleukin-2 and other cytokines that activate memory T cells and produce interferon-gamma that allows cytotoxic T lymphocytes (CTLs) to target HIV-infected cells.
Autran, CROI 2002
Manifestations of an activated immune system in HIV infection (1)

Hyperactivation of B cells Hypergammaglobulinemia Spontaneous lymphocyte proliferation Activation of monocytes with secretion of proinflammatory cytokines
Manifestations of an activated immune system in HIV infection (2)

Increased expression of activation markers on T cells Follicular hyperplasia of lymphoid tissue Elevated circulating levels of neopterin, 2microglobulin, acid-labile interferon and soluble IL-2 receptors Autoimmune phenomena
Host factors favoring replication
HIV
Cellular activation Proinflammatory cytokines (TNF-, IL-1, IL-6, etc) CC-chemokines (T-tropic HIV strains)
Host factors interfering with HIV replication HIV-specific immune response CC-chemokines (RANTES, MIP-1, MIP-1) (Mtropic HIV strains) SDF-1 (T-tropic HIV strains) Inhibitory cytokines (IL-10, TGF-) CD8+ T cell derived suppressor factors (MDC, 1, -2, -3 proteins)
T-cell turnover
In HIV-infected individuals, CD4+ T-cell proliferation rates were increased 6.3-fold and CD4+ T-cell death rates were 2.9-fold higher than in normal subjects. CD8+ proliferation rates were increased 7.7-fold, but no change in CD8+ death rate was seen.
Perelson, Ho, CROI 2002
T-cell turnover
The rate of activation of CD8+ cells and peripheral proliferation increased with HIV infection. CD4+ cell decline in HIV is likely due to increased CD4+ cell depletion and not to decreased cellular production.
Mechanisms of CD4+ T cell dysfunction and depletion

Direct Mechanisms
Accumulation of unintegrated viral DNA Interference with cellular RNA processing Intracellular gp 120 CD4 autofusion events Loss of plasma membrane integrity because of viral shedding Elimination of HIV-infected cells by virus-specific immune responses
Mechanisms of CD4+ T cell dysfunction and depletion

Indirect Mechanisms
Aberrant intracellular signaling events Syncitium formation Autoimmunity Superantigenic stimulation Innocent bystander killing of viral antigen-coated cells Accelerated apoptosis Inhibition of lymphopoiesis
CD4+ cell depletion

CD4+ cells undergo rapid proliferation and destruction in HIVinfected patients. This is driven not by T-cell homeostasis but by HIVinduced immune activation. The loss of naive cells through immune activation and the shift in viral phenotype from a nonsyncytium-inducing (C5) to a syncytiuminducing (X4) type results in more rapid destruction of the pools of naive CD4+ cells. Coupled with adults' lack of thymic ability to regenerate cells, this ultimately leads to the depletion of CD4+ cells.
Miedema et al, CROI 2002
CD4+ cell depletion

With HAART, the rate of T-cell activation and destruction of cells is reduced, allowing for peripheral proliferation of residual T cells. Thymic production of T cells cannot correct the irrevocable loss of clones of T cells destroyed by HIV. Early intervention to prevent activation-induced apoptosis of naive cells and perhaps administration of cytokines that can induce peripheral proliferation of cells may maintain effective CD4+ immunity.
Miedema et al, CROI 2002
In chronic HIV infection

Loss of CD4+ cells leads to:
loss of clones of the pathogen-specific memory cells for opportunistic infections, inhibition of T-cell help for HIV-specific CTLs.
Autran, CROI 2002
Effect on HIV specific CTLs

HIV-specific CD4+ cells are lost early in infection. HIV-specific CTLs are not generated or are less effective due to loss of CD4+ T-cell help and -following initiation of HAART -- low exposure to HIV antigen. The exception is when therapy is initiated during acute infection: In this setting, HIV-specific CD4+ cells are preserved and HIV-specific CTLs are delayed in developing but are still capable of responding.
Autran, CROI 2002
Effect of HAART on T-cell turnover

With highly active antiretroviral therapy (HAART), the proliferation and death rates of both CD4+ and CD8+ cells were reduced, and were nearly normal after 1 year of suppressive therapy.
Effect of therapeutic interventions on T-cell proliferation
HIV might induce cells to move from the slowly to rapidly proliferating pool. HAART slows this process down. Drugs like interleukin-2, which may facilitate proliferation of T lymphocytes, might help to restore T-cell numbers, a process that may otherwise take longer because of the shift to the more slowly proliferating pool with HAART.
Kovacs, CROI 2002
Viral dynamics of HIV infection

Life span of productively infected cells Total HIV production Minimum duration of HIV life cycle Virus life span in plasma Virus intracellular phase Average HIV generation time
Perelson 1996
2.2 days 10.3 x 109 virions/d 1.2 days 0.3 days 0.9 days 2.6 days
What about the reservoir?

Long-lived latently infected cells have a half-life of 16 months. It is estimated that 23 years of continuous antiretroviral therapy would be required to eradicate HIV-1. The virus persisting in this reservoir appears to remain wild-type.
HIV reservoirs and eradication

The virus is present in rapidly replicating short lived cells as well as in long lived cells No real hope for viral eradication for the near term and for the long term
Viral reservoirs
HIV hides in reservoirs when it is suppressed from the blood or plasma. Three major tissue compartments are generally recognized as being reservoirs:
lymphoid tissue, the central nervous system (CNS) the male and female genital tracts.
Richman, CROI 2002
Reservoirs in the lymphoid system
Pool of latently infected resting CD4 cells. This reservoir is established early in HIV infection and is continually replenished through very low level viral replication.
Richman, CROI 2002
The Central Nervous System Early in HIV infection, HIV is brought into the CNS where viral loads in cerebrospinal fluid (CSF) mirror the viral load in the plasma. The relation of CSF to plasma viral load changes late in the disease where less HIV in brought in and more HIV is actually produced in the CNS.
Richman, CROI 2002
The Central Nervous System Combined with differential penetration of antiretrovirals into the CNS, the distinct possibility of differing viral resistance patterns and evolution exists. Discordant resistance patterns have been identified in some patients in CSF and plasma.
Richman CROI 2002
The genital tract

Important reservoir with special implication for sexual transmission. Viral load in genital secretions:
correlates with plasma, including decreasing with antiretroviral treatment, but can be discordant in terms of quantity and resistance pattern; is highest in primary infection; rises with local inflammation that occurs with sexually transmitted diseases (STDs) and subsequently declines with resolution of the treated STD.
Richman, CROI 2002
Current Issues
The spread of HIV is not halted, particularly in developing countries. Renewed interest and progress in HIV preventive interventions. Accessibility and availability of antiretroviral therapy: generics V/S multinational producers of drugs.
Spread of the epidemic

Rapid spread in South-East Asia and South China. Alarming rates in Eastern Europe. Continuous high rates in Africa. Local spread (indigenous) in most countries
Extension to younger groups

Epidemic proportions in the young male homosexual population Different patterns of transmission in different countries
Over 5 millions new cases per year

Failure of social and behavioral interventions. Complacency of the 90s. Over confidence in antiretroviral therapy.
Tableau Recapitulatif de lEpidemie de VIH/SIDA dans le Monde

Decembre 2003
Nombre de personnes vivant avec le VIH/SIDA
Total Adultes Enfants < 15ans

Total Adultes Enfants < 15 ans
40 millions (34-46) 37 millions (31-43) 2.5 millions (2.1-2.9)

5 millions (4.2-5.8) 4.2 millions (3.6-4.8) 700,000 (590-810)
Nouveaux cas dinfection a VIH en 2003
Deces dus au SIDA en 2003
Total 3 milliions (2.5-3.5) Adultes 2.5 millions (2.1-2.9) Enfants < 15 ans 500,000 (420-580)
OMS / ONUSIDA Decembre 2003
Viral genetic variability

Diversity of HIV subtypes. Consequences on HIV vaccines development and testing. Efficacy of antiretroviral drugs. Surveillance of transmission patterns.
Geographical distribution of HIV-1 major (M) group subtypes

Western Europe: B, and CRF_04cpx Eastern Europe: A, B, and CRF_03AB North America: B South America: B, F Australia and New Zealand: B India: C South East Asia: B, and CRF_01AE China: A, C, and CRF_07BC
* CRF = circulating recombinant form

Africa:
Northern: B Central: A, C, D, F, H, J, CRF_01AE, CRF_02AG Western: A, CRF_02AG Eastern: C, D South Africa: B, C
* CRF = circulating recombinant form

Lebanon:
A, B, C, E Several CRF
Impact of genetic diversity

Impact on HIV testing: Serology and viral load assays. Antiviral susceptibilities and resistance. Transmission patterns and transmissibility. Pathogenicity. Selection of candidate vaccines.
The African Monkey Connection High prevalence rates of SIV with cross-reactivity on HIV1 antibody tests in monkeys, ranging from 28% in young monkeys to as high as 90% in older monkeys. High prevalence of SIV in bush meat -- slain monkeys used for food. Chimpanzees did not demonstrate such high prevalence rates.
Hahn, CROI 2002
The African Monkey Connection
The vast majority of infected chimps were from Central and West Central Africa. The highest levels of exposure to SIV are seen in Central Africa. The virus has been present in the monkeys and chimps in this region for hundreds but not thousands of years.
Hahn, CROI 2002
GLOBAL AIDS SUB-SAHARAN AFRICA

10% of world population
70% of new 1998 infections

90% of infected children 95% of AIDS orphans
Projected changes in life expectancy

6 5 6 0 5
Botswana Zimbabwe Zambi a Uganda Malawi

1960 1965 1970 1975 1980 1985 1990 1995 2000
5
5 01955
4
98036-E-23 1 December 1999
Source: United Nations Population Division, 1996
Modes of transmission
Sexual Injecting drug use Mother-to-child Blood and blood products Contaminated needles and sharps (health care workers)
FALKLAND ROAD, MUMBAI
CHILDREN SCAVENGING DIRTY SYRINGES FOR RESALE IN ASIA
Drucker E. Lancet 2001;358:1989
Epidemiology
More than 40 million people are living with HIV worldwide. 45% are women. 2.5 million women became infected in 2000:
Acquisition:
Heterosexual transmission (one third with an injecting drug user) Drug injection.
AFRICAN AIDS IMPACT ON WOMEN

Dependent
on men: less negotiation about sex, condoms Education levels lower than mens Multiple pregnancies Polygamy Widowhood status poor Male preference for younger women
3/20/2012
Epidemiology
Estimates 2000:
7.4% of all women aged 15 to 49 in sub-saharan Africa are infected with HIV. 6 million pregnant HIV-infected women in the developing world. So far, 8 million HIV-negative children have been orphaned by AIDS (mother, father or both).
Heterosexual transmission
1 per 1000 contacts in studies of discordant couples. But, the risk of male to female transmission was 17 times higher.
Padian et al, 1987, 1991
Anatomic and local risk factors
Sexually transmitted diseases (ulcerative or non-ulcerative diseases) Genital tract inflammation. Lack of circumcision. Cervical ectopy Leukocytospermia. Hormonal contraception ?
HIV disease related risk factors
Higher viral loads. Lower CD4+ cell counts. Acute viral infection. Lack of effective antiretroviral therapy. Lack of the inactivating 32 base pair deletion in the chemokine receptor gene CCR5. Syncitium inducing viral strain. Certain viral clades.
HIV genital infection
Viral shedding into semen and cervico-vaginal secretions: variable, unpredictable, does not correlate with plasma viral load. HAART does not minimize sufficiently the risk to women. HIV does not infect sperm cells. HIV might stick to the surface of the sperm cell???
HIV genital infection
Higher levels and better viability of HIV in the genital tract are seen in conditions that raise the vaginal pH: blood in vagina, bacterial vaginosis, menopause, intercourse, some birth control methods. Spermicidal agents (nonoxynol-9) and vaginal antiseptics (chlorhexidine) do not reduce sexual or materno-fetal transmission.
Sexual practices related risk factors
Sexual activity during menses. Receptive anal intercourse. Bleeding during intercourse. Lack of barrier protection.
Prevention
Treatment of STDs. Barrier contraceptives. Education.
Perinatal transmission
Frequency: 13 to 60%. Intrauterine transmission: As early as 8 weeks. The earlier the infection, the more rapid the progression to AIDS after birth. In most cases, transmission occurs near or during delivery: in non breast-feeding mothers, 92% of transmission occurs during the last 2 months of pregnancy (incl. 65% during the intra-partum period)
Breastfeeding
Risk of transmission to breast fed babies:
14% if the mother was infected prior to pregnancy. 26% if the mother was infected after delivery.
Dunn et al, 1992
87
Maternal-fetal transmission
Maternal factors
Advanced HIV disease:

Clinical staging CD4+ cell count Viral load p24 antigenemia
Primary HIV infection Viral phenotype (syncitium inducing) Viral genotype (virulent clade)
Maternal factors
Coinfection with other STDs Firstborn twin Obstetric events:

Vaginal delivery Invasive procedures or fetal monitoring during labor Prolonged premature rupture of membranes (>4h)
Maternal factors
Older maternal age Cigarette smoking and illicit drug use during pregnancy Breast-feeding Unprotected sexual intercourse with multiple partners
Fetal, placental or labor factors
Chorioamnionitis Prematurity Low birth weight Cervicovaginal viral load Local HIV-specific immune response Maternal-fetal transfusion of blood
Immune factors
Humoral:
Neutralizing antibodies Antibody dependent cellular cytotoxicity gp120 V3 loop antibody Major histocompatibility complex concordance
Cell-mediated:
Cytotoxic T lymphocytes CD8 suppression
Mucosal immunity
Elective cesarean section

C-section decreases the risk of perinatal transmission by 50% (O.R. 0.43; 95% CI of 0.33 to 0.56). C-section group: 1.8% transmission (3/170) Vaginal delivery group: 10.5% transmission (21/200).
N Engl J Med 1999; Lancet 1999
93
Antiretroviral drugs for prevention of maternal fetal transmission Zidovudine starting after the 14th week, during labor and to the baby during the first 6 weeks of life: reduce transmission by 67.5%. Zidovudine 300 mg bid starting on the 36th week until labor, then 300mg q 3h until delivery: 51% reduction in transmission risk. Single dose nevirapine at the onset of labor.
Antiretroviral drugs for prevention of maternal fetal transmission

BUT: risk of resistance mutations with monotherapy. The treatment of pregnant women should NOT be different from that of non-pregnant HIV infected persons; but risks of teratogenicity incompletely understood.
Management Issues in Women

Obstacles to obtain medical care:
socioeconomic status of women abusive home situations childcare responsibilities lower education lack of health insurance
Reproductive choices
Effect of HAART
No change in the rate of tubal ligation before (27%) and after HAART (24%). Termination of pregnancy changed from 23% to 8% after the report on zidovudine efficacy on materno-fetal transmission. Another study demonstrated no change. Disease status is not the most important factor that determines reproductive choices.
Intrauterine insemination an option ?

Ensure that the sperm fraction is HIV free before any insemination. Italian program of semen processing: no seroconversion among almost 2000 intrauterine inseminations (Semprini 1992).
Reproductive Options for Seropositive Women

Who should decide? The woman. Goal is to optimize health status and understand the possible effects of HAART on the fetus. Level of risk and comfort: in a woman on HAART with undetectable viral load, the risk of transmission to the fetus is ~ 1%.
Viral load and progression to AIDS

Initial HIV RNA level Median time to AIDS
> 36,270 copies/ml 3.5 years
13,021-36,270 copies/ml 5.3 years 4,531-13,020 copies/ml < 4,530 copies/ml

Mellors 1996
7.7 years >10 years
Opportunistic Infections and CD4 count
Stages of HIV Disease

Acute/Early Infection: Following HIV transmission, approximately 50% of individuals will develop a febrile, flu-like illness with some or all of the following conditions:
- Swollen glands - Oral ulcers - Sore throat - Rash - Muscle aches - Headache
- Diarrhea
- Nausea or vomiting

Acute/Early Infection (cont) Small % of newly infected individuals will develop liver and/or spleen enlargement Onset of illness is generally 1-6 weeks following exposure and can last 1-3 weeks Acute Retroviral Syndrome is often mistaken for the flu An inmate presenting with some or all of the previously mentioned conditions should be questioned about recent potential HIV exposures so that testing can be done:
- Needle sharing? Tattooing? Unprotected sex/new partner?

Acute/Early Infection (cont)
Testing for HIV antibody may be negative at this time. Diagnosis of acute HIV can made by obtaining a quantitative HIV RNA PCR (viral load test) or a pro viral cDNA test. A positive HIV antibody usually develops by 4-6 weeks following transmission, but rarely could be up to 12-24 weeks. Infection must ultimately be confirmed with an HIV Elisa/Western Blot assay

Window period: interval between where HIV actually appears, and is ultimately detectable by an antibody test.
Inmates potentially exposed to HIV must be counseled that a negative antibody test during this period does not guarantee HIV transmission has not occurred.
If an inmates HIV test is negative, but suspicion for HIV exposure is high, repeated antibody testing should be performed at 12-26 weeks.

HIV Antibody Testing Timeline:
- Baseline - 6 weeks post-exposure - 12 weeks post-exposure - 26 weeks post-exposure
Serocoversion virtually always detected by 6 months

Extremely high levels of HIV in the blood during acute infection (hallmark of this disease stage) Within days, HIV disseminates into sanctuary sites (lymph nodes, central nervous system) where it hides out and remains dormant. Safer sex practices should be stressed as there is a high risk of spreading infection to others. HIV viral levels decrease over the first 4 months post-transmission until plateauing to a set point (varies person to person) Lower HIV viral setpoint = longer time it will take for an individual's disease to progress over time

Intermediate Stage
T cell destruction by HIV begins to weaken the immune system over time (in contrast to the acute stage, where the immune system keeps pace by producing an equivalent amount of CD4 cells). In general if untreated, there is an 8-10 year period during which an HIV+ individual undergoes a gradual decline in immune function (monitored by laboratory testing of CD4 count) and increase in HIV viral load (monitored by laboratory testing of viral load). Often no symptoms exhibited during the intermediate disease stage

Intermediate Stage (cont)
Factors which influence how long individuals will remain in this stage before progressing to advanced disease: 1) How high the viral setpoint is 2) If and when antiretroviral treatment is initiated More than 50% of people do not know they are HIV-infected until they become symptomatic (an indicator of advanced disease). As the correctional setting is often an inmates first interaction with the health care system, a thorough history of risk factors is important and HIV testing should be recommended to all new intakes.
www.thebody.com (HIV testing)

Advanced Stage
Untreated, the rapid replication of HIV will eventually deplete the immune system in most people to such an extent that the patient will lose critical body defenses and can succumb to infections, AIDS and ultimately death.
Symptomatic HIV can present in a variety of forms. Hallmarks of this stage of the disease include: - Opportunistic infections or malignancies
- Rashes - Recurrent vaginal candidiasis - Herpes zoster - Thrush - Neuropathy - Diarrhea - Recurrent infections - Cancers - Anemia

Advanced Stage (cont)
Actual diagnosis of AIDS is made when the CD4 count falls below 200 cells/cmm or when an AIDS-defining condition is diagnosed. Once a diagnosis of AIDS has been made, it remains with the patient even if his/her CD4 count returns to above 200 with antiretroviral therapy.
Clinical Manifestations of AIDS

Opportunistic infections Malignancies HIV specific manifestations Immunologic manifestations
AIDS Indicator Diseases

Wasting Syndrome Recurrent oral thrush PCP Kaposis sarcoma Esophageal candidiasis CMV disease CMV retinitis Mycobacterium avium infection Diarrhea (cryptosporidium, isosporiasis) Lymphoma (CNS, Burkitt) Toxoplasmosis (CNS) Cryptococcosis Histoplasmosis

AIDS-Defining Conditions
Candidiasis of esophagus, trachea, Herpes simplex with mucocutaneous ulcer bronchi or lungs for > 1 month or bronchitis, pneumonitis, esophagitis Cervical cancer, invasive Coccidioidomycosis, extrapulmonary Histoplasmosis, extrapulmonary HIV-associated dementia: disabling cognitive and/or motor dysfunction interfering with occupation or activities of daily living
Cryptococcosis, extrapulmonary
HIV-associated wasting: involuntary weight loss of >10% of baseline plus chronic diarrhea (>2 loose stools/day for >30 days) or chronic weakness and documented enigmatic fever for > 30 days
Cryptosporidiosis with diarrhea for > 1 Isoporosis with diarrhea for >1 month month
Cytomegalovirus of any organ other Kaposis sarcoma in patient younger than 60 than liver, spleen, or lymph nodes (or older than 60 with positive HIV serology)

AIDS-Defining Conditions (cont)
Lymphoma of brain in patient Pneumocystis carinii pneumonia younger than 60 (or older than 60 with positive HIV serology) Lymphoma, non-Hodgkins Pneumonia, recurrent bacterial with positive HIV serology
Mycobacterium avium or M. kansasii, disseminated

Mycobacterium tuberculosis, disseminated Mycobacterium tuberculosis, pulmonary
Progressive multifocal leukoencephalopathy

Salmonella septicemia (nontyphoid), recurrent with positive HIV serology Toxoplasmosis of internal organ

The Centers for Disease Control (CDC) has a disease classification system based on immune function and clinical status.
Each patient is classified with a number which is reflective of CD4 count, and a letter reflective of clinical status. This provides prognostic information for providers where a patient fits along the continuum of illness and as to what conditions, if any, he or she may be at risk.

CDC Classification of HIV Disease
A Asymptomatic or Acute HIV Infection A1 A2 B Symptomatic (Not A or C) C AIDS Indicator Condition
CD4 Cell Categories (cells/cmm) > 500 (>29%) 200-499 (14-28%) < 200 (<14%)
B1 B2
C1 C2
A3
B3
C3
Opportunistic Infections
When CD4 count is in normal range (500-1,600 cells/cmm or 28-50%), the immune system defends itself against most antigens.
As T-cell count declines with HIV disease progression, the HIV+ patient is at increased risk for infection.
When the T-cell count drops below 200 cells/cm (14%), there is increased risk of an AIDS-defining condition occurring.
Treatment guidelines recommend prophylactic treatment against pneumocystis carinii pneumonia (PCP) for patients in this category. This is given as TMP-SMZ (Bactrim) 1 DS or 1 SS a day, Dapsone 100 mg a day, or Atovaquone (Mepron) 1500 mg at (10 ml)/day. Alternate prophylaxis options are listed in the prophylaxis guidelines (Department of Health & Human Services).
If the patient develops oral candidiasis (thrush), PCP prophylaxis is recommended, regardless of CD4 count.
Thrush is an independent risk factor for development of PCP, presumably because it indicates a decline in immune function. Primary prophylaxis (treatment in an individual who has never had PCP) can be discontinued if the CD4 count rises above 200 cells/cmm for a period of at least 3-6 months.
When the CD4 count falls below 50 cells/cmm, the patient should be started on prophylaxis to protect against mycobacterium avium complex (MAC). Lifelong treatment is recommended unless the CD4 count rises above 100 cells/cmm for at least 3-6 months. Prophylaxis options include: Azithromycin (Zithromax) 1200 mg/week, Clarithromycin (Biaxin) 500 mg BID, or Mycobutin (Rifabutin) 300 mg/day.
200-500 cells/cmm CD4 count
pneumococcal pneumonia
type
bacterial
pulmonary tuberculosis
Kaposis sarcoma Herpes zoster Thrush Cryptosporidium Oral hairy leukoplakia Oro-pharyngeal candida
bacterial
viral viral fungal parasitic viral fungal
<200 cells/cmm CD4 count
pneumocystis carinii pneumonia candida esophagitis recurrent/disseminated viral herpes simplex toxoplasmosis histoplasmosis Coccidioidomycosis progressive multifocial leukoencephalopathy
type
fungal (previously thought to be parasitic) fungal viral parasitic fungal fungal viral
microsporidiosis
extrapulmonary tuberculosis
parasitic
bacterial
<50 cells/cmm CD4 count
cytomegalovirus
type
viral
mycobacterium avium complex
bacterial
The Acute Retroviral Syndrome

Fever Adenopathy Pharyngitis Rash Myalgia and arthralgia Thrombocytopenia Leukopenia Diarrhea 96% 74% 70% 70% 54% 45% 38% 32%
Niu et al, JID 1993
The Acute Retroviral Syndrome

Headache Nausea, vomiting Elevated transaminases Hepatosplenomegaly Thrush Neuropathy Encephalopathy 32% 27% 21% 14% 12% 6% 6%
Niu et al, JID 1993
Opportunistic infections
Oral Cutaneous Pulmonary GI and hepatic Neurologic Other
Oral manifestations
Periodontitis Oral hairy leukoplakia Oral herpes Oral papilloma virus Oral candidiasis
Skin
Seborrhea Cutaneous mycosis Bacillary angiomatosis Zoster and varicella Molluscum contagiosum
Pulmonary
Pneumonia LIP (lipoid interstitial pneumonitis)
Neurologic and eye

CNS toxoplasmosis Cryptococcal meningitis CMV encephalitis Progressive multifocal leukoencephalopathy Listeria meningitis Radiculomyelitis Retinitis Retinal necrosis
GI and hepatic
Esophagitis Hepatitis Cholecystitis Enteritis Colitis Proctitis
Malignancies
Kaposis sarcoma Non Hodgkin lymphoma and primary brain lymphoma Hodgkins lymphoma Other solid malignancies
HIV specific manifestations

Neurologic: encephalitis (ADC), myelopathy, peripheral neuropathy Enteritis Glomerulonephritis
Immunologic
Hematologic manifestations Rheumatoid manifestations Thrombophlebitis Psoriasis
Candidiasis
Almost exclusively mucosal
75% of HIV : oropharyngeal candidiasis 30-40% of HIV women : vulvovaginal candidiasis
Candidiasis
Symptomatic of oral discomfort
Thrush: creamy white plaques on an erythematous base Other manifestations: atrophic form/glossitis angular cheilitis (cracking, fissuring or
ulceration of the corner of the mouth)
Oral Hairy Leukoplakia

Verrucous white lesions on the lateral margins of the tongue
Due to EBV infection
Mimic thrush but are not scraped off.
Pneumocystis Pneumonia
DHS/HIV/PP
Pneumocystis carinii Pneumonia

CD4 count (<200/mm) is the best predictor for developing PCP Insidious onset, duration of symptoms 3-4 weeks Progressive dyspnea, dry cough, low grade fever, weight loss CXR: bilateral interstitial alveolointerstitial perihilar peripheral Atypical presentations: apical, cavity, nodules, pneumothorax, effusion Extra pulmonary manifestations
Pneumocystis Pneumonia
New Developments
Basic Science - Pneumocystis carinii changed to Pneumocystis jiroveci* - Characterization of 14- demethylase enzyme
Epidemiology - Reactivation of latent organisms versus acute acquisition

New Diagnostics - PCR-based test on oral washes Resistance to TMP-SMX - Mutations identified in dihydropterate synthase (DHPS) - Presence of mutation associated with increased mortality Immune Reconstitution - Marked inflammatory response about 15-30 days after HAART
DHS/HIV/Clin Manifestations/PP
Pneumocystis in Asymptomatic Individuals
Methods - N = 16 HIV-infected patients - BAL samples (n = 47) - Genotyping of P. jiroveci Results - 35/47 from patients positive for P. jiroveci - 7 with P. jiroveci 7-10 months after acute PCP; all 7 had different genotype at follow-up than found during acute PJP - TMP-SMX did not always clear infection
From: Wakefield AE et al. J Infect Dis 2003;187:901-8.
DHS/ HIV/PP
Recommendations from USPHS/IDSA Guidelines
Discontinuation of PCP Prophylaxis
Setting
Primary Prophylaxis
Secondary Prophylaxis
Criteria
CD4 > 200 for > 3 months

From: MMWR 2001;50 (RR-11):1-52.

DHS/HIV/OIs/PP
Pneumocystis & Immune Reconstitution
Timing - Typically 7 to 30 days after starting HAART Clinical Manifestations - High grade-fever - Patchy infiltrates - BAL: few Pneumocystis organisms, severe inflammatory foci Treatment - Restart corticosteroids
From: Wislez M et al. Am J Respir Crit Care Med 2001;164:847-51.
DHS/ HIV/PP
Toxoplasmosis
DHS/HIV/PP
Toxoplasmosis
Usually occurs when CD4 count < 100/mm Encephalitis(80%), chorioretinitis (10%), pneumonitis, myocarditis Single/multiple intra cerebral enhancing abscess Fever headaches, confusion, seizures Retinitis: thick, dense, opaque appearence
Toxoplasmosis
Retinitis
Decreased acuity, defects in visual fields, floaters, loss of peripheral vision Thick, dense, opaque appearance,with intense vitreal inflammation No hemorrhage
Toxoplasmosis
Encephalitis
Usually occurs when CD4 count < 100/mm Encephalitis(80%), chorioretinitis (10%), pneumonitis, myocarditis Single/multiple intra cerebral enhancing abscess Fever headaches, confusion, seizures
Discontinuation of Toxoplasmosis Prophylaxis

Setting
Primary Prophylaxis Secondary Prophylaxis
Criteria CD4 > 200 for > 3 months CD4 > 200 for > 6 months and Completed Initial Rx and Asymptomatic for Toxo
DHS/HIV/OIs/PP
From: MMWR 2001;50 (RR-11):1-52.
Mycobacterium avium Complex
DHS/HIV/PP
MAC: Immune Reconstitution Syndrome
Low CD4 (< 50): more severe illness; fevers, weight loss, leukocytosis, positive blood cultures (Race, Lancet, 1998) High CD4 (> 100-150): fewer systemic symptoms, more localized suppurative disease (Phillips, JAIDS, 1998) Treatment: continue HAART and MAC therapy, NSAIDS, steroids (for severe symptoms), local surgery?
Slide From Bob Harrington, MD DHS/ID/Cases/PP
Discontinuation of MAC Prophylaxis
Setting
Primary Prophylaxis Secondary Prophylaxis
Criteria
CD4 > 100 for > 6 months and Completed 12 months MAC RX and Asymptomatic for MAC
DHS/HIV/OIs/PP
From: MMWR 2001;50 (RR-11):1-52.
Cytomegalovirus
DHS/HIV/PP
Induction Therapy for CMV Retinitis
Valganciclovir (Valcyte)
Non-progressor %
Study Design Methods - N = 160 - Newly diagnosed CMV retinitis
Week 4: Non-progression
Valganciclovir (PO) Ganciclovir (IV) 100 80 60 40 20 0 90% 90%
Regimens
- Valganciclovir: 900 mg PO bid x 21d, 900 mg PO qd x 7d - Ganciclovir: 5 mg/kg IV bid x 21d, 5 mg/kg IV qd x 7d
From: Martin DF et al. N Engl J Med 2002;346:111926.
DHS/OIs/HIV
Discontinuation of CMV Prophylaxis
Setting
Primary Prophylaxis
Criteria Not Applicable

CD4 > 100-150 for > 6 months and No evidence of active disease and Regular ophtho examinations
Secondary Prophylaxis
From: MMWR 2001;50 (RR-11):1-52.
DHS/HIV/OIs/PP
CMV infection
Usually results from reactivation of latent infection CMV end organ disease occur at CD4 < 50 Retinitis is the most common manifestation (85%) Other clinical presentation:
Esophagitis, colitis, polyradiculopathy, encephalitis, pneumonitis, adrenalitis, pancreatitis
With HAART incidence markedly decreased
CMV retinitis
Progressive , Necrotizing Unilateral Bilateral Blurred vision, floaters, loss of vision Fundoscopy: White, fluffy, granular lesions Perivascular white exsudates Retinal hemorrhages
Gastrointestinal CMV Disease

GI is the 2nd most common site involved in CMV disease Esophageal ulcers, esophagitis, gastritis, gastric and duodenal ulcers, enteritis Enterocolitis (diarrhea), plaque like pseudomembranes, superficial ulcers, hemorrhages
Esophageal Candidiasis
DHS/HIV/PP
Fluconazole-Resistant Esophageal Candidiasis Treatment Options
Drug
Fluconazole (Diflucan) Itraconazole Solution (Sporonox) Caspofungin (Cancidas) Amphotericin B qd Liposomal Ampho B
Dose
400-800 mg PO qd 100 mg PO bid 50-70 mg IV qd 0.3-0.7 mg/kg IV ? Optimal Dose
DHS/HIV/OIs/PP
Cryptococcal Meningitis
DHS/HIV/PP
Cryptococcal Meningitis: 14-Day Induction Therapy
Suspected or Confirmed Cryptococcal Meningitis

*Serial LPs if Opening Pressure > 200 mm H2O
1
Ampho B 0.7-1.0 mg/kg/d + 5-Flucytosine 100 mg/kg/d
Ampho B 0.7-1.0 mg/kg/d
Fluconazole 400-800 mg/d
Initial LP: Reduce opening pressure by 50% Daily LPs: Maintain opening < 200 mm H2O Cessation of LPs: once opening pressure normal for several consecutive days
DHS/OI/PP
Cryptococcal Meningitis: 10 Week Consolidation Therapy
Cryptococcal Meningitis
2 Week Lumbar Puncture with Negative Culture
1 2 3
Fluconazole 400 mg/d
Ampho B 0.7-1.0 mg/kg/d
Itraconazole 400 mg/d
DHS/OI/PP
Cryptococcosis
Subacute meningitis or meningoencephalitis
Time to diagnosis: 2-4 weeks Neck stiffness, photophobia: 30% Lethargy, altered mentation, memory loss
Pneumonia:
Dyspnea, cough, abnormal CXR Usually part of disseminated disease
Skin lesions
Bacillary angiomatosis
Tender red vascular lesions Subcutaneous nodules Bartonella henselae agent of Cat Scratch Disease Differentiation from KS on pathology Treatment with macrolide or tetracycline
Associated Malignancies
Kaposis sarcoma Non Hodgkins lymphoma (body cavity based lymphoma) Hodgkins disease Primary central nervous system lymphoma Invasive cervical cancer Anogenital squamous cancer Anal cancer
Kaposis sarcoma
Late manifestation of AIDS Role of HHV 8 Disseminated skin lesions Often lymph nodes and visceral involvement Macular/papularnodules Skin lesions associated to GI in 50%
Pulmonary disease associated with HIV infection

Mycobacterial:

Mycobacterium tuberculosis Mycobacterium kansasii Mycobacterium avium complex

Other nontuberculous mycobacteria

Other bacterial:

Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae

Enterobacteriaceae
Pseudomonas aeruginosa Moraxella catarrhalis Streptococcus pyogenes (Group A) Nocardia Legionella Rhodococcus equi Chlamydia pneumoniae

Fungal:

Pneumocystis carinii Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Aspergillus Blastomyces dermatitidis Penicillium marneffei

Viral:
Cytomegalovirus Herpes simplex infection Adenovirus Respiratory syncitial virus Influenza viruses Parainfluenza viruses

Parasitic:
Toxoplasma gondii Stongyloides stercoralis

Malignancy:
Kaposis sarcoma Lymphoma Lung cancer

Other:
Lymphocytic interstitial pneumonitis Nonspecific interstitial pneumonitis Bronchiolitis obliterans with organizing pneumonia Pulmonary hypertension Emphysema-like or bullous disease Pneumothorax Congestive heart failure Diffuse alveolar damage Pulmonary embolus
Hepatic disease in HIV infection

Viruses
Hepatitis A Hepatitis B Hepatitis C Hepatitis D (with HBV) Epstein-Barr virus Cytomegalovirus Herpes simplex virus Adenovirus Varicella zoster virus

Mycobacteria:
Mycobacterium avium complex Mycobacterium tuberculosis

Fungi:

Histoplasma capsulatum Cryptococcus neoformans Coccidioides immitis Candida albicans Pneumocystis carinii Penicillium marneffei

Protozoa:

Toxoplasma gondii Cryptosporidium parvum

Microsporidia
Schistosoma

Bacteria:
Bartonella henselae (peliosis hepatis)

Malignancy:
Kaposis sarcoma Non-Hodgkins lymphoma Hepatocellular carcinoma

Medications:
Zidovudine Didanosine Ritonavir Other protease inhibitors Nevirapine Fluconazole Macrolides Isoniazid Rifampin Trimethoprim-Sulfamethoxazole
Causes of alterations in hepatic biochemistry in HIV patients

Antiretroviral drug toxicity Drug and alcohol abuse Hepatitis C co-infection Hepatitis B +/- hepatitis D co-infection Other opportunistic infections Other liver illness
Neurologic complications in HIV infection

Early infection:
Aseptic meningitis Meningoencephalitis Ataxic neuropathy Acute rhabdomyolysis Guillain-Barr syndrome Acute myelopathy Multiple sclerosis-like illness Acute brachial neuritis Bells palsy Acute meningoradiculitis
Neurologic complications in HIV infection Asymptomatic infection:

Headache Depression Drug abuse Pain syndromes Anxiety Endemic neurologic disease
Laboratory Diagnosis
Serology is the usual method for diagnosing HIV infection. Serological tests can be divided into screening and confirmatory assays. Screening assays should be as sensitive whereas confirmatory assays should be as specific as possible. Screening assays - EIAs are the most frequently used screening assays. The sensitivity and specificity of the presently available commercial systems now approaches 100% but false positive and negative reactions occur. Some assays have problems in detecting HIV-1 subtype O. Confirmatory assays - Western blot is regarded as the gold standard for serological diagnosis. However, its sensitivity is lower than screening EIAs. Line immunoassays incorporate various HIV antigens on nitrocellulose strips. The interpretation of results is similar to Western blot it is more sensitive and specific.
ELISA for HIV antibody
Microplate ELISA for HIV antibody: coloured wells indicate reactivity
Western blot for HIV antibody
There are different criteria for the interpretation of HIV Western blot results e.g. CDC, WHO, American Red Cross.
The most important antibodies are those against the envelope glycoproteins gp120, gp160, and gp41
p24 antibody is usually present but may be absent in the later stages of HIV infection
Other diagnostic assays
It normally takes 4-6 weeks before HIV-antibody appears following exposure. A diagnosis of HIV infection made be made earlier by the detection of HIV antigen, pro-DNA, and RNA. However, there are very few circumstances when this is justified e.g. diagnosis of HIV infection in babies born to HIV-infected mothers.
Prognostic tests
Once a diagnosis of HIV infection had been made, it is important to monitor the patient at regularly for signs of disease progression and response to antiviral chemotherapy. HIV Antigen tests - they were widely used as prognostic assays. It was soon apparent that detection of HIV p24 antigen was not as good as serial CD4 counts. The use of HIV p24 antigen assays for prognosis has now been superseded by HIV-RNA assays. HIV viral load - HIV viral load in serum may be measured by assays which detect HIV-RNA e.g. RT-PCR, NASBA, or bDNA. HIV viral load has now been established as having good prognostic value, and in monitoring response to antiviral chemotherapy.
Initial Health Care Management

HIV risk reduction Drug rehabilitation Smoking cessation Counseling for partner notification Reproductive counseling Psychosocial support Identify family member or significant other Immunizations: pneumococcal, influenza, HBV Preventive dentistry
Current Issues
The spread of HIV is not halted, particularly in developing countries. Renewed interest and progress in HIV preventive interventions. Accessibility and availability of antiretroviral therapy: generics V/S multinational producers of drugs.
Issues in Management
Design appropriate antiretroviral treatment strategies Identify patient issues and design effective longterm treatment strategies Recognize and discuss the current knowledge of antiretroviral drug resistance patterns and its impact on subsequent treatment protocols Define current understanding of immune reconstitution and how it impacts HIV treatment
Changing aspect of HIV disease

Highly active antiretroviral therapy (HAART) is changing the pattern of HIV-associated diseases Certain opportunistic infections (MAC, CMV) are virtually disappearing The incidence of community-acquired pneumonia and NHL remained unchanged
Degree and quality of immune repair Most patients aggressively treated achieve a significant rise in CD4 cells This is also seen even in patients who do not achieve complete viral suppression This paradox impacts decisions of changing regimens prematurely
HIV reservoirs and eradication

The virus is present in rapidly replicating short lived cells as well as in long lived cells No real hope for viral eradication for the near term and for the long term
Update: HIV Eradication by HAART Is Impossible

Updated data from Siliciano (Johns Hopkins)
One important reservoir = HIV-infected resting T cells

Transcriptionally silent, so invisible to immune surveillance Unaffected by current drugs Replenished by cell division, not from viral replication Half-life is at least 6 months, so decay rate is measured in decades No decrease in decay rate in optimally treated, chronically infected patients with no blips of viremia Even if this reservoir could be flushed, others exist
Abstract: MoOr103
Update: HIV Eradication by HAART Is Impossible

However, long-term suppression appears possible
In patients with long-term suppression, virus released into circulation is wild-type No resistance even to drugs with low genetic barrier in many patients with long-term suppression
Controversies
When should antiretroviral therapy be initiated ? What should be included in the initial regimen ? What constitutes success ? Should we utilize the ultrasensitive assays ? When should resistance assays be used ? How do we assess adherence ? What interventions are useful ? What combinations of drugs will allow the best hope for sustained control of HIV replication ?
What are we faced with?

Treatment of a chronic illness Long term toxicities Development of resistance Adherence to therapy Cost
What are the targets?

Improve quality of life. Improve survival. Reduce the risk of opportunistic infections, malignancies and neurologic complications (progression to AIDS). Decrease hospital stays.
What are the markers?

Absence of AIDS-defining illnesses. Increase weight. Increase CD4+ cell count. Decrease plasma viremia.
When to measure plasma viral load?

Acute retroviral syndrome: diagnosis Initial evaluation If not on therapy: Every 3-4 months If on therapy:
At 2 8 weeks At 3 4 months Every 3 4 months Clinical or lab event
US DHHS, April 2004
When to do drug resistance assays?
Virologic failure Suboptimal suppression Before initiating therapy ? In case of occupational exposure ?
US DHHS, April 2004
Potential benefits of early therapy

Earlier suppression of viral replication Preservation of immune function Prolongation of disease free survival Lower risk of resistance with complete viral suppression Possible decrease of HIV transmission
US DHHS, April 2004
Potential risks of early therapy

Drug related adverse effects on QOL Serious drug related toxicities Early development of drug resistance If suboptimal Transmission of resistant virus Limitation of future treatment options Unknown durability
US DHHS, April 2004
Potential benefits of delayed therapy

Avoid negative effects on QOL Avoid drug related adverse events Preserve future treatment options Delay in development of drug resistance
US DHHS, April 2004
Potential risks of delayed therapy

Possible Possible Possible Possible irreversible immune system compromise greater difficulty in viral suppression increase risk of HIV transmission higher rate of adverse effects
US DHHS, April 2004
Goals of HIV therapy

Maximal and durable suppression of viral load Restoration or preservation on immune function Improvement in quality of life Reduction of HIV-related morbidity and mortality
US DHHS, April 2004
Tools to achieve goals

Maximize adherence Rational sequencing Preserve future treatment options Drug resistance testing
US DHHS, April 2004
As low as possible for as long as possible Best predictors of durable response and absence of resistance development:
Nadir of virologic response Rapidity of shutting down viral replication Absence of blips of plasma HIV-1 RNA
Problems with treatment regimens
Complexity Short- and long-term toxicities Cross-resistance Drug-drug interactions
When to start ARVs?

Clinical category CD4+ cell count /mm3 Plasma HIV RNA Recommendation
Symptomatic Asymptomatic Asymptomatic
Any < 200 200 350
Any Any Any
TREAT TREAT Controversial
Asymptomatic
Asymptomatic
350
350
> 55,000 Consider ?

< 55,000 Defer
US DHHS, April 2004
WHEN TO START THERAPY
When the patient is ready
When the doctor is ready
When the provider is ready
220
221
When the immune status is down:

Opportunistic infections Drop in CD4 count (or total lymphocyte count)
When the patient understands the treatment, its side effects and how to take it When the patient understands that treatment is for life When the patient understands food restrictions
When the patient understands need for follow-up

When the patient wants to start treatment
222
223
When the doctor is well trained When he has experience in antiretroviral therapy When he has guidelines When he keeps up with the new literature
When he understands the side-effects of treatment
224
225
When drugs are purchased regularly When drugs are stored appropriately When the supply is sustained and maintained When there are regular reevaluations of protocols and guidelines When there is a regular upgrading of the list of drug to keep up with new developments in research and viral resistance
226
Changing Emphasis in HIV Management

1996
Efficacy
Hit Hard Hit Early
2000
Convenience/ Tolerability
Minimize Adverse Experiences Maximize Adherence
2002
Efficacy + Convenience/ Tolerability
Manage Total Patient Health
When to start therapy in asymptomatic chronically HIV-infected patients ?

Plasma HIV RNA Level, Copies/mL CD4+ Cells, x106/L < 200 200-350 > 350 < 5000 Recommend therapy Consider therapy Defer therapy 5 000-30 000 Recommend therapy Consider therapy Defer therapy > 30 000 Recommend therapy Consider therapy Defer therapy*
245
*In patients with CD4+ > 350 cells/L, some would consider therapy if HIV RNA levels > 100,000 copies/mL
246
When to start anti-HIV therapy in asymptomatic patients with chronic infection? (IAS-USA panel)
CD4 count < 200 cells/L Treatment is recommended CD4 count > 200 cells/L Treatment decision should be individualized; recommendations are based on: CD4 cell count1 and rate of decline2 HIV-RNA level in the plasma3
1<350
cells/L 2>100 cells/L /annum 3>50K-100K copies/mL

247
JAMA 2002
Patient interest and potential to adhere to therapy Individual risks of toxicity and drugdrug pharmacokinetic interaction
When to start
CD4 testing available:
WHO Stage IV irrespective of CD4 cell count WHO Stage III disease (including but not restricted to HIV wasting, chronic diarrhea of unknown etiology, prolonged fever of unknown etiology, pulmonary tuberculosis, recurrent invasive bacterial infections, or recurrent persistent mucosal candidiasis) with consideration of using CD4 cell counts <350/mm3 to assist decision making WHO stage I or II disease with CD4 cell counts <200/mm3
When to start
CD4 testing unavailable:
WHO Stage IV disease irrespective of total lymphocyte count WHO Stage III disease (including but not restricted to HIV wasting, chronic diarrhea of unknown etiology, prolonged fever of unknown etiology, pulmonary tuberculosis, recurrent invasive bacterial infections, or recurrent persistent mucosal candidiasis) irrespective of total lymphocyte count WHO Stage II disease with a total lymphocyte count <1200/mm3
Problem patients
Patients with high HIV-1 RNA levels Extensive prior treatment Advanced disease
Current classes of antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTI) Non-nucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors (PI) Nucleotides Entry inhibitors
Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Zidovudine (ZDV) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) [RETROVIR*] [VIDEX*] [HIVID*] [ZERIT*] [3TC*, EPIVIR*] [ZIAGEN*] [EMTRIVA*]
Non- Nucleoside Reverse Transcriptase Inhibitors

(NNRTI)
Nevirapine (NVP) Delavirdine (DLV) Efavirenz (EFZ)
[VIRAMUNE*] [LOVIRIDE*] [STOCRIN*]
Nucleotide Reverse Transcriptase Inhibitors Tenofovir DF [VIREAD*]
Protease Inhibitors (PI)

Saquinavir (SQV) Ritonavir (RTV) Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Fos-Amprenavir (FOS) Lopinavir/ritonavir (LPV/r) Atazanavir (ATV) [FORTOVASE*] [INVIRASE*] [NORVIR*] [CRIXIVAN*] [VIRACEPT*] [AGENERASE* [ [KALETRA*] [REYATAZ*]
Fixed combinations
Zidovudine/Lamivudine
Zidovudine/Lamivudine/Abacavir
Lamivudine/Abacavir Tenofovir/Emtricitabine
[COMBIVIR*] [TRIZIVIR*] [EPZICOM*] [TRUVADA*]
Combinations to be avoided
ZDV d4T : antagonism d4T ddI : toxicity TDF 3TC ABC : high virologic failure (49%) and high incidence of the K65R mutation TDF ddI 3TC : high virologic failure (91%) and high incidence of the K65R mutation d4T ddI ABC : low efficacy and high frequency of adverse events
New Drugs in Existing Classes

RTIs:
Emtricitabine DAPD (-)dOTC Capravirine TMC 120 DPC 083
New Drugs in Existing Classes

PIs:
Tipranavir Atazanavir Fos-Amprenavir DPC 681, DPC 684 TMC 126
New Classes of ARVs
Integrase inhibitors Entry inhibitors
Fusion inhibitor
Enfuvirtide
Entry Inhibitors
T-20, Enfuvirtide [FUZEON*]: inhibits gp41 (approved in the US). Schering-C: inhibits the CCR5 co-receptor (second step). AMD-3100: CXCR4 co-receptor inhibitor. (withdrawn from further development). BMS 806: inhibitor of gp120 binding (first step).
Integrase inhibitors
S-1360 Inhibitor of HIV integrase. It is active in vitro and synergistic in vitro with NRTIs, NNRTIs and PIs. (Phase I/II studies currently).
Background: DHHS Recommendations

Preferred regimens Those ARVs for which suggest optimal Lopinavir/ritonavirclinical trial data Efavirenz* + + efficacy and durability with acceptable tolerability or d4T) 3TC 3TC + (ZDV or d4T)ease of use. + (ZDV or TDF and Alternative regimens PI-based NNRTI-based Those ARVs for which clinical trial data show efficacy, Lopinavir/ritonavir + FTC + (ZDV or d4T) EFV to disadvantages but it is or FTC) + (ZDV alternative due + FTC + (ZDV or TDF or d4T) Atazanavir + (3TC consideredor d4T) Amprenavir + RTV + (3TC or FTC) + (ZDV or d4T) Efavirenz* compared to (ZDV or d4T) the preferred regimens in + (3TC or FTC) + ddI terms of Indinavir + (3TC or FTC) + Nevirapine + (3TC or FTC) + (ZDV or d4T or TripleddI) NRTI** antiviral FTC) + (ZDV or d4T) Indinavir + RTV + (3TC oractivity, demonstrated durable effect, tolerability Abacavir Nelfinavir + (3TC or FTC) + (ZDV or d4T)or ease of use.+ 3TC + (ZDV or d4T)
Saquinavir + RTV + (3TC or FTC) + (ZDV or d4T)
*EFV safety in pregnancy not established: avoid in pregnant women or women with pregnancy potential **Only when an NNRTI- or a PI-based regimen cannot or should not be used as first line therapy
Note: Fosamprenavir was not considered in this revision since it was not approved on the date the draft had been completed. An update with the role of fosamprenavir as initial therapy will appear in the next revision of this document. AIDSinfo. Available at: http//:www.aidsinfo.nih.gov/guidelines. Accessed March 3, 2004.

Preferred regimens
Lopinavir/ritonavir + 3TC + (ZDV or d4T)
Efavirenz* + 3TC + (ZDV or TDF or d4T)
Alternative regimens PI-based NNRTI-based Those ARVs for which clinical trial data show efficacy, Lopinavir/ritonavir + FTC + (ZDV or d4T) EFV to disadvantages but it is or FTC) + (ZDV alternative due + FTC + (ZDV or TDF or d4T) Atazanavir + (3TC consideredor d4T) Amprenavir + RTV + (3TC or FTC) + (ZDV or d4T) Efavirenz* compared to (ZDV or d4T) the preferred regimens in + (3TC or FTC) + ddI terms of Indinavir + (3TC or FTC) + Nevirapine + (3TC or FTC) + (ZDV or d4T or TripleddI) NRTI** antiviral FTC) + (ZDV or d4T) Indinavir + RTV + (3TC oractivity, demonstrated durable effect, tolerability Abacavir Nelfinavir + (3TC or FTC) + (ZDV or d4T)or ease of use.+ 3TC + (ZDV or d4T)
Saquinavir + RTV + (3TC or FTC) + (ZDV or d4T)

Preferred regimens Those ARVs for which suggest optimal Lopinavir/ritonavirclinical trial data Efavirenz* + + efficacy and durability with acceptable tolerability or d4T) 3TC 3TC + (ZDV or d4T)ease of use. + (ZDV or TDF and Alternative regimens PI-based
Lopinavir/ritonavir + FTC + (ZDV or d4T) Atazanavir + (3TC or FTC) + (ZDV or d4T) Amprenavir + RTV + (3TC or FTC) + (ZDV or d4T) Indinavir + (3TC or FTC) + (ZDV or d4T) Indinavir + RTV + (3TC or FTC) + (ZDV or d4T) Nelfinavir + (3TC or FTC) + (ZDV or d4T) Saquinavir + RTV + (3TC or FTC) + (ZDV or d4T)
NNRTI-based
EFV + FTC + (ZDV or TDF or d4T) Efavirenz* + (3TC or FTC) + ddI Nevirapine + (3TC or FTC) + (ZDV or d4T or ddI)
Triple NRTI**
Abacavir + 3TC + (ZDV or d4T)
NNRTI based regimens

NNRTI
Preferred regimens Efavirenz
NRTI 1
Lamivudine
NRTI 2
Alternative Efavirenz regimens Alternative Efavirenz regimens
Zidovudine or Tenofovir DF or Stavudine Emtricitabine Zidovudine or Tenofovir DF or Stavudine Lamivudine or Didanosine or Emtricitabine abacavir
Alternative Nevirapine Lamivudine or Zidovudine or regimens Emtricitabine Stavudine or Didanosine or Abacavir

US DHHS, April 2004
PI based regimens
PI
Preferred regimens
Alternative regimens
NRTI 1
Lamivudine
NRTI 2
Zidovudine or Stavudine
Lopinavir/ ritonavir
Atazanavir
Lamivudine Zidovudine or or Stavudine or Emtricitabine Abacavir
Fos amprenavir
Fos amprenavir/ ritonavir
Lamivudine or Emtricitabine Lamivudine or Emtricitabine

US DHHS, April 2004
Zidovudine or Stavudine or Abacavir Zidovudine or Stavudine or Abacavir
PI based regimens
PI
Alternative regimens Alternative regimens Indinavir/ ritonavir Lopinavir/ ritonavir
NRTI 1
Lamivudine or Emtricitabine Emtricitabine
NRTI 2
Alternative regimens Alternative regimens
Lopinavir/ ritonavir
Nelfinavir
Lamivudine
Lamivudine or Emtricitabine Lamivudine or Emtricitabine
US DHHS, April 2004
Abacavir
Saquinavir/ ritonavir
ARVs not recommended as part of initial regimen in a nave individual

Modest activity:
Delavirdine Zidovudine + zalcitabine
US DHHS, April 2004

Dosing inconvenience:
Amprenavir (16 caps/d) Amprenavir + ritonavir (10 caps/d) Indinavir (6 pills, fluids, fat) Saquinavir soft gel (18 caps/d) Nelfinavir + saquinavir (16 22 caps/d)
US DHHS, April 2004

Toxicity:
Ritonavir as sole PI Stavudine + didanosine
US DHHS, April 2004

No data:
Enfuvirtide
US DHHS, April 2004
Unacceptable ARVs regimens

Monotherapy
Dual therapy
Abacavir + Tenofovir + Lamivudine Tenofovir + Didanosine + Lamivudine
US DHHS, April 2004
ARVs not recommended as part of antiretroviral regimen

Saquinavir hard gel as sole Pharmacokinetics
PI Activity Stavudine + Didanosine Toxicity Efavirenz in pregnancy Toxiciy Amprenavir oral solution Propylene glycol (pregnancy, pediatrics, renal or liver failure)
US DHHS, April 2004
ARVs not recommended as part of antiretroviral regimen

Stavudine + Zidovudine Antagonism
Stavudine + Zalcitabine
Didanosine + Zalcitabine Atazanavir + Indinavir
Toxicity
Toxicity Toxicity
Emtricitabine + Lamivudine
Hydroxyurea
Resistance
Poor efficacy,
toxicity
US DHHS, April 2004
XV International AIDS Conference
First-line Antiretroviral Regimens
NRTI Backbone
Viral Suppression with Efavirenz-Based Regimens

ITT Analysis
100 Patients with HIV-1 RNA < 50 copies/mL (%) 80
60
40 20 0
73% 69%
TDF + 3TC + EFV d4T + 3TC + EFV
24
48
72
96
120
144
Weeks
Gallant JE, et al. XV IAC Bangkok, 2004. Abstract TuPeB4538.
GS 903 Study: Week-144 Virologic Outcomes of Tenofovir DF vs Stavudine + 3TC/EFV

100
Intent to Treat (Missing = Failure)
Patients with HIV-1 RNA < 50 copies/mL (%)
80
60 40
73% 69%
TDF + 3TC + EFV

20 0 0 24 48 72 96 120 144
d4T + 3TC + EFV
Weeks
Gallant et al. Abstract TuPeB4538.
GS 903 Study: Greater Effect of Stavudine on Triglycerides
Change from Baseline (mg/dL)
Increased TG elevations in TDF vs d4T,[1] and in men vs women on d4T[2]

TDF+3TC+EFV d4T+3TC+EFV
160 140 120 100 80 60 40 20 0 -20 0
134
Change from Baseline (mg/dL)
160 140 120 100 80 71

TDF arm d4T arm
151
90
103
P < .001 at Wk 48, 96, 144
60
40 20 0 -20 Women Men -4 2
24
48
72
96
120
144
Weeks
TDF: d4T: 234 200 184 183 177 175 171
250
211
194
182
179
170
162
1. Gallant et al. Abstract TuPeB4538. 2. De Ruiter et al. Abstract MoOrB1083.
GS 903 Study: Development of Resistance Mutations During TDF Treatment

Patients with mutations (n) 18 16 14 12 10 8 6 4 2 0
16 12 7
n = 299
K65R M184V/I EFV-R*
4 4
1
0-48 Weeks
2 0
96-144 Weeks
* K103N, V106M, Y188C/L G190A/S/E/Q
48-96 Weeks
Gallant et al. Abstract TuPeB4538.
DP-006 Study: Week 168 Follow-up; Suppression < 400 Copies/mL

EFV+AZT+3TC
Proportion With VL < 400 (%)
100 80 60 40 20 0 B/L 12 24 36 48 60 72 84 Weeks 96 108 120 132 144 156 168
n = 422
EFV+IDV
n = 429
IDV+AZT+3TC
n = 415
P < .0001 EFV vs IDV triple-drug arms at Week 168
ITT, M=F analysis: Proportion of subjects with response according to TLOVR definition of treatment success. Tashima et al. Abstract TuPeB4547.
CLASS Study Final Data: Efavirenz vs Amprenavir/r vs Stavudine (+ 3TC/ABC)

100 90
Proportion With VL < 50 (%)
80 70 60 50 40 30 20 10 0
0 8 16 24 32 40 48 56 Weeks 64 72 80 88 96 No significant differences at Wk 96 in ITT analysis
NNRTI (ITT) PI (ITT) NRTI (ITT)
NNRTI (Obs) PI (Obs) NRTI (Obs)
Bartlett et al. Abstract TuPeB4544.
Early Failure of Triple Nucleoside Regimen

Open-label, noncomparative study of 24 treatment-nave patients treated with ddI EC + 3TC + TDF QD
Male Mean Age Median HIV RNA (log10) Median CD4 count (cells/mm3) 83% 39 4.91 133
8% 8%
Virologic Success Withdrew or LTFU
Results
22 evaluable patients
Week 12: median log10 HIV RNA change from baseline: -0.61 (-2.66 to +0.73) 20 patients virologically failed (<2 log10 viral load (VL) by week 12) Genotypes (n=20): M184I/V in 100% with K65R in 50% Phenotypes (n=19): 100% TDF sensitive (<1.4-fold); 5/10 patients with K65R had ddI resistance (>1.7 fold)
Virologic Failure
84%
Jemsek et al. 11th CROI, 2004, Abstract 51.
SOLO Study: Virologic Response at Week 48 by Baseline Viral Load and CD4+ Count
fAPV/r vs NFV in treatment-naive patients
Similar overall rates of virologic response at Week 48

100% 80%
fAPV/r QD
69% 68%
74%
55% 44% 53%
NFV BID 51% 33%
60%
40% 20% 0%
Overall High VL / Low CD4
Overall
High VL / Low CD4
< 400 c/mL
< 50 c/mL
Intent to treat; rebound or discontinuation = failure DeJesus et al. Abstract TuPeB4503.
SOLO Study: Resistance Mutations at Week 48

20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0%
fAPV/r QD NFV BID fAPV/r QD NFV BID 1.3% 0% 7.4%
fAPV/r QD NFV BID

11.4%
Analysis of all randomized patients, not just those with failure Among patients with high VL/low CD4 at baseline, fewer mutations with fAPV vs NFV
PR Mutns
DeJesus et al. Abstract TuPeB4503.
RT Mutns
Association Between WHO 3x5 Regimens and Survival in San Francisco

First-line Regimen d4T-3TC-EFV AZT-3TC-EFV d4T-3TC-NVP AZT-3TC-NVP d4T-3TC-NFV AZT-3TC-NFV d4T-3TC-IDV AZT-3TC-IDV d4T-3TC-SQV AZT-3TC-SQV 0 1 3 5 7 9 11 28 Adjusted Odds Ratio for Death Compared With d4T-3TC-EFV
Chen et al. Abstract MoOrC1082.
Case-control study 310 cases; all died before 2003
1161 controls; all alive through 2002

4 regimens recommended by WHO 3x5 associated with best survival However, analysis does not account for subsequent switches; may not be available in developing countries
NRTI Backbone
Choosing an NRTI Backbone

DHHS guidelines: First-line regimens should be based on either a potent NNRTI (efavirenz) or a potent ritonavirboosted PI (lopinavir/ritonavir)
Multiple options are available for the NRTI backbone
d4T + 3TC + EFV NRTI dose frequency Clinical trial HIV-1 RNA < 50 copies/mL, % Twice-daily GS 903 TDF + 3TC + EFV Once-daily GS 903 ABC + 3TC + EFV Once- or Twice-daily ZODIAC ddI + FTC + EFV Once-daily FTC-301
74% Week 96
78% Week 96
66-68% Week 48
85% Week 48*
* Median follow-up of 48 weeks; study stopped due to virologic inferiority and increased toxicity of d4T/ddI comparator arm
NRTI Backbone
Advantages and Disadvantages of Coformulated NRTIs

Advantages
Convenient and easy dosing
May improve adherence (Not confirmed by clinical trials)
Disadvantages
Lack of flexibility in dosing
Dose reduction of only 1 of the agents is not possible If changes are needed, patient must revert to individual drugs
Specific issues
Abacavir/lamivudine: abacavir hypersensitivity
5-8% of patients will need to discontinue abacavir
Tenofovir DF/emtricitabine
Tenofovir DF dose reduction required in patients with creatinine clearances < 50
ART Cohort Collaboration: Prognosis After Initiating HAART
N = 19,086 patients (12 cohorts) who initiated therapy with 3 drugs; 55,307 person-years of follow-up
Significant decline in AIDS and death between 1995 and 1998 No significant change in prognosis between 1998 and 2003
Slightly increased death rate in some cohorts
Progression/death strongly associated with low CD4+; weak association with VL Older age, history of IDU, CDC stage C, and low hemoglobin stronger risk factors for death than for progression Possible explanations for lack of further improvement in prognosis
Aging cohorts; treatment failure in IDUs; comorbidities
Egger et al. Abstract TuOrC1157.
Regimens Associated With Increased Risk of Viral Rebound in EuroSIDA Study
N = 1951 pts with VL < 50 copies/mL and no prior HAART failure

Viral rebound = VL > 400 copies/mL on 2 consecutive occasions Among pts naive prior to HAART:
Lowest rate of rebound with EFV-based regimens: 3.1/100 PY Compared with EFV-based, significantly higher rate with NFV-based (8.0/100 PY; P = .006) ABC-based not significantly different from EFV-based
Among pts with NRTI experience pre-HAART:

Lowest rate of rebound with EFV-based Compared with EFV-based, significantly higher rate with
NFV-based ABC-based NVP-based
Phillips et al. Abstract TuPeB4542.
Effect of moderate viremia on disease progression during ART

3010 patients evaluated Mean follow-up 4.3 years
343 developed AIDS defining events or died
Effect of moderate viremia on disease progression during ART

< 400
Number of patients 1299
400 20,000
989
> 20,000
722
Incidence of AIDS defining events
6%
7% P = 0.5
26% P = 0.001
Deaths
2%
2%
9% P < 0.001
JAIDS Sep 2004
Reasons for drug failure:

Resistance Non-adherence Pharmacologic factors and drug interactions Insufficiently potent regimens Sanctuaries Cellular mechanisms of resistance Host immune status
NRTI Backbone
ICONA Study: Reasons for Failure of Initial HAART
8%
n = 25
20%
n = 61
Toxicity Failure Nonadherence Other
58% 14%
n = 44 n = 182
d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.
What to change to ?
Failure of first line regimen: d4T or ZDV + 3TC + NVP or EFV Change to: TDF or ABC + ddI + LPV/r or SQV/r
Common NRTI Switching Scenarios

Stavudine or zidovudine abacavir or tenofovir DF
Interest usually due to potential to reduce toxicity, and potential for once-daily therapy
Stavudine or zidovudine didanosine

Interest due to potential for once-daily therapy
Lamivudine emtricitabine
Interest due to anticipated availability of TDF/FTC coformulation
Zidovudine stavudine or stavudine zidovudine

Less common due to diminished role of d4T in clinical practice
Evaluating Success of NRTI Switching

Main outcomes to consider when evaluating the likely success of switching:
Maintenance of virologic control Maintenance of CD4+ cell count response (and immune function) Improvement/resolution/prevention of toxicity Improvement in patient adherence and quality of life
Reasons to Consider NRTI Switching

Improve adherence
Reduce pill burden, remove food requirements, reduce dosing frequency (ie, to establish a compact once-daily regimen)
Manage an actual or possible toxicity

Including not only morphologic and metabolic disturbances but also anemia, hypersensitivity reactions, peripheral neuropathy, and so on
Reduce the risk of clinically important drug interactions

eg, didanosine with ribavirin
Take advantage of a more convenient formulation or newly-approved indication or agent
Side-effects of HAART
More gastro-intestinal adverse effects related to protease inhibitors, as compared to men. Lipodystrophy and cosmetic changes. Difficulty to use anabolic steroids to fight wasting.
The Importance of Adherence

Adherence is key to successful outcomes
Achieving viral suppression Preventing drug resistance
STO 2002-W-6148-SS
What is Adherence?
The therapy is taken according to the prescribing instruction at the: - Recommended dose - Recommended time - Recommended way (food restriction)
STO 2002-W-6148-SS
Adherence is a critical issue

1996 2000 2003
CONVENIENCE / TOLERABILITY
EFFICACY
EFFICACY
CONVENIENCE / TOLERABILITY
EFFICACY
Hit Hard Hit Early
Adverse Experiences, Treatment Fatigue
HIV As a Chronic Disease
STO 2002-W-6148-SS
Effectiveness = Efficacy x Adherence
STO 2002-W-6148-SS
Relation between therapeutic response and adherence to antiretroviral therapy

80 70 60 50 40 30 20 10 0 >95% 90-95% 80-90% 70-80% <70%
STO 2002-W-6148-SS
% of Patients w ith VL <400 copies/mL
Paterson et al. (2000) Ann Intern Med. Vol (133) 1
% of Adherence
Adherence is an act of devotion
The program proposed by the physician: adherence to antiretrovirals The patient wants to adhere to life
STO 2002-W-6148-SS
Adherence and HIV Therapeutics
Failure to achieve and maintain plasma HIV RNA below detection may lead to treatment failure and development of resistant variants Suboptimal patient adherence is a common cause of treatment failure
Suboptimal adherence is most commonly due to: Regimen complexity Forgetfulness Drug intolerance adverse events
STO 2002-W-6148-SS
HAART Has Been Shown to Be Highly Effective When Taken as Directed

Directly Observed Therapy (DOT) vs. Self-Administered Therapy (SAT)
% of Patients Reaching Undetectable HIV RNA < 400 copies/ml
Patients: Antiretroviral-naive patients on 3- or 4-drug combinations under DOT vs. SAT Conclusions: DOT group greater virologic responses vs. SAT at all time points
100 80 60 40
DOT <400
Within SAT group, 4-drug regimens had lowest response (57%)

EFV-containing regimens had the best virologic response rates Results suggest that simplified regimens may improve adherence and outcomes
20 0
4 8 16
SAT <400
24
32
48
64
72
80
Week
Fischl M et al. 8th CROI; 2001, Chicago, IL.
STO 2002-W-6148-SS
Data Show High Levels of Adherence Required for Virologic Success

% of Patients with Virologic Failure 100
Relationship of adherence (measured by MEMS) to virologic failure

82 71 67 55
75
50
Results show that 95% adherence is required for optimal virologic suppression
25
22
0
95% 90%-94.9% 80%-89.9% 70%-79.9% <70%
Adherence, %
MEMS = Medication Events Monitoring System
Paterson DL et al. Ann Intern Med 2000;133:2130.
STO 2002-W-6148-SS
As Regimen Complexity Increases, Adherence Rates Decrease

Taking all medication Taking all medication on time Taking all medication on time according to food requirements
100
% of Patients
80
60
40 20 0 IDV + NRTIs NFV + NRTIs SQV/RTV + NRTIs NVP + NRTIs
* Indicates group Taking all medication on time according to food requirements not assessed. Nieuwkerk PT et al. Arch Intern Med 2001;161:19621968.
STO 2002-W-6148-SS
NRTI Backbone
Factors Affecting Adherence

Important to recognize factors that influence adherence However, physicians ability to identify patients who will or will not be adherent is limited Race, sex, and socioeconomic status are not independent risk factors for nonadherence
Factors associated with increased adherence Patient belief in HAART Physician experience Social supports Regular office visits Active injection-drug use Active alcohol abuse Active psychiatric disease (especially depression) Younger age Chaotic lifestyle Low functional literacy
Factors associated with nonadherence
NRTI Backbone
Why Do Patients Miss Doses?

% 0 Too busy/simply forgot Away from home Change in daily routine Felt depressed/overwhelmed Took drug holiday/medication break Ran out of medication Too many pills Worried about becoming 'immune' Felt drug was too toxic Wanted to avoid side effects Didn't want others to notice Reminder of HIV infection Confused about dosage direction Didn't think it was improving health To make it last longer Were told the medicine is no good
Gifford et al. JAIDS 2000;23:386395.
10
20
30
40
46 45
50
52
60
27 20 20 19 19 18 17 17 16 14 13 10 9
Reasons given for missing antiretroviral doses (structured questionnaire)

POSSIBLE INTERVENTIONS
Simplify dosing schedule Decrease pill burden Other
NRTI Backbone
Adherence is Inversely Related to the Number of Doses Per Day

Dose-taking adherence rates
P < .001
Dose-timing adherence rates

P values not calculated
Mean dose-taking adherence (%)
100 80 60 40 20 0 Overall QD 71
P = .008 P = .001
79
69 65 51 59
74 58 46 40
BID
TID
QID
Overall QD
BID
TID
QID
Studies of electronic monitoring of adherence

Dose-taking adherence: appropriate number of doses taken during the day (optimal adherence variously defined as 70%, 80%, 90%) Dose-timing adherence: doses taken at appropriate time intervals, within 25% of the dosing interval (e.g. BID should be taken 12 3 hours apart)
Claxton et al., Clin Ther .2001;23:12961310.
Strategies to improve adherence Patient and medication related

Inform patient, anticipate and treat side
effects Simplify food requirements Avoid adverse drug interactions Reduce dose frequency and number of pills Negotiate a clear and understandable treatment plan, develop a concrete plan Educate, explain
US DHHS, April 2004
Strategies to improve adherence Patient and medication related

Understand patients readiness
Recruit family and friends

Provide schedules Develop adherence groups, educational
sessions, practical strategies Consider pill trials
US DHHS, April 2004
Strategies to improve adherence Physician and health team related

Establish trust
Be an educator, resource, support

Be available for questions Monitor adherence
US DHHS, April 2004
Strategies to improve adherence Physician and health team related

Understand the impact of clinical events on
adherence All in the team should convey adherence message Train the health team on adherence enforcing and monitoring
US DHHS, April 2004
Interventions to improve adherence

Pharmacist based adherence visits
Multidisciplinary adherence visits

Reminders, alarms, pagers, timers, pill boxes Patient aids, calendars, stickers Clinician education
US DHHS, April 2004
Once-daily Antiretrovirals
6 ARVs approved as low pill number,
once-daily therapies:
Atazanavir
Didanosine
Efavirenz Emtricitabine
Lamivudine
Tenofovir
DF
Abacavir submitted for approval as once-
daily agent
Prospective Studies of Potential Once-daily Regimens

Once-daily regimens have performed at least as
effectively as standard (thymidine analogue-based) regimens
Trial
GS 903 CNA30024 ABCDE FTC 301
Comparative regimens
TDF vs d4T, each with 3TC/EFV ABC vs AZT, each with 3TC/EFV ABC vs d4T, each with 3TC/EFV FTC vs d4T, each with ddI/EFV
Extended-release d4T development studies
d4T extended vs immediate release, each with 3TC/EFV
Alize: Switch from Twice-daily to Oncedaily

100
95%
Patients with HIV-1 RNA < 50 copies/mL (%) 90
87%
80
70 Switched to once-daily ddI/FTC/EFV Continued twice-daily, high pill-burden, PI-based regimen
P = .01
12
16
20
24
28
32
36
40
44
48
Time since treatment allocation (weeks)

Molina JM, et al. 2nd IAC, Paris, 2003. Abstract 37.
NRTI Half-life
A regimen with a longer half-life may be optimal for some patients with adherence and dose-timing accuracy difficulties
Value of pharmacologic forgiveness not tested in clinical trials
Name Zidovudine
Serum t1/2 (hrs) 1.1
Intracellular t1/2 (hrs) 3
Zalcitabine Stavudine Abacavir Lamivudine Didanosine Emtricitabine Tenofovir DF
1.2 1.0 1.5 3-6 1.6 10 17
3 3.5 (IR); 12-24 (XR) 12-14 14-18 25-40 39 10 - 50
Potential Concern When Stopping Drugs With Different Half-lives

Last Dose
Drug Concentration
Day 1
Day 2+
MONOTHERAPY
Zone of potential replication IC90 IC50
36 48
12
24 Time (Hours)
S. Taylor et al. 11th CROI Abs 131
SummaryImplications for Clinical Practice

Persons with HIV appear to have a strong preference for once-daily dosing and compact therapy Clinical studies indicate that potential once-daily antiretroviral regimens are as effective as past standardof-care regimens
However, once-daily therapy has not been fully tested in the setting of HIV infection
Thymidine analogues have an increased relative risk of adverse events within the NRTI class
Switching to a better tolerated agent (eg, ABC, TDF) may help avoid or ameliorate thymidine analogue-associated toxicities
SummaryImplications for Clinical Practice

d4T carries higher relative risk than other NRTIs for morphologic changes
3TC, FTC, ABC, and TDF appear not to be associated with limb fat loss
Switching from d4T to TDF, but not to ABC, is associated with lipid improvements
Represents new treatment approach to lipid management
NRTIs are associated with few clinically important drug interactions, and most can be managed by dose modification rather than drug substitution
Exception: Patients planning to start hepatitis C therapy with ribavirin recommended to switch from ddI to an alternative NRTI
Metabolic Complications
NRTI Backbone
Toxicities Occurring in Several NRTIs

Lactic Acidosis
All NRTIs carry black box warning: lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination.
Lipodystrophy
Significantly more prevalent in HAART era, especially with regimens containing NRTIs Advisory warning for lipodystrophy now included in labeling for all antiretrovirals
Distal Symmetric Polyneuropathy
NRTI Backbone
NRTI-Associated Lactic Acidosis

Usually occurs 1 to 20 months after initiating NRTI Potential risk factor:
Female sex, obesity, prolonged exposure to NRTIs Acute infection and pregnancy may also put patient at risk Unclear which asymptomatic patients are at risk for acidosis
Risk increases with number of NRTIs used and with concomitant use of d4T, ddI, and hydroxyurea d4T, ddI, and perhaps AZT should be avoided in patients who have recovered from lactic acidosis After resolution of symptoms, many patients can tolerate NRTI-containing regimens, especially ABC or 3TC and probably also FTC and TDF
NRTI Backbone
NRTI-Associated Lipodystrophy
No universal case definition for lipodystrophy Typically involves the following, either separately or together
Accumulation of visceral fat in the abdomen (central obesity), dorsocervical area (buffalo hump), and breasts Loss of subcutaneous fat in the face, extremities, and buttocks Metabolic disturbances
Dyslipidemias
High levels of triglycerides, total cholesterol, LDL cholesterol Low HDL cholesterol
Insulin resistance
Diabetes mellitus Glucose intolerance
NRTI Backbone
HIV Outpatient Study: Risk Factors for Lipodystrophy

A number of risk factors apart from antiretroviral therapy contribute to lipodystrophy, including:
Age > 40 years History of AIDS > 3 years CD4+ cell count nadir < 100 cells/mm3 or CD4+ % nadir < 15% Body mass index (BMI) loss of 1 kg/m2 BMI change of 2 kg/m2 White race
Duration of treatment with indinavir or stavudine associated with increased risk of lipodystrophy, but only in presence of other risk factors
Lichtenstein KA, et al. J Acquir Immune Defic Syndr. 2003;32:48-56.
NRTI Backbone
A5005 Study: Change in Limb Fat by NRTI Assignment

ITT Analysis N = 156 20 10 0 -10 -20

ZDV/3TC ddI + d4T
-30
Entry 16
*
32 48 Study Week 64 80
*P < .05 between groups; P < .05 within groups

Dub et al. 4th Lipodystrophy Workshop, 2002. Abstract 27.
NRTI Backbone
TARHEEL Study: Effect of Switching d4T to ABC or AZT on Fat Quantities

Arm fat Leg fat Trunk fat
40
Median % Change from Baseline 30 20 10 0 -10
0 12
Week
24
48
McComsey G, et al. ICAAC 2002. Abstract 1929.
NRTI Backbone
Summary of NRTI-Related Adverse Events

Generic Name (Abbreviation)
Zidovudine (AZT/ZDV)
Year Approved
1987
Common Adverse Events* Gastrointestinal (GI) intolerance, headache, insomnia, asthenia Bone marrow suppression, anemia, neutropenia
Zalcitabine (ddC)
Lamivudine (3TC) Emtricitabine (FTC) Tenofovir DF (TDF)
1992
1995 2003
Peripheral neuropathy Stomatitis

Minimal side effects/toxicity Minimal side effects/toxicity Skin discoloration/hyperpigmentation, primarily on palms and soles Asthenia, headache, diarrhea, nausea, vomiting, flatulence
2001
* NRTIs have warning regarding lactic acidosis and hepatic steatosis (rare but potentially life-threatening)
CDC. MMWR Recommend Rep. 2002;51(RR-7); March 17, 2002.
NRTI Backbone
Summary of NRTI-Related Adverse Events

Generic Name (Abbreviation)
Didanosine (ddI, ddI EC)
Year Approved
1991
Common Adverse Events* Nausea/diarrhea, bloating Pancreatitis Peripheral neuropathy Cautious use with stavudine during pregnancy
Stavudine (d4T, d4T XR)
1994
Pancreatitis Peripheral neuropathy Cautious use with didanosine during pregnancy Nausea, GI disturbances HSR (potentially fatal on rechallenge)
Abacavir (ABC)
1998
* NRTIs have black box warning regarding lactic acidosis and hepatic steatosis (rare, potentially life-threatening) Fatal and nonfatal pancreatitis has occurred with ddI alone or in combination with d4T or d4T plus hydroxyurea Pregnant women may be at increased risk for lactic acidosis and liver damage when treated with d4T + ddI Patients who experience signs or symptoms of hypersensitivity should discontinue ABC immediately. ABC should not be restarted
CDC. MMWR Recommend Rep. 2002;51(RR-7); March 17, 2002.
NRTI Backbone
Summary - Implications for Clinical Practice

As a class, NRTIs are associated with mitochondrial toxicity and potentially related clinical syndromes
Lactic acidosis, hepatic steatosis, and possibly lipodystrophy
Some NRTIs have side effects that may be severe or treatment-limiting

These include AZT, d4T, ddI, ddC, and ABC
Other NRTIs are generally well tolerated and have only limited toxicity
These include 3TC, TDF, and FTC
In selecting antiretroviral therapy, clinicians should consider each agents side-effect and toxicity data carefully prior to selecting which NRTIs to use
GS 903
Prevalence of Lipodystrophy and Mean Limb Fat Changes

p <0.001
% patients with lipodystrophy
20 18 16 14 12 10 8 6 4 2 0
p <0.001
19
12
4 1
Week 48
3 1
Week 96 Week 144
Total limb fat (mean): 96 weeks: TDF 7.9 Kg vs d4T 5.0 Kg (p<0.001) 144 weeks: TDF 8.7 Kg vs d4T 4.4 Kg (p<0.001)
Gilead Sciences: Data on file. Press release, February 2004.
GS 903
70
Change from baseline (mg/dL)
Cholesterol
60 50 40 30 20 10 0
Mean Change in Fasting Cholesterol and Triglycerides * *
160
Change from baseline (mg/dL)
140 120 100 80 60 40 20 0 -20 24 48 72 96 120 144
Triglycerides
Weeks
*Weeks 48, 96, 144, p <0.001
Gilead Sciences: Data on file. Press release, February 2004.
Other Complications
Renal Safety of Tenofovir DF
Several studies of renal safety[1-3]

Follow-up ranging from 48 weeks to 3 years Very little evidence of progressive renal dysfunction in pts with normal renal function at baseline
Some very slight decreases in renal function by very sensitive measure, despite no change in creatinine clearance[3]
1. Lewis et al. Abstract TuPeB4599. 2. Staszewski et al. Abstract WePeB5917. 3. Mauss et al. Abstract WePeB5941.
Other Complications
Gynecomastia
Largely related to hypogonadism[1]
After controlling for hypogonadism, no associations with antiretroviral therapy
Rate similar to that of general population
Preeclampsia
HIV infection independent risk factor for preeclampsia and infant death[2] Appears related to chronic maternal use of antiretrovirals, ie, before pregnancy
Osteonecrosis
Significant relationship between duration of exposure and osteonecrosis[3]

Also associated with low CD4+ cell count Note: No evidence that these are drug-related toxicities
1. Biglia et al. Abstract ThOrB1357. 2. Suy et al. Abstract ThOrB1359. 3. Mary-Krause et al. Abstract ThOrB1358.
Longer Duration of HAART Associated With Increased Incidence of Osteonecrosis

8 7 6 5 4 3 2 1 0
6.8
Incidence Ratio
5.1
2.9 1 1.5 3.2
3.4
Mary-Krause et al. Abstract ThOrB1358.
New Antiretrovirals and Novel Applications of Existing Agents
BI 1182.51: Tipranavir in Double-Boosted PI Regimens

Open-label, parallel-group, multicenter study N = 315 randomized
N = 296 included in interim analysis All twice daily

LPV/r + OB (400 mg/100 mg) (n = 79) APV/r + OB (600 mg/100 mg) (n = 76) SQV/r + OB (1000 mg/100 mg) (n = 75) TPV/r + OB (500 mg/200 mg) (n = 66)
TPV/r 500/100 mg added at 2 weeks Final RTV dose 200 mg in all arms
OB = optimized background regimen
Highly PI-resistant patients, excluded from phase 3 RESIST studies 3 PRAMS at baseline (codons 33, 82, 84, and/or 90 )
41- to 350-fold phenotypic resistance to PIs
Walmsley et al. Abstract WeOrB1236.
BI 1182.51: Tipranavir in Double-Boosted PI Regimens

Median VL change from baseline
Monotherapy TPV added to boosted LPV, APV, SQV
Ratio of PI concentrations with TPV: without TPV

Geometric Mean Ratio (+/- 90% Confidence Interval)
0 HIV RNA (log10 copies) -0.2 -0.4 -0.6
TPV/r TPV/SQV/r
TPV/APV/r TPV/LPV/r
1.2
1 0.8 0.6
APV
LPV
SQV
-0.8
-1 -1.2 -1.4 0 2 4 6 Weeks of Treatment
0.4
0.2 0 AUC
8
Cmax Cmin
Walmsley et al. Abstract WeOrB1236.
Activity of D-d4FC (Reverset) in Treatment-Experienced Patients

Previous data in naive pts: nearly 1.8 log VL reduction at day 10 New data on 8 experienced pts; mean -0.8 log VL reduction at day 10
200 mg QD 100 mg QD 50 mg QD Placebo
Naive pts Log10 Change in HIV-1 RNA 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 0
Experienced pts Log10 Change in HIV-1 RNA 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 0
Dosing Period
200 mg QD
Dosing Period
10
20 Days
30
40
10
20 Days
30
40
Murphy et al. Abstract MoOrB1056.
Monotherapy With UK-427,857: a Novel CCR5 Inhibitor

25 mg QD mean
1 0.5 0 -0.5 -1 -1.5 -2 -2.5 -3

0 1000 2000 3000
VL Reduction, Day 11
100 mg QD mean 150 mg BID fasted mean Observed
100 mg BID mean 150 mg BID fed mean 150 mg BID mean Predicted
50 mg BID mean 300 mg QD mean
4000
5000
6000
7000
8000
9000
AUC24 (ng/mLh)
Relationship between AUC and antiviral activity

Doses 1000 mg QD or BID 1 log VL reduction at day 11
50% reduced bioavailability with food, but no in antiviral activity
Ftkenheuer et al. Abstract TuPeB4489.
Other New Entry Inhibitors

Novel CCR5 inhibitor: 873140[1]
Limited interassay variability in different cell lines and viruses Difficulty selecting resistance in serial passage No evidence of switch in coreceptor usage in vitro
Small molecule fusion inhibitors[2]

In vitro activity similar to enfuvirtide Potential for oral administration
Oral CXCR4 inhibitor: KRH-2731-5HCl[3]

Potent activity against X4 HIV-1 in SCID mice Further safety and PK studies ongoing
Oral CXCR4 inhibitor: AMD070[4]

PK profiling in seronegative patients
1. Demarest et al. Abstract WeOrA1231. 2. Jiang et al. Abstract WeOrA1232. 3. Murakami et al. Abstract LbOrA01. 4. Stone et al. Abstract TuPeB4475.
Novel Applications of Tenofovir

Oral tenofovir for protection from oral SIV transmission[1]
Oral tenofovir protected infant macaques against SIV infection by oral exposure Supports studies of TDF prophylaxis against HIV from breast milk
Tenofovir vaginal gel[2]

Safety and tolerability in HIV-infected and HIV-uninfected women
Trials under way exploring oral tenofovir as pre-exposure prophylaxis against sexual transmission
1. Van Rompay et al. Abstract LbOrB10. 2. Mayer et al. ThOrB1373.
Coverage of Adults on Antiretroviral Treatment as of June 2004

WHO region Africa Americas Europe (Eastern Europe, Central Asia) Eastern Mediterranean South East Asia Western Pacific All WHO regions Number of people on treatment 150,000 220,000 11,000 Estimated need Coverage 3,840,000 410,000 120,000 4% 54% 9%
4,000 40,000 15,000 440,000
100,000 860,000 170,000 5,500,000
4% 5% 9% 8%
CDC AIDS mortality data

60000 50000 40000 30000 20000 10000 0 1993 1994 1995 1996 1997 1998 1999 2000
Access to treatment
90% of cases of HIV infection worldwide are in the developing world. > 10 million HIV-infected individuals are without access to antiretroviral therapy. Cost reduction: Role of advocacy groups. Controversial effects on research and drug development.
Conclusions
HIV/AIDS continues to spread. There is a treatment, but no cure. It is never late for active prevention and management programs, based on understanding, human rights, and access to care.
NEJM 2002;347:553
Conclusion
The heart of the problem:
Human rights. Women rights. Sexual rights.
AIDS is a social disease before being a disease of the immune system.
Thankyou

AIDS Presentation Damascus Oct 2004

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AIDS Presentation Damascus Oct 2004

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The Acquired Immunodeficiency Syndrome

Damascus, October 2004

Human Immunodeficiency Virus

Acquired Immunodeficiency syndrome first described in 1981

pol - p16 (protease), p31 (integrase/endonuclease)

Stages of Retrovirus Reproduction

Mc Clure et al, 1988; Geijtenbeek et al, 2000

Moore et al, 1997; Berger et al, 1998

Berger et al, 1999

Moore et al, 1998

HIV Viral Dynamics

HIV Viral Dynamics

HIV Viral Dynamics

Normal cellular immune response to HIV

Autran, CROI 2002

Manifestations of an activated immune system in HIV infection (1)

Manifestations of an activated immune system in HIV infection (2)

Host factors favoring replication

Perelson, Ho, CROI 2002

Perelson, Ho, CROI 2002

Mechanisms of CD4+ T cell dysfunction and depletion

Mechanisms of CD4+ T cell dysfunction and depletion

CD4+ cell depletion

Miedema et al, CROI 2002

CD4+ cell depletion

Miedema et al, CROI 2002

In chronic HIV infection

Autran, CROI 2002

Effect on HIV specific CTLs

Autran, CROI 2002

Effect of HAART on T-cell turnover

Perelson, Ho, CROI 2002

Effect of therapeutic interventions on T-cell proliferation

Kovacs, CROI 2002

Viral dynamics of HIV infection

What about the reservoir?

HIV reservoirs and eradication

Richman, CROI 2002

Reservoirs in the lymphoid system

Richman, CROI 2002

Richman, CROI 2002

Richman CROI 2002

The genital tract

Richman, CROI 2002

Spread of the epidemic

Extension to younger groups

Over 5 millions new cases per year

Tableau Recapitulatif de lEpidemie de VIH/SIDA dans le Monde

Nombre de personnes vivant avec le VIH/SIDA

Total Adultes Enfants < 15ans

40 millions (34-46) 37 millions (31-43) 2.5 millions (2.1-2.9)

Nouveaux cas dinfection a VIH en 2003

Deces dus au SIDA en 2003

OMS / ONUSIDA Decembre 2003

Viral genetic variability

Geographical distribution of HIV-1 major (M) group subtypes

* CRF = circulating recombinant form

Geographical distribution of HIV-1 major (M) group subtypes

* CRF = circulating recombinant form

Geographical distribution of HIV-1 major (M) group subtypes

Impact of genetic diversity

Hahn, CROI 2002

The African Monkey Connection