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Human Immunodeficiency Virus 1
(HIV-1 )

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Treatment: current and future


Post-exposure prophylaxis (PEP)

Post-exposure prophylaxis (PEP) is an administration of highly potent antiretroviral drugs within 72 hours of a high-risk exposure, including unprotected sex, needle sharing, or occupational needle-stick injury to prevent virus from spreading in the organism and establishing viral reservoirs. Drugs that prevent HIV entry into host cells are especially effective. The efficacy of such regimen depends on the timing and duration of treatment, use of highly potent antiretroviral drugs and by immune responsiveness of the host.

Major barriers to the success of the program are uncertainty as to the time of virus exposure and poor compliance in completing treatment regimen, partly due to drug toxicity. For example, enfuvirtide could have been successful in some cases, but the drug requires two injections per day, and the frequent local injection site reactions make it poorly acceptable for post-exposure prophylaxis. Increasing number of HIV-infected patients harbor multi-resistant strains makes formulation of post-exposure prophylaxis regimens even trickier. Success was reported when using regimen that included maraviroc. Post-exposure prophylaxis was well tolerated. Exposed health care worker remained HIV-negative after a 6-month follow-up.

There have been more than 20 cases of HIV seroconversion among health care workers despite use of prophylaxis. The side effects of antiretroviral prophylaxis can be severe: in one case an HIV-exposed health care worker suffered fulminant hepatic failure requiring liver transplantation after a nevirapine-containing regimen. Because a randomized, placebo-controlled clinical trial of antiretroviral prophylaxis is not likely to take place, the efficacy of currently recommended prophylactic regimens in each case highly depends on HIV-1 strain, immune status of recipient, time passed between exposure and the prophylaxis, drug availability, and, some luck. Generally, the sooner post-exposure treatment begins the greater chances patient has to avoid infection. A 4-week, uninterrupted treatment with tenofovir completely prevents simian immunodeficiency virus (SIVmne) infection in cynomolgus macaques if treatment begins within 24 hours after SIVmne inoculation, but is less effective if treatment is delayed or duration of treatment is shortened.

On June 7, 1996, the U.S. Public Health Service (USPHS) published provisional recommendations for chemoprophylaxis after occupational exposure. Final recommendations approved in May 1998 were updated in June 2001, and September 2005. Although it has been recommended in the past that prophylaxis should begin within 1 to 2 hours following exposure, the time period after which initiation of prophylaxis is no longer indicated has not been established. When an exposed individual does not seek evaluation and treatment until many hours after exposure, initiation of prophylaxis may still be indicated, even if the interval since exposure exceeds 36 hours. The prophylaxis should be administered for a 4-week period. Serological follow-up to determine whether HIV seroconversion has taken place should be carried out at 6 weeks, 3 months, and 6 months after exposure. ELISA testing is currently considered to be the test of choice for such monitoring. If an individual is exposed to both HIV and hepatitis C, and becomes infected with hepatitis C, monitoring for HIV seroconversion should be extended to 12 months, due to a possible delay of HIV seroconversion in hepatitis C-infected individuals.

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Highly Active Anti-Retroviral Therapy (HAART)

General principles of HIV therapy

Antiretroviral therapy (ART) of HIV-1 was initiated in 1987 with the use of zidovudine (AZT). Although it was initially hoped that HIV- 1 could be eradicated from the body, it is now clear that virus suppression is the best that can be achieved by continuous ART. Therapy can fail due to low adherence or the evolution of drug-resistant HIV-1 variants, while drug-toxicity may be another reason to stop therapy.

HAART aims to prevent emergence of drug-resistant HIV-1 variants by suppressing its replication to negligible levels. Also, it is very difficult for the virus to acquire complex combination of mutations required for multi-drug resistance. In cases when the virus succeeds, it usually pays great fitness costs and becomes less aggressive within the given host and less transmissible to other hosts. A major barrier to curing HIV infection remains the ability of HIV to integrate in the host genome and remain latent. HAART cannot completely eradicate the virus from the organism and patients have to commit to the therapy for life.

One of the most hotly debated areas of HIV medicine is the right time to start treatment. This is because, once started, the antiretroviral regimens must be continued indefinitely. This requirement makes it desirable to preserve patients in their drug-free period for as long as possible. Currently, it is widely held that treatment should be considered once CD4+ T-cell count falls below 350 cells/ml, and should start immediately when it is close to or <200 cells/ml. The main aim of HIV therapy is therefore to prevent the CD4+ T-cell count dropping to <200 cells/ml. Regular monitoring of CD4+ T-cell count of HAART naïve patients is therefore essential. Once treatment is started, regular monitoring of CD4+ T cells and plasma viral loads becomes necessary because a plasma viral load below the level of detection (50 copies/ml) is the target of treatment. This target is generally reached within 12 weeks after start of therapy. Successful viral suppression is followed by CD4+ T cell recovery to the normal range. As long as patients continue taking their HAART regimen, their plasma viral load should remain suppressed and their immune status will stay normal.

Current treatment strategies benefit the infected individual alone. However, in lights of HAART's ability to greatly decrease viral transmission, targeting and treating individuals with primary HIV-1 infection as a public health intervention strategy represents a paradigm shift from the current practices of delaying the therapy as long as possible. Moreover, there is an increasing evidence that early HAART may increase longevity of HIV-1 patients.

ART regimens typically include two nucleoside (or nucleotide) analogue reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (NNRTI). NRTIs and NNRTIs both interfere with reverse transcriptase function, preventing new viral particles from being formed. Nucleoside RTIs differ from their non-nucleoside counterparts in how they are designed to interfere with HIV reverse transcriptase. NRTIs interact with the chemically active binding site to prevent enzyme activity. However, NNRTIs bind to an allosteric regulation site, altering the transcriptase enzyme’s shape and function. Protease inhibitors, the third component to most cART regimens, prevent the processing of manufactured viral particles through inhibition of HIV protease. Other classes of antiretroviral drugs include the integrase enzyme inhibitors, viral entry (fusion) inhibitors, and HIV maturation inhibitors. A regimen commonly prescribed to naïve patients is efavirenz (an NNRTI) plus tenofovir and emtricitabine (NRTIs) co-formulated as a single pill given once a day, known as Atripla.

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Antiretroviral drugs

Class/Description Mechanism of action Drugs Comments
Nucleoside reverse transcriptase inhibitors (NRTs, slang: Nukes) Competitive inhibitors of viral reverse transcriptase and DNA chain terminator. Zidovudine (AZT), Zalcitabine (ddC), Didanosine (ddI), Stavudine (d4T), Abacavir, Emtricitabine (FTC), Lamivudine (3TC) Possibility of class resistance. Toxicities include lipodystrophy (specifically zidovudine/lamivudine), lactic acidosis.
Non-nucleoside reverse transcriptase inhibitors (NNRTs) Non-competitive inhibitors of reverse transcriptase. Efavirenz, Nevirapine, Delaviridine Low threshold for development of resistance.
Nucleotide reverse transcriptase inhibitors (NtRTs) Competitive inhibitors of viral reverse transcriptase. Tenofovir (PMPA) Low threshold for development of resistance. Severe side effects.
Protease inhibitors Inhibit the post-translational processing of gag and pol polyproteins and enzymes. Saquinavir, Ritonavir, Amprenavir, Indinavir, Nelfinavir, Lopinavir, Atazanavir, Fosamprenavir, Tipranavir, Darunavir Significant interaction with wide array of drugs. Severe side effects.
Fusion inhibitors Inhibit the fusion of HIV with the cell membrane. Enfuvirtide Administered by subcutaneous injection. Effective only after CD4 binding and prior to gp41-mediated membrane fusion.
Integrase inhibitors (INIs) Inhibit the viral integration into the host's genome. Raltegravir Used in salvage therapy.
Chemokine antagonists Block the chemokine receptors on the cell membrane, and prevent viral entry into the cell. Maraviroc (CCR5 inhibitor) First drug that targets host's factor. Only effective against R5-tropic viruses. Good for post-exposure prophylaxis. Can cause virus to switch to R4-tropism.
Maturation inhibitors Prevents the maturation of P-25 to P-24, and stops release of viable viral particles from the cell. Bevirimat Under investigation. Occurrence of drug-resistant mutants and viral augmentation were reported.
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Antiretroviral drugs and viral resistance

The problem with ART is that suppression of HIV-1 replication is often not absolute, which enables mutations to emerge that eventually render the virus a certain level of resistance against the administered drug. Although the generation of mutations is largely a random process, the same resistance mutations generally accumulate in different patients, which indicates that a restricted set of changes confer the drug-resistance phenotype. Many of these mutations impose a fitness cost on the virus by impairing its replication. The fitness cost may become clear when the mutant virus is assayed against the wild type virus in a drug-free environment. The origin of the fitness cost of the drug-resistance mutations often lies in modulation of key viral functions such as the activity of the protease, the processivity of RT or a decrease in the rate of RNase H cleavage. However, such resistant mutants have a clear advantage over the wild type virus in the presence of the drug. For example, the AZT-resistant 215Y variant commonly evolves from the wild type 215T virus by accumulating two mutations. The resistant variant has a 16-fold higher fitness than wt in the presence of AZT but it pays a large fitness cost in the absence of the drug. Despite the emergence of high-level drug resistance mutations, plasma RNA levels may remain low during drug treatment. Terminating HAART usually leads to rapid reappearance of the wild type virus and its fast rebound to high RNA plasma levels. On the other hand, sustained ART can potentially cause a higher viral mutation rate in some patients, which may drive faster adaptation to host's environmental selective pressures and select for virus variants that are cross-resistant to other drugs. In addition, appearance of compensatory mutations may occur that not only can overcome the fitness loss induced by the primary mutations but also create viral strains that is more fit than the wild type virus.

The serious clinical consequences of multi-drug resistance require the use of alternative treatment regimens, known as salvage therapy.

Strategic Treatment Interruptions (STIs)

STI (also called drug holiday) as a treatment strategy in HIV-infected patients with chronic unsuppressed viremia involves interrupting ART in controlled clinical settings, for a pre-specified duration of time. These interruptions have various aims, including the following: 1) to allow wild virus to re-emerge and replace the resistant mutant virus, with the hope of improving the efficacy of a subsequent ART regimen; 2) to halt development of drug resistance and to preserve subsequent treatment options; 3) to alleviate treatment fatigue and reduce drug-related adverse effects; and 4) to improve quality of life. The current available evidence primarily supports a lack of benefit of STI before switching therapy in patients with unsuppressed HIV viremia despite ART. There is evidence of harm in attempting STI in patients with relatively advanced HIV disease, due to the associated CD4+ cell decline and the increased risk of clinical disease progression.

Mortality rates of HIV-1 patients on HAART therapy
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Purging viral reservoirs

Mechanisms of latent infection

Current therapies for treating HIV-1 infection are capable of suppressing virus load in blood to undetectable levels and result in marked clinical improvement. Despite this suppression, interruption of treatment results in a rapid viral rebound arising from the persistent, residual viremia. Notably, this persistent viremia is present even after 7 years of therapy. There are two general mechanisms by which replication competent HIV can evade the effects of current therapies. First, virus might be maintained for years in a near quiescent, latent state in infected cells. A latent virus reservoir is established in memory CD4+ T cells early in infection. This reservoir has such a slow rate of decay during HAART that its eradication during a human lifespan is unlikely. Second, virus might persist if therapy does not completely suppress viral replication due to the emergence of drug resistant viruses, incomplete adherence to drug regimens, or poor drug penetration.

HIV latency was first discovered in cultured T-cells from HIV-infected patients. A subset of these T-cells only produced virus after stimulation with strong T-cell activators indicating they contained a replication competent transcriptionally silent provirus. Since this discovery, it has become evident that HIV latency depends on establishment of so-called viral reservoirs early in course of infection that is promoted by several cellular and viral mechanisms. Viral reservoir can be defined as a cell type or anatomical site where a replication competent form of the virus persists for a longer time than in the main pool of actively replicating virus. Stimulating the production of HIV from viral reservoirs in order of making the virus vulnerable to host immune responses can be a viable future strategy for complete eradication of HIV in host organism.

The curve of viral load decline dynamics after starting HAART reflects presence of several possible reservoirs of persistent low level viremia during the treatment. Because plasma virions have a half life of only 6 hours, the level of HIV RNA in plasma should strongly correlate to the half lives of the infected cells that produce HIV. By measuring HIV RNA levels in plasma and using mathematical modeling it becomes evident that after the initiation of HAART plasma viremia goes through four phases of decay corresponding to the half lives of different populations of HIV-infected cells. The first phase of decay corresponds to a population of cells with a half life of approximately 1–2 days, and the second phase 1–4 weeks. Two additional phases of decay has recently been identified during suppressive therapy in individuals with <50 copies/ml: a third phase of decay corresponding to cells with a half life of approximately 39 weeks and a fourth phase with no appreciable decay. During the fourth phase the levels of HIV normally ranges from 1 to 5 copies/ml. It has been shown that the level of persistent viremia is not related to treatment regimen but to pretreatment viral RNA levels suggesting that all treatment regimens completely inhibit viral replication and that the pre-treatment viral set-point is correlated to the number of long-lived HIV-infected cells.

HIV-infected activated CD4+ T-cells are probably responsible for the first phase of decay after initiating HAART as they have a half life of 1–2 days. Several cell types could alone, or in combination with others, be linked to the second phase of decay. One is macrophages, which is less susceptible to the cytopathic effects of HIV than activated CD4+ T-cells. The half life of tissue macrophages depends on the type of tissue but can be several weeks. Unlike infected CD4 T cells, the productive infection of monocytes and macrophages does not result in cell lyses and in fact infected macrophages live longer than non infected ones. Partially activated HIV-infected CD4+ T-cells may also contribute to the second phase of viral decay as they have been reported to have a longer turnover time than fully activated CD4+ T-cells. Dendritic cells (DCs) can also contribute to this phase. In vitro studies show that infected myeloid dendritic cells (MDC) can survive for more than 45 days.

The sources of the third and fourth phases of decay have not been fully characterized but these phases most likely represent at least two additional classes of long-lived virus-producing cells. Resting memory CD4+ T-cells are a well-defined latent reservoir of HIV that most probably contribute to the fourth phase of viral decay. HIV latency is established in these cells when an activated CD4+ T-cell becomes infected by HIV but transitions to a terminally differentiated memory cell before HIV infection eliminates the cell. Transition to a memory cell involves a complex interaction between the cell and the virus which results in the cell's harboring a latent infection for a long time. Switching to a memory cell allows this infected host cell to persist for decades until it receives a stimulatory signal that activates the cell, concomitantly inducing viral production. During antiretroviral therapy these cells decay very slowly with an average half life of 44 months, indicating that under current treatment it will take over 60 years to deplete this reservoir.

Research suggests that there are at least two mechanisms by which the reservoir of infected resting memory CD4+ T-cells is maintained: the long-term survival of infected central memory T-cells (TCM) cells and the homeostatic proliferation of infected transitional memory T-cells (TTM) cells. However, other cells may be responsible for the persistent viremia during the fourth phase of decay during HAART. Although hematopoietic stem cells (HSC) are the only cell type that resist HIV infection despite the presence of HIV receptors, CD4 (expressed at low levels), CCR5 and CXCR4, it has been proposed that the mechanism behind this homogenous long-lived viral population could be a rare infection event that establishes an integrated viral genome in a cell that has proliferative capacity, for example, a stem cell in the monocyte–macrophage lineage. This infected cell proliferates, copying the viral genome without introducing errors and generating an expanded set of progeny cells that release virus.

Hiv viral load dynamics after HAART

It has been also suggested that there might be anatomical compartments where HIV replication can take place in the presence of HAART due to poor penetration of ARVs or due to special biological properties of the compartments such as being an immuno privileged site. Only about 2% of lymphocytes are in the circulation, the remainder are spread throughout the body, especially in lymphoid organs such as the spleen, lymph nodes and gut-associated lymphoid tissue (GALT) where the majority of viral replication takes place during untreated infection. These tissues could also be the source of persistent viremia or be a reservoir for HIV during HAART. HIV can penetrate into the central nervous system (CNS), presumably by the migration of infected monocytes/macrophages. The genitourinary tract has also been suggested to serve as a reservoir for HIV. In untreated patients there is viral compartmentalization between genital secretions and plasma. During HAART, HIV can be found in the semen, both as free virus and integrated in latently infected cells. It remains to be determined to what extent GALT, CNS and the genitourinary tract contributes to the production of virions and the persistence of HIV during HAART.

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Bone marrow transplantation

Interaction with the chemokine receptor, CCR5, is a necessary precondition for maintaining HIV-1 infection. Individuals with the CCR5-delta32 deletion who lack this receptor are highly resistant to infection by the most common forms of HIV-1. Recent report on the successful transplantation in an HIV-1-positive patient of allogeneic stem cells homozygous for the CCR5-delta32 allele, which stopped viral replication for more than 27 months without antiretroviral therapy, raised the possibility of the novel approach to ultimate HIV-1 infection control.

Hütter G, Schneider T, Thiel E. Transplantation of selected or transgenic blood stem cells - a future treatment for HIV/AIDS? J Int AIDS Soc. 2009 Jun 28;12(1):10.

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Vaccine

The major biological obstacles to the development of a preventative vaccine are (i) the fact that HIV incorporates its DNA into active sites of the hosts chromosomes, leading to persistent infection for the life of that cell, its progeny and often the destruction of those cells; (ii) the lack of a small, readily available animal model; (iii) the genetic variability of HIV meaning that an effective vaccine must be broadly active to prevent emergence of resistant viruses; and, (iv) the fact that HIV uses the same immune activation pathways for its own replication that are also required for successful vaccination. As vaccines and microbicides target transmitted viruses there is intense interest in understanding the genetic characteristics of these variants, which may differ from those of chronic infection. It has been shown that despite a swarm of closely related viruses present in the donor, there is a genetic bottleneck associated with transmission so that only a limited number of variants get transmitted to the recipient. Studies estimated that approximately 80% of productive infections were the result of a single virus or a single virus-infected cell. The transmission of a single infectious unit provides a window of opportunity for vaccines which, at least in the majority of cases, would need to protect against a very small incoming viral dose of limited diversity.

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Literature

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