Académique Documents
Professionnel Documents
Culture Documents
Jacques E. Mokhbat, MD
Division of Infectious Diseases
HIV particles
HIV Genome
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.
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
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.
Conformation changes
Interaction between gp120 and the chemokine receptor. Unmasking of epitopes of gp120 and gp41 (even shedding of gp120).
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 is completely dependent upon CD4 cells for replication and survival.
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.
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.
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
Aberrant intracellular signaling events Syncitium formation Autoimmunity Superantigenic stimulation Innocent bystander killing of viral antigen-coated cells Accelerated apoptosis Inhibition of lymphopoiesis
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.
2.2 days 10.3 x 109 virions/d 1.2 days 0.3 days 0.9 days 2.6 days
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.
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.
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.
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.
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.
Total 3 milliions (2.5-3.5) Adultes 2.5 millions (2.1-2.9) Enfants < 15 ans 500,000 (420-580)
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.
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.
5
5 01955
4
98036-E-23 1 December 1999
Modes of transmission
Sexual Injecting drug use Mother-to-child Blood and blood products Contaminated needles and sharps (health care workers)
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.
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.
Heterosexual transmission
Anatomic and local risk factors
Sexually transmitted diseases (ulcerative or non-ulcerative diseases) Genital tract inflammation. Lack of circumcision. Cervical ectopy Leukocytospermia. Hormonal contraception ?
Heterosexual transmission
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.
Heterosexual transmission
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???
Heterosexual transmission
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.
Heterosexual transmission
Sexual activity during menses. Receptive anal intercourse. Bleeding during intercourse. Lack of barrier protection.
Heterosexual transmission
Prevention
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.
87
Maternal-fetal transmission
Maternal factors
Primary HIV infection Viral phenotype (syncitium inducing) Viral genotype (virulent clade)
Maternal-fetal transmission
Maternal factors
Maternal-fetal transmission
Maternal factors
Older maternal age Cigarette smoking and illicit drug use during pregnancy Breast-feeding Unprotected sexual intercourse with multiple partners
Maternal-fetal transmission
Fetal, placental or labor factors
Chorioamnionitis Prematurity Low birth weight Cervicovaginal viral load Local HIV-specific immune response Maternal-fetal transfusion of blood
Maternal-fetal transmission
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
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.
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.
- Diarrhea
- Nausea or vomiting
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.
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)
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.
Opportunistic Infections
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).
Opportunistic Infections
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.
Opportunistic Infections
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.
Opportunistic Infections
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
Opportunistic Infections
<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
Opportunistic Infections
<50 cells/cmm CD4 count
cytomegalovirus
type
viral
bacterial
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)
GI and hepatic
Esophagitis Hepatitis Cholecystitis Enteritis Colitis Proctitis
Malignancies
Kaposis sarcoma Non Hodgkin lymphoma and primary brain lymphoma Hodgkins lymphoma Other solid malignancies
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)
Pneumocystis Pneumonia
DHS/HIV/PP
Pneumocystis Pneumonia
New Developments
Basic Science - Pneumocystis carinii changed to Pneumocystis jiroveci* - Characterization of 14- demethylase enzyme
DHS/HIV/Clin Manifestations/PP
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
Setting
Primary Prophylaxis
Secondary Prophylaxis
Criteria
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
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
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
DHS/HIV/PP
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?
Setting
Primary Prophylaxis Secondary Prophylaxis
Criteria
CD4 > 100 for > 3 months
CD4 > 100 for > 6 months and Completed 12 months MAC RX and Asymptomatic for MAC
DHS/HIV/OIs/PP
Cytomegalovirus
DHS/HIV/PP
Valganciclovir (Valcyte)
Non-progressor %
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
DHS/OIs/HIV
Setting
Primary Prophylaxis
Secondary Prophylaxis
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
CMV retinitis
Progressive , Necrotizing Unilateral Bilateral Blurred vision, floaters, loss of vision Fundoscopy: White, fluffy, granular lesions Perivascular white exsudates Retinal hemorrhages
Esophageal Candidiasis
DHS/HIV/PP
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
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
2 Week Lumbar Puncture with Negative Culture
1 2 3
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%
Pseudomonas aeruginosa Moraxella catarrhalis Streptococcus pyogenes (Group A) Nocardia Legionella Rhodococcus equi Chlamydia pneumoniae
Pneumocystis carinii Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Aspergillus Blastomyces dermatitidis Penicillium marneffei
Histoplasma capsulatum Cryptococcus neoformans Coccidioides immitis Candida albicans Pneumocystis carinii Penicillium marneffei
Schistosoma
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.
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
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.
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
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
Abstract: MoOr103
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 ?
Virologic failure Suboptimal suppression Before initiating therapy ? In case of occupational exposure ?
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
Asymptomatic
Asymptomatic
350
350
220
221
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
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
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
2000
Convenience/ Tolerability
Minimize Adverse Experiences Maximize Adherence
2002
Efficacy + Convenience/ Tolerability
Manage Total Patient Health
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
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
Nucleoside reverse transcriptase inhibitors (NRTI) Non-nucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors (PI) Nucleotides Entry inhibitors
Fixed combinations
Zidovudine/Lamivudine
Zidovudine/Lamivudine/Abacavir
Lamivudine/Abacavir Tenofovir/Emtricitabine
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
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).
*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.
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.
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)
*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.
NRTI 1
Lamivudine
NRTI 2
Zidovudine or Tenofovir DF or Stavudine Emtricitabine Zidovudine or Tenofovir DF or Stavudine Lamivudine or Didanosine or Emtricitabine abacavir
PI based regimens
PI
Preferred regimens
Alternative regimens
NRTI 1
Lamivudine
NRTI 2
Zidovudine or Stavudine
Lopinavir/ ritonavir
Atazanavir
Alternative regimens
Alternative regimens
Fos amprenavir
Fos amprenavir/ ritonavir
PI based regimens
PI
Alternative regimens Alternative regimens Indinavir/ ritonavir Lopinavir/ ritonavir
NRTI 1
Lamivudine or Emtricitabine Emtricitabine
NRTI 2
Zidovudine or Stavudine or Abacavir Zidovudine or Stavudine or Abacavir
Alternative regimens
Alternative regimens Alternative regimens
Lopinavir/ ritonavir
Nelfinavir
Lamivudine
Lamivudine or Emtricitabine Lamivudine or Emtricitabine
US DHHS, April 2004
Abacavir
Zidovudine or Stavudine or Abacavir Zidovudine or Stavudine or Abacavir
Saquinavir/ ritonavir
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)
Enfuvirtide
Dual therapy
Abacavir + Tenofovir + Lamivudine Tenofovir + Didanosine + Lamivudine
PI Activity Stavudine + Didanosine Toxicity Efavirenz in pregnancy Toxiciy Amprenavir oral solution Propylene glycol (pregnancy, pediatrics, renal or liver failure)
Stavudine + Zalcitabine
Didanosine + Zalcitabine Atazanavir + Indinavir
Toxicity
Toxicity Toxicity
Emtricitabine + Lamivudine
Hydroxyurea
Resistance
Poor efficacy,
toxicity
NRTI Backbone
60
40 20 0
73% 69%
24
48
72
96
120
144
Weeks
Gallant JE, et al. XV IAC Bangkok, 2004. Abstract TuPeB4538.
80
60 40
73% 69%
Weeks
Gallant et al. Abstract TuPeB4538.
134
Change from Baseline (mg/dL)
151
90
103
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
16 12 7
n = 299
4 4
1
0-48 Weeks
2 0
96-144 Weeks
* K103N, V106M, Y188C/L G190A/S/E/Q
48-96 Weeks
EFV+IDV
n = 429
IDV+AZT+3TC
n = 415
ITT, M=F analysis: Proportion of subjects with response according to TLOVR definition of treatment success. Tashima et al. Abstract TuPeB4547.
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
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%
SOLO Study: Virologic Response at Week 48 by Baseline Viral Load and CD4+ Count
fAPV/r vs NFV in treatment-naive patients
fAPV/r QD
69% 68%
74%
55% 44% 53%
60%
40% 20% 0%
Overall High VL / Low CD4
Overall
< 50 c/mL
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
NRTI Backbone
74% Week 96
78% Week 96
66-68% Week 48
* Median follow-up of 48 weeks; study stopped due to virologic inferiority and increased toxicity of d4T/ddI comparator arm
NRTI Backbone
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
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
400 20,000
989
> 20,000
722
6%
7% P = 0.5
26% P = 0.001
Deaths
2%
2%
9% P < 0.001
NRTI Backbone
8%
n = 25
20%
n = 61
58% 14%
n = 44 n = 182
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
Lamivudine emtricitabine
Interest due to anticipated availability of TDF/FTC coformulation
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.
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
CONVENIENCE / TOLERABILITY
EFFICACY
EFFICACY
CONVENIENCE / TOLERABILITY
EFFICACY
STO 2002-W-6148-SS
STO 2002-W-6148-SS
% of Adherence
The program proposed by the physician: adherence to antiretrovirals The patient wants to adhere to life
STO 2002-W-6148-SS
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
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
20 0
4 8 16
SAT <400
24
32
48
64
72
80
Week
STO 2002-W-6148-SS
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, %
STO 2002-W-6148-SS
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
NRTI Backbone
10
20
30
40
46 45
50
52
60
27 20 20 19 19 18 17 17 16 14 13 10 9
NRTI Backbone
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
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
adherence All in the team should convey adherence message Train the health team on adherence enforcing and monitoring
Once-daily Antiretrovirals
6 ARVs approved as low pill number,
once-daily therapies:
Atazanavir
Didanosine
Efavirenz Emtricitabine
Lamivudine
Tenofovir
DF
daily agent
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
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
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
Day 1
Day 2+
MONOTHERAPY
Zone of potential replication IC90 IC50
36 48
12
24 Time (Hours)
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
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
Lipodystrophy
Significantly more prevalent in HAART era, especially with regimens containing NRTIs Advisory warning for lipodystrophy now included in labeling for all antiretrovirals
NRTI Backbone
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
Duration of treatment with indinavir or stavudine associated with increased risk of lipodystrophy, but only in presence of other risk factors
NRTI Backbone
-30
Entry 16
*
32 48 Study Week 64 80
NRTI Backbone
40
Median % Change from Baseline 30 20 10 0 -10
0 12
Week
24
48
NRTI Backbone
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
2001
* NRTIs have warning regarding lactic acidosis and hepatic steatosis (rare but potentially life-threatening)
NRTI Backbone
Year Approved
1991
Common Adverse Events* Nausea/diarrhea, bloating Pancreatitis Peripheral neuropathy Cautious use with stavudine during pregnancy
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
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
20 18 16 14 12 10 8 6 4 2 0
TDF+3TC+EFV d4T+3TC+EFV
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
Cholesterol
60 50 40 30 20 10 0
TDF+3TC+EFV d4T+3TC+EFV
160
Triglycerides
Weeks
Other Complications
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
Preeclampsia
HIV infection independent risk factor for preeclampsia and infant death[2] Appears related to chronic maternal use of antiretrovirals, ie, before pregnancy
Osteonecrosis
1. Biglia et al. Abstract ThOrB1357. 2. Suy et al. Abstract ThOrB1359. 3. Mary-Krause et al. Abstract ThOrB1358.
Incidence Ratio
5.1
2.9 1 1.5 3.2
3.4
TPV/r 500/100 mg added at 2 weeks Final RTV dose 200 mg in all arms
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
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
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
VL Reduction, Day 11
100 mg BID mean 150 mg BID fed mean 150 mg BID mean Predicted
4000
5000
6000
7000
8000
9000
AUC24 (ng/mLh)
1. Demarest et al. Abstract WeOrA1231. 2. Jiang et al. Abstract WeOrA1232. 3. Murakami et al. Abstract LbOrA01. 4. Stone et al. Abstract TuPeB4475.
Trials under way exploring oral tenofovir as pre-exposure prophylaxis against sexual transmission
4% 5% 9% 8%
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.
Thankyou