LESSON 8
HIV/AIDS – IN UKRAINIAN, THEIR MAIN CLINICAL FEATURES. DERMATOLOGICAL ASPECTS OF THIS PROBLEM. PRINCIPLES OF PROPHYLAXIS AND THERAPY.
UKRAINE HIV/AIDS STATISTICS
http://crossroads.org.ua/index.php?option=com_content&view=article&id=91:ukraine-hivaids-statistics&catid=26:2008-10-03-09-38-53&Itemid=75
Ukraine has one of the most severe HIV/AIDS epidemics in Europe, contributing nearly 21 percent of the newly reported HIV diagnoses in 2006 in the Europe and Eurasia (E&E) region. Ukraine’s first case of HIV/AIDS was detected in 1987, and the epidemic appeared to be confined to a small population of foreign students until the mid-1990s, when a sudden and explosive epidemic emerged among injecting drug users (IDUs) in the southern and eastern regions of the country. The Joint United Nations Program on HIV/AIDS estimated that 440,000 people were living with HIV/AIDS at the end of 2007, representing 1.6 percent of the population. The Ukraine National Council on TB and HIV/AIDS estimated adult prevalence of HIV had decreased to 1.28 percent by 2009. While prevalence appears to have decreased due to overall population growth, the number of new cases continues to increase.
Since 2002, USAID/Ukraine has worked with the Government of Ukraine, other donors, multilateral and international agencies, nongovernmental organizations and the private sector to prevent transmission of HIV and contain the spread of HIV among most at risk populations (MARPs). The current U.S. Government programs support Government of Ukraine efforts to strengthen the HIV/AIDS policy and legislative environment; provide prevention and care information and services for MARPs, reaching IDUs (including access to methadone-based assisted treatment), commercial sex workers, and men who have sex with men; reduce the stigma and discrimination associated with HIV/AIDS; and build governmental and nongovernmental capacity to plan, implement, manage, and monitor Ukraine’s National AIDS Program.
Human Immunodeficiency Virus (HIV) Infection
http://emedicine.medscape.com/article/211316-overview
http://www.youtube.com/watch?v=hdgNnXLY8LU
http://www.emedicinehealth.com/slideshow_pictures_hiv_aids_myths_and_facts/article_em.htm
is a progressive process that mostly leads to the development of Acquired Immune Deficiency Syndrome(AIDS).
Ú The first cases of AIDS occurred in the USA in 1981.
Ú AIDS is caused by the virus HIV.
Ú HIV is part of a family or group of viruses called lentiviruses.
Where do viruses come from?
Three major mechanisms have been proposed for the evolution of viruses:
1. ‘Escaped gene’ theory:
Viruses derive from normal cellular nucleic acids and ‘gain independence’ from the cell. DNA viruses could come from plasmids or transposable elements, while RNA viruses could derive from mRNA.
2. Regressive theory:
Gradual degeneration of procaryotes living parasitically in eucaryotic cells. Enveloped forms such as poxviruses are most likely to have been formed in this way.
3. Coevolution theory:
Independent evolution alongside cellular forms from primordial soup. Some scientists consider it unlikely that the same mechanism could account for the diversity of viruses we see today, and therefore propose that viruses must have evolved many times over. A study published in 2004 conversely proposes that all viruses share a common ancestor and may even have developed before cellular life forms.
How many people does HIV/AIDS affect?
AIDS is the sixth leading cause of death among people aged 25 – 44 in the United States. This is an improvement since it was the number one killer in 1995.
At the end of 2010, an estimated 91,500 people in the UK were living with HIV. Of these, around 1 in 4 (22,000 in total) did not know they were infected.
The World Health Organization (WHO) estimates that around 34 million people in the world are living with HIV. The virus is particularly widespread in sub-Saharan African countries, such as South Africa, Zimbabwe and Mozambique.
The population groups at risk:
AIDS has almost exclusively been a disease of certain ‘at risk ’groups of population viz:
Homosexuals;
Parenteral drug abusers;
Haitians;
Haemophilics;
Those receiving repeated blood products transfusions;
Heterosexual partners of AIDS victims;
Offsprings of AIDS victims;
Other contacts of AIDS victims, like the laboratory technicians and doctors.
HIV DISEASE
Background
Human immunodeficiency virus (HIV) is a blood-borne, sexually transmissible virus (see the image below.) The virus is typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding.
The most common route of infection varies from country to country and even among cities, reflecting the population in which HIV was introduced initially and local practices. Co-infection with other viruses that share similar routes of transmission, such as hepatitis B, hepatitis C, and human herpes virus 8 (HHV8; also known as Kaposi sarcoma herpes virus [KSHV]), is common.
Two distinct species of HIV (HIV-1 and HIV-2) have been identified, and each is composed of multiple subtypes, or clades. All clades of HIV-1 tend to cause similar disease, but the global distribution of the clades differs. This may have implications on any future vaccine, as the B clade, which is predominant in the developed world (where the large pharmaceutical companies are located), is rarely found in the developing countries that are more severely affected by the disease.
HIV-1 probably originated from one or more cross-species transfers from chimpanzees in central Africa.HIV-2 is closely related to viruses that infect sooty mangabeys in western Africa.[Genetically, HIV-1 and HIV-2 are superficially similar, but each contains unique genes and its own distinct replication process.
HIV-2 carries a slightly lower risk of transmission, and HIV-2 infection tends to progress more slowly to acquired immune deficiency syndrome (AIDS). This may be due to a less-aggressive infection rather than a specific property of the virus itself. Persons infected with HIV-2 tend to have a lower viral load than people with HIV-1, and a greater viral load is associated with more rapid progression to AIDS in HIV-1 infections.
HIV-2 is rare in the developed world. Consequently, most of the research and vaccine and drug development has been (perhaps unfairly) focused on HIV-1.
Initial description and early spread
In the United States, HIV disease was first described in 1981 among 2 groups, one in San Francisco and the other in New York City. Numerous young homosexual men presented with opportunistic infections that, at the time, were typically associated with severe immune deficiency: Pneumocystis pneumonia (PCP) and aggressive Kaposi sarcoma.
HIV itself was not identified for another 2 years.During that time, various other causes were considered, including lifestyle factors, chronic drug abuse, and other infectious agents.The HIV epidemic spread rapidly and silently in the absence of testing.
However, clear clinical implications arose before society became aware of the disease; for example, prior to the recognition of HIV, only one case of Pneumocystis pneumonia not clearly associated with immune suppression was diagnosed in the United States between January 1976 and June 1980. In 1981 alone, 42 similar diagnoses were made, and by December 1994, 127,626 cases of Pneumocystis pneumonia with HIV infection as the only identified cause of immune suppression had been reported to the Centers for Disease Control and Prevention (CDC). Also, Kaposi sarcoma is up to 30,000 times more likely to develop in persons with HIV infection than in immunocompetent persons.
The spread of HIV was retrospectively shown to follow the trucking routes across Africa from logging camps, and the bush-meat trade combined with aggressive logging and improved transportation in the mid-20th century may have allowed what was likely occasional cross-species transmission events to propagate across the country and, eventually, the globe.
Stigma of HIV infection
A considerable amount of stigma has been attached to HIV infection, mostly because of the virus’s association with sexual acquisition and the inference of sexual promiscuity. Consequences of this stigma have included discrimination and reluctance to be tested for HIV infection. The stigma of HIV infection is also associated with a fear of acquiring a rapidly fatal infection from relatively casual contact.
Such attitudes are inappropriate because HIV is poorly transmissible without sexual contact or blood contact. In addition, the expected survival is long in patients with HIV infection who are receiving treatment. HIV is not transmitted during casual contact and is readily inactivated by simple detergents. Much of the concern regarding HIV infection is due to the incurability of the infection and the relentless immune decline and eventual premature death in the vast majority of infected people.
AIDS denialism
A small but vocal minority of people, including some scientists, continue to argue that HIV does not exist, or does not cause AIDS, and that the HIV tests are unreliable or that the therapies are toxic. Such misinformation is usually based on a lack of understanding of the scientific literature, deliberate misrepresentation, or logical fallacies based on pseudoscientific arguments.
All of the arguments proposed by these dissenters have been addressed and rebutted in the scientific literature and public discussion and even tested and rejected in the legal system. Nevertheless, they persist, and such views can have extremely harmful effects on people who are exposed to HIV infection unnecessarily or who refuse treatment for their progressing infection.
Clinicians should be aware of these issues, should be able and willing to address misinformation, and should direct their patients to reliable sources of information.
Political denial and inaction have also likely caused considerable damage. Several governments in countries with high HIV infection rates were slow to admit that they had an HIV epidemic, and at least one (South Africa) initially rejected that AIDS was even a problem, then that the disease was caused by HIV infection, and, most recently, that antiretroviral therapy was effective in treating HIV infection and preventing MTCT. Changes have now occurred but have been slow and have cost hundreds of thousands of lives.
A regularly updated reference for addressing AIDS denial and misinformation can be found at AIDSTruth.org.
The quest for understanding of HIV
Since the discovery of HIV and its link to AIDS, great strides have been made in understanding its biology and in developing effective treatments. The difficulty in dealing with HIV on a global scale is largely due to the fact that HIV infection is far more common in resource-poor countries.
In the developed world, antiretroviral therapy has greatly improved prognosis and increased survival rates. Public education programs have raised awareness such that testing and prevention of infection are more common. Both of these approaches are difficult in countries with undereducated or underfunded populations.
A thorough discussion of the history of AIDS and the biologic link between HIV and AIDS can be found in an article entitled ” The relationship between the human immunodeficiency virus and the acquired immunodeficiency syndrome ” at the National Institute of Allergy and Infectious Diseases Web site. The document was originally written in September 1995, prior to the advent of highly active antiretroviral therapy (HAART), which has significantly improved AIDS-free survival in persons infected with HIV. This version was updated March 2010.
Patient confidentiality
HIV-related health information is typically considered separate from other health information and may require separate consent to share or divulge.
Health care workers who are infected with HIV may be required to divulge their status to their employer or patients and may be restricted in the types of procedures they can perform.
Pathophysiology
HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4+ cells). The loss of CD4+ cells results in the development of opportunistic infections and neoplastic processes.
Virology of HIV
HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA.
HIV contains 3 species-defining retroviral genes: gag, pol, and env. The gag gene encodes group-specific antigen; the inner structural proteins. The pol gene encodes polymerase; it also contains integrase and protease (the viral enzymes) and is produced as a C-terminal extension of the Gag protein). The env gene encodes the viral envelope—the outer structural proteins responsible for cell-type specificity. Glycoprotein 120, the viral-envelope protein, binds to the host CD4+ molecule.
HIV-1 has 6 additional accessory genes: tat, rev, nef, vif, vpu, and vpr. HIV-2 does not have vpu but instead has the unique gene vpx. The only other virus known to contain the vpu gene is simian immunodeficiency virus in chimpanzees (SIVcpz), which is the simian equivalent of HIV. Interestingly, chimpanzees with active HIV-1 infection are resistant to disease.
The accessory proteins of HIV-1 and HIV-2 are involved in viral replication and may play a role in the disease process. The outer part of the genome consists of long terminal repeats (LTRs) that contain sequences necessary for gene transcription and splicing, viral packaging of genomic RNA, and dimerization sequences to ensure that 2 RNA genomes are packaged. (See the image below.)
The biologic basis for AIDS
The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS.
There is a specific decline in the CD4+ helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.Immune responses to certain antigens begin to decline, and the host fails to adequately respond to opportunistic infections and normally harmless commensal organisms. Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral).
The pattern of opportunistic infections in a geographic region reflects the pathogens that are common in that area. For example, persons with AIDS in the United States tend to present with commensal organisms such as Pneumocystis and Candida species, homosexual men are more likely to develop Kaposi sarcoma because of co-infection with HHV8, and tuberculosis is common in developing countries.
Gut-associated lymphoid tissue (GALT) plays a role in HIV replication. Although the portal of entry for HIV infection is typically through direct blood inoculation or exposure of the virus to genital mucosal surfaces, the GI tract contains a large amount of lymphoid tissue, making this an ideal site for HIV replication.
GALT has been shown to be a site of early viral seeding and establishment of the proviral reservoir. This reservoir contributes to the difficulty of controlling the infection, and efforts to reduce the levels of HIV provirus through sustained antiretroviral therapy (alone or in combination with interleukin-2 activation of resting HIV-infected T cells) have consistently failed.
A feature of HIV replication in GALT is that it is compartmentalized, even among different areas of the gut.Measurements of CD4+ T cells in GALT show relatively less reconstitution with antiretroviral therapy than that observed in peripheral blood.At least one report has suggested that early treatment may result in better GALT CD4+ T-cell recovery, but clinical data generally argue against early initiation of therapy, which has not been shown to improve long-term survival.
In addition, HIV replication can be detected even in patients with supposedly suppressed replication, as judged by plasma viral load measurements. CD8+ killer T-cell responses to HIV occur in GALT and do not decline with antiviral therapy as much as peripheral measurements do.These findings underscore the limitations of peripheral measurements in what is really a central viral replication.
One theory for the discrepancy between GALT and blood measurements is that ongoing viral replication in the lymphoid tissue, and the resulting immune activation, may actually hamper efficient CD4+ T-cell replenishment.
Studies of T-cell–replication kinetics have revealed that untreated HIV infection is characterized by rapid T-cell turnover but a defect in T-cell replication from the thymus. These changes can be reversed with effective long-term antiviral therapy, suggesting that they are due to a direct effect of the virus or are a feature of the immune response against HIV.
It is known that normal cell cycling is necessary to produce a normal cytokine profile and that HIV causes cell-cycle arrest. Whether this is the exact mechanism is unresolved, however. Analysis of cytokine levels in HIV infected, uninfected, and HAART-treated patients with HIV show that cytokines involved in T-cell homeostasis were definitely affected, and therapy partially corrected these defects. In particular there was decreased IL-7, IL-12, IL-15 and FGF-2, and increased TNF-alpha and IP-10.
Several of the HIV proteins directly affect T-cell function, either by disrupting cell cycling or down-regulating the CD4 molecule. The loss of T cells is clearly a primary issue, as the T-cell repertoire narrows in terms of which antigens the immune system will recognize and respond to. Antiviral therapy is able to reverse these changes, but the degree of reversal is decreased if therapy is initiated very late in the infection and is further decreased when therapy is initiated when CD4 T-cell counts are 200/µL and below.
Direct cytotoxic effects of viral replication are likely not the primary cause of CD4 T-cell loss; a significant bystander effect is likely secondary to T-cell apoptosis as part of immune hyperactivation in response to the chronic infection. Infected cells may also be affected by the immune attack.
One interesting issue is that the co-receptor usage of the virus strains tends to change over time. The initial infectioearly always involves a strain that uses the chemokine receptor 5 (CCR5), which is found on macrophages and dendritic cells, as a co-receptor with CD4. People who are homozygous for deletions in the CCR5 gene (ie, CCR5-delta32) tend to be resistant to infection, and those with heterozygosity for the polymorphism tend to show slower progression of disease.
Over time, the receptor usage shifts to chemokine-related receptor (CXCR4) and other related receptors found on CD4+ T cells. These virus strains are more likely to cause cell fusion (syncytia formation). This trend is far from absolute but does correlate in many people with disease progression.
A single case report detailed a possible cure resulting from stem-cell transplantation from a CCR5-delta32 homozygous donor (performed to treat acute myelocytic leukemia). Although this important finding is unlikely to impact routine management of HIV infection, it does suggest that reconstitution of a host immune system with a population of mutant cells is a possible avenue of research to explore.
Regardless of the cause for the disruption, a loss of thymic replacements in the face of an induced state of immune activation and T-cell loss seems to be a key component of the mechanism by which HIV narrows the T-cell repertoire and progresses to AIDS.
Visible effects of HIV infection come in the form of disrupted lymph-node architecture. This disruption is temporal, and, at one point, lymph-node biopsy was considered as a form of staging the disease. The disruption of the follicular dendritic network in the lymph nodes and subsequent failure of normal antigen presentation are likely contributors to the disease process.
HIV replicates in activated T cells (its promotor contains a nuclear factor kappa B [NF-kappa-B]–binding region, the same protein that promotes other proteins in activated T cells and macrophages), and activated T cells migrate to the lymph nodes. As such, much of the viral replication occurs outside of the peripheral blood, even though serum viral load is still a useful surrogate marker of viral replication.
As mentioned above, with regards to GALT, HIV infection may be compartmentalized; specifically, areas of immune-privilege may occur such as in the testes and central nervous system where not only will there be differences in HIV pseudospecies but also different degrees of antiretroviral drug penetration. There is evidence that even with good peripheral control of HIV, the virus may still be detectable in the CSF and semen of some infected patients.
Phases of HIV infection
Clinical HIV infection undergoes 3 distinct phases: acute seroconversion, asymptomatic infection, and AIDS.
Acute seroconversion
Animal models show that Langerhans cells are the first cellular targets of HIV, which fuse with CD4+ lymphocytes and spread into deeper tissues. In humans, rapid occurrence of plasma viremia with widespread dissemination of the virus is observed 4-11 days after mucosal entrance of the virus.
There is no fixed site of integration, but the virus tends to integrate in areas of active transcription, probably because these areas have more open chromatin and more easily accessible DNA. greatly complicates eradication of the virus by the host, as latent proviral genomes can persist without being detected by the immune system and cannot be targeted by antivirals. See the image below.
During this phase, the infection is established and a proviral reservoir is created. This reservoir consists of persistently infected cells, typically macrophages, and appears to steadily release virus. Some of the viral release replenishes the reservoir, and some goes on to produce more active infection.
The proviral reservoir, as measured by DNA polymerase chain reaction (PCR), seems to be incredibly stable. Although it does decline with aggressive antiviral therapy, the half-life is such that eradication is not a viable expectation.
The size of the proviral reservoir correlates to the steady-state viral load and is inversely correlated to the anti-HIV CD8+ T-cell responses. Aggressive early treatment of acute infection may lower the proviral load, but generally, treatment iewly infected (but postseroconversion) patients yields no long-term benefit.
At this point, the viral load is typically very high, and the CD4+ T-cell count drops precipitously. With the appearance of anti-HIV antibodies and CD8+ T-cell responses, the viral load drops to a steady state and the CD4+ T-cell count returns to levels within the reference range, although slightly lower than before infection.
Seroconversion may take a few weeks, up to several months. Symptoms during this time may include fever, flulike illness, lymphadenopathy, and rash. These manifestations develop in approximately half of all people infected with HIV.
Asymptomatic HIV infection
At this stage in the infection, persons infected with HIV exhibit few or no signs or symptoms for a few years to a decade or more. Viral replication is clearly ongoing during this time, and the immune response against the virus is effective and vigorous. In some patients, persistent generalized lymphadenopathy is an outward sign of infection. During this time, the viral load, if untreated, tends to persist at a relatively steady state, but the CD4+ T-cell count steadily declines. This rate of decline is related to, but not easily predicted by, the steady-state viral load.
No firm evidence has shown that the initiation of therapy early in the asymptomatic period is effective. However, very late initiation is known to result in a less effective response to therapy and a lower level of immune reconstitution.
AIDS
When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. For surveillance purposes in the United States, a CD4+ T-cell count less than 200/µL is also used as a measure to diagnose AIDS, although some opportunistic infections develop when CD4+ T-cell counts are higher than 200/µL, and some people with CD4 counts under 200/µL may remain relatively healthy.
Many opportunistic infections and conditions are used to mark when HIV infection has progressed to AIDS. The general frequency of these infections and conditions varies from rare to common, but all are uncommon or mild in immunocompetent persons. When one of these is unusually severe or frequent in a person infected with HIV and no other causes for immune suppression can be found, AIDS can be diagnosed.
Immunologic control of HIV
The primary mechanism for immunologic control of HIV appears to be CD8+ cytotoxic T-cells. T-cell responses are correlated with the steady-state viral load and hence, the rate of progression. Cellular immunity is apparently responsible for some multiply-exposed, but uninfected individuals.
Although antibodies against HIV can be detected, it is clear that they are not sufficiently neutralizing to assist with immunologic control of the infection.
The role of NK (Natural Killer) cells may be important in the initial control of HIV. Escape mutations have been detected, implying that immunologic pressure on HIV exists from NK cells.
Opportunistic infections and conditions
Even after starting therapy and with effective suppression of viral load, patients with persistently low CD4 counts remain at high risk for opportunistic infections. In general, all patients remain at a relatively high risk for opportunistic infections and other AIDS-related events for the first 6 months of antiretroviral therapy.An observational study of 20,730 HIV patients in Uganda found that, among patients with more than six months of follow-up after the initiation of antiretroviral therapy, the pre-therapy CD4 count was still predictive of mortality.
Opportunistic infections and conditions include the following (* added in the 1993 AIDS surveillance case definition):
Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasive*
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (duration >1 mo)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with vision loss)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcer or ulcers (duration >1 mo) or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (duration >1 mo)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of the brain
Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary
M tuberculosis infection, any site (pulmonary* or extrapulmonary)
Mycobacterium infection with other species or unidentified species, disseminated or extrapulmonary
Pneumocystis pneumonia
Pneumonia, recurrent*
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of the brain
Wasting syndrome due to HIV infection
Although malaria is not typically considered an opportunistic infection, its incidence was found to be significantly higher among children in Tanzania that were perinatally infected with HIV than those without HIV infection. This was true for physician-diagnosed clinical malaria, probable malaria involving laboratory testing for parasitemia as well as malaria that was confirmed by blood smear.
There also appears to be an increased rate of anal cancer in high-risk groups (in particular, men who have sex with men). This is unsurprising considering the link between anal cancer and human papillomavirus (HPV), and the fact that cervical cancer, also caused by HPV, is considered an AIDS-defining condition.
HIV Encephalopathy is a severe condition usually seen in end-stage disease. Milder cognitive impairments may exist with less advanced disease. For example, one study found significant deficits in cognition, planning, coordination and reaction times in HIV-infected compared to uninfected children, effects that were more pronounced in those with higher viral loads.
HIV Disease Clinical Presentation
History
The history should be carefully taken to elicit possible exposures to human immunodeficiency virus (HIV).
Risk factors include the following:
Unprotected sexual intercourse, especially receptive anal intercourse (8-fold higher risk of transmission)
A large number of sexual partners
Prior or current sexually transmitted diseases (STDs): Gonorrhea and chlamydia infections increase the HIV transmission risk 3-fold, syphilis raises the transmission risk 7-fold, and herpes genitals raises the transmission risk up to 25-fold during an outbreak
Sharing of intravenous drug paraphernalia
Receipt of blood products (before 1985 in the United States)
Mucosal contact with infected blood or needle-stick injuries
Maternal HIV infection (for newborns, infants, and children): Steps taken to reduce the risk of transmission at birth include cesarean delivery and prenatal antiretroviral therapy in the mother and antiretroviral therapy in the newborn immediately after birth.
The patient may present with signs and symptoms of any of the stages of HIV infection. Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash. The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom.
AIDS manifests as recurrent, severe, and occasionally life-threatening infections and/or opportunistic malignancies. The signs and symptoms are those of the presenting illness, meaning that HIV infection should be suspected as an underlying illness when unusual infections present in apparently healthy individuals.
HIV infection itself does cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause).
Diagnostic Considerations
Human immunodeficiency virus (HIV) infection should be considered in any patient with unusual or recurrent serious infections without another cause, especially in those with risk factors for HIV infection.
Any of the opportunistic infections or cancers associated with acquired immune deficiency syndrome (AIDS) can also occur in the absence of HIV infection, although they usually develop in patients with some other form of immune suppression or defect. The possibility of HIV infection must be considered on a case-by-case basis. Other causes of immune suppression (eg, chemotherapy, immune disorders, severe combined immune deficiency [SCID], severe malnutrition) should be considered. For example, a young adult with leukemia undergoing chemotherapy is at high risk for many opportunistic infections.
4. Cutaneous Manifestations of AIDS
Ú There is no skin condition reported so far that is specific for HIV infection.
Ú During the course of HIV infection, skin diseases tend to be:
– more chronic,
– more severe,
– more resistant to conventional treatments,
– and often display unusual clinical presentations
TYPES OF CUTANEOUS MANIFESTATIONS
1. Infection
2. Non-specific dermatitis
3. Neoplasm
VIRAL INFECTIONS
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
A. Herpes Simplex
Severe, chronic, or recurrent infection with herpes simplex virus (HSV) can be a complication of HIV infection in children.
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Herpes Simplex |
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Perianal herpes simplex. Used with permission from the American Academy of Dermatology.
This series demonstrates a severe primary herpes stomatitis in an 18 year old male. Note the crusting at the vermillion border on both upper and lower lips, as well as the crusting herpes blister on the upper right lip. Also note the extremely red and swollen gingiva in all three images.
B. Herpes Zoster (Varicella-Zoster Virus)
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Herpes Zoster (Varicella-Zoster Virus) |
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* Occasionally, in children with immune deficiency, shingles can affect multiple dermatomes and/or both sides of the body. |
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Ú Hemorragic and necrotic lesions may occur in young-patients.
Severe hemorrhagic and necrotic lesions may extend over several dermatomes, or disseminated allover the body.
HIV should be considered in patients less than 40 years old presenting with herpes zoster. The typical presentation is a grouped vesicular (blistering) eruption involving one or more
dermatomes with prodromal pain.5,6 The lesions become pustular and haemorrhagic within a few days, then crusting and scaring occurs
C. Molluscum Contagiosum
Widespread molluscum contagiosum can occur in HIV-infected children but has been rarely noted since the introduction of HAART.
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Molluscum Contagiosum |
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D. Human Papillomavirus Infection
Recommendation:
When prepubescent children beyond infancy present with anogenital warts, clinicians should consider the possibility of sexual abuse.
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Human Papillomavirus Infection |
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Unusual location lip wart in HIV. Used with permission from Dr M Whitfeld of St Vincent’s Hospital, Sydney.
BACTERIAL INFECTIONS
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
Cellulitis, impetigo, ecthyma, and abscesses may occur in children with HIV infection.
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Bacterial Infections |
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Staph aureus
FUNGAL INFECTIONS
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
A. Candidiasis
Candidiasis may be an initial presentation of HIV disease. Oral thrush and recalcitrant monilial diaper dermatitis are the most common mucocutaneous manifestations of HIV infection in children.
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Candidiasis |
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Candidiasis (Moniliasis, Thrush) This HIV/AIDS patient presented with a secondary oral pseudomembranous candidiasis infection. Courtesy of Centers for Disease Control and Prevention/Sol Silverman, Jr., DDS
Angular Cheilitis
B. Dermatophyte Infection
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
HIV-infected children may develop severe or widespread tinea corporis or tinea capitis. They are also more likely to have onychomycosis or fungal infections of the nails.
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Dermatophyte Infection |
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T. corporis
PARASITIC INFECTIONS
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
Scabies
HIV-infected children with scabies may also develop crusted, or “Norwegian,” scabies. Children with crusted scabies harbor hundreds of mites and are extremely contagious to family members and healthcare workers.
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Scabies |
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Exaggerated scabies of the hand. Used with permission from HIV Treatment and Care, Family Health International, Vietnam.
Pruritic papular eruption
Left arm demonstrating the presentation of papular pruritic eruption (PPE) of HIV. Used with permission from Dr Toby Maurer of University of California, San Francisco.
INFLAMMATORY DERMATOSES
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
A. Seborrheic Dermatitis
Severe seborrheic dermatitis has beeoted in children with HIV infection. Although manifestations may be worse in HIV-infected children, the treatment is the same as in healthy children.
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Seborrheic Dermatitis |
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Axillary seb. Dermatitis
Photo of marked facial seborrhoeic dermatitis in the setting of HIV. Used with permission
from Dr Toby Maurer, University of California San Francisco.
CUTANEOUS MANIFESTATIONS OF DRUG REACTIONS
http://www.hivguidelines.org/clinical-guidelines/infants-children/dermatologic-manifestations/
Pharmacologic drug reactions are more common in HIV-infected children than in the general population, with the incidence of reaction to drugs increasing in proportion to the degree of the host’s level of immune dysfunction.The most common cause of drug-induced rashes is from antibiotics and ARV therapy. Among antibiotics, drug reactions resulting from trimethoprim/sulfamethoxazole (TMP/SMZ) are relatively common, although they are much less common in HIV-infected children than adults. Penicillins and cephalosporins are also common antibiotics resulting in exanthems. Although skin rashes are fairly common side effects of many ARV drugs, the most serious drug reactions that are associated with life-threatening situations have been ascribed to nevirapine, abacavir, and amprenavir.
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Cutaneous Manifestations of Drug Reactions |
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Mr AS is a 39-year-old man. He is a homosexual and has a history of injecting drug use.
Recently he has been given a course of penicillin antibiotic therapy for a newly diagnosed
penile syphilitic chancre. He has developed diffuse, total body erythema with an additional
rash on his hands and back following his first dose of antibiotics
Kaposi Sarcoma
Ú Red, purplish or brown colored macula’s, nodules or plaque.
Ú Common sites are trunk, legs, face and oral cavity.
Viral associated signs of HIV
Hairy Leukoplakia
Differential Diagnoses
Coccidioidomycosis (Infectious Diseases)
Lymphoma, High-Grade Malignant Immunoblastic
Mycobacterium Avium-Intracellulare
Approach Considerations
Screening for human immunodeficiency virus (HIV) infection is paramount, since infected individuals may remain asymptomatic for years while the infection progresses. Serologic tests are the most important studies in the evaluation for HIV infection.
Secondary testing that may be performed to assist with diagnosis or staging includes the following:
- Viral culture
- Lymph node biopsy
- Proviral DNA polymerase chain reaction (PCR)
- Genotyping of viral DNA/RNA
Staging of HIV disease is based partially on clinical presentation, but other laboratory tests can help in deciding whether to initiate or modify treatment.
Baseline laboratory studies for other infections (eg, tuberculosis) are important in the initial workup of a patient with newly diagnosed HIV infection. In addition, baseline levels of factors that may be affected by antiretroviral therapy (eg, lipids) should be measured.
Screening for HIV Infection
Citing the benefits of early diagnosis and treatment and the failure of risk-based screening to identify a substantial proportion of HIV-infected patients early in the disease, the American College of Physicians recommends that clinicians adopt routine screening for HIV and encourage all patients to be tested.
Screening assays
A high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) should be used for screening. Most ELISAs can be used to detect HIV-1 types M, N, and O and HIV-2.
A positive ELISA result should be followed with confirmatory testing in the form of one or more Western blot assays or similar specific assay. Specific diagnostic criteria vary by test. Results are typically reported as positive, negative, or indeterminate.
Testing for HIV-2 should be ensured for patients from an HIV-2 endemic area or those who have indeterminate results on HIV-1 Western blot testing. Not all HIV tests include detection of HIV-2 or Group O. In New York City, 62 cases of HIV-2 were detected over an 8-year period, of which 40 were initially misdiagnosed as HIV-1.
Early detection using combination screens may be more effective than simply using serology. The additional detection of p24 antigen or viral RNA may detect a greater number of very recent infections before seroconversion occurs. This would likely result in significant reductions in transmission as well as overall health costs and healthcare burden.
CD4+ T-cell Count
The CD4 T-cell count is a reliable indicator of the current risk of acquiring opportunistic infections. CD4 counts vary, and serial counts are generally a better measure of any significant changes. The reference range for CD4 counts is 500-2000 cells/μL. After seroconversion, CD4 counts tend to decrease (around 700/μL on average) and continue to decline over time. For surveillance purposes, a CD4 count under 200/μL is considered AIDS-defining in the United States owing to the increased risk of opportunistic infections at this level. The magnitude of discordance between absolute CD4 T-cell numbers and CD4 T-cell percentages is greatest in those with active hepatitis C virus and more advanced liver disease.
In children under five years of age, the CD4 T-cell percentage is considered more important than the absolute count. (Less than 25% is considered worthy of starting therapy, regardless of the total CD4 count). In adults with chronic hepatitis C and low absolute CD4 T-cells, the CD4 percentage may also be more useful, due to probable T-cell sequestration in the liver.
Viral Load
Viral load in peripheral blood is used as a surrogate marker of viral replication rate. This is a surrogate because most of the viral replication occurs in the lymph nodes rather than in the peripheral blood.
The test is a quantitative amplification of the viral RNA using nucleic acid sequence-based amplification (NASBA), reverse-transcription polymerase chain reaction (RT-PCR), or similar technologies. Quantitative viral-load assays should not be used as a diagnostic tool because several false-positive misdiagnoses have been reported in the literature.
The rate of progression to AIDS and death is related to the viral load, although, on an individual level, it is poorly predictive of the absolute rate of CD4 T-cell loss. Patients with viral loads greater than 30,000/μL are 18.5 times more likely to die of AIDS than those with undetectable viral loads.
With therapy, viral loads can often be suppressed to an undetectable level (ie, < 20-75 copies/mL, depending on the assay used); this is considered optimal viral suppression. At the same time, the CD4 count rises and the risk of opportunistic infections and death is reduced. Complete inhibition of viral replication appears impossible and may be unnecessary.
Not uncommonly, successfully treated patients will demonstrate intermittent viremia, with viral loads transiently detectable at low levels (typically, < 400 copies/mL); this appears to occur more commonly with some viral load assays than others. Such “blips” are not thought to represent viral replication or to predict virologic failure.Virologic failure is defined as a confirmed viral load of more than 200 copies/mL; although this is a research definition, it may be useful in clinical practice.
Secondary HIV Testing
Viral culture is expensive and time-consuming and is less sensitive in patients with low viral loads. Viral culture may be performed as part of phenotypic drug-resistance testing.
Lymph node architecture is disrupted during HIV infection. HIV DNA, RNA, and proteins may be detected with molecular techniques, and electron microscopy may reveal virions.
Proviral DNA PCR is usually performed only iewborns because conventional serologic testing is useless in these patients (maternal antibodies may persist for 9 months or longer). Two or more negative results separated by at least one month is considered a negative result.
Genotyping of viral DNA/RNA can guide therapy. Because patterns of mutations that lead to resistance to specific drugs or drug classes are now well-recognized, sequencing of the viral genome allows for the selection of specific antivirals that are more likely to elicit a response.
Baseline Studies
Baseline studies for other infections that are important in the initial workup of a patient with newly diagnosed HIV infection include the following:
Purified protein derivative (PPD) skin testing for tuberculosis
Cytomegalovirus (CMV) testing
Syphilis testing
Rapid amplification testing for gonococcal and chlamydial infection
Hepatitis A, B, and C serology
Anti-Toxoplasma antibody
Ophthalmologic examination
A purified protein derivative skin test is placed to evaluate for tuberculosis infection. Chest radiography should be performed in patients with a positive PPD test result.
Serology should be performed to test for CMV infection. The presence of anti-CMV IgG indicates previous exposure to CMV. Ophthalmologic examination is used to evaluate for CMV retinitis in people with very low CD4 T-cell counts.
For syphilis screening, rapid plasma reagent (RPR) testing can be used initially, but more specific testing should be used for follow-up, as RPR can yield false-positive results. Lumbar puncture is used to evaluate neurologic symptoms.
Rapid amplification testing is used to evaluate for gonococcal infection and chlamydia in cases of sexual HIV transmission. Pelvic examination is performed in females (with wet mount for trichomoniasis).
Hepatitis A, B, and C serology is performed to determine the need for vaccination or treatment and to evaluate for chronic infection. Patients infected with hepatitis C may be candidates for treatment. Genotyping and baseline liver function tests are crucial.
Anti-Toxoplasma antibody is measured to determine whether patients have had toxoplasmosis, and thus are at risk for reactivation of infection in the event of immunocompromise. Patients with prior Toxoplasma infection require prophylaxis if their CD4+ T-cell counts drop below 100/µL.
Tests to establish baseline values of factors that may be affected by antiretroviral therapy include the following:
Liver function tests
Serum chemistries
Blood urea nitrogen (BUN)/serum creatinine
Fasting lipid panel
Vitamin B12 and folate levels
Staging
The CDC classifies HIV infection into 3 categories, according to the presence of certain infections or diseases. These conditions may be exacerbated by the HIV infection or represent true opportunistic infections.
Category A is asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions.
Category B is HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection. These include, but are not limited to, the following:
Oropharyngeal candidiasis (thrush)
Vulvovaginal candidiasis, persistent or resistant
Pelvic inflammatory disease (PID)
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Idiopathic thrombocytopenic purpura
Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting more than 1 month
Peripheral neuropathy
Herpes zoster (shingles), involving 2 or more episodes or 1 or more dermatomes
Category C is HIV infection with AIDS-defining opportunistic infections, as outlined in Pathophysiology.
These 3 categories are further subdivided based on the CD4+ T-cell count. Categories A1, B1, and C1 are characterized by CD4+ T-cell counts greater than 500/µL. Categories A2, B2, and C2 are characterized by CD4+ T-cell counts between 200/µL and 400/µL. HIV infections in patient with CD4+ T-cell counts under 200/µL are designated as A3, B3, or C3.
Importantly, once an HIV infection has been staged into a higher clinical category, it remains in that category permanently. In addition, the infection is classified based on the lowest CD4+ T-cell count in that patient.
For example, if a given HIV-positive patient recovers from a bout of Pneumocystis pneumonia (PCP) and the CD4+ T-cell count improves from 50/µL to 250/µL, that patient’s HIV infection remains classified as C3. Persons with A3, B3, and C1-3 HIV infection are considered to have AIDS. This is important to recognize, as this designation is not based solely on the previous occurrence of opportunistic infections but rather on the current risk of infection based on a reduced CD4+ T-cell count.
HIV DISEASE TREATMENT & MANAGEMENT
Approach Considerations
The treatment of human immunodeficiency virus (HIV) disease depends on the stage of the disease and any concomitant opportunistic infections.In general, the goal of treatment is to prevent the immune system from deteriorating to the point that opportunistic infections become more likely. Immune reconstitution syndrome is also less likely in patients whose immune systems are weakened to this point.
Highly active antiretroviral therapy (HAART) is the principal method for preventing immune deterioration. In addition, prophylaxis for specific opportunistic infections is indicated in particular cases.
Successful long-term HAART results in a gradual recovery of CD4 T-cell numbers and an improvement of immune responses and T-cell repertoire (previously lost antigen responses may be restored). The peripheral T-cell counts initially surge after therapy is initiated, but this represents redistribution of activated T cells from the viral replication centers in the lymph nodes rather than a true increase in total-body CD4 T-cell counts.
In addition to virologic response and reduced risk of opportunistic infection, there is evidence to suggest that non-AIDS-defining illnesses, in particular psychiatric and renal disease, may also be reduced when on HAART. Although multifactorial iature (transmission mode and patient educational level are independent risk factors for these events) there may also be a direct role of HIV in these events, or an indirect role mediated through the subsequent immune dysfunction. Some non-AIDS-defining illnesses, such as liver and cardiovascular disease, are not improved by HAART.
PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS
Prophylaxis for Pneumocystisjiroveci (a normally harmless commensal organism) is most important, as this causes a common, preventable, serious infection. In patients with CD4 counts of less than 200/μL, prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim) has been shown to prevent Pneumocystis pneumonia (PCP).
In patients whose CD4+ T-cell counts rise above 200/μL with effective therapy, PCP prophylaxis may be discontinued. When TMP-SMX cannot be used, alternatives include dapsone (after screening for glucose-6-phosphate dehydrogenase [G6PD] deficiency) and atovaquone or monthly nebulized pentamidine treatments.
TMP-SMX also prevents toxoplasmosis and should be administered when the CD4+ T-cell count drops to below 100/µL if the patient is not already receiving it to prevent PCP.
CD4+ counts below 50/µL place the patient at risk for Mycobacterium avium complex infection, and weekly azithromycin or clarithromycin is recommended as prophylaxis.
Prophylaxis for fungal or viral infections is not routinely necessary, but some have recommended fluconazole in patients with CD4+ T-cell counts under 50/µL to prevent candidal or cryptococcal infections and to protect against endemic fungal infections in geographic locales of hyperendemicity for histoplasmosis or coccidioidomycosis. However, the emergence of resistant Candida strains is a realistic concern.
Oral ganciclovir is indicated for prophylaxis of cytomegalovirus infection in patients with advanced AIDS and is about 50% effective in reducing invasive disease.As with fluconazole, there are concerns about resistance, and prophylaxis should be reserved for those with CD4+ T-cell counts under 50/µL and evidence of previous cytomegalovirus infection.
DETERRENCE AND PREVENTION OF HIV INFECTION
On an individual level, the most effective methods for prevention of HIV infection include (1) avoidance of sexual contact outside a monogamous relationship, (2) the use of safer sex practices for all other sexual encounters, and (3) abstinence from nonmedical parenteral drug use.
Sexual transmission
Prevention measures include the following:
Abstinence when possible
Reduction iumber of sexual partners
Using barrier contraception
Treatment of concurrent sexually transmitted diseases (STDs)
Testing of self and partner for HIV infection and other STDs
Concomitant infection with other STDs (eg, gonorrhea, herpes, syphilis) is the most well-known risk factor that predisposes to transmission of HIV. These STDs may cause mucosal ulcerations or tears or a higher concentration of inflammatory cells in the mucosa, which are targets for HIV infection. Comprehensive testing for these should be obtained when a sexual transmission is suspected or the source of infection is unknown, both in the patient and in sexual partners.
Certain sexual acts are more likely to lead to HIV infection than others. For example, fellatio carries the lowest risk of transmission (with very few case reports in the literature), while receptive anal intercourse carries the highest risk (a likelihood of approximately 1.5% per act with an infected individual).
An apparent effect of hormonal contraception on HIV transmission to and from women has been reported, with a slight but statistically significant increase in transmission involving women on hormonal contraception. In a study of 3790 serodiscordant couples from Africa, the hazard ratios for transmission were 1.98 to, and 1.97 from women on hormonal contraception. Although barrier contraception should be employed in instances of serodiscordance anyway, this finding further strengthens that recommendation in those couples where the female partner is using hormonal contraception.
Vertical transmission
Prevention measures include the following:
Maternal testing
Effective control of maternal infection
Prenatal antiviral therapy and treatment of mother and infant during labor, delivery, and the neonatal period
Cesarean delivery
Avoidance of breastfeeding (unless local conditions make this unsafe or unfeasible)
A retrospective cohort study reviewed the records of 3,273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009. Patients were treated with triple antiviral therapy during pregnancy until 6 months postpartum for prevention of vertical transmission. Regardless of CD4 count, ART provided a protective effect against mortality, fetal demise, and premature birth.
The prevention of mother-to-child transmission of HIV-2 is less certain than for HIV-1, from which most of the recommendations have been derived. Transmission of HIV-2 is less frequent (perhaps 10-fold less efficient), but HIV-2 is intrinsically resistant to the non-nucleoside RTI nevirapine, removing one option for pharmacologic prophylaxis at the time of delivery.
In a large French cohort study, the mother-to-child transmission rate of HIV-2 infection was 0.6%.Transmission was related to poor control of HIV-2 infection in the mother or due to breastfeeding.
In the absence of definitive clinical trial data, the only definite conclusion is that effective control of maternal infection is paramount, and other nonspecific measures (identification of infected mothers, caesarean section, avoidance of breastfeeding) are probably effective at preventing transmission.
Empiric prophylaxis with zidovudine, as in HIV-1 infection, is probably warranted and effective but does not appear to be evidence-based.
Blood-borne transmission
Prevention measures include the following:
Blood-product and donor screening
Avoidance of reusing needles for intravenous drug abuse (needle-exchange programs are widespread in the developed world, but the evidence that they have had a significant effect is debatable)
Postexposure prophylaxis
The CDC has recommended basic and expanded HIV postexposure prophylaxis (PEP) regimens. For details, see the Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. Also see the Medscape Reference articles Antiretroviral Therapy for HIV Infection and Body Fluid Exposures.
An overview of the CDC recommendations for PEP are as follows:
- Basic PEP 2-drug regimen: zidovudine plus lamivudine, zidovudine plus emtricitabine, tenofovir plus lamivudine, or tenofovir plus emtricitabine
- Alternative basic PEP regimen: lamivudine plus stavudine, lamivudine plus didanosine, emtricitabine plus stavudine, or emtricitabine plus didanosine
- Expanded PEP regimen: basic PEP regimen plus lopinavir-ritonavir
An alternative expanded PEP regimen includes the basic PEP regimen plus one of the following:
Atazanavir with or without ritonavir
Fosamprenavir with or without ritonavir
Indinavir with or without ritonavir
Saquinavir with or without ritonavir
Nelfinavir
Efavirenz
Use of nevirapine for PEP is generally not recommended because of a risk of early onset rash and severe hepatotoxicity.
Vaccination efforts
The initial hope of an effective vaccine against HIV has not been fulfilled. Aside from the virus being able to rapidly mutate antigenic portions of key surface proteins, HIV infection progresses despite the host’s humoral and cellular immune responses; therefore, any vaccination effect needs to surpass the normal host response to HIV.
A study from Thailand suggests a possible benefit of vaccines in heterosexuals at risk for HIV-1 transmission. In the randomized, multicenter, double-blind, placebo-controlled trial by Rerks-Ngarm et al, 16,402 healthy participants aged 18-30 years received either 4 priming injections of recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus 2 booster shots of recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) or placebo.
In the per-protocol analysis, which excluded subjects who seroconverted during the vaccination series, the vaccine efficacy was 26.2%. In the modified-intention-to-treat analysis, which excluded subjects who had baseline HIV-1 infection, the vaccine efficacy was 31.2%. However, the 95% confidence intervals in these analyses were extremely wide (-13.3 to 51.9 and 1.1 to 52.1, respectively), which precludes concluding that the vaccine had proven efficacy.
Among study subjects who developed HIV-1 infection, viremia and CD4+ T cell counts were unchanged by vaccination. This suggests that, if infection did occur, there was no apparent immunologic benefit from having received the vaccine.
With respect to risk behavior, a post-hoc analysis of efficacy found that the combination of the HIV vaccines, ALVAC-HIV (vCP1521) and AIDSVAX B/E, was more effective in those who maintained lower-risk sexual behavior compared to those that reported high or increasing-risk behavior.
Chemoprophylaxis
An innovative and controversial strategy for preventing HIV transmission is regular use of antiretroviral medications by uninfected individuals. Although no data are currently available on the benefits of this strategy in heterosexuals or injection-drug users, clinical trial results indicate that preexposure prophylaxis can be safe and effective for men who have sexual intercourse with men.
A multinational study called the Pre-exposure Prophylaxis Initiative (iPrEx) trial found that once-daily emtricitabine plus tenofovir disoproxil fumarate (FTC-TDF) provided an additional 44% protection against HIV infection in a study population of 2499 high-risk, HIV-negative men or transgender women who have sex with men.
Over a median 1.2 years of follow up, 36 patients in the FTC-TDF group and 64 in the placebo group became infected with HIV. All study subjects also received comprehensive prevention services that included monthly HIV testing, condom provision, counseling, and management of other STDs.
The Centers for Disease Control and Prevention (CDC) will determine how to most effectively use FTC-TDF in combination with other prevention strategies to reduce new HIV infections. The CDC, National Institutes of Health, and other institutions are also conducting trials to determine the safety and effectiveness of pre-exposure prophylaxis in these populations.
There remain policy considerations surrounding costs, opportunity costs, and ethical issues that must be addressed before broad implementation in the United States. Potential drawbacks include the possibility that pre-exposure prophylaxis may encourage some recipients to practice less-safe sex; it does not address transmission of other STDs; and it could encourage the development of drug resistance.
Compliance is essential. In studies, the level of protection varied widely depending on how consistently participants used pre-exposure prophylaxis. Among those whose data (based on self-reports, bottles dispensed, and pill counts) indicate use on 90% or more days, HIV risk was reduced by 73%. Among those whose adherence by the same measure was less than 90%, HIV risk was reduced by only 21%.
Topical antivirals could potentially help with preventing transmission, but studies to date have failed to produce positive results. For example, a double-blinded, randomized, controlled trial of a vaginal microbicide gel with in vitro activity against HIV failed to show protective effects. The study involved 9385 women from South Africa, Tanzania, Uganda, and Zambia who used a synthetic naphthalene sulphonate polymer. Infection rates per 100 person-years were similar between groups (4.7 for 2% gel, 4.6 for 0.5% gel, and 3.9 for placebo).
Long-Term Monitoring
Guidelines from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents recommend performing the following tests every 3 months in patients on antiretroviral therapy:
Basic chemistry profile
Liver function studies
Complete blood count with differential
The basic chemistry studies should include serum sodium, potassium, bicarbonate, chloride, blood urea nitrogen (BUN), and creatinine, and glucose (preferably fasting), plus an estimate of creatinine clearance. Fasting glucose is repeated every 3-6 months if abnormal at the last measurement, or every 6 months if normal at the last measurement.
A fasting lipid profile is measured every 6 months if abnormal at the last measurement, or every 12 months if normal at the last measurement.
In a clinically stable patient on an regimen whose viral load is suppressed and whose CD4+ T-cell count is well above the threshold for opportunistic infection risk, 2011 DHHS guidelines recommend that the CD4+ T-cell count may be monitored every 6-12 months (instead of every 3-6 months), unless there are changes in the patient’s clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents.
Medication Summary
Effective antiretroviral therapy is the most important intervention in terms of improving longevity and preventing opportunistic infections in patients with human immunodeficiency virus (HIV) infection. Therapy should involve combinations of drugs—two nucleoside-analogue reverse-transcriptase inhibitors combined with either a protease inhibitor or a non-nucleoside–analogue reverse-transcriptase inhibitor.Antiretroviral drug classes and agents within each class are listed in Table 1, below (see individual medication tables for more detail).
As of August 2012, a total of 27 antiretroviral drugs have been approved for use in HIV-infected adults and adolescents; 14 of these have an approved pediatric treatment indication and 13 are available as a pediatric formulation or capsule size. Of the 27 antiretroviral drugs that have been approved, 3 are no longer being manufactured either because of the development of improved formulations (ie, amprenavir replaced by fosamprenavir) or because of limited use (ie, delavirdine and zalcitabine [ddC]).
Antiretroviral Drug Classes and Agents
|
Nucleoside reverse transcriptase inhibitors (NRTIs) |
Abacavir (Ziagen, ABC) Didanosine (Videx, Videx EC, ddI) Emtricitabine (Emtriva, FTC) Lamivudine (Epivir, 3TC) Stavudine (Zerit, Zerit XR, d4T) Tenofovir DF (Viread, TDF) Zalcitabine (Hivid, ddC)* Zidovudine (Retrovir, ZDV, AZT)
|
|
Protease inhibitors (PIs) |
Amprenavir (Agenerase, AVP)* Atazanavir (Reyataz , ATV) Darunavir (Prezista, DRV) Fosamprenavir (Lexiva, f-APV) Indinavir (Crixivan, IDV) Lopinavir and ritonavir (Kaletra, LPV/r) Nelfinavir (Viracept, NFV) Ritonavir (Norvir, RTV) Saquinavir (Invirase [hard gel] capsule, SQV) Tipranavir (Aptivus, TPV)
|
|
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) |
Delavirdine (Rescriptor, DLV) Efavirenz (Sustiva, EFV) Etravirine (Intelence, ETR) Nevirapine (Viramune, NVP)Rilpivirine (Edurant)
|
|
Fusion inhibitors |
Enfuvirtide (Fuzeon, T-20) |
|
Cellular chemokine receptor (CCR5) antagonists |
Maraviroc (Selzentry, MVC) |
|
Integrase inhibitors |
Raltegravir (Isentress, RAL) Elvitegravir (Stribald, EVG [available as combination product only])
|
|
*No longer available on market |
|
Combination therapy has been shown to dramatically reduce the likelihood of drug resistance (many drug-resistant mutations are mutually exclusive) and to suppress viral replication to the point that progression to AIDS is significantly slowed. Antiviral-resistance mutations often affect more than one drug simultaneously because of similar development pipelines and the ultimate molecular structure of the drug, and combination choices should account for this possibility.
Ritonavir, a protease inhibitor that may be used in its own right, boosts blood levels of other protease inhibitors. This permits a reduced dosage of the coadministered drug. Various products have been formulated to include PIs combined with ritonavir.
Numerous antiretroviral combination products are available on the market to assist patients with compliance and decrease the daily number of tablets and capsules required (see Table 2, below).
Antiretroviral Combination Products
|
Drug Content per Tablet/Capsule* |
Brand Name |
Adult Dose (≥40 kg) |
|
Elvitegravir 150 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir 300 mg
|
Stribild |
1 tab PO qd |
|
Abacavir 600 mg Lamivudine 300 mg
|
Epzicom |
1 tab PO qd |
|
Abacavir 300 mg Lamivudine 150 mg Zidovudine 300 mg
|
Trizivir |
1 tab PO bid |
|
Efavirenz 600 mg Emtricitabine 200 mg Tenofovir DF 300 mg
|
Atripla |
1 tab PO qd on empty stomach |
|
Emtricitabine 200 mg Rilpivirine 25 mg Tenofovir DF 300 mg
|
Complera |
1 tab PO qd with a meal |
|
Emtricitabine 200 mg Tenofovir DF 300 mg
|
Truvada |
1 tab PO qd CrCl 30-49 mL/min: 1 tab PO q48h CrCl < 30 mL/min: Do not administer
|
|
Lamivudine 150 mg Zidovudine 300 mg
|
Combivir |
1 tab PO bid |
|
*Not indicated for patients requiring dosage adjustments (eg, weight < 40 kg, renal impairment, hepatic impairment, dose-limiting adverse effects) unless otherwise stated. |
||
ANTIRETROVIRAL AGENT, NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR
Abacavir (Ziagen)
Didanosine (Videx, Videx EC)
Emtricitabine (Emtriva)
Lamivudine (Epivir)
Stavudine (Zerit, Zerit XR)
Tenofovir disoproxil fumarate (Viread)
ANTIRETROVIRAL AGENT, PROTEASE INHIBITOR
Atazanavir (Reyataz)
Darunavir (Prezista)
Fosamprenavir (Lexiva)
Lopinavir and ritonavir (Kaletra)
Nelfinavir (Viracept)
Indinavir (Crixivan)
Ritonavir (Norvir)
Saquinavir (Invirase)
Tipranavir (Aptivus)
ANTIRETROVIRAL AGENT, NON-NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR
Delavirdine (Rescriptor)
Efavirenz (Sustiva)
Etravirine (Intelence)
Nevirapine (Viramune)
Rilpivirine (Edurant)
ANTIRETROVIRAL AGENT, INTEGRASE INHIBITOR
Raltegravir (Isentress)
ANTIRETROVIRAL AGENT, FUSION INHIBITOR
Enfuvirtide (Fuzeon)
ANTIRETROVIRAL AGENT, CCR5 ANTAGONIST
Maraviroc (Selzentry)
. ANTIRETROVIRAL COMBINATIONS
Abacavir, lamivudine, zidovudine (Trizivir)
Abacavir/lamivudine (Epzicom)
Efavirenz/emtricitabine/tenofovir (Atripla)
Elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild)
Emtricitabine/rilpivirine/tenofovir (Complera)
Emtricitabine/tenofovir (Truvada)
Lamivudine/zidovudine (Combivir)
ANTIBIOTIC, SULFONAMIDE DERIVATIVE
Sulfamethoxazole and Trimethoprim (Bactrim, Bactrim DS, Septra, Septra DS, Sulfatrim)
GROWTH HORMONE RELEASING FACTOR
Tesamorelin (Egrifta)
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NEWS FROM AIDS 2012
http://www.aidsmap.com/aids2012
Prof. Francoise Barré-Sinoussi and Anthony S. Fauci, MD at the ‘ Towards an HIV cure’ opening session. Image ©IAS/Steve Shapiro – Commercialimage.net
‘Berlin patient’ Timothy Brown has “inspired the field”
Scientists launched a road map for research into an HIV cure ahead of the 19th International AIDS Conference (AIDS 2012) in Washington DC, promising international collaboration and calling for more funding to be devoted to research that can eventually deliver a course of treatment that will, at the minimum, allow people with HIV to remain off medication for life even it can’t eradicate HIV from the body.
The Towards an HIV Cure declaration marks a substantial shift in the scientific consensus regarding the feasibility of HIV cure research. Over the past four years funding has begun to flow towards small intensive studies that will contribute towards cure research. Worldwide attention has been grabbed by the case of the ‘Berlin patient’, Timothy Brown, who was pronounced cured of HIV infection after a gruelling course of chemotherapy, immunosuppressive treatment and a bone marrow transplant from a donor with a rare genetic resistance to HIV infection.
“I don’t think anyone would want to go through what he went through to get that cure, but it has inspired the field,” Dr Steven Deeks of the University of California San Francisco, told a press conference launching the International AIDS Society’s cure research strategy prior to a pre-conference symposium, Towards an HIV Cure.
Support for a comprehensive effort to cure HIV infection is also driven by the mounting long-term cost of HIV treatment. By 2015, US$24 billion will be required to provide treatment for 15 million people; at least 35 million people are estimated to be infected with HIV, and eventually all will be eligible for HIV treatment. A cure which can be feasibly delivered at a large scale in countries with weak health systems, and which is affordable, will begin to look more and more attractive to major international donors as treatment costs continue to rise.
What do scientists mean by an HIV cure?
An HIV cure requires either the clearance of HIV from every cell in the body, or the establishment of a sufficiently strong immune response to keep HIV in check when medication is stopped. The difficulty of achieving eradication of the virus lies in the fact that HIV can remain latent within CD4+ T-cells and some other immune system cells for many years, and cannot be detected by the immune system. It is only when those cells are activated by an external stimulus that they begin to produce HIV. These cells form a ‘reservoir’ of latent virus that could cause viral rebound as soon as antiretroviral treatment is stopped. It would take the activation of only a few infected cells to cause viral rebound; the reservoir of latently infected cells probably comprises thousands of cells.
The case of Timothy Brown is the only example of an HIV cure that has been scientifically validated, but even this case raises questions about what a cure means. Scientists talk about two possible outcomes from cure research: eradication, where the virus is cleared from the body, and a ‘functional cure’, where tiny amounts of virus may persist, but the virus remains controlled without medication.
The HIV field had thought that the case of the Berlin patient represented the first example of HIV eradication, but recent data presented at the International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies in Sitges, Spain, in June, indicated that some laboratories which had tested samples of plasma and tissue from the ‘Berlin patient’ Timothy Brown, had been able to detect very low levels of HIV DNA or RNA several years after the interventions. This suggests that HIV has not been completely eradicated from this patient’s body. Yet, not all laboratories were able to detect HIV, and the finding remains controversial.
Professor Sharon Lewin of the Alfred Hospital, Melbourne, commented: “My gut feeling is that it’s not real. My take on it is that the DNA and RNA samples were looked at by labs that are very experienced in this work, and in a sub-set of these laboratories there was some evidence of RNA and DNA, which may or may not be contamination. There may be contamination in the best-run labs. He certainly doesn’t have virus that is infectious or that has rebounded to a detectable level. If it’s real, we still have a fantastic example of a functional cure.”
Dr Steve Deeks said that the findings, which his “gut feeling” tells him to be evidence of real virus, suggest three take-home messages. Firstly, more sensitive tests are needed for measurement in HIV eradication studies. Secondly, immune responses may be the most important indicators of the achievement of a functional cure, even where evidence of virus persists; Timothy Brown’s antibody levels continue to decline, suggesting that not enough HIV is being produced to stimulate immune responses. Finally, all the clinical signs suggest that the patient is doing well in the absence of antiretroviral therapy, again suggesting that any persisting low-level HIV infection that might exist is causing no physical harm.
Indeed, given all the sites and cell types that HIV may infect, a functional cure may be more feasible – and may be perfectly satisfactory for people with HIV, depending on how that affects their everyday lives.
“I asked patients in Asia recently what they wanted and they didn’t say a cure, they said ‘a treatment I can stop’,” Professor Francoise Barré- Sinoussi told the press conference.
Research conducted among people living with HIV in the Netherlands, on the other hand, suggests that when presented with different attributes of a potential curative course of treatment, people want a treatment that removes long-term uncertainty about health and side-effects, ends stigmatisation and ends the risk that they will infect partners. People living with HIV rate the psychosocial benefits of a cure very highly when asked to rank a range of possible health and psychosocial benefits, Fred Verdult told the Towards an HIV Cure symposium.
A cure, functional or otherwise, and an end to AIDS will also depend on reaching people who have HIV: those who know it and those who don’t. “What would a cure have to look like to access that group of people who are currently not either diagnosed or on treatment?” asked Steven Deeks.
Path to a cure
Views differ on what might be the most productive approach towards curing HIV infection, and researchers emphasise that there is still a great deal of ground to be covered. Tony Fauci, director of the US National Institute of Allergy and Infectious Diseases, described the ‘false start’ of the mid-1990s, when some researchers assumed that viral suppression on HAART, and the absence of new rounds of infection or evolving HIV DNA, meant that replication had been halted and that eradication was only a question of waiting a few years for all the HIV-infected cells to die a natural death. Robert Siliciano and others soon demonstrated that HIV was infecting cells that might persist for years, and that estimates of HIV eradication after a few years of HAART were wildly optimistic.
All researchers agree that a cure, functional or otherwise, will depend on a combination of approaches. Where they disagree is on the ingredients of the cocktail.
A cure for every patient will need to start with a prolonged period of antiretroviral therapy to reduce HIV to undetectable levels. This period of treatment itself could be important in determining the success of subsequent drug therapies. Will attempts to purge the HIV reservoir be more successful in people who began treatment very soon after infection? A French cohort has produced tantalising data suggesting that some people treated in acute infection can stop treatment and go for very long periods – an average of 72 months so far – without experiencing viral rebound. What is it about these people that prevents viral rebound? Is it the time they started treatment, their genes, or just random chance?
Scientists are also interested to learn whether any form of intensified antiretroviral drug regimen could shrink the pool of latently infected cells, making them easier to purge later. So far, studies have shown little or no impact of regimens drawing on the maximum number of drug classes on the size of the reservoir of latently infected cells, but further studies are planned, using more sensitive measurement techniques, to see whether five-drug combinations that target every possible step in the viral lifecycle have more effect.
Studies are also underway or planned to determine the extent to which the viral reservoirs can be emptied by using a range of drugs that will activate latently infected cells so that they can be identified and killed by the immune system, or self-destruct.
Sharon Lewin of the Alfred Hospital, Melbourne, described the range of studies already taking place using compounds called HDAC inhibitors, which stimulate latently infected cells to begin producing HIV. A number of experimental studies with HDAC inhibitors are already underway, most notably with vorinostat (SAHA). This drug is already approved for the treatment of cutaneous lymphoma, and is currently undergoing phase II tests for a range of other malignancies, so its short-term toxicities are well characterised. In vitro toxicity studies suggest a potential long-term risk of malignancy, but at this point no human studies have reported an increased risk of malignancy. Sharon Lewin’s team is studying the effect of 14 days of vorinostat (SAHA) in 20 patients with fully suppressed viral load, and will measure the effect of vorinostat on cell-associated HIV RNA to determine the effect of the drug on HIV latency.
Professor David Margolis at the University of North Carolina is conducting a similar experimental study, measuring the effect of a sequence of single doses of vorinostat on virus production in up to 20 volunteers with fully suppressed viral load. Steven Deeks at the University of California San Francisco is testing the anti-alcohol agent disulfiram, which also activates latently infected cells. Preliminary data presented at CROI in 2012 showed that this agent stimulated HIV RNA production in a sub-set of chronically infected patients who received the drug.
In addition to these agents, there are six or seven known targets for therapies that could disrupt HIV latency, and in collaboration with Merck Prof. Margolis’s research group has identified 83 compounds with differing mechanisms of action that are being tested for their potential as disruptors of latency. Two other companies, Gilead and Janssen-Tibotec, are also engaged in major screening programmes to identify agents that could contribute towards cure research.
Ultimately a number of different agents may need to be used in combination, said Warner Greene of the Gladstone Institute, San Francisco, in order to target the different points in the transcription pathway that govern the integration and latency of HIV in cells.
Activating agents might also need to be used in combination with a therapeutic vaccine to stimulate the immune system to clear the activated cells, because researchers are still uncertain how long the activated cells will continue to produce virus once activated, and whether cells which are not fully activated are nevertheless capable of producing virus that will go to infect other cells. (Activation is a cycle rather than an on/off process.)
Researchers are also investigating gene therapy approaches that can gradually establish a pool of HIV-resistant CD4 cells. This approach is already being studied in people with HIV, but more work is needed to refine the technique and determine whether this approach can contribute towards an HIV cure.
The long and winding road
Questions of cost and scaleability will loom ever larger as researchers make progress towards a cure, but at this stage leading players are stressing the need for realistic expectations about how long this research will take.
“I can’t tell you how long it will take or how much it will cost, but now we are collaborating, it will take a considerably shorter time,” said Rowena Johnston of AmFAR, who is leading the organisation’s efforts to fund innovative cure research as a means of kick-starting a larger cure research effort.
How much it will cost and how long it will take to get there are matters of pure conjecture at the moment, and advocates and researchers are reluctant to commit themselves on either question. “The reason we don’t want someone saying it’s going to take X million dollars and X years is because we don’t want to over-promise what we can’t deliver. But if we put in more money we will get there sooner,“ said Johnston.
The research effort will also need to overcome the scepticism of a field that has seen several major breakthroughs fail to materialise.
Tony Fauci pointed out how many times the “you can’t do it” school have been proved wrong in HIV research, starting with antiretroviral therapy, all the way through efforts to deliver treatment in the developing world, to the recent PrEP studies. HIV research requires great feats of discovery, but it also requires the discovery of an approach to a scaleable cure to mobilise the resources, he told researchers.
Controlling the HIV Pandemic with Antiretrovirals: Treatment as Prevention and Pre-Exposure Prophylaxis
June 11-12, 2012 • Royal Garden Hotel, London
The concepts of antiretroviral-based treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP) gained formidable ground in 2011, both cited iumerous 2011 Top 10 lists of clinical developments in HIV medicine. In addition, PrEP has recently been a topic of heated debate as regulatory bodies – most notably the US Food and Drug Administration (FDA) – entertain approving expanded indications for existing antiretroviral drugs for HIV prevention. However, there is much to learn about and plan for as we prepare for their potential integration into clinical practice. In addition, there are numerous challenges facing a variety of stakeholders as we seek to achieve the impact these biomedical prevention interventions promise in the third decade of the HIV pandemic.
The International Association of Physicians in AIDS Care (IAPAC), in partnership with the British HIV Association (BHIVA), hosted a two-day Controlling the HIV Epidemic with Antiretrovirals summit with a goal of providing a venue for the presentation of data related to and discussion about the practical aspects of TasP and PrEP implementation in a variety of clinical settings. Audience response system-facilitated sessions throughout the summit attempted to identify consensus points (or the lack thereof) around TasP and PrEP implementation, which are featured in a Consensus Statement released at the XIX International AIDS Conference in Washington, DC, USA.
Following are the presentations delivered at the evidence summit. The conference organizers request that any use of these presentations should include citations to both their presenting authors and relevant summit information (e.g., Controlling the HIV Pandemic with Antiretrovirals: Treatment as Prevention and Pre-Exposure Prophylaxis, June 11-12, 2012, London).
Gus Cairns
Published: 20 July 2011
Anthony Fauci, National Institute of Allergy and Infectious Diseases at the National Institute of Health, USA. Photo©IAS/Steve Forrest/Workers’ Photos
Two consecutive sessions at the sixth International AIDS Society conference (IAS 2011) in Rome yesterday were devoted, now we have convincing scientific data on the benefits of treatment as prevention and PrEP, to putting these new prevention methods into practice.
“We have moved from ‘What if?’ to ‘What now?’” was the comment of Mitchell Warren, Executive Director of the AIDS Vaccine Advocacy Coalition (AVAC), on what else we need to know, what barriers need to be addressed , and what resources might be required, to maximise the promise of antiretroviral-based prevention.
Anthony Fauci, Director of the US National Institute of Allergies and Infectious Diseases (NIAID), said: “We now have a solid scientific foundation to say that even in the absence of a vaccine we have the capacity to end the epidemic. I can’t go to the US President and say: ‘We can cure HIV.’ But I can say ‘Ending the epidemic is scientifically doable’.”
“I can say ‘Ending the epidemic is scientifically doable’.” Anthony Fauci
Earlier, however, Nancy Padian from the Office of the US Global AIDS Coordinator had outlined formidable challenges still to be answered if antiretroviral treatment could bring about this goal.
She said that questions still needing answers include whether antiretroviral drugs (ARVs) really are a durable and reliable means of viral load suppression over a period of years and whether increasing the proportion of people on treatment would lead to increased levels of resistance. The biggest practical question, however, was whether treatment as prevention would work in situations where a high proportion of transmissions came from people with acute, recent HIV infections.
The biggest barriers to treatment as prevention, however, are stigma and lack of resources. Implementing ARV-based prevention would not only be expensive in terms of drugs; it would require added human resources and increased training and task-shifting for prevention counsellors so they can deal with biomedical data. There would also be added costs in terms of tests and monitoring.
The other big barrier will be the stigma of being tested, she said, particularly for at-risk populations in societies where injecting drug use, male-male sex, or sex work were criminalised and stigmatised. Treatment as prevention would require people not simply to test and then go to more supportive community organisations for prevention advice; it required a much closer relationship with medical personnel who might be prejudiced or feared to be so.
Mitchell Warren issued a call to action to implement the new strategies, but his presentation was tempered by realism. “We have evidence, we have data, and we now need to make decisions,” he said.
“We have evidence, we have data, and we now need to make decisions,” Mitchell Warren
Firstly, he said, we need “smart combinations” of prevention interventions tailored to different people and populations. “It can be seen as frustrating to have all these tools (he counted 13 different ones for which there is now evidence) and not know what to choose or how to pay for them,” he said, “but it’s a better kind of frustration than in 2004” (at the time of the closing of the first PrEP study in Cambodia).
Given that, eveow, only 8 to 9% of people who need them have ready access to condoms or cleaeedles, only 11% of gay men have access to behaviour-change programmes, and only a third of HIV-positive mothers have access to ARVs to prevent transmission to their baby, making ARVs more widely available as prevention or PrEP would be a big challenge.
Using ARVs for prevention would continue to be a behavioural issue, he added, in terms of people coming forward for testing and, crucially, for adherence.
One important consideration was to match the prevention intervention to the person. PrEP, for instance, had been criticised as a ‘niche intervention’, but niche interventions were important for specific groups of people and could be extremely effective; an example from another context was injectable contraceptives.
Lastly, of course, money and resource allocation would be a huge issue. “Scientific data do not change the world – programmes and policies backed by civil society, donors, implementers and governments do,” he said.
In this context, Tim Farley of the World Health Organization, presenting a comprehensive review of the licensing processes needed for ARV-based prevention methods in the USA, Europe and Africa, remarked on the extreme range of prices paid for tenofovir and Truvada in different contexts, from $35.82 as the US list price (almost always discounted) for one Truvada tablet, to $0.87 as the ‘no profit’ price paid to the developers Gilead in low-income countries and the even lower $0.28 for a generic equivalent. He noted, however, that Gilead was already licensing generic companies to produce tenofovir and Truvada at lower prices.
Helen Rees, University of Witwatersrand in South Africa, said that the new data from the treatment-as-prevention and PrEP studies had come along just as she was involved in writing the country’s new National Plan for HIV. She said that the new prevention choices offered could feel bewildering. “Do we put more people on treatment, circumcise all men or buy millions of condoms?” she asked. As an initial step, the country had extended its CD4 criteria to 350 cells/mm3 in line with WHO guidelines and had decided that, with still only 45% of those who need it on treatment, that treatment access remained South Africa’s biggest priority.
She added, however, that the data from serodiscordant-couple studies did not necessarily provide the kind of data needed on the likely effectiveness of treatment as prevention, or of PrEP. “South Africa is a country of female-dominated households and a low level of marriage,” she said, “and serodiscordant couples are hard to identify: men still won’t come forward.” It had been decided that HIV-negative women wishing to conceive who were or might be having sex with HIV-positive men were a logical first population who might need PrEP, but setting up PrEP as a service was a much bigger step than expanding existing HIV treatment, as it involved a new type of service that didn’t yet exist.
Myron Cohen, principal investigator of the HPTN 052 study, said that if the world did not pay for ARVs now it would do so later, in terms of an indefinitely increasing number of people needing HIV treatment. He said that his study’s findings did not imply a huge expansion of treatment to groups not previously entitled to it; for the study’s purposes, it had needed to offer ARVs to people with relatively high CD4 counts but the reduction in infectiousness should apply to people with CD4 counts below 350 cells/mm3 too, and should serve as a further incentive to get ARVs to the two-thirds of people with CD4 counts below this figure who were not yet on treatment.
Above all, moving from the data provided by scientific studies to the business of trying to make HIV prevention work in the real world was an exercise in dealing in uncertainty. Microbicide researcher Ian McGowan of the University of Pittsburgh commented that: “In an ideal world, we’d treat all the HIV-positive people and the negative ones would use condoms. But people may not go on treatment, may fail treatment, and may fail to use condoms. The world has never been black and white, and the debate about moving from treatment, to treatment-as-prevention, to PrEP is the kind of debate we have been having on access to medications for HIV ever since we’ve had them.”
